Idiopathic Pulmonary Fibrosis

Although the name idiopathic pulmonary fibrosis (IPF) 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 connective tissue disease a separate entity. Other names that have been used interchangeably with IPF are cryptogenic fibrosing alveolitis and usual interstitial pneumonia. The latter term is now generally used as a description of the pathologic pattern associated with IPF, a pattern occasionally seen in clinical settings other than IPF.

As implied by the name, IPF does not yet have a recognizable inciting agent, although most studies demonstrate an association with tobacco smoke exposure. Whether the primary agent, if one exists, reaches the lung via the airways or bloodstream has not been determined. The theory behind the pathogenesis of IPF has changed considerably over the past several 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.

Over the past several years, a newer conceptual framework has emerged. According to the newer theory, alveolar inflammation does not play a critical role in the eventual development of fibrosis. Rather, fibrosis is believed to result directly from alveolar epithelial injury and is thought to be a manifestation of abnormal wound healing within the lung parenchyma. According to the newer paradigm, injury to alveolar epithelial cells (still from an unidentified source or agent) is the primary initiating event. Whereas 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 reepithelialization process. 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 Figure 11-1.

Recently, the development of IPF has been associated with gene mutations in two biological pathways known to be related to lung injury and repair. Mutations in the first pathway affect genes encoding surfactant proteins A2 (SFPA2) and C (SFPC), 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 (TERT and TERC), the multimeric enzyme system that repairs shortened telomeres. Abnormalities in telomerase function appear to impair wound healing by decreasing replication of progenitor cells. Although these mutations are not present in all patients with IPF, identification of the pathways involved has led to better understanding of the mechanism of disease in IPF, raising hopes of new therapies.

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 crackles or rales on physical examination, patients frequently have evidence of 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 pleural effusions nor hilar enlargement is common on the radiograph. High-resolution computed tomography (HRCT) scanning often 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 connective tissue 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.

The diagnosis is definitively made by surgical lung biopsy, but only in the appropriate clinical setting when other etiologic factors for interstitial lung disease cannot be identified. Some patients are too frail for lung biopsy, and if HRCT scan shows the classic pattern of honeycombing, the diagnosis can be made with relative certainty without a lung biopsy. The histologic expression of IPF is in the form of usual interstitial pneumonia (UIP) (see Fig. 9-3), and patients who have a pathologic pattern more compatible with desquamative interstitial pneumonia or nonspecific interstitial pneumonia (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. If they are found, granulomas indicate the presence of another disorder.

From the time of clinical presentation, patients have a relatively poor prognosis; mean survival ranges from 2 to 5 years. Although steroids and cytotoxic agents have been used frequently in the past for IPF, newer studies unfortunately demonstrate that these agents are ineffective and appear to be harmful. Older studies suggested that a small group of patients would respond to corticosteroids. However, it is now thought that this subgroup actually had other corticosteroid-responsive diffuse parenchymal lung disease that was misidentified as IPF.

Currently there is no proven effective therapy for IPF. Clinical investigators are now focusing on identifying and testing agents that suppress fibrosis or interfere with mediators involved in the fibrotic process. In some patients with severe IPF, especially those who are younger, lung transplantation is used as the only therapeutic alternative to progressive respiratory failure and death.

Other Idiopathic Interstitial Pneumonias

Several other disorders besides IPF fall under the category of the idiopathic interstitial pneumonias and have often been confused with IPF. Although these disorders are uncommon, some are briefly described here, largely to clarify how their pathologic features differ from UIP and how their clinical features differ from IPF. They are also mentioned in Chapter 9 as part of the discussion on the pathology of the interstitial pneumonias.

Desquamative interstitial pneumonia (DIP) occurs largely in smokers. It generally has a subacute rather than a chronic onset. Imaging studies with chest radiography and HRCT scanning often show a ground-glass (hazy) pattern. Lung biopsy shows a uniform accumulation of intraalveolar macrophages, with little or no fibrosis. The prognosis is better than in IPF, and patients often can improve after cessation of smoking and may respond to corticosteroids.

