Diffuse Parenchymal Lung Diseases Associated with Known Etiologic Agents

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Diffuse Parenchymal Lung Diseases Associated with Known Etiologic Agents

This chapter focuses on several of the major categories of diffuse parenchymal (interstitial) lung disease for which an etiologic agent has been identified. The general principles discussed in Chapter 9 apply to most of these conditions, and the features emphasized here are those peculiar to or characteristic of each cause. Considering the vast number of diffuse parenchymal lung diseases, this chapter only scratches the surface of information available. When a physician is confronted with a patient having a particular type of diffuse parenchymal lung disease, it is best to relearn the details of the disease at that time.

Diseases Caused by Inhaled Inorganic Dusts

Many types of diffuse parenchymal lung disease are caused by inhalation of inorganic dusts; the term pneumoconiosis is used for these conditions. Examples of the many responsible agents include silica, asbestos, coal, talc, mica, aluminum, and beryllium. In most cases, contact has occurred for a prolonged time as a result of occupational exposure. In some of these diseases, the parenchymal process progresses even in the absence of continued exposure.

For an inhaled inorganic dust to initiate injury to the lung parenchyma, it must be deposited at an appropriate area of the lower respiratory tract. If particle size is too large or too small, deposition tends to be in the upper airway or in the larger airways of the tracheobronchial tree. Particles with a diameter of approximately 0.5 to 5 µm are most likely to deposit in the respiratory bronchioles or the alveoli.

Particles with a diameter of 0.5 to 5 µm are most likely to be deposited in respiratory bronchioles or alveoli.

No effective treatment is available for parenchymal lung disease caused by most inhaled inorganic dusts. Therefore, the important issues facing physicians are recognition and prevention of these disorders. Total avoidance of exposure is the optimal form of prevention, but when exposure is necessary, appropriate precautions with effective masks or respirators are essential.

Four types of pneumoconiosis are considered here: silicosis, coal worker’s pneumoconiosis, asbestosis, and berylliosis. For information about the numerous other agents, consult the more detailed references at the end of this chapter.

Silicosis

Silicosis is the diffuse parenchymal lung disease resulting from exposure to silica (silicon dioxide). Of several crystalline forms of silica, quartz is the one most frequently encountered, usually as a component of rock or sand. Persons at risk include sandblasters, rock miners, quarry workers, and stonecutters. In most cases, development of disease requires at least 20 years of exposure. However, with particularly heavy doses of inhaled silica, as are found in sandblasters, much shorter periods are sufficient.

Although the pathogenesis of silicosis is not known with certainty, theories have focused on the potential toxicity of silica for macrophages. Silica particles in the lower respiratory tract are phagocytosed by alveolar macrophages. Freshly cut silica particles are more pathogenic than older particles. This property is thought to be due to the increased redox potential of the fresh surface, which is highly reactive. After engulfing the silica particle, the macrophage is activated and releases inflammatory mediators, including tumor necrosis factor (TNF)-α, interleukin-1, and arachidonic acid metabolites. Phagocytosis of silica particles leads to apoptotic cell death, and toxic silica particles are released that are capable of repeating the process after they are reingested by other macrophages. With their activation and destruction, the macrophages release chemical mediators that initiate or perpetuate an alveolitis, eventually leading to development of fibrosis. Pathologically, the inflammatory process initially is localized around the respiratory bronchioles but eventually becomes more diffuse throughout the parenchyma. The ongoing inflammatory process causes scarring and results in characteristic acellular nodules called silicotic nodules that are composed of connective tissue (Fig. 10-1). At first the nodules are small and discrete. With disease progression they become larger and may coalesce. Silicotic nodules are believed to be areas in which the cycle of macrophage ingestion, activation, destruction, and release of the toxic silica particles occurs.

The pulmonary effects of silica may be related to a toxic effect on alveolar macrophages.

