10: Diffuse parenchymal lung diseases associated with known etiologic agents
OUTLINE
Diseases Caused by Inhaled Inorganic Dusts, 136
Silicosis, 136
Coal Worker’s Pneumoconiosis, 138
Asbestosis, 139
Berylliosis, 140
Hypersensitivity Pneumonitis, 141
Drug-Induced Parenchymal Lung Disease, 143
Radiation-Induced Lung Disease, 145
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, exposure has occurred for a prolonged time as a result of the occupational environment. 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 (CWP), asbestosis, and berylliosis. For information about the numerous other agents, consult the more detailed Suggested Readings 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. Despite the known toxicity, silica exposure continues to be a problem world-wide. Persons at risk include sandblasters, hard rock miners, quarry workers, and stonecutters. More recently, severe disease is recognized in those working in the manufacture of engineered stone typically used in countertops. In most cases, development of disease requires at least 20 years of exposure. However, with particularly heavy doses of inhaled silica, as can occur in sandblasters, an acute form of the disease may occur with much shorter periods of exposure.
The pathogenetic effect of silica is due to generation of oxygen radicals and toxicity to macrophages. Inhaled silica particles that reach the lower respiratory tract are phagocytosed by pulmonary macrophages. Freshly cut silica particles are more pathogenic than older particles, likely because the freshly cut surface is highly reactive and generates more reactive oxygen species. After engulfing the silica particle, the macrophage is activated and releases inflammatory mediators, including tumor necrosis factor (TNF)-α and interleukin (IL)-1. Phagocytosis of silica particles leads to apoptotic cell death of the macrophage and release of the previously engulfed toxic silica particles, with repeat of the process after the particles are re-ingested by other macrophages. With each cycle of 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). Silicotic nodules are believed to be areas in which the cycle of macrophage ingestion, activation and destruction, and release of the toxic silica particles occurs. At first the nodules are small and discrete. With disease progression, they become larger and may coalesce.
Данная книга находится в списке для перевода на русский язык сайта https://meduniver.com/
FIGURE 10.1 Silicosis (low-power photomicrograph). The silicotic nodules are
sharply circumscribed and densely collagenous (Masson trichrome stain).
Source: (From Leslie, K. O., & Wick, M. R. [2018]. Practical pulmonary
pathology. A diagnostic approach [3rd ed.]. Philadelphia, PA: Elsevier.)
The pulmonary effects of silica are related in part to a toxic effect on macrophages that ingest the particles.
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). Typically, the upper lung zones in patients with silicosis are affected more heavily than the lower zones. Enlargement of the hilar lymph nodes, which frequently calcify, may be seen.
FIGURE 10.2 Radiographic appearance of (A) simple and (B) complicated
silicosis in same patient. A, Small nodules are present throughout both lungs,
particularly in upper zones. A reticular component is also seen. B, Nodules have
become larger and are coalescent in upper zones. One of the confluent shadows on
left shows cavitation (arrow). Interval between radiographs shown in A and B is 11
years. Source: (From Fraser, R. G., Müller, N. L., Colman, N., Paré, P. D. [1999].
Diagnosis of diseases of the chest [Vol. 4, 4th ed.]. Philadelphia, PA: WB
Saunders.)
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. Patients with silicosis are also 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 25). The term silicotuberculosis is used when pulmonary tuberculosis develops in a patient with background silicosis, and longer courses of antituberculous medications may be required for treatment versus when silicosis is absent.
Silicosis is associated with immune dysregulation and is a predisposing factor for secondary infection 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 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. In addition to its role in the development of CWP, coal mining also appears to be associated with an increased risk of chronic obstructive pulmonary disease (COPD), including anatomic evidence of emphysema that is most commonly centrilobular in distribution.
Данная книга находится в списке для перевода на русский язык сайта https://meduniver.com/
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.
FIGURE 10.3 Histologic appearance of a coal dust macule shows focal interstitial
pigment deposition. In this example, destruction of the adjacent alveolar septa is
also seen. Source: (From Leslie, K. O., & Wick, M. R. [2018]. Practical
pulmonary pathology. A diagnostic approach [3rd ed.]. Philadelphia, PA:
Elsevier.)
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. Pulmonary function may show restrictive disease, obstructive disease, or a mixed pattern, depending on the relative amounts of fibrosis, airway disease, and emphysema.
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. Some studies indicate that genetic polymorphisms may help to explain the different clinical responses to inhalational exposures.
Symptoms and pulmonary function changes in CWP are related to the extent of fibrosis and coexistent COPD, if present.
Asbestosis
Asbestos, widely used because of its thermal and fire resistance, 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 neoplasms, particularly bronchogenic carcinoma and mesothelioma. These latter problems are discussed in Chapters 15, 20, and 21. The term asbestosis is reserved for the diffuse parenchymal lung disease that occurs due to asbestos exposure, not simply asbestos exposure itself.
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 demolishing, 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 directly injure pulmonary epithelial cells in the respiratory bronchioles and alveolar duct bifurcations, inducing the release of mediators that attract inflammatory cells, including macrophages, neutrophils, and lymphocytes. 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 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 microscopic 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.
Данная книга находится в списке для перевода на русский язык сайта https://meduniver.com/
FIGURE 10.4 High-power photomicrograph of asbestos bodies in a sputum
cytology specimen. Rod-shaped bodies with clubbed ends represent “coated”
asbestos fibers. Source: (From Leslie, K. O., & Wick, M. R. [2018]. Practical
pulmonary pathology. A diagnostic approach [3rd ed.]. Philadelphia, PA:
Elsevier.)
In asbestosis, light 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. 10.5A). 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 (Fig. 10.5B). 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.
FIGURE 10.5 Chest radiographs showing parenchymal and pleural disease
secondary to asbestos exposure. A, Extensive interstitial lung disease in a patient
with asbestosis. B, Increased interstitial markings and pleural disease (arrows) with
diaphragmatic calcification (arrowhead), due to prior asbestos exposure.
Source: (Courtesy Dr. Paul Stark.)
Pulmonary complications of asbestos exposure are as follows:
1.Diffuse parenchymal lung disease (asbestosis)
2.Diffuse pleural thickening
3.Localized pleural plaques
4.Pleural effusions
5.Lung cancer
6.Pleural malignancy (mesothelioma)
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 dust of the metal beryllium. The disease initially was described in individuals who manufactured fluorescent light bulbs, but more recent cases involve workers in the aerospace, nuclear weapons, and electronics industries and other businesses where beryllium is used. The histologic appearance of disease caused by beryllium is quite different from that seen with the other pneumoconioses described earlier. In berylliosis, 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.
Данная книга находится в списке для перевода на русский язык сайта https://meduniver.com/