Nonspecific interstitial pneumonia (NSIP) differs from UIP in its radiographic pattern, histologic appearance, prognosis, and response to treatment. As with DIP, imaging studies often show a ground-glass pattern that usually reflects inflammation rather than fibrosis. Lung biopsy shows a predominantly inflammatory response in the alveolar walls, with relatively little fibrosis. Although NSIP is often idiopathic and not associated with any underlying disease or inciting agent, it can represent the histologic appearance of parenchymal lung disease associated with one of the connective tissue diseases or with drug-induced pulmonary toxicity. The prognosis of NSIP appears to depend on the degree of fibrotic involvement present on both imaging and pathology. If inflammation predominates rather than fibrosis, the prognosis is significantly better than in IPF, and patients often respond to treatment with corticosteroids.

Cryptogenic organizing pneumonia is a disorder characterized by connective tissue plugs in small airways accompanied by mononuclear cell infiltration of the surrounding pulmonary parenchyma. As noted in Chapter 9, the terms cryptogenic organizing pneumonia (COP) and bronchiolitis obliterans with organizing pneumonia (BOOP) have often been used interchangeably, but the term BOOP is best reserved for the pathologic picture rather than the clinical syndrome. Although the histologic picture of BOOP can be associated with connective tissue disease, toxic fume inhalation, or infection, the large majority of cases have no identifiable cause and are considered idiopathic. The term COP is most appropriate for patients who have “idiopathic BOOP”—that is, the histologic pattern of BOOP but no apparent cause for this pattern.

Like chronic eosinophilic pneumonia (see later), COP often has a subacute presentation (over weeks to months) with systemic (constitutional) as well as respiratory symptoms. The chest radiograph shows patchy infiltrates, generally with an alveolar rather than an interstitial pattern, often mimicking a community-acquired pneumonia (Fig. 11-3). Like chronic eosinophilic pneumonia, the response to corticosteroids is often dramatic and occurs over days to weeks. Therapy is usually prolonged for months to prevent relapse.

Acute interstitial pneumonia (AIP) is a more acute or fulminant type of pulmonary parenchymal disease that begins with the clinical picture of acute respiratory distress syndrome (ARDS; see Chapter 28) but without any of the usual inciting events associated with development of ARDS. Imaging studies of AIP typically show features of ARDS, including areas of ground-glass opacification and alveolar filling (as opposed to a purely interstitial pattern). The histologic pattern is that of diffuse alveolar damage, often showing some organization and fibrosis. Although mortality is high overall, a small percentage of patients do well, with clinical resolution of the disease and no long-term sequelae.

One confusing aspect of the nomenclature of the idiopathic interstitial pneumonias is the relationship underlying AIP, UIP (or IPF), and a disorder called Hamman-Rich syndrome. More than 75 years ago, Hamman and Rich described a number of cases of parenchymal lung disease that subsequently were thought to represent the first described cases of IPF, and for many years the term Hamman-Rich syndrome was used synonymously with IPF. However, the cases described by Hamman and Rich now are believed to be cases of AIP rather than IPF, and it is more appropriate that Hamman-Rich syndrome be considered synonymous with AIP rather than either UIP or IPF.

Pulmonary Parenchymal Involvement Complicating Connective Tissue Disease

The connective tissue diseases, also commonly called collagen vascular diseases or systemic rheumatic diseases, include rheumatoid arthritis, systemic lupus erythematosus, progressive systemic sclerosis (scleroderma), polymyositis-dermatomyositis, Sjögren syndrome, and some overlap syndromes that have features of more than one of these disorders. Although they form a diverse group, all are multisystem inflammatory diseases that are mediated immunologically. The organ systems likely involved vary with each disease and are mentioned briefly in the following discussion of each entity.

Each disease is complicated and has been the focus of extensive research into etiology and pathogenesis. However, because none of them primarily affects the lung, they are not considered in detail here. Rather, a brief discussion notes how they affect the respiratory system, particularly with regard to development of parenchymal lung disease. Some clinicians include additional disorders among connective tissue diseases, but this discussion is limited to those in the preceding paragraph, each of which has the potential for pulmonary involvement.

