A. Introduction. Interstitial lung disease (ILD) represents a heterogeneous collection of disorders grouped together because they share similar clinical, radiographic, physiologic, and/or pathologic findings. ILD is often characterized by progressive breathlessness, nonproductive cough, abnormal chest radiographs, and lung function abnormalities. There are more than 100 causes of interstitial lung disease. A thorough history is the most informative tool to identify an etiology.
a. Classification. Interstitial lung diseases can be divided into two broad categories: those associated with known causes and those that are idiopathic. Being thorough with occupational history and environmental and drug exposures is key in honing in on a diagnosis.
b. Common features
i. Symptoms. Often insidiously progressive dyspnea and dry cough are present.
ii. Physical examination. Listen for coarse crackles (or “Velcro” rales), especially at lung bases.
iii. Pulmonary function test. Usually shows a restrictive ventilatory defect and/or impaired gas exchange. Restriction is characterized by decreased lung volumes on testing: total lung capacity (TLC), vital capacity (VC), residual volume (RV). The flow-volume loop is narrowed.
iv. It should be noted that the differential for a restrictive ventilatory defect includes not only ILD but also diseases of the chest wall, pleura, lung parenchyma, and nervous system. Use the PAINT mnemonic to remember causes of restrictive lung disease.
MNEMONIC: Causes of Restrictive Lung Diseases “PAINT”
Pleural (scarring, effusions, pneumothorax)
Alveolar (edema, hemorrhage, inflammation)
Interstitial lung disease
Neuromuscular (myasthenia, phrenic nerve dysfunction, myopathy)
Thoracic or extrathoracic (kyphoscoliosis, obesity, ascites, pregnancy)
B. Causes of Interstitial Lung Disease
a. ILD can be divided into three categories based on etiology: ILD caused by an unknown cause (idiopathic); by a known cause; and by other diseases (Table 20.1). Use the mnemonic I need a PhD and a CV, PLEASE to remember important causes of ILD.
Table 20.1 Causes of Interstitial Lung Disease
Interstitial Lung Disease Group
Idiopathic interstitial pneumonias (includes idiopathic pulmonary fibrosis)
Collagen Vascular disease
Pulmonary histiocytosis X
Alveolar proteinosis/Alveolar hemorrhage
Eosinophilic granulomatosis and polyangiitis
i. Idiopathic interstitial pneumonia (IIP) has several subtypes, defined by radiographic and pathologic appearance. The most common of these is idiopathic pulmonary fibrosis (IPF), which occurs in the sixth to seventh decade of life with the insidious onset of dyspnea and cough.
1. Diagnosis. A careful history must be taken to exclude other causes of ILD. The chest radiograph generally shows interstitial abnormalities, but a high-resolution computed tomography (HRCT) scan is more sensitive and can be helpful in identifying subtypes [e.g., IPF, desquamative interstitial pneumonia (DIP), nonspecific interstitial pneumonia (NSIP), respiratory bronchiolitis interstitial lung disease (RBILD), cryptogenic organizing pneumonia (COP), acute interstitial pneumonia (AIP)]. A multidisciplinary approach is critical in determining if and when a lung biopsy is appropriate. In certain cases, HRCT findings of peripheral, basilar fibrosis with septal thickening and honeycombing may be enough to make the diagnosis of IPF and obviate the need for a lung biopsy.
2. Treatment. Although some subtypes of IIP respond well to steroids, IPF does not. Newer immunologic therapies aimed at stopping fibroproliferation are now used in IPF to slow disease progression with modest results. For IPF or other progressive IIPs, early referral to a lung transplantation program is imperative.
ii. Pneumoconioses. Environmental exposures can include exposure to organic dusts (e.g., mold, grain, bird droppings), leading to a hypersensitivity pneumonitis, or to inorganic dusts (e.g., asbestos, silica, beryllium), leading to pneumoconioses. Particle deposition leads to inflammation, which can progress to fibrosis. There are dozens of known pneumoconioses, and a careful occupational and environmental history is critical in identifying an etiology. Diagnosis is usually made by history and chest radiography or computed tomography (CT) scan of the chest. Treatment entails removal from the source of exposure. Steroids are occasionally helpful.
iii. Hypersensitivity pneumonitis is an immune-mediated inflammatory process that results from repeated inhalation of organic dusts (e.g., mold, grain, bird droppings). The disease can be acute, subacute, or chronic in presentation. Unrecognized disease can progress to fibrosis.
