Published: August 2010
The term interstitial lung disease (ILD) refers to a broad category of lung diseases rather than a specific disease entity.1,2 It includes a variety of illnesses with diverse causes, treatments, and prognoses. These disorders are grouped together because of similarities in their clinical presentations, plain chest radiographic appearance, and physiologic features.
Because there are more than 100 separate disorders, it is helpful to group them based on cause, disease associations, or pathology. An organizational scheme is presented in Figure 1. First, the diseases are broken down into those with known causes or associations and those of unknown cause. Diseases with known causes are further classified based on specific exposure, association with systemic disease, or association with a known genetic disorder. These groups are further divided into specific disease entities. Using this organizational scheme, one can perform a careful and complete history, working toward an accurate diagnosis and appropriate therapy.
As the name implies, the histologic abnormalities that characterize ILD generally involve the pulmonary interstitium to a greater extent than the alveolar spaces or airways, although exceptions exist. The interstitium is the area between the capillaries and the alveolar space. In the normal state, this space allows close apposition of gas and capillaries with minimal connective tissue matrix, fibroblasts, and inflammatory cells such as macrophages. The interstitium supports the delicate relation between the alveoli and capillaries, allowing efficient gas exchange. When responding to any injury, whether from a specific exposure (e.g., asbestos, nitrofurantoin, moldy hay), an autoimmune-mediated inflammation from a systemic connective tissue disease (e.g., rheumatoid arthritis), or unknown injury (e.g., idiopathic pulmonary fibrosis), the lung must respond to the damage and repair itself. If the exposure persists or if the repair process is imperfect, the lung may be permanently damaged, with increased interstitial tissue replacing the normal capillaries, alveoli, and healthy interstitium.
These pathologic abnormalities can lead to profound impairment in lung physiology. Gas exchange is impaired due to ventilation-perfusion (Figure 1) mismatching, shunt, and decreased diffusion across the abnormal interstitium. Work of breathing is markedly increased because of decreased lung compliance. Together, these physiologic impairments lead to the exercise intolerance seen in all of the ILDs. Unfortunately, if the initiating injury or abnormal repair from injury is not halted, progressive tissue damage can lead to worsening physiologic impairment and even death.
Many of the ILDs have similar clinical features and are not easily distinguished on examination. Symptoms are generally limited to the respiratory tract. Exertional breathlessness (dyspnea) and a nonproductive cough are the most common reasons patients seek medical attention. However, sputum production, hemoptysis, or wheezing are helpful in classifying the disease. If the patient also has prominent nonrespiratory symptoms, such as myalgia, arthralgia, or sclerodactyly, ILD might be the result of underlying connective tissue disease.
Most patients with ILD have bilateral inspiratory fine crackles, which usually are most prominent at the lung bases. However, some diseases, such as sarcoidosis and lymphangioleiomyomatosis, have only decreased breath sounds without adventitious sounds despite markedly abnormal chest radiographs. Expiratory wheezing is relatively uncommon, and its presence suggests either airway involvement as part of the primary disease process or concomitant airways disease such as emphysema or asthma. Occasionally, wheezing is a clue to a particular diagnosis, such as sarcoidosis, which can involve the airways as well as the interstitium.
Signs of pulmonary arterial hypertension with right ventricular dysfunction, such as lower-extremity edema or jugular venous distention, can occur late in the course of any ILD and are not helpful in diagnosing a specific ILD.
Examination also can disclose features of underlying connective tissue disease, including active joint inflammation (synovitis), joint deformities, or skin rash.
