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Approach to the adult with interstitial lung disease:

Clinical evaluation
AUTHOR: Talmadge E King, Jr, MD
SECTION EDITOR: Kevin R Flaherty, MD, MS
DEPUTY EDITOR: Paul Dieffenbach, MD

All topics are updated as new evidence becomes available and our peer review process is complete.

Literature review current through: Apr 2025.

This topic last updated: Jun 28, 2024.

INTRODUCTION

The diffuse parenchymal lung diseases, often collectively referred to as the interstitial lung
diseases (ILDs), are a heterogeneous group of disorders that are classified together because
of similar clinical, radiographic, physiologic, or pathologic manifestations ( algorithm 1) [1-
7]. The descriptive term "interstitial" reflects the pathologic appearance that the abnormality
begins in the interstitium, but the term is somewhat misleading, as most of these disorders
are also associated with extensive alteration of alveolar and airway architecture.

An overview of the clinical findings that can aid in the diagnosis of ILD will be presented here
( algorithm 2). The individual causes of ILD and the diagnostic testing that is helpful in
evaluating patients with ILD are discussed separately.

● (See "Idiopathic interstitial pneumonias: Classification and pathology".)

● (See "Approach to the adult with interstitial lung disease: Diagnostic testing".)
● (See "Role of bronchoalveolar lavage in diagnosis of interstitial lung disease".)
● (See "Role of lung biopsy in the diagnosis of interstitial lung disease".)
● (See "Interpretation of lung biopsy results in interstitial lung disease".)
● (See "Overview of the management of adults with interstitial lung disease".)

CLASSIFICATION

The diffuse parenchymal lung diseases are divided into those that are associated with known
causes and those that are idiopathic. The treatment choices and prognosis vary among the
different causes and types of ILD, so ascertaining the correct diagnosis is important.
A variety of infections can cause interstitial opacities on chest radiograph, including fungal
pneumonias (eg, coccidioidomycosis, cryptococcosis, Pneumocystis jirovecii), atypical
bacterial pneumonias, and viral pneumonias. These infections often occur in
immunocompromised hosts and are discussed separately. (See "Approach to the
immunocompromised patient with fever and pulmonary infiltrates".)

The most common identifiable causes of ILD are exposure to occupational and
environmental agents, especially to inorganic or organic dusts ( table 1A-B), drug-induced
pulmonary toxicity, and radiation-induced lung injury. (See "Asbestos-related
pleuropulmonary disease" and "Chronic beryllium disease (berylliosis)" and "Silicosis" and
"Pulmonary toxicity associated with systemic antineoplastic therapy: Clinical presentation,
diagnosis, and treatment" and "Radiation-induced lung injury" and "Hypersensitivity
pneumonitis (extrinsic allergic alveolitis): Epidemiology, causes, and pathogenesis".)

ILD can also complicate the course of most of the connective tissue diseases (eg,
polymyositis/dermatomyositis, rheumatoid arthritis, systemic lupus erythematosus,
scleroderma, mixed connective tissue disease).

Idiopathic causes of ILD include sarcoidosis, cryptogenic organizing pneumonia, and the
idiopathic interstitial pneumonias ( algorithm 1). The idiopathic interstitial pneumonias
have been further characterized: idiopathic pulmonary fibrosis (usual interstitial pneumonia),
desquamative interstitial pneumonia, respiratory bronchiolitis-interstitial lung disease, acute
interstitial pneumonia, and nonspecific interstitial pneumonia. (See "Idiopathic interstitial
pneumonias: Classification and pathology".)

CLINICAL PRESENTATION

Patients with ILD commonly come to clinical attention in one of the following ways:

● Symptoms of progressive breathlessness with exertion (dyspnea) or a persistent

nonproductive cough. (See "Approach to the patient with dyspnea" and "Causes and
epidemiology of subacute and chronic cough in adults".)

● Pulmonary symptoms associated with another disease, such as a connective tissue disease
( table 2)

● History of occupational exposure (eg, asbestosis, silicosis)

● An abnormal chest imaging study

● Lung function abnormalities on simple office spirometry, particularly a restrictive

ventilatory pattern (ie, reduced total lung capacity and forced vital capacity). (See
 "Overview of pulmonary function testing in adults".)

HISTORY

The most important step in the initial evaluation of a patient with suspected interstitial lung
disease is obtaining a complete history. Careful documentation of the past medical history is
important in the initial assessment because the cause of the illness is often recognized from
the patient's history. In addition to a thorough review of past systemic conditions and HIV
risk factors, several other aspects of the history are particularly important and include the
following features.

Age and gender — Some of the ILDs are more common in certain age groups or have a
male or female predominance. For example, most patients with sarcoidosis, connective
tissue disease-associated ILD, lymphangioleiomyomatosis, pulmonary Langerhans cell
histiocytosis, and inherited forms of ILD (familial IPF, Gaucher's disease, Hermansky-Pudlak
syndrome) present between the ages of 20 and 40 years. In contrast, most patients with
idiopathic pulmonary fibrosis (IPF, also called cryptogenic fibrosing alveolitis in Europe) are
over age 50.

Lymphangioleiomyomatosis and pulmonary involvement in tuberous sclerosis occur

exclusively in premenopausal women. Other diseases with a less pronounced female
preponderance include lymphocytic interstitial pneumonitis, ILD in Hermansky-Pudlak
syndrome, and the connective tissue diseases [8,9]. In contrast, ILD associated with
rheumatoid arthritis is more common in men. Because of occupational exposures, men are
also more likely to have a pneumoconiosis.