The most common radiographic appearance of silicosis is notable for small, rounded opacities or nodules. This pattern is described as simple chronic silicosis. Uncommonly, the nodules become larger and coalescent, in which case the pneumoconiosis is called complicated; the term progressive massive fibrosis has also been used (Fig. 10-2). As a general rule, in patients with silicosis the upper lung zones are affected more heavily than the lower zones. Enlargement of the hilar lymph nodes, which frequently calcify, may be seen.

In addition to the potential problem of progressive pulmonary involvement and eventual respiratory failure, abnormal immune regulation is associated with silicosis. Patients are at increased risk for certain autoimmune diseases including rheumatoid arthritis and systemic sclerosis. In addition, patients with silicosis are particularly susceptible to infections with mycobacteria, perhaps because of impaired macrophage function. The specific organisms may be either Mycobacterium tuberculosis, the etiologic agent for tuberculosis, or other species of mycobacteria, often called atypical or nontuberculous mycobacteria (see Chapter 24).

Silicosis is associated with immune dysregulation and is a predisposing factor for secondary infections by mycobacteria.

Coal Worker’s Pneumoconiosis

Individuals who have worked as part of the coal mining process and have been exposed to large amounts of coal dust are at risk for development of coal worker’s pneumoconiosis (CWP). In comparison with silica, coal dust is a less fibrogenic material, and the tissue reaction is much less marked for equivalent amounts of dust deposited in the lungs.

Tissue reaction to inhaled coal dust is much less than that to silica.

The pathologic hallmark of CWP is the coal macule, which is a focal collection of coal dust surrounded by relatively little cellular infiltration or fibrosis (Fig. 10-3). The initial lesions tend to be distributed primarily around respiratory bronchioles. Small associated regions of emphysema, termed focal emphysema, may be seen.

As with silicosis, the disease is often separated into simple and complicated forms. In simple CWP, the chest radiograph consists of relatively small and discrete densities that usually are more nodular than linear. In this phase of the disease, patients have few symptoms, and pulmonary function usually is relatively preserved. In later stages of the disease, to which only a small minority of individuals progress, chest radiographic findings and clinical symptoms are more pronounced. With extensive disease and coalescent opacities on chest radiographs, patients are said to have complicated CWP, also called progressive massive fibrosis.

Why complicated disease develops in some patients with CWP is not clear. At one time, it was speculated that patients with progressive massive fibrosis had also been exposed to toxic amounts of silica and that the simultaneous silica exposure was responsible for most of the fibrotic process. However, although some patients do have a mixed form of pneumoconiosis from both coal dust and silica exposure, progressive massive fibrosis can result from coal dust in the absence of concomitant exposure to silica. More recently, genetic polymorphisms have been identified that may help explain the different clinical responses to inhalational exposures.

Symptoms and pulmonary function changes in coal worker’s pneumoconiosis (CWP) occur primarily in patients with progressive massive fibrosis.

Asbestosis

Asbestos has been widely used because of its thermal and fire resistance. It is a fibrous derivative of silica, termed a fibrous silicate. It is a naturally occurring mineral that, because of its long narrow shape, can be woven into cloth. Among the health hazards it presents are the development of diffuse interstitial fibrosis, benign pleural plaques and effusions, and the potential for inducing several types of neoplasm, particularly bronchogenic carcinoma and mesothelioma. These latter problems are discussed in Chapters 15, 20, and 21. The term asbestosis should be reserved for the diffuse parenchymal lung disease that occurs as a result of asbestos exposure.

Asbestos still presents a major health issue in many developing countries where the mineral is mined and used in industrial applications. Individuals at risk for development of asbestosis include asbestos miners; insulation, shipyard, and construction workers; and persons who have been exposed by working with brake linings. Even though the health hazards of asbestos are well recognized and use of asbestos has been curtailed in industrialized countries, workers still may be exposed in the course of remodeling or reinsulating pipes or buildings in which asbestos had been used. The duration of exposure necessary for development of asbestosis usually is more than 10 to 20 years but can vary depending on the intensity of the exposure.