1. Diagnosis is usually made by history and characteristic radiographic findings. Occasionally lung biopsy is required; noncaseating granulomas are the key pathologic finding.
2. Treatment. The source of the antigen should be avoided and may involve moving, changing occupation, or removing pets. High-dose steroids may be necessary as well.
iv. Drugs. The most common drugs to cause ILD are antineoplastic drugs, antibiotics (sulfa drugs, penicillins, nitrofurantoin), sulfonylureas, gold, phenytoin, penicillamine, and amiodarone. The diagnosis is made by history. Removal of the offending agent is key because continued exposure can lead to progressive fibrosis.
v. Collagen vascular disease. ILD is not uncommonly a manifestation of these diseases. Typically, other manifestations of rheumatologic disease are apparent before lung disease. Treatment of the underlying disease is key to preventing progression of lung disease.
vi. Pulmonary histiocytosis X (eosinophilic granuloma) is an idiopathic disorder that may progress to fibrosis.
1. Diagnosis. The typical patient is a 30- to 40-year-old smoker. The upper lung zones are most frequently involved. Birbeck granules (also called X bodies) are seen within mononuclear cells on biopsy under electron microscopy.
2. Treatment involves smoking cessation and high-dose steroids.
vii. Lymphangioleiomyomatosis (LAM) is a rare interstitial lung disease that affects women of childbearing age. Classically, women present with progressive dyspnea and pneumothorax. Although LAM is classified as a neoplasm of the soft tissue, it is considered a benign tumor. Typically, diffuse thin-walled cysts are seen throughout the lung fields. Because the disease can be rapidly progressive, referral to a lung transplantation center for evaluation should occur early in the course of the disease.
viii. Eosinophil-associated lung diseases are generally characterized by a triad of pulmonary infiltrates, eosinophilic bronchoalveolar lavage fluid, and peripheral eosinophilia. These diseases are usually diagnosed by history, chest radiograph, and bronchoalveolar lavage. Occasionally, lung biopsy is required. Most of these conditions are exquisitely steroid responsive, although prolonged therapy is sometimes required.
ix. Alveolar proteinosis is a rare disorder resulting from accumulation of lipoproteinaceous material in the alveolar space due to an acquired inability of the alveolar macrophage to digest and clear surfactant. This defect is thought to be due to an antibody-mediated depletion of granulocyte-macrophage colony-stimulating factor (GM-CSF). Diagnosis can be made by HRCT scanning (which shows a characteristic “crazy paving” pattern) and bronchoalveolar lavage (which is often described as having a milky appearance). Whole lung lavage is the primary therapy in severe disease. Inhaled GM-CSF, although experimental at this time, has accumulating evidence supporting use.
x. Sarcoidosis is an idiopathic systemic granulomatous disease that often presents in the third to fourth decade of life. The incidence is higher in African Americans, Northern Europeans, and women. The lung is involved in 90% of cases.
1. Diagnosis is suggested by lymphadenopathy (bilateral hilar involvement), rash, erythema nodosum, and hepatosplenomegaly. An elevated angiotensin-converting enzyme (ACE) level may be noted; however, this finding is neither sensitive nor specific and should not be used to rule in or out the diagnosis. In later stages, ILD may be seen on imaging, and bronchoscopy with biopsy may help rule out other ILDs. Noncaseating granulomas on tissue biopsy in the right clinical setting are diagnostic of the disease.
2. Treatment. Many patients with mild disease improve without therapy. Glucocorticoids may be appropriate for some patients. A multidisciplinary approach is often required given the systemic nature of the disease.
xi. Eosinophilic granulomatosis and polyangiitis (EGPA) and granulomatosis with polyangiitis (GPA). Both are one of a few ANCA-associated vasculitides. EGPA (formerly known as Churg-Strauss syndrome) presents with symptoms of asthma and progression is associated with eosinophilia, fever, and vasculitis of various organs. GPA, formerly known as Wegener’s granulomatosis, is an example of vasculitis that can present with life-threatening alveolar hemorrhage. GPA can present with the triad of upper airway inflammation, interstitial lung disease, and glomerulonephritis. Rapid recognition is important. Appropriate immunosuppressive therapy can prevent permanent lung or kidney damage and death.