Onset of symptoms — The duration of symptoms prior to presentation may help focus the
differential diagnosis. The acute or subacute processes (eg, acute eosinophilic pneumonia,
cryptogenic organizing pneumonia, connective tissue associated ILD) often share features
with atypical infectious pneumonias, such as the rapid onset of symptoms, diffuse
radiographic opacities, and fever ( table 3).

ILDs with a chronic or indolent presentation (eg, idiopathic pulmonary fibrosis, sarcoidosis,
pneumoconioses) need to be differentiated from each other and from diseases such as
chronic obstructive pulmonary disease and heart failure.

Some ILDs, such as hypersensitivity pneumonitis and sarcoidosis, may have an acute,
subacute, or chronic presentation. (See "Hypersensitivity pneumonitis (extrinsic allergic
alveolitis): Clinical manifestations and diagnosis" and "Clinical manifestations and diagnosis
of sarcoidosis".)
Past medical history — Any history of connective tissue disease, inflammatory bowel
disease, or malignancy might be a clue to an associated ILD, either due to the underlying
disease or to medications used to treat the disease ( table 4). A number of medications
used to treat cardiac disease have also been associated with ILD, notably amiodarone. A
history of allergic rhinitis and asthma may implicate chronic eosinophilic pneumonia, while
nasal polyposis and asthma may suggest eosinophilic granulomatosis with polyangiitis
(EGPA, Churg-Strauss). An immunocompromised state due to an underlying disease or
immunomodulatory therapy may suggest an infectious cause of ILD.

Smoking history — A history of tobacco use is important, since some diseases occur largely
among current or former smokers (eg, pulmonary Langerhans cell histiocytosis,
desquamative interstitial pneumonitis, respiratory bronchiolitis-interstitial lung disease, and
idiopathic pulmonary fibrosis) or among never or former smokers (eg, sarcoidosis and
hypersensitivity pneumonitis).

Active smoking can contribute to complications in patients with Goodpasture's syndrome, in

which pulmonary hemorrhage is far more frequent among current smokers. In this setting, it
is thought that smoking damages the alveolar wall, making the alveolar basement
membrane more accessible to the circulating antibasement membrane antibodies [10]. (See
"Anti-GBM (Goodpasture) disease: Pathogenesis, clinical manifestations, and diagnosis".)

Family history — The family history is occasionally helpful, as several familial associations
have been identified [11-16]. However, different types of ILD (eg, idiopathic pulmonary
fibrosis and nonspecific interstitial pneumonitis) may occur within a single family [17]. (See
"Pathogenesis of idiopathic pulmonary fibrosis", section on 'Genetic predisposition'.)

Familial aggregation and racial differences in incidence support the notion that sarcoidosis
occurs in genetically susceptible hosts. However, the familial sarcoidosis studies clearly
exclude a simple mode of inheritance, suggesting a more complex genetic background. (See
"Pathology and pathogenesis of sarcoidosis", section on 'Possible etiologic agents'.)

An autosomal dominant pattern of inheritance has been reported for familial pulmonary
fibrosis (FPF), tuberous sclerosis, and neurofibromatosis (see "Pathogenesis of idiopathic
pulmonary fibrosis", section on 'Genetic predisposition' and "Neurofibromatosis type 1 (NF1):
Pathogenesis, clinical features, and diagnosis", section on 'Pathogenesis' and "Tuberous
sclerosis complex: Genetics and pathogenesis", section on 'Genetics'). In a study of 111
families with two or more cases of pulmonary fibrosis, 20 pedigrees demonstrated vertical
transmission, consistent with autosomal dominant inheritance, and 45 demonstrated
phenotypic heterogeneity [17]. Having ever smoked cigarettes was strongly associated with
the development of pulmonary fibrosis, suggesting that an interaction between
environmental exposure and gene or gene(s) may contribute to the pathogenesis of this
disease.
An autosomal recessive pattern of inheritance has been identified for Niemann-Pick disease,
Gaucher's disease, and Hermansky-Pudlak syndrome [18,19]. (See "Overview of acid
sphingomyelinase deficiency and Niemann-Pick disease type C" and "Gaucher disease:
Pathogenesis, clinical manifestations, and diagnosis" and "Hermansky-Pudlak syndrome".)

Prior medication use — A detailed history of all medications taken and any exposure to
therapeutic irradiation is needed to exclude the possibility of drug-induced lung disease [20-
22]. The medication history should include over-the-counter medications, oily nose drops or
petroleum products, and amino acid supplements ( table 4) [20,21]. In some cases, lung
disease may occur weeks to years after the drug has been discontinued (eg, carmustine).
Reports of drug-induced pulmonary fibrosis are rising, with disease-modifying antirheumatic
drugs and antineoplastics being the most commonly implicated drug classes [23]. (See
"Pulmonary toxicity associated with systemic antineoplastic therapy: Clinical presentation,
diagnosis, and treatment" and "Nitrosourea-induced pulmonary injury".)

A list of drugs reported to cause pulmonary toxicity is available at Pneumotox.

Irradiation — Radiation-induced lung injury is directly related to the volume of irradiated

lung and the cumulative dose of irradiation. Symptoms associated with acute radiation
pneumonitis usually develop approximately four to twelve weeks following irradiation,
whereas symptoms of late or fibrotic radiation pneumonitis develop after six to twelve
months. Radiation recall pneumonitis can occur months to years after irradiation, when
certain antineoplastic agents (eg, Adriamycin, etoposide, gemcitabine, paclitaxel) are
administered to a patient who has received prior radiation therapy to the lung. (See
"Radiation-induced lung injury".)