There is considerable variability among the specific diseases in the character and distribution of radiographic abnormalities. However, for most ILDs, the plain chest radiograph reveals reduced lung volumes with bilateral reticular or reticulonodular opacities. The ready availability of high-resolution computed tomography (HRCT) has highlighted significant radiographic differences between diseases that have similar plain chest radiographic patterns.3 HRCT has the ability to better define the specific characteristics of lung parenchyma seen in each disease, increasing the chance of making a confident diagnosis.4
The plain chest radiograph and HRCT features of idiopathic pulmonary fibrosis (IPF) are important patterns to recognize because, next to sarcoidosis, IPF is the most common ILD, several other ILDs have a similar appearance, and IPF images are the prototypic pattern of fibrotic injury response in the lung. The plain radiograph and HRCT in IPF reveal bilateral, peripheral and basilar predominant disease with reticulonodular infiltrates, often with honeycomb, cystic changes. Figure 2 shows a plain radiograph with bibasilar reticulonodular infiltrates. Note the overall volume loss and poorly demarcated pleural-parenchymal borders along the hemidiaphragms and heart, indicating parenchymal abnormalities extending to the pleura. Figure 3 shows an HRCT image of IPF, with distortion of the lung architecture and traction bronchiectasis, especially at the lung bases. As predicted by the plain radiograph, the abnormalities are strikingly located in the subpleural and dependent areas of the lung. Ground glass abnormalities, increased attenuation of the lung tissue without distortion of the underlying blood vessels or bronchi, are absent or minimal in classic IPF. Pleural disease and significant lymphadenopathy are not seen, although up to two thirds of IPF patients have mild mediastinal adenopathy.5 As the burden of disease increases, the chest x-ray examination can reveal multiple tiny cysts in the most markedly involved regions. This cystic pattern, called honeycombing, reflects end-stage fibrosis and is a feature of many end-stage ILDs.
In contrast to the fibrotic type of injury, some diseases cause an inflammatory abnormality with a much different radiographic image. In cellular nonspecific interstitial pneumonia, the predominant abnormality is ground glass without distortion of the lung architecture or loss of volume, as seen in Figure 4. In addition, the central and mid lung zone locations of abnormalities are distinct from IPF. Understanding these two patterns as ends of an extreme, we shall see how the clinician is able to evaluate other diseases in a similar context.
Similar to the radiographic findings, among the specific diseases there can be considerable variability in the physiologic abnormalities seen. However, a restrictive physiologic impairment is the common finding.6 Thus, both forced expiratory volume in one second (FEV1) and forced vital capacity (FVC) are diminished, and the FEV1/FVC ratio is preserved or even supranormal. Lung volumes are reduced, as is the diffusing capacity of the lung for carbon monoxide (DLCO). This reduction in diffusing capacity reflects a pathologic disturbance of the alveolar-capillary interface.
Although not commonly pursued, the compliance characteristics of the lungs can be evaluated with an esophageal balloon to measure intrathoracic pressure at various lung volumes. In almost all of the ILDs, the lungs have reduced compliance and require supranormal transpleural pressures to ventilate. This lack of compliance results in small lung volumes and increased work of breathing.
Less often, physiologic obstruction may be the pattern seen. This can be the result of the primary disease process (e.g., lymphangioleiomyomatosis, pulmonary Langerhans cell histiocytosis; some sarcoid patients) or concomitant emphysema or asthma.7 Thus, if ILD develops in a patient with significant emphysema, the opposing physiologic effects of the two diseases can result in deceptively normal spirometry and lung volume measurements, as well as apparently normally compliant lungs. However, because both emphysema and ILD result in impaired gas exchange, the DLCO is significantly decreased.
The three most common types of occupational ILD are asbestosis, chronic silicosis, and coal worker's pneumoconiosis (CWP). Predictable clinical and radiographic abnormalities occur in susceptible patients who have been exposed to asbestos.8 These abnormalities include pleural changes (plaques, fibrosis, effusions, atelectasis, and mesothelioma), parenchymal scarring, and lung cancer. Asbestos exposure alone increases the risk of lung cancer only minimally (1.5-3.0 times). Asbestos exposure and cigarette smoking, however, act synergistically to greatly increase the risk of cancer.
Asbestos exposure also can result in benign asbestos pleural effusions (BAPE) or an entity known as rounded atelectasis. BAPE may be asymptomatic or may be associated with acute chest pain, fever, and dyspnea. Generally, lag time is shorter between the initial asbestos exposure and the development of BAPE (<15 years) than that seen with other manifestations of asbestos exposure. The effusions are characteristically exudative and are often bloody. In a patient with a history of asbestos exposure and a bloody pleural effusion, the major differential diagnostic concern is malignant pleural effusion, particularly associated with mesothelioma, another asbestos-related disease. The clinical course of BAPE is that of spontaneous resolution, often with recurrences, and treatment is drainage to alleviate symptoms. Rounded atelectasis typically manifests as a pleural-based parenchymal mass that may be mistaken for carcinoma. The characteristic computed tomography (CT) features, however, such as evidence of local volume loss, pleural thickening, and the comet tail appearance of bronchi and vessels curving into the lesion may be used to help distinguish rounded atelectasis from carcinoma.
