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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: Helen Hollingsworth, MD

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

Literature review current through: Apr 2019. | This topic last updated: Jul 11, 2017.

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) [1-6]. 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: Clinical
manifestations and pathology" and "Clinical manifestations and diagnosis of pulmonary sarcoidosis"
and "Pulmonary toxicity associated with systemic antineoplastic therapy: Clinical presentation,
diagnosis, and treatment" and "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".)

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: Clinical manifestations 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 "Evaluation 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, the majority of 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 (figure 1). 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 [7,8]. 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 pulmonary 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 [9]. (See "Pathogenesis and diagnosis of anti-GBM
antibody (Goodpasture's) disease".)

Family history — The family history is occasionally helpful, as several familial associations have
been identified [10-14]. However, different types of ILD (eg, idiopathic pulmonary fibrosis and
nonspecific interstitial pneumonitis) may occur within a single family [15]. (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 idiopathic pulmonary fibrosis
(IPF), tuberous sclerosis, and neurofibromatosis (see "Pathogenesis of idiopathic pulmonary fibrosis",
section on 'Genetic predisposition' and "Tuberous sclerosis complex: Genetics, clinical features, and
diagnosis", section on 'Genetics' and "Neurofibromatosis type 1 (NF1): Pathogenesis, clinical
features, and diagnosis", section on 'Pathogenesis'). 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 [15]. 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 [7,16]. (See "Overview of Niemann-Pick
disease" and "Gaucher disease: Pathogenesis, clinical manifestations, and diagnosis".)

Prior medication use and irradiation — A detailed history of all medications taken and any
exposure to therapeutic irradiation is needed to exclude the possibility of drug-induced or radiation-
induced lung disease [17-19]. The medication history should include over-the-counter medications,
oily nose drops or petroleum products, and amino acid supplements (table 4) [17,18]. In some cases,
lung disease may occur weeks to years after the drug has been discontinued (eg, carmustine). (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.

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 [20-23]. 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 [20]. 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)".)

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 a number of 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. In particular, 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 [24]. 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). 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. A productive cough is unusual for most
ILDs; rarely, a mucoid, salty-tasting sputum is reported by patients with bronchoalveolar cell
carcinoma. (See "Evaluation of subacute and chronic cough in adults" and "Clinical
manifestations and diagnosis of pulmonary sarcoidosis", section on 'Clinical manifestations' and
"Bronchiolitis 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 "Etiology and evaluation of
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 rales" 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 [25]. 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 2) 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 [26]. When clubbing occurs in the course of 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. (See "Clinical manifestations and diagnosis of
the 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

● Diffuse parenchymal lung diseases, often collectively referred to as 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). An approach to
evaluating immunocompetent patients with ILD is shown in the algorithm (algorithm 2). (See
'Introduction' above.)

● A variety of infectious processes 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 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.)

● Crackles or "velcro rales" 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 2). (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.)

● 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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REFERENCES

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lton, CT 2011.

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pulmonary fibrosis: evidence-based guidelines for diagnosis and management. Am J Respir Crit
Care Med 2011; 183:788.

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5. Travis WD, Hunninghake G, King TE Jr, et al. Idiopathic nonspecific interstitial pneumonia:
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6. Bradley B, Branley HM, Egan JJ, et al. Interstitial lung disease guideline: the British Thoracic
Society in collaboration with the Thoracic Society of Australia and New Zealand and the Irish
Thoracic Society. Thorax 2008; 63 Suppl 5:v1.

7. Pierson DM, Ionescu D, Qing G, et al. Pulmonary fibrosis in hermansky-pudlak syndrome. a

case report and review. Respiration 2006; 73:382.

8. Tian X, Yi ES, Ryu JH. Lymphocytic interstitial pneumonia and other benign lymphoid disorders.
Semin Respir Crit Care Med 2012; 33:450.

9. Donaghy M, Rees AJ. Cigarette smoking and lung haemorrhage in glomerulonephritis caused
by autoantibodies to glomerular basement membrane. Lancet 1983; 2:1390.

10. Garcia CK, Raghu G. Inherited interstitial lung disease. Clin Chest Med 2004; 25:421.

11. Marshall RP, Puddicombe A, Cookson WO, Laurent GJ. Adult familial cryptogenic fibrosing
alveolitis in the United Kingdom. Thorax 2000; 55:143.

12. Diaz de Leon A, Cronkhite JT, Katzenstein AL, et al. Telomere lengths, pulmonary fibrosis and
telomerase (TERT) mutations. PLoS One 2010; 5:e10680.

13. Alder JK, Chen JJ, Lancaster L, et al. Short telomeres are a risk factor for idiopathic pulmonary
fibrosis. Proc Natl Acad Sci U S A 2008; 105:13051.

14. Grutters JC, du Bois RM. Genetics of fibrosing lung diseases. Eur Respir J 2005; 25:915.

15. Steele MP, Speer MC, Loyd JE, et al. Clinical and pathologic features of familial interstitial
pneumonia. Am J Respir Crit Care Med 2005; 172:1146.