Occupational and environmental exposures — Review of the home and work

environment, including that of spouse and children, is invaluable [24-29]. A strict
chronological listing of the patient's entire lifelong employment must be sought, including
specific duties and known exposures to dusts, gases, and chemicals [24]. The degree of
exposure, duration, latency of exposure, and the use of protective devices should be elicited.
The patient may need to obtain material safety data sheets (MSDS) from the employer, if it is
unclear what exposures may have occurred in the workplace. A written questionnaire can be
used to obtain this information in a systematic manner ( table 1A-B). (See "Hypersensitivity
pneumonitis (extrinsic allergic alveolitis): Clinical manifestations and diagnosis" and
"Silicosis", section on 'Silica in the work environment' and "Asbestos-related
pleuropulmonary disease", section on 'Asbestos exposure' and "Chronic beryllium disease
(berylliosis)", section on 'Risk factors'.)

In hypersensitivity pneumonitis (extrinsic allergic alveolitis), the development of respiratory

symptoms, fever, chills, and an abnormal chest radiograph are often temporally related to
the workplace (farmer's lung) or to a hobby (pigeon breeder's disease). Symptoms may
diminish or disappear after the patient leaves the exposure for several days and often
reappear upon returning to the exposure. Thus, it is important to determine if the patient
has had exposures to pets (especially any birds), air conditioners, humidifiers, hot tubs,
evaporative cooling systems (eg, swamp coolers), or if there has been water damage to walls
and carpets in the home or work environment. Family members may develop disease as a
result of "passive" exposure to dusts from the hobby or occupation of another member of
the family (eg, asbestosis, berylliosis). (See "Hypersensitivity pneumonitis (extrinsic allergic
alveolitis): Epidemiology, causes, and pathogenesis".)

Symptoms — Patients with ILD can present with several symptoms, and it is important to
ascertain the duration, severity, and progression of symptoms. Most of the symptoms are
nonspecific, but some will help to narrow the differential. Patients should be asked about
extrapulmonary symptoms that might suggest a systemic disorder.

● Dyspnea – A sense of shortness of breath, ie, dyspnea, is a common complaint of patients

with cardiac or pulmonary disease [30]. In most instances, the patient has attributed the
insidious onset of breathlessness with exertion to aging, deconditioning, obesity, or a
previous unresolved upper respiratory tract illness. Some patients deny the presence of
dyspnea even when questioned. This usually occurs because they have limited their activity
and therefore rarely experience any significant discomfort. Frequently, a spouse or friend
brings the problem to the patient's attention.

Grading the level of dyspnea is useful as a method to gauge the severity of the disease and
to follow its course ( table 5) [31]. However, some patients, especially those with
sarcoidosis, silicosis, or pulmonary Langerhans cell histiocytosis, may have extensive
parenchymal lung disease on chest radiograph without significant dyspnea. This most often
occurs early in the course of the disease. (See "Approach to the patient with dyspnea" and
"Physiology of dyspnea".)

Sudden worsening of dyspnea, particularly if associated with pleural pain, may indicate a
spontaneous pneumothorax. Spontaneous pneumothorax is a characteristic finding that
may occur in diseases such as pulmonary Langerhans cell histiocytosis, tuberous sclerosis,
lymphangioleiomyomatosis, and neurofibromatosis.

● Cough – A dry cough is common and can be particularly bothersome in conditions that
involve the airways, such as sarcoidosis, bronchiolitis obliterans with or without organizing
pneumonia, respiratory bronchiolitis, pulmonary Langerhans cell histiocytosis,
hypersensitivity pneumonitis, lipoid pneumonia, and lymphangitic carcinomatosis [32]. A
productive cough is unusual for most ILDs; rarely, a mucoid, salty-tasting sputum is
reported by patients with bronchoalveolar cell carcinoma. (See "Causes and epidemiology
of subacute and chronic cough in adults" and "Clinical manifestations and diagnosis of
sarcoidosis", section on 'Typical presentations' and "Overview of bronchiolar disorders in
 adults" and "Hypersensitivity pneumonitis (extrinsic allergic alveolitis): Clinical
manifestations and diagnosis" and "Cryptogenic organizing pneumonia" and "Pulmonary
Langerhans cell histiocytosis" and "Respiratory bronchiolitis-associated interstitial lung
disease" and "Aspiration pneumonia in adults", section on 'Lipoid pneumonia'.)

● Hemoptysis – Grossly bloody or blood-streaked sputum may occur in the diffuse alveolar
hemorrhage syndromes, lymphangioleiomyomatosis, tuberous sclerosis, pulmonary veno-
occlusive disease, longstanding mitral valve disease, and granulomatous vasculitides. In
some patients, diffuse alveolar bleeding may be present without hemoptysis; the clinical
manifestations in such patients may be dyspnea and an iron deficiency anemia. The new
onset of hemoptysis in a patient with known ILD suggests a complicating malignancy. (See
"Evaluation of nonlife-threatening hemoptysis in adults".)

● Wheezing – Wheezing is an uncommon manifestation of ILD. It has been described in

cases of lymphangitic carcinomatosis, chronic eosinophilic pneumonia, EGPA, and
respiratory bronchiolitis.

● Chest pain – Chest pain is uncommon in most ILDs. However, pleuritic chest pain may
occur in ILD associated with rheumatoid arthritis, systemic lupus erythematosus, mixed
connective tissue disease, and some drug-induced disorders. In addition, the acute onset
of pleuritic chest pain may indicate a pneumothorax. Substernal discomfort or pain is
common in sarcoidosis.