One theory for the pathogenesis of asbestosis suggests that asbestos fibers activate macrophages and pulmonary epithelial cells, inducing the release of mediators that attract other inflammatory cells, including neutrophils, lymphocytes, and more alveolar macrophages. Unlike silica, asbestos probably is not cytotoxic to macrophages. That is, it does not seem to destroy or “kill” macrophages in the way that silica does. The mechanism of the often significant fibrotic reaction that occurs with asbestos may be related to the release of mediators from macrophages (e.g., transforming growth factor [TGF]-β, TNF-α, fibronectin, insulin-like growth factor [IGF]-1, and platelet-derived growth factor) that can promote fibroblast recruitment and replication. An area of active research involves studying the effects of asbestos fibers on initiating abnormalities in alveolar epithelial cell apoptosis and proliferation. Genetic polymorphisms in TGF-β and TNF-α have been associated with increased susceptibility to the toxic effects of asbestos.

The earliest microscopic lesions appear around respiratory bronchioles, with inflammation that progresses to peribronchiolar fibrosis. The fibrosis subsequently becomes more generalized throughout the alveolar walls and can become quite marked. Areas of the lung that are heavily involved by the fibrotic process include the lung bases and subpleural regions.

A characteristic finding of asbestos exposure is the ferruginous body, a rod-shaped body with clubbed ends (Fig. 10-4) that appears yellow-brown in stained tissue. Ferruginous bodies represent asbestos fibers that have been coated by macrophages with an iron-protein complex. Although large numbers of these structures are commonly seen by light microscopy in patients with asbestosis, not all such coated fibers are asbestos, and ferruginous bodies may be seen even in the absence of parenchymal lung disease. Uncoated asbestos fibers, which are long and narrow, cannot be seen by light microscopy and require electron microscopy for detection.

In asbestosis, microscopic examination of lung tissue often shows large numbers of ferruginous bodies.

The chest radiograph in patients with asbestosis shows a pattern of linear streaking that is generally most prominent at the lung bases (Fig. 10-5). In advanced cases, the findings may be quite extensive and associated with cyst formation and honeycombing. Commonly there is evidence of associated pleural disease, either in the form of diffuse pleural thickening or localized plaques (which may be calcified) or, much less frequently, in the form of pleural effusions. Because asbestos is a predisposing factor in development of malignancies of the lung and pleura, either of these complications may be seen on the chest radiograph.

Pulmonary complications of asbestos exposure are:

The clinical, pathophysiologic, and diagnostic features of asbestosis usually follow the general description of diffuse parenchymal lung disease discussed in Chapter 9. However, of the pneumoconioses already discussed, asbestosis is much more likely than either silicosis or CWP to be associated with clubbing of digits seen on physical examination.

Berylliosis

Berylliosis is a pneumoconiosis that results from inhalation of the metal dust beryllium. The disease initially was described in individuals who make fluorescent light bulbs, but more recent cases involve workers in the aerospace, nuclear weapons, and electronics industries and other industries where beryllium is used. The histologic appearance of disease caused by beryllium is quite different from that seen with the other pneumoconioses described earlier. Instead, the pathologic reaction is found in the lungs as well as hilar and mediastinal lymph nodes and involves formation of granulomas resembling those seen in sarcoidosis.

Berylliosis, which resembles sarcoidosis in many respects, represents a cellular immune response to beryllium.

Berylliosis is now known to represent a cellular immune (delayed hypersensitivity) response to beryllium. Lymphocytes harvested from blood or bronchoalveolar lavage fluid of patients with berylliosis demonstrate transformation (i.e., proliferation) when exposed to beryllium salts in vitro. Not only does this “beryllium lymphocyte transformation test” confirm the pathogenesis of the disease, it also serves as a useful diagnostic test in individuals with a clinical picture consistent with berylliosis. In addition, sensitization to beryllium can be demonstrated in some workers before the onset of clinical disease, a finding that may be important for prevention or early intervention to arrest progression from subclinical to clinical disease.