16. Rouhani FN, Brantly ML, Markello TC, et al. Alveolar macrophage dysregulation in Hermansky-
Pudlak syndrome type 1. Am J Respir Crit Care Med 2009; 180:1114.

17. Camus P, Bonniaud P, Fanton A, et al. Drug-induced and iatrogenic infiltrative lung disease. Clin
Chest Med 2004; 25:479.
 18. Camus P. Drug-induced interstitial lung disease. In: Interstitial Lung Disease, 4th ed, King TE Jr,
Schwarz MI (Eds), B.C. Decker, Hamilton, ON, Canada 2003. p.485.

19. Fernández AB, Karas RH, Alsheikh-Ali AA, Thompson PD. Statins and interstitial lung disease:
a systematic review of the literature and of food and drug administration adverse event reports.
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pathobiology. Am J Respir Crit Care Med 2012; 186:314.

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Topic 4310 Version 19.0

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 idiopathic interstitial pneumonias,
granulomatous lung disorders (eg, sarcoidosis), and other forms of interstitial
lung disease including lymphangioleiomyomatosis, pulmonary Langerhans cell
histiocytosis/histiocytosis X, 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 10.0

Interstitial lung disease

PFT: pulmonary function tests; HRCT: high resolution computed tomography; ILD:
interstitial lung disease; BAL: bronchoalveolar lavage; UIP: usual interstitial pneumonia;
IPF: idiopathic pulmonary fibrosis; NSIP: nonspecific interstitial pneumonia; OP: organizing
pneumonia; PLCH: pulmonary Langerhans cell histiocytosis; TBB: transbronchial lung
biopsy.
* Serology as indicated by clinical findings: rheumatoid factor, anti-cyclic citrulinated
peptide, antinuclear antibody, antisynthetase antibodies, creatine kinase, aldolase, Sjögren's
antibodies and scleroderma antibodies.
¶ Classic HRCT features of UIP:
1. Reticular opacities in basal and peripheral distribution.
2. Traction bronchiectasis.
3. Honeycombing (clustered airspaces 3 to 10 mm diameter) in subpleural location.
 4. Ground glass opacities may be present but are less extensive than reticular
opacities.

Adapted from: Raghu G. Am J Respir Crit Care Med 1995; 151:909.

Graphic 69044 Version 4.0

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
Granulomatosis with polyangiitis (Wegener's)
Eosinophilic granulomatosis with polyangiitis (Churg-Strauss)

Hemorrhagic syndromes
Anti-glomerular basement membrane antibody (Goodpasture's) disease
Idiopathic pulmonary hemosiderosis

Pulmonary Langerhans cell histiocytosis (eosinophilic granuloma)

Chronic gastric aspiration

Amyloidosis

Lymphangioleiomyomatosis

Neurofibromatosis

Lymphangitic carcinomatosis

Chronic pulmonary edema

Chronic uremia

Respiratory bronchiolitis

Alveolar proteinosis

Gaucher's disease

Niemann-Pick disease

Hermansky-Pudlak syndrome

Pulmonary veno-occlusive disease

Graphic 64034 Version 4.0

Age at onset of presentation in different interstitial lung
diseases

Idiopathic pulmonary fibrosis (IPF) has an older age distribution than either
pulmonary Langerhans cell histiocytosis (LCH) or sarcoidosis.

Data from King, TE, Jr. Interstitial lung diseases: General approaches. In: Parsons, PE,
Heffner, JE, (Eds), Pulmonary and Respiratory Therapy Secrets, Philadelphia, Handley
&Belfus, Inc. 1997, p. 234.

Graphic 81455 Version 1.0

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; ability to lift 0
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 stairs; less than 4
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 stairs; dyspnea 6
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 stairs; 10
scrubbing; truck driving; assembly-line work ¶

Upon walking 50 to 150 feet (15.2 to 45.7 m) on level ground at approximately 3 mph; light 12
janitorial work ¶

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

With minor exertion, such as dressing, walking less than 20 feet (6.1 meters), or prolonged 16
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 degrees, whereas in clubbing it is >180
degrees.

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 4.0

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 IPF, SLE, drug-induced SLE

Maculopapular rash Drug-induced, amyloidosis, systemic rheumatic disease,

Gaucher's 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, nail Dyskeratosis congenita

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 extremities) syndrome; inflammatory bowel disease; 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 marrow Dyskeratosis congenita

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, abdominal Pneumonitis related to inflammatory bowel disease
pain, hematochezia)

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),

abestosis

GBM: glomerular basement membrane; IPF: idiopathic pulmonary fibrosis; SLE: systemic lupus erythematosus; ANCA:
antineutrophil cytoplasmic antibodies; LAM: lymphangioleiomyomatosis; TSC: tuberous sclerosis complex; IgG4:
immunoglobulin G4.

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 6.0

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 © 2017 American College of Rheumatology. Used with permission.

Graphic 50909 Version 15.0

Gottron's sign in a patient with amyopathic dermatomyositis

Copyright © 2017 American College of Rheumatology. Used with permission.

Graphic 51110 Version 13.0

Heliotrope euption 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 4.0

Heliotrope eruption in dermatomyositis

Courtesy of John H Stone, MD, MPH.

Graphic 53713 Version 3.0