● Extrapulmonary symptoms – Clinical findings suggestive of a connective tissue disease

should be carefully recorded. These include musculoskeletal pain, weakness, fatigue, fever,
joint pains or swelling, photosensitivity, Raynaud phenomenon, pleuritis, dry eyes, and dry
mouth. However, the absence of these symptoms does not exclude connective tissue
disease, as the pulmonary manifestations occasionally precede the more typical systemic
manifestations by months or years (especially in rheumatoid arthritis, systemic lupus
erythematosus, and polymyositis-dermatomyositis).

PHYSICAL EXAMINATION

The physical examination of patients with ILD is usually nonspecific, except when
extrapulmonary findings suggest a particular systemic disease.

Lung examination — The lung examination is frequently abnormal in ILD, but the findings
are generally nonspecific. Crackles or "velcro râles" are present on chest examination in most
forms of ILD, although they are less likely to be heard in the granulomatous lung diseases,
especially sarcoidosis [33]. Crackles may be present in the absence of radiographic
abnormalities on the chest radiograph. When listening for crackles in patients with
suspected ILD, it is helpful to listen at the lung bases in the posterior axillary line, as crackles
may be audible only in this location in early disease.

Scattered late inspiratory high-pitched rhonchi, so-called inspiratory squeaks, are frequently
heard on chest examination in patients with bronchiolitis but may also be heard in patients
with traction bronchiectasis due to pulmonary fibrosis.

Cardiac examination — The cardiac examination is usually normal except in more advanced
stages of pulmonary fibrosis, when findings of pulmonary hypertension and cor pulmonale
(augmented P2, right-sided lift, right-sided gallop) may become evident. Pulmonary
hypertension may also be a primary manifestation of some connective tissue disorders (eg,
progressive systemic sclerosis).

Findings of cor pulmonale (eg, peripheral edema, right ventricular heave, accentuated
second heart sound) are rare in ILD. When present, these findings are usually indicative of
advanced disease. (See "Pulmonary hypertension due to lung disease and/or hypoxemia
(group 3 pulmonary hypertension): Epidemiology, pathogenesis, and diagnostic evaluation in
adults", section on 'Clinical evaluation'.)

Clubbing — Clubbing of the digits ( figure 1) is common in some pulmonary disorders

(idiopathic pulmonary fibrosis, asbestosis) and rare in others (sarcoidosis, hypersensitivity
pneumonitis, pulmonary Langerhans cell histiocytosis). Other disorders associated with
clubbing include cystic fibrosis, pulmonary arteriovenous malformations, cyanotic heart
disease, malignancies of the lung and pleura, and inflammatory bowel disease [34]. When
clubbing occurs during ILD, it is typically a late manifestation and suggests advanced fibrosis
of the lung. The pathophysiology of clubbing is discussed separately. (See "Malignancy and
rheumatic disorders", section on 'Hypertrophic osteoarthropathy'.)

Extrapulmonary findings of systemic disease — The identification of extrapulmonary

manifestations of diseases such as amyloidosis, connective tissue diseases, Hermansky-
Pudlak syndrome, neurofibromatosis, sarcoidosis, or tuberous sclerosis can help to narrow
the differential diagnosis ( table 6). In particular, patients are examined for evidence of
alopecia, angiofibromas, cutaneous sarcoidosis, Gottron's papules ( picture 1A-C),
heliotrope rash ( picture 2A-B), joint inflammation, "mechanics" hands, muscle weakness,
nasal obstruction, peripheral neuropathy, and sclerodactyly. Nailfold capillary microscopy
may help with early identification of connective tissue disease in patients who report
Raynaud phenomenon [35]. (See "Clinical manifestations and diagnosis of Raynaud
phenomenon", section on 'Nailfold capillary microscopy'.)

SOCIETY GUIDELINE LINKS

Links to society and government-sponsored guidelines from selected countries and regions
around the world are provided separately. (See "Society guideline links: Interstitial lung
disease".)

INFORMATION FOR PATIENTS

UpToDate offers two types of patient education materials, “The Basics” and “Beyond the
Basics.” The Basics patient education pieces are written in plain language, at the 5th to 6th
grade reading level, and they answer the four or five key questions a patient might have
about a given condition. These articles are best for patients who want a general overview
and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are
longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th
grade reading level and are best for patients who want in-depth information and are
comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to
print or e-mail these topics to your patients. (You can also locate patient education articles
on a variety of subjects by searching on “patient info” and the keyword(s) of interest.)

● Basics topics (see "Patient education: Idiopathic pulmonary fibrosis (The Basics)" and
"Patient education: Interstitial lung disease (The Basics)")

SUMMARY AND RECOMMENDATIONS

● Classification and approach – Diffuse parenchymal lung diseases, often collectively

referred to as interstitial lung diseases (ILDs), are divided into those that are associated
with known causes and those that are idiopathic ( algorithm 1). An approach to
evaluating immunocompetent patients with ILD is shown in the algorithm ( algorithm 2).
(See 'Introduction' above and 'Classification' above.)

A variety of infectious processes (eg, atypical bacterial, viral, and fungal pneumonia) can
cause opacities on chest radiograph that mimic ILD. These infections often occur in
immunocompromised hosts and are discussed separately. (See "Approach to the
immunocompromised patient with fever and pulmonary infiltrates".)

