findings of a ground-glass pattern superimposed over their preexisting disease, and a pathologic appearance consistent with acute lung injury that resembles the acute respiratory distress syndrome (ARDS) (see Chapter 29). Acute exacerbations are frequently treated with corticosteroids and antibiotics (because of the difficulty in definitively excluding infection), although it is unclear whether they provide any benefit, and the mortality associated with an acute exacerbation is relatively high.
Currently, there is no proven effective therapy to arrest or reverse the progressive fibrosis of IPF. Although corticosteroids and cytotoxic agents have been used frequently in the past for IPF, subsequent studies unfortunately demonstrated that these agents are ineffective and appear to be harmful. It is now thought that the small subgroup of patients previously believed to respond to corticosteroids actually had a corticosteroid-responsive diffuse parenchymal lung disease that was misidentified as IPF. Treatment for IPF now focuses on agents that suppress fibrosis or interfere with mediators involved in the fibrotic process. Two available drugs have been shown to reduce (but not stop) progression of disease, as measured by loss of pulmonary function. One of these, pirfenidone, inhibits TGF-β-mediated collagen synthesis and fibroblast proliferation. The other agent, nintedanib, a tyrosine kinase inhibitor, blocks the receptors and the downstream signaling of several fibrogenic growth factors, including PDGF, fibroblast growth factor, and vascular endothelial growth factor. In some patients with severe IPF, especially those who are younger, lung transplantation is the only therapeutic alternative to progressive respiratory failure and death. Although the overall prognosis is generally poor, with average survival less than 5 years, some patients have a more prolonged course, with survival that can exceed a decade.
Prognosis in idiopathic pulmonary fibrosis is generally poor. Treatment options include drugs aimed at slowing progression of disease (nintedanib, pirfenidone) or, in selected patients, lung transplantation.
Other idiopathic interstitial pneumonias
Several other disorders besides IPF fall under the category of the idiopathic interstitial pneumonias and previously 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 (see Table 9.2).
Respiratory bronchiolitis–interstitial lung disease (RB-ILD) and DIP are often considered together as part of a spectrum because of their strong association with smoking, although they are currently classified as separate smoking-related interstitial pneumonias. RB-ILD typically has relatively mild symptoms, occurs exclusively in smokers, and usually is reversible with cessation of smoking. HRCT scans in RBILD often show a ground-glass (hazy) pattern of opacification accompanied by centrilobular nodules. The pathologic pattern that corresponds to this appearance on HRCT is an accumulation of pigmented macrophages in the lumen of small airways accompanied by some peribronchiolar inflammation with lymphocytes and macrophages (see Fig. 9.5).
DIP is almost always associated with smoking, although rarely cases have also been described in nonsmokers. It generally has a subacute rather than a chronic onset. Imaging studies with chest radiography and HRCT scanning often show a ground-glass pattern. On lung biopsy, there is a uniform accumulation of intra-alveolar macrophages, with little or no fibrosis. In comparison with the peribronchiolar distribution in RB-ILD, DIP demonstrates more diffuse parenchymal involvement. The prognosis is better than in IPF, and patients often can improve after cessation of smoking and may respond to corticosteroids.
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 reflecting inflammation rather
than fibrosis. Lung biopsy shows a predominantly inflammatory response in the alveolar walls, with relatively little fibrosis (see Fig. 9.4). Although NSIP is often idiopathic, it can represent the histologic appearance of parenchymal lung disease associated with one of the systemic rheumatic 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 (COP) is a disorder characterized by connective tissue plugs in small airways accompanied by mononuclear cell infiltration of the surrounding pulmonary parenchyma (see Fig. 9.6). 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 pathologic pattern of BOOP can be associated with systemic rheumatic disease, toxic fume inhalation, or infection, the 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 findings of BOOP without an apparent cause.
On chest radiograph, cryptogenic organizing pneumonia (COP) often mimics a pneumonia with one or more alveolar infiltrates.
Like chronic eosinophilic pneumonia (see later), COP often has a subacute presentation (over weeks to months) with systemic (constitutional) as well as respiratory symptoms. Chest imaging studies show 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 maintained for months in order to prevent relapse.
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FIGURE 11.3 Chest CT scan demonstrating patchy alveolar opacities in a patient
with cryptogenic organizing pneumonia.
Acute interstitial pneumonia (AIP) is a more acute or fulminant type of pulmonary parenchymal disease characterized by the clinical picture of ARDS (see Chapter 29) 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 80 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 are now 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 systemic rheumatic disease
The systemic rheumatic diseases, also commonly called collagen vascular or connective tissue diseases, include rheumatoid arthritis, systemic lupus erythematosus, systemic sclerosis (scleroderma), polymyositis-dermatomyositis, Sjögren syndrome, and overlap syndromes that have features of more than one of these disorders. Although they comprise a diverse group, all are multisystem inflammatory diseases that are mediated immunologically and often considered as autoimmune disorders. 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 under the label of 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 systemic rheumatic 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 in these autoimmune conditions than clinically suspected. Third, the histopathology of interstitial lung disease associated with the systemic rheumatic diseases is usually either NSIP or UIP and is indistinguishable from idiopathic NSIP or IPF, respectively. Occasionally, however, the histopathology demonstrates organizing pneumonia that is indistinguishable from COP. 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.
Histologic and physiologic changes suggest that pulmonary involvement in most systemic rheumatic diseases is common, usually with a histologic pattern of nonspecific interstitial pneumonia or usual interstitial pneumonia.
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. A pathologic picture of UIP is most common, NSIP is slightly less common, and occasional patients have a pattern of organizing pneumonia resembling COP. Less commonly, patients with rheumatoid arthritis develop airway complications in the form of bronchiolitis (an inflammatory process involving small airways) or bronchiectasis. Because patients with rheumatoid arthritis are frequently treated with drugs that can be associated with pulmonary toxicity, such as methotrexate or rituximab, the possibility of drug-induced lung disease must also be considered.
In rheumatoid arthritis and lupus, pleural disease is more common than clinically evident diffuse parenchymal lung disease.
Systemic lupus erythematosus is a multisystem disease that primarily affects joints and skin but often has more serious involvement of several organ systems, including the 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 that resembles AIP, with infiltrates often involving the alveolar spaces as well as the alveolar walls. Another acute pulmonary complication in lupus is the development of diffuse alveolar hemorrhage. Less frequently, patients with lupus can develop chronic interstitial lung disease that has either NSIP or UIP pathology, although extensive fibrosis is relatively uncommon in lupus.
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. As with other systemic rheumatic disease, the pulmonary parenchymal involvement with scleroderma can represent either NSIP or UIP. Pulmonary fibrosis
complicating scleroderma appears to be strongly associated with the presence of a particular serologic
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