11: Diffuse parenchymal lung diseases of unknown etiology
OUTLINE
Idiopathic Pulmonary Fibrosis, 148
Other Idiopathic Interstitial Pneumonias, 151
Pulmonary Parenchymal Involvement Complicating Systemic Rheumatic Disease, 152
Sarcoidosis, 154
Miscellaneous Disorders Involving the Pulmonary Parenchyma, 158
Pulmonary Langerhans Cell Histiocytosis, 158
Lymphangioleiomyomatosis, 159
Goodpasture Syndrome, 160
Granulomatosis With Polyangiitis, 160
Chronic Eosinophilic Pneumonia, 161
Pulmonary Alveolar Proteinosis, 162
Approximately 65% of patients with diffuse parenchymal lung disease are victims of a process for which no etiologic agent has been identified, even though a specific name may be attached to the disease entity. Included in this category are idiopathic pulmonary fibrosis (IPF), parenchymal lung disease associated with systemic rheumatic disease (e.g., systemic lupus erythematosus, scleroderma, rheumatoid arthritis), sarcoidosis, pulmonary Langerhans cell histiocytosis (PLCH), and a variety of other disorders. Many general aspects of these problems were discussed in Chapter 9. This chapter focuses on the specific diseases and their particular characteristics.
Idiopathic pulmonary fibrosis
Although the name idiopathic pulmonary fibrosis has often been used nonspecifically to describe fibrotic interstitial lung disease without an identifiable diagnosis, most clinicians and investigators believe IPF represents a specific disease entity. This chapter adopts that assumption and considers pulmonary fibrosis associated with an underlying systemic rheumatic disease a separate entity. Another name that has been
used interchangeably with IPF is cryptogenic fibrosing alveolitis. The term usual interstitial pneumonia
(UIP) is not a clinical disease but refers to the pathologic pattern associated with IPF, but also can be seen in clinical settings other than IPF, such as when lung disease is associated with a systemic rheumatic disease.
As implied by the name, IPF does not have a recognizable inciting agent, although most studies demonstrate an association with tobacco smoke exposure. The theory behind the pathogenesis of IPF has changed considerably over the past 25 years. For many years the prevailing thought was that exposure to an unknown agent (perhaps an antigen leading to formation of antigen-antibody complexes) led to alveolar inflammation, which was perpetuated by release of chemotactic factors from inflammatory cells. The ongoing inflammation was believed to be responsible for subsequent development of fibrosis.
However, the current widely accepted paradigm is that recurrent microinjuries to susceptible alveolar epithelial cells result in an abnormal wound healing process, ultimately causing fibrosis. According to this current theory, alveolar inflammation does not play a critical role in the eventual development of fibrosis, and injury to alveolar epithelial cells is the primary initiating event. Although injury to type I alveolar epithelial cells normally would be followed by a repair process that includes proliferation of type II cells and differentiation into type I cells, this repair process is impaired, at least in part because of disruption of the basement membrane, which normally is important for the re-epithelialization process. Several defects in type II cell function have been associated with IPF pathogenesis, including abnormalities in autophagy, apoptosis, and progenitor cell function. At the same time, alveolar epithelial cells express a variety of profibrotic cytokines and growth factors, including platelet-derived growth factor (PDGF) and transforming growth factor (TGF)-β1, which enhance fibroblast migration and proliferation. Fibroblastic foci develop at sites of alveolar injury and appear to be responsible for increased extracellular matrix deposition. This process is summarized in Fig. 11.1.
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FIGURE 11.1 Proposed pathogenetic sequence in idiopathic pulmonary fibrosis.
Dotted lines indicate that although there is an influx of inflammatory cells, this is not
thought to be a primary component of pathogenesis. PDGF, platelet-derived growth
factor; TGF-β1, transforming growth factor-β1.
The development of IPF is associated with gene mutations in several biological pathways known to be related to lung injury, lung repair, or production of mucins in peripheral airways. Mutations in the first pathway affect genes encoding surfactant proteins A2 (SFP-A2) and C (SFP-C), which may act to increase susceptibility to chronic lung injury by causing increased endoplasmic reticulum stress in alveolar type II epithelial cells. Mutations in the second pathway affect genes encoding telomerase reverse transcriptase (TERT) and telomerase RNA component (TERC), the multimeric enzyme system that repairs shortened telomeres. Abnormalities in telomerase function appear to impair wound healing by decreasing replication of progenitor cells. Finally, a variant that leads to overexpression of the MUC5B gene, involved in mucin production in peripheral airways, has also been associated with an increased risk of IPF by one or more mechanisms that have not yet been elucidated. Although these various mutations are not present in many patients with IPF, identification of these involved pathways has led to better understanding of the mechanism of disease in at least some IPF patients, raising hopes of new therapies.
Idiopathic pulmonary fibrosis is thought to represent a dysregulated pattern of fibrosis in response to alveolar epithelial injury.
Clinically, the most common age at presentation of patients with IPF is between 50 and 70 years. Disease onset is generally insidious, and symptoms are similar to those of other interstitial lung diseases; dyspnea is the most prominent complaint. In addition to the classic finding of dry inspiratory crackles or rales on physical examination, patients frequently display clubbing of the digits.
The chest radiograph shows an interstitial (reticular) pattern that is generally bilateral and relatively
diffuse but typically is more prominent at the lung bases, particularly in the peripheral subpleural regions (see Fig. 3.6). Neither hilar enlargement nor pleural effusions are common. High-resolution computed tomography (HRCT) scanning typically has a characteristic appearance, showing interstitial densities that are patchy, peripheral, subpleural, and associated with small cystic spaces (Fig. 11.2). The pattern of small cystic peripheral abnormalities on HRCT is termed honeycombing and indicates irreversible fibrosis. Many patients have serologic abnormalities, such as a positive test result for antinuclear antibodies, which are generally found in patients with autoimmune or systemic rheumatic disease. However, in the absence of other suggestive clinical features, these abnormalities are thought to be nonspecific and not indicative of an underlying rheumatologic disease.
FIGURE 11.2 High-resolution computed tomography scan of idiopathic pulmonary
fibrosis shows scattered reticular densities, especially in subpleural regions.
The chest radiograph in IPF demonstrates a diffuse interstitial pattern without pleural disease or hilar enlargement.
The diagnosis is definitively established by surgical lung biopsy. However, if the HRCT scan shows a classic pattern that includes honeycombing and several other features, the diagnosis can be made with relative certainty without a lung biopsy. Traditional methods of bronchoscopic lung biopsy do not yield sufficiently large samples to establish the diagnosis, although a newer technique called transbronchial cryobiopsy, which obtains a larger tissue sample, appears more useful. The histologic expression of IPF is in the form of UIP (see Fig. 9.3), and patients who have a pathologic pattern more compatible with desquamative interstitial pneumonia (DIP) or NSIP (see Other Idiopathic Interstitial Pneumonias; also see Chapter 9) should not be considered to have IPF. Granulomas should not be seen on an IPF biopsy specimen and, if present, suggest another disorder.
Although IPF represents a chronic, fibrotic disease, some patients develop an acute exacerbation of IPF. This intercurrent problem is characterized by a relatively acute increase in symptoms, radiographic
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