● Clinical presentation and history – The initial recognition that a patient may have an ILD
usually follows the onset of progressive breathlessness with exertion (dyspnea), a
persistent nonproductive cough, or pulmonary symptoms associated with another
disease, such as a connective tissue disease ( table 2). (See 'Clinical presentation' above.)
 Careful documentation of the past medical history is important in the initial assessment
because the cause of the illness is often recognized from the patient's medical history.
Attention is also given to history of smoking, medication use, occupational and
environmental exposures, and familial occurrence of ILD ( table 1A-B). (See 'History'
above.)

● Physical examination – Crackles, also described as "velcro râles," are a nonspecific finding
present in most forms of ILD, although they are less likely to be heard in the
granulomatous lung diseases, especially sarcoidosis. Crackles may be present in the
absence of radiographic abnormalities on the chest radiograph. (See 'Physical
examination' above.)

Clubbing of the digits is common in some ILDs (idiopathic pulmonary fibrosis, asbestosis)
and rare in others (sarcoidosis, hypersensitivity pneumonitis, pulmonary Langerhans cell
histiocytosis) ( figure 1). (See 'Physical examination' above.)

An important part of the physical examination of patients with an undiagnosed ILD is

looking for extrapulmonary evidence of a systemic disease that might be associated with
ILD ( table 2). (See 'Extrapulmonary findings of systemic disease' above.)

● Diagnostic testing – The diagnostic testing (eg, laboratory tests, imaging studies,
bronchoalveolar lavage, and lung biopsy) that is helpful in evaluating patients with ILD is
discussed separately. (See "Approach to the adult with interstitial lung disease: Diagnostic
testing" and "Role of bronchoalveolar lavage in diagnosis of interstitial lung disease" and
"Role of lung biopsy in the diagnosis of interstitial lung disease".)

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Topic 4310 Version 32.0

GRAPHICS

Diffuse parenchymal lung diseases

Diffuse parenchymal lung diseases consist of disorders of known causes (rheumatic disease,
environmental or drug related) as well as disorders of unknown cause. The latter include IIPs,
granulomatous lung disorders (eg, sarcoidosis), and other forms of interstitial lung disease including
LAM, PLCH, and eosinophilic pneumonia. The interstitial pneumonias are further categorized as
chronic fibrosing, acute or subacute fibrosing, or smoking-related. Lymphoid interstitial pneumonia is
typically associated with other disease processes, such as rheumatic disease or immunosuppression;
idiopathic lymphoid interstitial pneumonia is rare.

DPLD: diffuse parenchymal lung disease; IIP: idiopathic interstitial pneumonia; LAM:
lymphangioleiomyomatosis; PLCH: pulmonary Langerhans cell histiocytosis/histiocytosis X.

Graphic 77345 Version 11.0

Diagnostic evaluation of patients with unclassified interstitial lung disease
This algorithm represents our approach to the diagnostic evaluation of patients presenting with
suspected ILD of unknown classification or etiology. This algorithm is intended for use in conjunction
with additional information provided in UpToDate content on the clinical manifestations and
diagnosis of ILD.

ANA: antinuclear antibody test; BAL: bronchoalveolar lavage; COP: cryptogenic organizing
pneumonia; cryo-TBB: transbronchial cryobiopsy; DIP: desquamative interstitial pneumonitis; EBUS:
endobronchial ultrasound; HP: hypersensitivity pneumonitis; HRCT: high-resolution computed
tomography; IIP: idiopathic interstitial pneumonia; ILD: interstitial lung disease; IPF: idiopathic
pulmonary fibrosis; NSIP: nonspecific interstitial pneumonia; PLCH: pulmonary Langerhans cell
histiocytosis; TBB: transbronchial lung biopsy; UIP: usual interstitial pneumonia.

* ILD protocols for HRCT of the chest include volumetric inspiration, expiration, and prone imaging to
assess for air-trapping, small airways disease, and dependent atelectasis.

¶ Additional testing for connective tissue disease and myositis may be performed either during the
initial work-up, especially for those with demographic or known imaging features atypical for IPF, or
as indicated by clinical or radiologic findings after the initial work-up. This testing includes creatine
kinase, aldolase, myositis/antisynthetase antibody panel, and an extractable nuclear antigen antibody
panel (including Sjögren-associated antibodies [anti-Ro60, anti-Ro52, and anti-La] and scleroderma-
associated antibodies [anti-SCL-70 and anti-centromere]).

Δ Common environmental or iatrogenic etiologies include: drug toxicities (bleomycin, immune

checkpoint inhibitors, nitrofurantoin, nitrosoureas), radiation therapy to the thorax, inhaled inorganic
dusts (eg, silica, asbestos, beryllium, coal), and inhaled organics (hay and grains, humidifiers/indoor
pool, feathers, molds). Any of these exposures in the setting of appropriate history and imaging
findings may explain the presence of ILD.
◊ Features of definite and probable UIP include: reticular opacities in a basal and peripheral
distribution, traction bronchiectasis, honeycombing (clustered airspaces 3 to 10 mm diameter) in a
subpleural location, and lack of extensive ground-glass opacities.

§ IIPs are non-granulomatous diffuse parenchymal lung disease of unknown etiology, including: IPF,
NSIP, COP, acute interstitial pneumonia, respiratory bronchiolitis ILD, and DIP.

¥ For patients who have a nondiagnostic cryo-TBB, subsequent surgical lung biopsy may be
appropriate to obtain a diagnosis.