Aspects of the pathogenesis of beryllium lung disease are still being elucidated. According to current understanding, after being inhaled, beryllium reaches the alveoli, where it is engulfed by macrophages and other antigen-presenting cells. CD4+ lymphocytes are sensitized, and granuloma formation ensues. Some macrophages undergo apoptosis, but there appears to be a subset population that is resistant to beryllium-induced apoptosis. The resistant macrophages phagocytose the apoptotic cells—a process that causes release of the beryllium in a manner that promotes beryllium presentation to the beryllium-sensitized CD4+ cells. Studies also suggest a genetic susceptibility to development of the disease in response to beryllium exposure. One form of this susceptibility is identified by the presence of glutamate in position 69 of the human leukocyte antigen DPB1 molecule.

Clinically and radiographically, the disease closely mimics sarcoidosis (see Chapter 11). Specifically, patients with berylliosis demonstrate granulomatous inflammation in multiple organ systems, especially the pulmonary parenchyma and intrathoracic lymph nodes.

Hypersensitivity Pneumonitis

In hypersensitivity pneumonitis, immunologic phenomena directed against an antigen are responsible for the production of diffuse parenchymal lung disease. This disorder is sometimes referred to as extrinsic allergic alveolitis.

The antigens that induce the series of immunologic events are inhaled particulates and aerosol antigens from a variety of sources. Almost all the antigens are derived from microorganisms, plant proteins, and animal proteins. Exposure often is related either to the patient’s occupation or to some avocation. The first of the hypersensitivity pneumonitides to be described was farmer’s lung, which is due to antigens from microorganisms (thermophilic actinomycetes) that may be present on moldy hay. The list of antigens and types of exposure is quite extensive and includes entities such as air conditioner or humidifier lung (caused by antigens from microorganisms contaminating a forced air system) and bird breeder’s or bird fancier’s lung (attributable to avian proteins).

Hypersensitivity pneumonitis represents an immunologic response to an inhaled organic antigen.

Interestingly, even when a large number of individuals are exposed to a given antigen by virtue of their occupation or avocation, disease develops in only a small percentage. Studies indicate that polymorphisms in TNF-α are important in determining the development of bird breeder’s lung. Clearly, additional factors, perhaps genetic, determine who will contract the disease, but these factors are not yet identified.

Despite much research, we do not yet have a complete understanding of the pathogenesis of hypersensitivity pneumonitis. However, a type IV immune reaction (cell-mediated or delayed hypersensitivity, mediated by T lymphocytes) causing a lymphocytic alveolitis is known to be of prime importance in producing the disease. A type III (immune complex disease) mechanism plays a contributory role, especially early in the disease process. Evidence suggests that T lymphocytes in the lower respiratory tract become sensitized to the particular organic antigen. They may then release soluble cytokines that attract macrophages and possibly induce them to form granulomas in the lung. Antigen-antibody immune complexes also may be involved, with binding of complement and the resulting production of chemotactic factors and activation of macrophages.

Pathologic examination of the lung in patients with hypersensitivity pneumonitis reveals an alveolitis composed primarily of lymphocytes (especially cytotoxic/suppressor CD8+ cells) and macrophages, as well as the presence of granulomas. The granulomas often are loosely formed, unlike the well-defined granulomas characteristic of sarcoidosis (see Chapter 11). Often the pathologic changes have a peribronchiolar prominence, thus accounting for the frequent physiologic evidence for obstruction of small airways.

Clinically, hypersensitivity pneumonitis manifests in different ways, ranging from acute episodes of dyspnea, cough, fever, and infiltrates on chest radiograph (occurring approximately 4 to 6 hours after exposure to the offending antigen) to a chronic form of diffuse parenchymal lung disease. The latter presentation is more insidious. The patient often reports gradual onset of shortness of breath and cough, along with systemic symptoms of fatigue, loss of appetite, and weight loss. Long-term antigen exposure has been occurring in these circumstances, and because acute episodes are not necessarily an important feature, the patient does not associate the symptoms with any particular exposure.