The term asbestos-related pulmonary disease may be used to encompass all of these entities, and asbestosis is reserved for patients who have evidence of parenchymal fibrosis. Most patients with asbestosis have had considerable asbestos exposure many years before manifestation of the lung disease. Exposure is often associated with occupations such as shipbuilding or insulation work. Patients report very slowly progressive dyspnea on exertion9 and have crackles on lung examination. Physiologic testing shows restrictive impairment, with reduced DLCO. The chest x-ray examination reveals bilateral lower-zone reticulonodular infiltrates similar to those seen in IPF. With an appropriate exposure history, the presence of radiographic pleural plaques or rounded atelectasis can indicate asbestos as the cause of the ILD, although neither of these findings is required for establishing the diagnosis.
No medical therapy has been demonstrated to improve or decrease the progression of asbestosis. Unfortunately, severe impairment typically occurs 30 to 40 years after exposure, making almost all patients ineligible for lung transplantation because of age. Management of asbestosis is therefore supportive.
Chronic silicosis results from chronic exposure to inhaled silica particles. Occupations that commonly entail exposure to silica include mining, tunneling, sandblasting, and foundry work. The chest radiograph commonly shows upper lung zone–predominant abnormalities characterized by multiple small nodular opacities in the central lung tissue. These nodules can slowly coalesce into large masses known as progressive massive fibrosis (PMF). Enlargement and eggshell calcification of the hilar lymph nodes are common. Functional and physiologic impairments in chronic silicosis are quite variable. Some patients with abnormal chest radiographs report few, if any, symptoms and can have normal lung examination and pulmonary function tests. Unfortunately many patients are impaired and have mixed restrictive and obstructive impairments with reduced diffusion capacity. The physiologic impairment can remain stable or, if PMF occurs, can progress even in the absence of continued exposure. Symptoms are typically exertional dyspnea and variable mucus production.
It is important to recognize the association of silicosis with lung cancer and active tuberculosis.10 Patients with silicosis are at increased risk for lung cancer, and the risk is increased when combined with exposure to tobacco smoke, diesel exhaust, or radon gas. Silicosis patients develop active tuberculosis 2- to 30-fold more often than coworkers without silicosis. This association is especially important in societies with a high incidence of human immunodeficiency virus (HIV) infection, which markedly increases the risk of silicosis-associated active tuberculosis.
CWP develops as the result of chronic inhalation of coal dust. In the past, it was assumed that silica dust was responsible for the pulmonary disease seen among coal miners because the clinical and radiographic features are quite similar to those of chronic silicosis. However, it is now recognized that CWP and silicosis are the results of distinct exposures. Simple CWP, characterized by multiple small nodular opacities on the chest x-ray film, is asymptomatic. Cough and shortness of breath do not develop unless the disease progresses to PMF similar to that seen in silicosis.
There are no proven therapies for either silicosis or CWP other than eliminating future exposure. In patients with significant obstructive impairment or mucus production, inhaled bronchodilators and corticosteroids might relieve some symptoms. Exacerbations can be frequent and are treated with antibiotics and systemic corticosteroids.
Many drugs have been associated with pulmonary complications of various types, including interstitial inflammation and fibrosis, bronchospasm, pulmonary edema, and pleural effusions.11 Drugs from many different therapeutic classes can cause ILD, including chemotherapeutic agents, antibiotics, antiarrhythmic drugs, and immunosuppressive agents (Box 1). There are no distinct physiologic, radiographic, or pathologic patterns of drug-induced ILD, and the diagnosis is usually made when a patient with ILD is exposed to a medication known to result in lung disease, the timing of the exposure is appropriate for the development of the disease, and other causes of ILD have been eliminated. Treatment is avoidance of further exposure and systemic corticosteroids in markedly impaired or declining patients.
|Box 1: Drugs Associated with the Development of Interstitial Lung Disease
|Drugs Inducing Systemic Lupus Erythematosus|
Data from Camus P: Drug induced infiltrative lung diseases. In Schwarz MI, King TE (eds): Interstitial lung disease, 4th ed. Hamilton, Ontario, BC Decker, 2003, pp 485-534.