References:
1. Raghu G. Interstitial lung disease: A diagnostic approach. Are CT scan and lung biopsy indicated in every patient? Am J
Respir Crit Care Med 1995; 151:909.
2. Raghu G, Remy-Jardin M, Myers JL, et al. Diagnosis of idiopathic pulmonary fibrosis. An official ATS/ERS/JRS/ALAT clinical
practice guideline. Am J Respir Crit Care Med 2018; 198:e44.
3. Hariri LP, Roden AC, Chung JH, et al. The role of surgical lung biopsy in the diagnosis of fibrotic interstitial lung disease:
Perspective from the Pulmonary Fibrosis Foundation. Ann Am Thorac Soc 2021; 18:1601.
4. Dias Rohr JT, Rodrigues Isaac C, de Almeida de Lima A, et al. Study of geometric illusory visual perception - A new
perspective in the functional evaluation of children with strabismus. Front Hum Neurosci 2022; 16:769412.

Graphic 69044 Version 7.0

Occupational and environmental exposures associated with interstitial lung
disease

Inhaled inorganic dust

Silicates

Silica ("silicosis")

Asbestos ("asbestosis")

Talc (hydrated Mg silicates; "talcosis")

Kaolin or "china clay" (hydrated aluminum silicate)

Diatomaceous earth (Fuller's earth, aluminum silicate with Fe and Mg)

Nepheline (hard rock containing mixed silicates)

Aluminum silicates (sericite, sillimanite, zeolite)

Portland cement

Mica (principally K and Mg aluminum silicates)

Beryllium ("berylliosis")

Carbon

Coal dust ("coal worker's pneumoconiosis")

Graphite ("carbon pneumoconiosis")

Metals

Tin ("stannosis")

Aluminum

Powdered aluminum

Bauxite (aluminum oxide)

Hard metal dusts

Cadmium

Titanium oxide

Tungsten

Hafnium

Niobium

Cobalt

Vanadium carbides

Iron ("siderosis", "arc welder's lung") Barium (powder of baryte or BaSO4; "baritosis")

Antimony (oxides and alloys)

Hematite (mixed dusts of iron oxide, silica and silicates; "siderosilicosis")

 Mixed dusts of silver and iron oxide ("argyrosiderosis")

CuSO4 neutralized with hydrated lime (Bordeaux mixture; "vineyard sprayer's lung")

Rare earths (cerium, scandium, yttrium, lanthanum)

Adapted from Crystal, RG. Interstitial lung disease. In: Wyngaarden, JB, Smith, LH, Jr, Bennett, JC, (Eds), Cecil Textbook of
Medicine, 19th ed, WB Saunders Co, Philadelphia, 1992.

Graphic 80757 Version 1.0

Occupational and environmental exposures associated with interstitial lung
disease

Inhaled organic dusts (examples of causes of hypersensitivity pneumonitis)

Thermophilic fungi (ie, Macropolyspora faeni, Thermactinomyces vulgaris, T. sacchari)

Farmer's lung

Grain handler's lung

Humidifier or air conditioner lung

Bacteria (ie, Bacillus subtilis, B. cereus)

Humidifier lung

True fungi (ie, Aspergillus, Cryptostroma corticale, Aureobasidium pullulans, Penicillium species)

Animal proteins (eg, bird fancier's disease)

Inhaled agents other than inorganic or organic dusts

Chemical sources

Synthetic - fiber lung (Orlon, polyesters, nylon, acrylic)

Bakelite worker's lung

Vinyl chloride, polyvinyl chloride powder

Gases

Oxygen

Oxides of nitrogen

Sulfur dioxide

Chlorine gas

Methyl isocyanate

Fumes

Oxides of zinc, copper, manganese, cadmium, iron, magnesium, nickel, brass, selenium, tin, and
antimony

Diphenylmethane diisocyanate

Trimellitic anhydride toxicity

Vapors

Hydrocarbons

Thermosetting resins (rubber tire workers)

Toluene diisocyanate (TDI - asthmatic reactions prominent)

Mercury

Aerosols
 Oils

Fats

Pyrethrum (a natural insecticide)

Adapted from Crystal, RG. Interstitial lung disease. In: Wyngaarden, JB, Smith, LH, Jr, Bennett, JC, (Eds), Cecil Textbook of
Medicine, 19th ed, WB Saunders Co, Philadelphia, 1992.

Graphic 62236 Version 2.0

Partial list of primary diseases associated with interstitial lung disease

Sarcoidosis

Vasculitides

Eosinophilic granulomatosis with polyangiitis (EGPA)

Granulomatosis with polyangiitis (GPA)

Microscopic polyangiitis (MPA)

Hemorrhagic syndromes

Anti-glomerular basement membrane antibody (Goodpasture) disease

Idiopathic pulmonary hemosiderosis

Pulmonary Langerhans cell histiocytosis

Chronic gastric aspiration

Amyloidosis

Lymphangioleiomyomatosis

Neurofibromatosis

Lymphangitic carcinomatosis

Chronic heart failure

End-stage kidney disease

Respiratory bronchiolitis

Pulmonary alveolar proteinosis

Gaucher disease

Niemann-Pick disease

Hermansky-Pudlak syndrome

Pulmonary veno-occlusive disease

Graphic 64034 Version 5.0

Duration of interstitial lung disease prior to diagnosis

Acute (days to weeks)

Acute idiopathic interstitial pneumonia (AIP, Hamman-Rich syndrome)

Eosinophilic pneumonia

Hypersensitivity pneumonitis

Cryptogenic organizing pneumonia

Subacute (weeks to months)