Hypersensitivity pneumonitis occurs either with acute episodes 4 to 6 hours after exposure to the offending antigen or with the more insidious course of chronic diffuse parenchymal lung disease.

Unlike the acute form, the chronic form of hypersensitivity pneumonitis behaves like other forms of diffuse parenchymal lung disease. Unless the physician is attuned to the possibility that hypersensitivity to an antigen in the environment might be responsible for the patient’s lung disease, the entity may easily be missed, and exposure to the antigen may continue.

With an acute episode of hypersensitivity pneumonitis, the chest radiograph shows patchy or diffuse infiltrates. As the disease becomes chronic, the abnormality may take on a more nodular quality, eventually appearing as the reticulonodular pattern characteristic of the other chronic diffuse parenchymal lung diseases. In the chronic form of disease, an upper lobe predominance to the radiographic changes is often seen. High-resolution chest computed tomography (CT) scanning may be particularly helpful in suggesting the diagnosis, often demonstrating a mosaic ground-glass pattern (see Fig. 3-9).

The diagnosis is more likely to be considered if the patient gives a history of acute episodes that either occur by themselves or punctuate a more chronic illness. Historic features concerning the patient’s occupation, hobbies, and other environmental exposures may provide valuable clues for detecting the responsible factor. One standard diagnostic test is a search for precipitating antibodies to the common organic antigens known to cause hypersensitivity pneumonitis. Unfortunately, false-positive and false-negative results for precipitins may cause diagnostic confusion. For example, the finding of precipitins to thermophilic actinomycetes, the agent responsible for farmer’s lung, is relatively common in healthy farmers without any evidence of the disease. In addition, making a diagnosis of hypersensitivity pneumonitis by the finding of precipitins requires that the responsible antigen be included in the panel of antigens tested. If a lung biopsy is performed for diagnosis of diffuse parenchymal lung disease, findings on microscopic examination may suggest this entity.

The best treatment is avoidance of exposure. Unfortunately, the chronic form of the disease often leads to irreversible changes in the lung that persist even after exposure is terminated. Corticosteroids are sometimes administered to patients with persistent disease, but the results are variable.

Drug-Induced Parenchymal Lung Disease

As the list of available pharmacologic agents expands every year, so does the list of potential complications. The lung is certainly one of the target organs for these adverse effects, and diffuse parenchymal lung disease is a particularly important (although not the only) manifestation of drug toxicity. It is imperative that drug toxicity be considered in all patients who develop diffuse parenchymal lung disease. Each drug cannot be considered in detail here, nor can a complete list of the growing number of drugs that have been implicated be provided. However, this chapter briefly discusses the general principles of drug-induced parenchymal lung disease and the major agents responsible.

The largest single category of drugs associated with disease of the alveolar wall includes chemotherapeutic or cytotoxic agents, drugs designed primarily as antitumor agents. Individual drugs that have been commonly implicated in the development of lung disease are bleomycin, mitomycin, busulfan, cyclophosphamide, methotrexate, and the nitrosoureas, although several others have been described in smaller numbers of cases. In general, the risk of developing diffuse parenchymal lung disease increases with higher cumulative doses of a particular agent, but occasional cases with even relatively low cumulative doses are described. In most cases, diffuse parenchymal lung disease develops in a period ranging from 1 month to several years after use of the agent. Busulfan is particularly notable for late development of complications, often several years after onset of therapy.

Chemotherapeutic and cytotoxic agents are the largest category of drugs associated with diffuse parenchymal lung disease.

The pathogenesis of chemotherapy-induced diffuse parenchymal lung disease often appears to involve either direct toxicity to normal lung parenchymal cells, especially epithelial cells, or oxidant injury induced by generation of toxic oxygen radicals. One exception is methotrexate, for which hypersensitivity mechanisms may also play a role. When oxidant damage is involved, as with bleomycin, other agents that promote formation of oxygen free radicals (e.g., radiation therapy, high concentrations of inhaled oxygen) can augment the injury caused by the chemotherapeutic agent.