Exposure to therapeutic radiation in the management of cancer can result in ILD. Patients presenting within 6 months of radiation therapy generally have ground glass abnormalities believed to represent acute inflammation. The ground glass abnormalities can occur in both radiation-exposed and unexposed tissue. Short-term systemic corticosteroid treatment can improve lung function. In contrast, dyspnea that develops more than 6 months after therapy typically appears as densely fibrotic tissue within the radiation port. On CT examination, a straight line indicating the margin of radiation is often evident, as seen in Figure 5. These patients do not improve with corticosteroid therapy, and treatment is supportive.
Hypersensitivity pneumonitis is a cell-mediated immune reaction to inhaled antigens in susceptible persons.12 Patients must be sensitized by an initial exposure, with subsequent re-exposure leading to acute hypersensitivity pneumonitis or chronic hypersensitivity pneumonitis. Patients with acute hypersensitivity pneumonitis usually present with sudden shortness of breath, chest pain, fever, chills, malaise, and a cough that may be productive of purulent sputum. In comparison, patients who are chronically exposed to low levels of inhaled antigens can develop subtle interstitial inflammatory reactions in the lung that do not result in noticeable symptoms for months to years; these patients present with severe, impairing disease, which can be very difficult to distinguish from IPF.
Common organic antigens known to cause hypersensitivity pneumonitis include bacteria and fungi, which may be found in moldy hay (farmer's lung) or in the home environment, particularly in association with central humidification systems (humidifier lung), indoor hot tubs, and animal proteins (e.g., bird fancier's lung). Inorganic antigens from vaporized paints and plastics can also lead to hypersensitivity pneumonitis. Numerous established antigens are listed in Table 1, along with the typical source of exposure and the associated syndrome.
|Acanthamoeba castellani||Contaminated water||Humidifier lung|
|Acanthamoeba polyphaga||Contaminated water||Humidifier lung|
|Naegleria gruberi||Contaminated water||Humidifier lung|
|Avian proteins||Bird droppings, feathers||Bird-breeder's lung|
|Urine, serum, pelts||Rats, gerbils||Animal handler's lung|
|Saccharopolyspora rectivirgula||Moldy hay||Farmer's lung|
|Thermoactinomyces vulgaris||Moldy sugarcane||Bagassosis|
|Thermoactinomyces sacchari||Mushroom compost||Mushroom worker's lung|
|Thermoactinomyces candidus||Heated water reservoirs||Humidifier lung, air conditioner lung|
|Bacillus subtilis, Bacillus cereus||Water, detergent||Humidifier lung, washing powder lung|
|Isocyanates, trimellitic anhydride||Paints, resins, plastics||Chemical worker's lung|
|Copper sulfate||Bordeaux mixture||Vineyard sprayer's lung|
|Phthalic anhydride||Heated epoxy resin||Epoxy resin lung|
|Sodium diazobenzene sulfate||Chromatography reagent||Pauli's reagent alveolitis|
|Pyrethrum||Pesticide||Pyrethrum hypersensitivity pneumonitis|
|Aspergillus spp||Moldy hay
|Aspergillus clavatus||Barley||Malt worker's lung||Alternaria spp.||Wood pulp||Woodworker's lung|
|Aureobasidium pullulans||Water||Humidifier lung||Cladosporium sp.||Hot-tub mists||Hot-tub hypersensitivity pneumonitis|
|Merulius lacrymans||Rotten wood||Dry rot lung||Penicillium casei, P. roqueforti||Cheese||Cheese washer's lung|
|Penicillium frequentans||Cork dust||Suberosis||Trichosporon cutaneum||Damp wood and mats||Japanese summer-type hypersensitivity pneumonitis|
Data from Selman M: Hypersensitivity pneumonitis. In Schwarz MI, King TE (eds): Interstitial Lung Disease, 4th ed. Hamilton, BC Decker, 2003.
Because the relation between an exposure and the lung disease might not be obvious, a careful systematic occupational, environmental, and avocational history is critical in evaluating patients with ILD. Elements that strongly suggest a diagnosis of hypersensitivity pneumonitis are exposure to an appropriate antigen and the correct temporal relation of symptoms to the exposure. Blood samples may be obtained to determine whether there has been an antibody response to certain antigens associated with hypersensitivity pneumonitis (serum precipitins); however, the presence of such antibodies is not sufficient to establish the diagnosis of hypersensitivity pneumonitis because many persons develop antibodies in the absence of disease. Likewise, the absence of detectable antibodies does not rule out the diagnosis of hypersensitivity pneumonitis because the culprit may be an antigen that is not included in the blood analysis.