Sarcoidosis

Some drug-induced ILDs

Alveolar hemorrhage syndromes

Cryptogenic organizing pneumonia

Connective tissue disease (systemic lupus erythematosus or polymyositis)

Chronic (months to years)

Idiopathic pulmonary fibrosis

Sarcoidosis

Pulmonary Langerhans cell histiocytosis

Chronic hypersensitivity pneumonitis

Graphic 80410 Version 2.0

Examples of drugs and biologics that can cause interstitial lung disease

Antibiotics Drug-induced systemic lupus

Ethambutol
erythematosus

Minocycline Hydantoins

Nitrofurantoin, acute and chronic Hydralazine

Isoniazid
Anti-inflammatory agents
Penicillamine
Abatacept
Procainamide
Azathioprine*

Cyclophosphamide* Illicit drugs

Gold Cocaine

Interleukin-1 blockers (anakinra) Heroin

Leflunomide Methadone

Methotrexate* Propoxyphene

Nonsteroidal antiinflammatory agents Talc

Penicillamine Miscellaneous

Rituximab (anti-CD20 monoclonal antibody) Bacille Calmette-Guerin (BCG)

Sulfasalazine Bromocriptine

Thalidomide* Drugs inducing pulmonary infiltrates and

eosinophilia
Tocilizumab
L-tryptophan
Tumor-necrosis factor-alpha blockers
Oxygen
Anti-arrhythmic agents
Radiation
Amiodarone
Statins
Tocainide

Antineoplastic agents
Alkylating agents

Busulfan

Chlorambucil

Cyclophosphamide*

Melphalan

Procarbazine

Antibiotics

Bleomycin sulfate
 Mitomycin C

Antimetabolites

Azathioprine*

Cytosine arabinoside

Methotrexate*

Nitrosoureas

BCNU (carmustine)

CCNU (lomustine)

Methyl-CCNU (semustine)

Other

Alpha interferon

Docetaxel

Etoposide (VP-16)

Gefitinib

Nilutamide

Paclitaxel

Temsirolimus

Thalidomide*

* Drugs that are used as both antineoplastic and anti-inflammatory agents.

Adapted from: Camus P. Interstitial lung disease from drugs, biologics, and radiation. In: Interstitial Lung Disease, 5th ed,
Schwarz MI, King TE Jr (Eds), People's Medical Publishing House, Shelton, 2011.

Graphic 56668 Version 4.0

Levels of dyspnea

Number of
Level of dyspnea
points

None (or same as peers) even after 30 min of vigorous activity, such as running; 0
ability to lift and carry 27 kg (60 lbs) for a prolonged period of time

After 5 flights of stairs or 10 min of vigorous activity/prolonged use of heavy tools 2

After walking more than a mile (1609 m) on level ground or up three flights of 4
stairs; less than 10 min of vigorous activity, such as running or tennis

Upon walking 0.25 to 1 mile (402 to 1604 m) on level ground or up 2 flights of 6

stairs; dyspnea with paper hanging

Upon walking 300 to 1,320 feet (91.4 to 402.3 m) on level ground; bed-making* 8

Upon walking 150 to 300 feet (45.7 to 91.4 m) on level ground or up 1 flight of 10
stairs; scrubbing; truck driving; assembly-line work ¶

Upon walking 50 to 150 feet (15.2 to 45.7 m) on level ground at approximately 3 12

mph; light janitorial work ¶

Upon walking 20 to 50 feet (6.1 to 15.2 m) on level ground; light steady work at 14
one's own pace; seated operation of heavy equipment ¶

With minor exertion, such as dressing, walking less than 20 feet (6.1 meters), or 16
prolonged talking ¶

With minimal activity, such as eating, defecating, writing, sitting up ¶ 18

At rest ¶ 20

* Defined as moderately severe breathlessness.

¶ Defined as severe breathlessness.

Redrawn from: Watters, LC, King, TE, Schwarz, MI, et al, Am Rev Respir Dis 1986; 133:97.

Graphic 55810 Version 2.0

Clubbing of the fingers

In a normal finger, the length of the perpendicular dropped from point A to point B should be greater
than a similar line from C to D. In clubbing, the relationships are reversed; that is, the distance C-D is
greater than the distance A-B. The other important change is the angle described by A-C-E. In the
normal finger, this is usually <180°, whereas in clubbing, it is >180°.

Panels A and C redrawn from: DeRemee RA. Facets of the algorithmic synthesis. In: DeRemee RA, (Ed), Clinical profiles of
diffuse interstitial pulmonary disease, Mount Kisco, NY, Futura Publishing Company, Inc, 1990, pp. 9-44.

Panel B redrawn from: Bates B. A Guide to Physical Examination and History Taking, 5th Ed. Philadelphia: J.B. Lippincott
Company, 1991.