Four assertions are true about each of these disorders. First, although patients generally have evidence of the underlying connective tissue disease before pulmonary manifestations develop, some patients have lung disease as the presenting problem, occasionally predating other manifestations of their illness by several years. Second, detailed histologic, physiologic, or autopsy evaluation of patients with these diseases shows that pulmonary involvement is much more common than clinically suspected. Third, the histopathology of interstitial lung disease associated with connective tissue disorders often is that of UIP and therefore is indistinguishable from the pattern seen in IPF. However, in many cases the histopathology demonstrates NSIP or occasionally COP rather than UIP. Fourth, the interstitial lung disease that may develop with each of these entities preferentially affects the lower rather than the upper lung zones. This fact usually is apparent on examination of the chest radiograph.

Rheumatoid arthritis is a disorder with primary manifestations consisting of inflammatory joint disease. The most common site of involvement within the thorax is the pleura. Involvement takes the form of pleurisy, pleural effusions, or both. The lung parenchyma may become involved, with one or multiple nodules or with development of interstitial lung disease. The latter usually is relatively mild, although severe cases are sometimes seen. Occasionally, patients with rheumatoid arthritis develop airway complications in the form of bronchiolitis (an inflammatory process involving small airways) or bronchiectasis.

Systemic lupus erythematosus is a multisystem disease that primarily affects joints and skin but often has more serious involvement of several organ systems, including kidneys, lungs, nervous system, and heart. Its most frequent presentation within the chest takes the form of pleural disease, specifically pleuritic chest pain, pleural effusion, or both. The lung parenchyma may be involved by an acute pneumonitis in which infiltrates often involve the alveolar spaces as well as the alveolar walls, or less frequently by chronic interstitial lung disease. In the latter, extensive fibrosis usually is not a prominent feature of the histology.

Progressive systemic sclerosis, or scleroderma, is a disease with the most obvious manifestations located in the skin and small blood vessels. Other organ systems, including the gastrointestinal tract, lungs, kidneys, and heart, are involved relatively frequently. Of all the connective tissue diseases, scleroderma is the one in which pulmonary involvement tends to be most severe and most likely associated with significant scarring of the pulmonary parenchyma. Pulmonary fibrosis complicating scleroderma appears to be strongly associated with the presence of a particular serologic marker, an autoantibody to topoisomerase I (antitopoisomerase I, also called Scl70). Another potential pulmonary manifestation of scleroderma is disease of the small pulmonary blood vessels, producing pulmonary arterial hypertension, which is discussed in Chapter 14. This involvement appears to be independent of the fibrotic process affecting the alveolar walls.

In polymyositis-dermatomyositis, muscles and skin are the primary sites of the inflammatory process. The interstitial lung disease of polymyositis-dermatomyositis is relatively infrequent and often has no particular distinguishing features. Patients may have respiratory problems as a result of muscle disease, with weakness of the diaphragm or other inspiratory muscles. Involvement of striated muscle in the proximal esophagus may lead to difficulty in swallowing and recurrent episodes of aspiration pneumonia.

In Sjögren syndrome, a lymphocytic infiltration affects salivary and lacrimal glands and is associated with dry mouth and dry eyes (keratoconjunctivitis sicca). When patients with Sjögren syndrome have pulmonary parenchymal involvement, the histologic appearance is most commonly that of a lymphocytic infiltrate within the alveolar walls (called lymphocytic interstitial pneumonia) rather than UIP or NSIP. Other lymphocytic complications of the lung can develop in patients with Sjögren syndrome, specifically either a localized masslike lesion called a pseudolymphoma or an actual lymphoma.

Finally, a number of overlap syndromes, often called undifferentiated connective tissue disease, have features of several of these disorders, particularly scleroderma, lupus, and polymyositis. Patients may develop any of the complications noted with the more classic individual disorders, including interstitial lung disease, pleural disease, and pulmonary vascular disease.

Sarcoidosis

Sarcoidosis is defined as a systemic disorder in which granulomas, typically described as noncaseating, can be found in affected tissues or organ systems. An important qualification is that these granulomas occur in the absence of any exogenous (infectious or environmental) agents known to be associated with granulomatous inflammation. The lung is the most frequently involved organ, with potential manifestations including parenchymal lung disease, enlargement of hilar and mediastinal lymph nodes, or both.