Specific therapies for hypersensitivity pneumonitis are strict antigen avoidance and immunosuppression with corticosteroids in patients with symptomatic or physiologically impairing disease. In acute hypersensitivity pneumonitis, corticosteroids appear to hasten recovery but do not improve ultimate lung function.13 In chronic hypersensitivity pneumonitis, patients with fibrosis on CT scan have shorter survival, and it is unknown if long-term immunosuppression is beneficial.14
Although the association between tobacco use and COPD is well known, the relation with ILD is less well appreciated. It is a risk factor for the development of IPF, but it is not the sole cause. However, three types of ILD have a strong association with cigarette smoking: desquamative interstitial pneumonitis, respiratory bronchiolitis associated-interstitial lung disease (RB-ILD), and pulmonary Langerhans cell histiocytosis (PLCH).
Approximately 90% of patients with desquamative interstitial pneumonitis and RB-ILD are current or former tobacco smokers. HRCT usually demonstrates micronodular central infiltrates in RB-ILD and diffuse ground glass in desquamative interstitial pneumonitis. Spirometry is variable; most patients have significant restriction and variable amounts of obstruction. As with other toxic exposures, complete avoidance of all smoke is important for these patients. In RB-ILD, physiologic stabilization and occasionally even improvement can occur after abstinence from tobacco. In desquamative interstitial pneumonitis, the benefits of smoking cessation are unclear.
PLCH is an interstitial lung disease found in adult smokers. Patients usually have a significant smoking history and develop cough and progressive dyspnea on exertion. Chest examination is notable for diffuse inspiratory crackles. HRCT demonstrates central mid lung zone stellate nodules with adjacent thin-walled cysts. Pulmonary physiology generally reveals obstructive impairment with a decreased DLCO. The pathologic pattern is unique; the hallmark Langerhans histiocytes are seen in groups of star-shaped nodules, with destruction of adjacent lung tissue. Although PLCH is pathologically similar to childhood LCH, the adult form does not typically involve bone and is not proven to respond to chemotherapy, as the childhood form does. The relation of these two disorders has yet to be defined.
Primary treatment is abstinence from all tobacco exposure, either primary or secondhand. In patients with mild or moderate disease, lung function can stabilize after smoking cessation, but some patients progressively decline. Stabilization or improvement with oral corticosteroids is described, but overall benefit is unproven. Patients with progressive disease despite avoidance of all smoke exposure may be offered lung transplantation.
ILD is a well-known complication of various connective tissue diseases.15 The most commonly implicated disorders are scleroderma, rheumatoid arthritis, Sjögren's syndrome, polymyositis or dermatomyositis, and systemic lupus erythematosus.
In any of these disorders, pulmonary involvement can remain undetected until significant impairment is present, because these patients may be inactive because of the underlying connective tissue disease. However, there is generally poor correlation between the severity of the pulmonary and nonpulmonary manifestations of these diseases. In some instances, the lung disease overshadows or even predates the other symptoms of the underlying disease. When symptoms develop, dyspnea and cough are common. On chest examination, rales, wheezing, or even a pleural rub may be heard because of the varied patterns of lung involvement in these disorders. Physiology is usually restrictive, with decreased DLCO, but it may be obstructive, depending on the anatomic location of the disease, especially with Sjögren's disease.
Unsurprisingly, HRCT findings are variable, and range from normal lung architecture to ground glass abnormalities to reticular and fibrotic changes.16 The pathologic pattern of injury with these diseases is as equally diverse and correlates with the HRCT findings. Nonspecific interstitial pneumonitis (NSIP) is an inflammatory injury pattern associated with ground glass on HRCT scan, and organizing pneumonia is seen with patchy consolidated lung on air bronchograms. Both of these pathologic patterns can improve with aggressive immunosuppression. At the other end of the pathologic response spectrum is usual interstitial pneumonitis, which is associated with reticular opacities and honeycomb cystic fibrosis on HRCT scan. It appears to respond little to immunosuppression, although long-term controlled studies are lacking.