The pathologic appearance of diffuse parenchymal lung disease caused by cytotoxic agents frequently is notable for the presence of atypical bizarre-appearing type II alveolar epithelial cells with large hyperchromatic nuclei. When this feature is associated with the other usual findings of diffuse parenchymal lung disease, the pathologist should suspect that a chemotherapeutic agent may be responsible. In conjunction with its presumed difference in pathogenesis, methotrexate does not produce the same degree of epithelial cell atypia as do the other cytotoxic agents. In contrast, granulomas, consistent with a hypersensitivity mechanism, are frequently seen.

Cytotoxic drug–induced diffuse parenchymal lung disease shows atypical bizarre-appearing alveolar type II epithelial cells.

Clinically, fever is a common accompaniment to the respiratory symptoms associated with drug-induced diffuse parenchymal lung disease. An increase in eosinophils in peripheral blood is often noted in patients with methotrexate-induced lung disease.

For those patients receiving these drugs in whom pulmonary infiltrates develop, often associated with fever, several diagnostic considerations routinely arise. In addition to the possibility of drug toxicity is concern about infection (because host defenses are generally impaired by the drug or the underlying malignancy), dissemination of the malignancy through the lung, bleeding into the lung, and in patients who have received radiation therapy, toxic effects from the irradiation. When the diagnosis is not clear, a lung biopsy often is performed, primarily to rule out an infectious process. If atypical epithelial cells but no infectious agents are found, a drug-induced process is suspected.

For patients who are believed to have a cytotoxic drug–related diffuse parenchymal lung disease, the particular chemotherapeutic agent generally is discontinued. Steroids may be administered, but, as with their use in other diffuse parenchymal diseases, the results are variable.

Several drugs that are not chemotherapeutic agents have been implicated in the development of parenchymal lung disease. Nitrofurantoin, an antibiotic, has been associated with both acute and chronic reactions. The acute problem, which presumably is a hypersensitivity phenomenon, often is characterized by pulmonary infiltrates, pleural effusions, fever, and eosinophilia in peripheral blood. The chronic problem, which does not appear to be related to prior acute episodes, is characterized by a nonspecific interstitial pneumonitis and fibrosis akin to that of the other interstitial pneumonitides.

Therapy with injections of gold, which is used in rheumatoid arthritis, has been associated with development of diffuse parenchymal lung disease. The diagnosis here may be confusing because the underlying disease (rheumatoid arthritis) also can be associated with alveolitis and pulmonary fibrosis.

The commonly used antiarrhythmic agent amiodarone is associated with clinically significant parenchymal lung disease in approximately 5% to 10% of treated patients. Amiodarone pulmonary toxicity is dose related and may be fatal. In addition to nonspecific inflammation and fibrosis, the pathologic appearance of amiodarone-induced diffuse parenchymal lung disease is notable for macrophages that appear foamy because of cytoplasmic phospholipid inclusions. However, similar foamy macrophages with cytoplasmic inclusions have been found in autopsy specimens of lung tissue from amiodarone-treated patients without interstitial inflammation and fibrosis. This finding suggests that the phospholipid inclusions are a marker of amiodarone use but are not necessarily directly responsible for the other pathologic and clinically important pulmonary consequences of amiodarone. Radiographically, patients with amiodarone-induced lung disease can develop either focal or diffuse infiltrates. CT scanning commonly shows a relatively high density of the infiltrates, resulting from a high iodine content within the amiodarone molecule.

Amiodarone-induced lung disease is an important cause of either focal or diffuse pulmonary infiltrates.

