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" 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: 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, 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. 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 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 . (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 [11-15]. However, different types of ILD (eg, idiopathic pulmonary fibrosis and nonspecific interstitial pneumonitis) may occur within a single family . (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 "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 . 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 [17,18]. (See "Overview of Niemann-Pick disease" and "Gaucher disease: Pathogenesis, clinical manifestations, and diagnosis" and "Hermansky-Pudlak syndrome".)
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 [19-21]. The medication history should include over-the-counter medications, oily nose drops or petroleum products, and amino acid supplements (table 4) [19,20]. 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 [22-27]. 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 . 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 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 . 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 "Causes and epidemiology of subacute and chronic cough in adults" and "Clinical manifestations and diagnosis of pulmonary sarcoidosis", section on 'Clinical manifestations' 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 . 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 . 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 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.)
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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