Specific treatment of these systemic inflammatory diseases is highly individualized. Patients with evidence of systemic inflammation, an inflammatory pathologic pattern such as NSIP or organizing pneumonia, or rapidly progressive symptoms are usually treated with prolonged immunosuppressive agents such as cyclophosphamide, azathioprine, mycophenolate, or tacrolimus.17,18
Recent studies have begun to provide evidenced-based therapy for these diverse patients. The Scleroderma Lung Study demonstrated that one year of oral cyclophosphamide modestly improved lung function compared with a modest decline in the control group. Curiously, those with the highest degree of fibrosis on HRCT improved most, and ground glass or an inflammatory pattern on bronchoalveolar lavage did not predict benefit. Unfortunately, after one year off immunosuppressive therapy, the cyclophosphamide-treated patients worsened and were indistinguishable from the untreated control group. Many hypothesize that to preserve any lung function gained by cyclophosphamide, continued immunosuppression, usually with mycophenolate, is necessary.
PM-ILD is being increasingly recognized as a common disease entity. Patients usually present with mechanics hands, consisting of thickened skin and painful fingertip fissures; 50% have Jo-1 antibodies on antinuclear antibody testing. Lung pathology is typically fibrotic NSIP or organizing pneumonia. As would be expected with these inflammatory patterns of injury, patients usually benefit from immunosuppression. Classic treatment is with cyclophosphamide, but tacrolimus is emerging as a salvage agent.
Sarcoidosis is an idiopathic multisystem inflammatory disorder that commonly involves the lungs.19 In fact, it is the most common of the ILDs in the United States. The tissue inflammation that occurs in sarcoidosis has a characteristic pattern in which the inflammatory cells collect in microscopic nodules called granulomas. Unlike IPF, sarcoidosis is more common among young adults than it is among older persons. Sarcoidosis often follows a benign course without symptoms or long-term consequences, and it can spontaneously remit.
The most common manifestation of sarcoidosis is asymptomatic hilar adenopathy. Less often, the chest x-ray demonstrates parenchymal opacities in the mid lung zone; these may be nodular, reticulonodular, or alveolar. When symptoms occur, cough, chest pain, dyspnea, and wheezing are most common. Pulmonary physiology may be normal, restrictive, obstructive, or mixed and can include a reduced DLCO. Obstructive impairment may be related to endobronchial granulomatous inflammation or scarring.20
Corticosteroids are commonly used in managing sarcoidosis, but treatment usually is reserved for patients with marked symptoms or physiologic impairment attributable to the disease.21 Other organs that can require corticosteroid therapy include the heart, uvea (uveitis), and central nervous system (cranial nerve abnormalities). Measurement of disease activity remains difficult in many patients. Serum angiotensin-converting enzyme levels and gallium scans are not well correlated with disease activity, and their routine use is discouraged. When there is active disease, acutely ill patients are treated with prednisone, and long-term immunosuppression is with methotrexate and cyclophosphamide, although infliximab is emerging as a useful agent in some patients.
Unfortunately, even after a comprehensive evaluation many patients with ILD do not have a well-defined specific exposure, a systemic illness, or an underlying genetic cause. Their ILD belongs to either the idiopathic interstitial pneumonia (IIP) group or to the group consisting of unique pathologic patterns as described by surgical lung biopsy.
Idiopathic pulmonary fibrosis (IPF) is the most common IIP and is defined as a progressive fibrotic lung disease isolated to the lung.22 The majority of patients are older than 60 years, and IPF is extremely unusual in persons younger than 40 years. Risk factors for developing IPF include exposure to smoke, metal dust, farming dust, and hairdressing chemicals. Patients present with chronic cough and exertional dyspnea, and HRCT demonstrates bibasilar, peripheral reticular abnormalities with focal honeycomb cystic change.
Usual interstitial pneumonitis is the pathologic pattern of injury seen in IPF patients. Usual interstitial pneumonitis is characterized by heterogeneous fibrosis most prominent in the peripheral areas, with minimal inflammation. Patients other than those with IPF can have usual interstitial pneumonitis on surgical lung biopsy (e.g., connective tissue disease), so this pattern of injury and repair is not unique to IPF.
Patients with an IIP and a classic presentation of age older than 60 years, progressive dyspnea and cough, basilar lung crackles, and HRCT findings of bibasilar, subpleural fibrosis and honeycomb cyst formation might not require a surgical lung biopsy for diagnosis.23,24 Transbronchial lung biopsies are often obtained at bronchoscopy during the evaluation of ILD and to identify mimics of IPF such as sarcoidosis and chronic hypersensitivity pneumonitis. The small biopsies obtained by this route may be able to identify granulomatous inflammation but cannot provide a definitive diagnosis of usual interstitial pneumonitis because this diagnosis requires a piece of tissue much larger than that obtained by transbronchial biopsy.