A large number of drugs have been linked with development of an illness that resembles systemic lupus erythematosus, and patients with this “drug-induced lupus” may have parenchymal lung disease as one manifestation. In addition, a variety of drugs have been associated with pulmonary infiltrates and peripheral blood eosinophilia. This constellation of pulmonary infiltrates with eosinophilia, of which drugs are just one of several possible causes, is often abbreviated as the PIE syndrome.

Radiation-Induced Lung Disease

Parenchymal lung disease is a potential complication of radiation therapy for tumors within the thorax or in close proximity to it, particularly lymphoma (Hodgkin’s disease) and carcinoma of the breast or lung. It is estimated that signs and symptoms of clinically apparent injury will develop in 5% to 15% of patients whose radiation therapy includes exposure of portions of normal lung. However, radiographic changes in the absence of symptoms are seen even more frequently, in 20% to 70% of exposed patients.

Radiation-induced pulmonary disease is generally divided into two phases: early pneumonitis and late fibrosis. The acute phase of radiation pneumonitis develops approximately 1 to 3 months after completion of a course of therapy, depending to a large extent on the total dose and the volume of lung irradiated. The later stage of radiation fibrosis may directly follow earlier radiation-induced pneumonitis, may occur after a symptom-free latent interval, or occasionally may develop without any prior clinical evidence of acute pneumonitis. Fibrosis, when it occurs, does so generally 6 to 12 months after radiation therapy has been completed.

Radiation-induced lung disease includes an early period of radiation pneumonitis and a later period of radiation fibrosis.

Although the pathogenesis of radiation-induced lung disease is not entirely known, toxicity to capillary endothelial cells and, to a lesser extent, to type I alveolar epithelial cells is believed to be the primary mode of injury, perhaps mediated by oxygen-derived free radicals. In the period preceding chronic fibrosis, an alveolitis probably contributes directly to development of fibrotic changes. The possibility of hypersensitivity playing a role in the pathogenesis of the alveolitis has been suggested by the finding of increased lymphocytes in the bronchoalveolar lavage fluid of the nonirradiated lung in patients with radiation-induced pneumonitis.

Early pathologic changes include swelling of endothelial cells, interstitial edema, mononuclear cell infiltrates, and atypical hyperplastic epithelial cells. Subsequent changes during the fibrotic stage consist of progressive fibrosis (indistinguishable from pulmonary fibrosis of other causes) and sclerosis of small vessels, with obliteration of a major portion of the capillary bed in the involved area.

Clinically, patients may have fever with the acute pneumonitis in conjunction with respiratory symptoms, and distinguishing radiation pneumonitis from an atypical pneumonia is often difficult. On chest radiograph, the acute pneumonitis is usually characterized by an infiltrate that conforms in shape and location to the region of lung irradiated. Chest CT scanning may be particularly useful, both because it may detect subtle abnormalities earlier than can be seen on chest radiograph and because the cross-sectional views readily show the correspondence of the radiographic abnormalities to the radiation ports. However, for reasons that are unclear, additional changes outside the field of radiation may develop in some patients. The pattern of chronic radiation fibrosis is an increase in interstitial markings, again generally corresponding in location to the irradiated region of lung, often with associated volume loss. The acute changes of the pneumonitis are potentially reversible, whereas the chronic fibrotic changes generally are permanent.

The interstitial pattern in radiation-induced lung disease generally conforms in distribution to the region of lung irradiated.

Diagnostic considerations are usually similar to those for drug-induced parenchymal lung disease. A history of recent irradiation occurring at the appropriate time is crucial to the diagnosis. In addition, the finding of radiographic changes that conform to the radiation port, often with a relatively sharp cutoff, is strongly suggestive of the diagnosis.

Corticosteroids are frequently used to treat radiation-induced pneumonitis, often with reasonably good results. When the chronic changes of fibrosis have supervened, corticosteroids are much less effective.

References

Diseases Caused by Inhaled Inorganic Dusts

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Hypersensitivity Pneumonitis

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Drug-Induced Parenchymal Lung Disease

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Radiation-Induced Lung Disease

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