Graphic 52839 Version 5.0

Extrapulmonary findings in the interstitial lung diseases

Physical findings Associated conditions

Systemic arterial hypertension

Systemic rheumatic disease, neurofibromatosis,

anti-GBM antibody syndrome, systemic vasculitis

Skin

Discoid lupus Idiopathic pulmonary fibrosis, SLE, drug-induced

SLE

Maculopapular rash Drug-induced, amyloidosis, systemic rheumatic

disease, Gaucher disease

Heliotrope rash, Gottron papules, poikiloderma Dermatomyositis

Mechanic's hands Antisynthetase syndrome

Palmar papules, ulcerating lesions Amyopathic dermatomyositis

Telangiectasia, sclerodactyly, Systemic sclerosis (scleroderma)

hyperpigmentation/hypopigmentation, digital
ulcers or pitting

Raynaud phenomenon Systemic rheumatic disease (scleroderma, SLE,

mixed systemic rheumatic disease)

Cafe-au-lait spots, neurofibromas Neurofibromatosis

Cutaneous vasculitis (eg, palpable purpura) Systemic vasculitides, systemic rheumatic disease

Reticulated or mottled skin hyperpigmentation, Dyskeratosis congenita

nail dystropy, mucosal leukoplakia

Albinism Hermansky-Pudlak syndrome

Calcinosis Dermatomyositis-polymyositis, scleroderma

Subcutaneous nodules Rheumatoid arthritis, neurofibromatosis, ANCA-

associated vasculitis

Erythema nodosum (deep, painful nodules Sarcoidosis, systemic rheumatic disease, Behçet
predominantly on anterior surfaces lower syndrome, inflammatory bowel disease,
extremities) histoplasmosis, coccidioidomycosis

Eyes

Uveitis Sarcoidosis (eg, mutton-fat keratic precipitates),

Behçet syndrome (eg, panuveitis, hypopyon),
ankylosing spondylitis (eg, acute anterior uveitis)

Scleritis ANCA-associated vasculitis, SLE, systemic sclerosis

(scleroderma), sarcoidosis

Keratoconjunctivitis sicca Lymphocytic interstitial pneumonia (in Sjögren

syndrome)
 Cherry red macula, macular halo Neiman-Pick disease

Hematologic and reticuloendothelial system

Peripheral lymphadenopathy Sarcoidosis, lymphangitic carcinomatosis,

lymphocytic interstitial pneumonia, lymphoma,
LAM-TSC

Hepatosplenomegaly Sarcoidosis, pulmonary Langerhans cell

histiocytosis, systemic rheumatic disease,
amyloidosis, lymphocytic interstitial pneumonia

Anemia, thrombocytopenia, hypocellular Dyskeratosis congenita

marrow

Heart

Pericarditis, pericardial effusion Radiation pneumonitis, systemic rheumatic

disease, LAM-TSC

Cardiomyopathy ANCA-associated vasculitis, sarcoidosis, SLE

Musculoskeletal/neurologic

Muscle weakness Systemic rheumatic disease, drugs (eg, statins),

sarcoidosis

Nervous system abnormalities Pulmonary Langerhans cell histiocytosis, Neiman-

Pick disease, neurofibromatosis, sarcoidosis, SLE,
systemic vasculitis, TSC

Arthritis ANCA-associated vasculitis, rheumatoid arthritis,

SLE, sarcoidosis (predominantly periarthritis of
ankles and knees)

Gastrointestinal/renal

Glomerulonephritis Anti-GBM antibody syndrome, ANCA-associated

vasculitis, sarcoidosis

Nephrotic syndrome Amyloid, drug-induced, sarcoidosis, SLE

Renal mass (eg, angiomyolipoma) TSC, LAM

Gastrointestinal symptoms (eg, diarrhea, Pneumonitis related to inflammatory bowel

abdominal pain, hematochezia) disease

Other

Salivary or lacrimal gland enlargement Sarcoidosis, lymphocytic interstitial pneumonia (in

Sjögren syndrome), IgG4-related disease

Pleural abnormalities Systemic rheumatic disease, LAM-TSC (chylous

effusion), asbestosis

ANCA: antineutrophil cytoplasmic antibodies; GBM: glomerular basement membrane; IgG4:

immunoglobulin G4; LAM: lymphangioleiomyomatosis; SLE: systemic lupus erythematosus; TSC:
tuberous sclerosis complex.
Adapted from:
1. Schwarz MI, King TE Jr, Cherniack RM. General principles and diagnostic approach to the interstitial lung diseases. In:
Murray JF, Nadel JA, (Eds), Textbook of Respiratory Medicine, 2nd ed, Philadelphia, WB Saunders Co, 1994, pp. 1803-
1826.
2. Cosgrove GP, Schwarz MI. Approach to the evaluation and diagnosis of interstitial lung diseases. In: Interstitial Lung
Disease, 5th ed, Shelton, CT, Peoples Medical Publishing House, 2011, pp. 3-33.

Graphic 73094 Version 8.0

Gottron's sign in dermatomyositis

An erythematous, scaly eruption over the extensor surfaces of the metacarpophalangeal joints and
digits in a patient with dermatomyositis. These lesions, called Gottron's sign, can mimic psoriasis.

Courtesy of John H Stone, MD, MPH.

Graphic 70904 Version 3.0

Gottron's sign in dermatomyositis

Erythematous to violaceous patches with overlying scale are present on the extensor surfaces of both
knees in this child with dermatomyositis.

Copyright (©) 2020 American College of Rheumatology. Used with permission.

Graphic 50909 Version 23.0

Gottron's sign in a patient with amyopathic dermatomyositis

Copyright (©) 2020 American College of Rheumatology. Used with permission.

Graphic 51110 Version 19.0

Heliotrope eruption in dermatomyositis

A reddish-purple eruption on the upper eyelid (the heliotrope eruption), accompanied by swelling of
the eyelid in a patient with dermatomyositis (DM). This is the most specific cutaneous eruption in DM,
although it is only present in a minority of patients.

Courtesy of John H Stone, MD, MPH.

Graphic 73090 Version 5.0

Heliotrope eruption in dermatomyositis

Courtesy of John H Stone, MD, MPH.

Graphic 53713 Version 3.0