The majority of patients die of progressive fibrosing lung disease within 4 years of diagnosis. Emerging data show that approximately one half of patients die following disease that gradually progresses over several years.25
The other one half experience stable lung function or minimal decline for months to years, only to have sudden worsening over a few weeks or months leading to death. Baseline parameters that predict an increased risk of death include severity of dyspnea, severity of restrictive physiologic defect, reduced DLCO, pulmonary arterial hypertension, degree of fibrosis on HRCT, and Sa
No medical therapy has proved beneficial for IPF. Trials have demonstrated no benefit with interferon gamma and etanercept. Several medications are currently under investigation, including bosentan, imatinib, and pirfenidone. Oral corticosteroids and cytotoxic agents such as azathioprine are most commonly used for immunosuppression, although they appear to benefit only a minority of patients and are the subjects of a current IPFnet trial.27-29
Studies have highlighted the importance of pulmonary arterial hypertension (PAH) in IPF.30 The degree of PAH does not always correlate with the burden of fibrosis on CT scan or FVC, implying that a vascular process other than obliteration of the capillary bed from fibrosis occurs.31 Significant PAH is suggested in patients with markedly impaired diffusion capacity but relatively preserved FVC. Several PAH agents are under investigation in IPF, but their use outside of trials is not recommended.
Nonspecific interstitial pneumonitis (NSIP) is an IIP with diffuse inflammation seen on surgical lung biopsy.32 These patients are on average 7 to 10 years younger than those with IPF, but considerable overlap exists. The degree of accompanying interstitial fibrosis varies between patients. The combination of fibrosis and inflammation (fibrotic NSIP) is most common. Pure cellular NSIP is less common. Patients present with chronic or subacute cough and dyspnea. HRCT demonstrates predominant ground glass abnormalities in cellular NSIP and both ground glass and fibrotic changes in fibrotic NSIP. Given that there are significant clinical and radiographic overlaps between fibrotic NSIP and IPF, surgical lung biopsy is often required to distinguish these two.
The prognosis is much better for NSIP than for IPF, and most patients survive 7 to 10 years. Immunosuppression with oral corticosteroids and cytotoxic immunosuppressive agents is the primary therapy. Type and duration of therapy are guided by disease activity and degree of inflammation on biopsy and ground glass on HRCT. Pathologic NSIP is not a unique pattern and can often be seen in connective tissue disease or hypersensitivity pneumonitis; a thorough investigation for these should be undertaken to rule out these alternative diagnoses.
Cryptogenic organizing pneumonia (COP), is the revised nomenclature for bronchiolitis obliterans organizing pneumonia (BOOP). Patients are younger than those with IPF, and they present with acute or subacute dyspnea and cough. About one third describe an antecedent viral illness; however, no other risk factors are known. HRCT demonstrates alveolar filling, with air bronchograms mimicking acute pneumonia. The classic COP patient presents after having failed to improve despite several courses of antibiotics. Diagnosis occasionally requires surgical lung biopsy, especially if the clinical and radiographic features are uncertain, because small areas of organizing pneumonia can be seen in a variety of inflammatory and fibrotic disorders on transbronchial lung biopsy.
Most patients improve with oral corticosteroids (0.5-1.0 mg/kg for 6-12 weeks). However, many patients have recrudescence after corticosteroid withdrawal and require long-term immunosuppression with cytotoxic immunosuppressive agents. A minority of patients develop progressive fibrosis despite aggressive immunosuppression and can be offered lung transplantation. Organizing pneumonia is not a unique pathologic pattern and is often associated with connective tissue disease. A thorough investigation must be undertaken to eliminate alternative diagnoses.
Lymphocytic interstitial pneumonia is a rare disorder of polyclonal lymphocyte aggregates that accumulate diffusely in the interstitium.33 The diagnosis almost always requires surgical lung biopsy. Patients are typically younger than IPF patients and present with subacute dyspnea and cough. Pulmonary function testing can show a mixed picture. HRCT typically shows diffuse ground glass attenuation with varying amounts of fibrosis. Most patients respond well to oral corticosteroids; a minority require long-term immunosuppression. Lymphocytic interstitial pneumonia is often associated with connective tissue diseases, especially Sjögren's syndrome and in patients with immunodeficiency, and these possibilities should be investigated in all patients with lymphocytic interstitial pneumonia.
Lymphangioleiomyomatosis (LAM) is a rare disorder of abnormal smooth muscle tissue proliferating around small airways leading to severe obstruction and destruction of alveoli with resultant thin-walled cyst formation.34 All patients are women, although both male and female patients with tuberous sclerosis complex can develop lung pathology identical to LAM termed tuberous sclerosis complex lymphangioleiomyomatosis (TSC-LAM).
Dyspnea on exertion and an obstructive ventilatory impairment with a reduced DLCO are almost always present except in very early disease. Disease progression is quite variable; some women have steadily worsening lung function during midlife, and some elderly women experience extremely slow decline over many years. Risk factors for worsening lung function include a significant bronchodilator response and possibly childbearing. Other important disease manifestations include pneumothorax from a ruptured subpleural cyst, occasionally associated with air travel. Unilateral or, less commonly, bilateral chylothorax is seen in about one third of patients. This results from lymphatic obstruction by abnormal smooth muscle tissue. Treatment with a low-fat diet or blocking gut fat absorption is usually ineffective, and pleurodesis is required. Importantly, pleurodesis does not preclude subsequent lung transplantation.
Treatment is with inhaled bronchodilators and inhaled corticosteroids. Younger patients might ultimately require lung transplantation. Early studies with the immunosuppressant rapamycin, which also inhibits LAM cell proliferation, have been promising, and larger trials are under way.
Because hypoxemia is common in ILD, supplemental oxygen therapy is often prescribed, although it has not been studied as extensively as in chronic obstructive pulmonary disease. Patients with ILD should have arterial oxygen saturation determined at rest and especially during exertion, because many patients with only mild disease desaturate with exertion despite normal saturation at rest. Although studies are limited, supplemental oxygen delivered via nasal cannula can prevent resting hypoxemia and allow greater exertion before desaturation. These benefits can improve quality of life and potentially ward off development of pulmonary arterial hypertension, although further studies are needed.
We favor continuous rather than pulse delivery because the desaturation with activity seen in most patients is not rectified with pulse therapy. For most patients, liquid oxygen is the best source to provide adequate flow rates. In motivated patients, transtracheal delivery of supplemental oxygen increases the efficiency of delivery and improves cosmesis. However, patients must be chosen carefully because of the need for frequent care and the risk of mucus desiccation and rare hemorrhage.
As with supplemental oxygen therapy, pulmonary rehabilitation in the management of ILD has not been as well studied as it has in obstructive lung disease. Pulmonary rehabilitation is important in building aerobic fitness, maintaining physical activity, and improving quality of life. We encourage all of our patients to enroll in outpatient pulmonary rehabilitation and to continue maintenance therapy.
Because many ILD patients are treated with immunosuppressive medications and are at some modest increased risk for the development of infections, patients with ILD should receive a pneumococcal vaccine per the Centers for Disease Control and Prevention (CDC) guidelines and a yearly influenza virus vaccine. Additionally, we recommend that patients practice good hand hygiene (e.g., frequent hand washing). We do not recommend the use of masks or special antibacterial products. Patients treated with certain specific immunosuppressive regimens should receive Pneumocystis prophylaxis.
The only therapy shown to prolong life in patients with end-stage, particularly fibrotic, ILD is lung transplantation.35 Transplantation has been performed successfully in the management of most ILDs. Enthusiasm for the procedure is tempered by the significant risk of mortality at 1 year (10%-25%) and 5 years (50%-60%). Many patients with ILD are older than the upper age limit of 65 years. Comorbidities such as gastroesophageal reflux disease, common in a number of ILDs, preclude lung transplantation due to the increased risk of chronic rejection and death.
The entities grouped as ILDs are a diverse group of illnesses of varied causation, treatment, and prognosis. In general, these diseases manifest as chronic, progressive dyspnea on exertion and cough. Findings on examination are often limited to the chest in the form of fine inspiratory crackles. The most common chest radiograph finding is diffuse reticular or reticulonodular infiltrates with reduced lung volumes. Pulmonary function testing usually reveals restrictive physiology and decreased diffusion capacity; however, other patterns can be seen. Therapy depends on the underlying disease and may consist of immunosuppressive drugs and avoidance of disease-inducing exposures.