C. Approach to the Patient. Whenever possible, a multidisciplinary approach should be taken when evaluating patients with interstitial lung disease. Inclusion of a clinician, radiologist, and, when appropriate, a pathologist that includes the elements below is the gold standard.
a. History and physical examination. Although the symptoms of cough and dyspnea are of foremost concern to the patient, they are almost universal and do not distinguish one disease from another. The history should focus on exposures to environmental agents and drugs. The review of systems should be comprehensive; look for symptoms of infection or evidence of collagen vascular disease (e.g., history of rash, arthralgia, photosensitivity, ulcers).
b. Chest radiograph. A chest radiograph is helpful. It will usually reveal bilateral interstitial (reticular) abnormalities. However, it can be diagnostic in other ways:
i. Pleural thickening or effusions in the absence of parenchymal disease suggest the pleura as the cause of the restrictive physiology. Calcified pleural plaques suggest asbestos exposure (which is benign) but should be differentiated from mesothelioma (which is malignant) and can also cause pleural thickening.
ii. A normal chest radiograph with evidence of restriction (low TLC) and an elevated RV on pulmonary function testing suggest the possibility of a neuromuscular disorder.
iii. A chest radiograph may be diagnostic if normal parenchyma is seen in combination with spinal pathology (e.g., kyphoscoliosis) or small lung volumes (e.g., ascites, obesity).
c. Other tests. It is not uncommon to see ILD on the chest radiograph with no revealing history and physical examination findings. In such cases, additional tests with varying sensitivities and specificities may be considered. Tests should be selected based on likely diagnostic possibilities.
i. HRCT is a logical next step after the history, physical examination, and chest radiograph. HRCT can help determine whether a biopsy is necessary for diagnosis. For example, the diagnosis of IPF can be made by HRCT if other causes of ILD are unlikely and an appropriate radiographic pattern is observed.
ii. Bronchoscopy. Bronchoalveolar lavage can identify infectious organisms or malignant cells. Cell count and differential analysis of lavage fluid is sometimes helpful, particularly when looking for eosinophilic lung disease, alveolar hemorrhage, pulmonary alveolar proteinosis, hypersensitivity pneumonitis, and sarcoidosis.
iii. Transbronchial biopsy increases the risk for pneumothorax and hemorrhage but may enable the diagnosis of diseases not identified on lavage, such as sarcoidosis and histiocytosis X. Although it cannot reliably diagnose between forms of ILD, transbronchial biopsy may be informative in patients who are too ill to tolerate surgical lung biopsy.
iv. Surgical lung biopsy is the diagnostic gold standard. It may be performed by open thoracotomy or thoracoscopy. Video-assisted thoracoscopic surgery (VATS) involves the insertion of a rigid thoracoscope into the pleural cavity to biopsy the lung. It has a similar yield to open thoracotomy, but decreased morbidity.
Suggested Further Readings
Adegunsoye A, Strek ME. Therapeutic approach to adult fibrotic lung diseases. Chest 2016;150:1371–86.Find this resource:
Jennette JC, Falk RJ, Bacon PA, et al. 2012 Revised International Chapel Hill Consensus Conference Nomenclature of Vasculitides. Arthritis Rheum 2013;65:1–11.Find this resource:
Lederer DJ, Martinez FJ. Idiopathic Pulmonary Fibrosis. N Engl J Med. 2018;378(19):1811–1823.Find this resource:
Martinez FJ, Chisholm A, Collard HR, et al. The diagnosis of idiopathic pulmonary fibrosis: current and future approaches. Lancet Respir Med 2017;5:61–71.Find this resource:
Travis WD, Costabel U, Hansell DM, et al. An official American Thoracic Society/European Respiratory Society statement: update of the international multidisciplinary classification of the idiopathic interstitial pneumonias. Am J Respir Crit Care Med 2013;188:733–48.Find this resource: