© 2002 American Thoracic Society
Nonspecific Interstitial Pneumonia and Systemic SclerosisSan Francisco General Hospital University of California, San Francisco San Francisco, California Systemic sclerosis is a multisystem disease that affects the skin and internal organs (i.e., gastrointestinal tract, lung, heart, kidney, and peripheral vasculature). Pulmonary manifestations—especially interstitial lung disease and pulmonary arterial hypertension—are common causes of death in patients with systemic sclerosis (1). Early descriptions of the pathologic features of systemic sclerosis came primarily from postmortem studies. These studies suggested that the predominant pattern was "pure" fibrosis with little inflammatory reaction (2). Recently it has been shown that there are indeed areas of patchy inflammation and fibrosis of the alveolar walls (2, 3). The pathologic features were felt to be identical to those found in idiopathic pulmonary fibrosis (3). Several major changes in our understanding of interstitial lung disease require a reevaluation of the histopathologic features of systemic sclerosis. First, there has been a revision of the histopathologic classification scheme for the idiopathic interstitial pneumonias into six distinct subgroups sufficiently different from each other to be considered separate disease entities: usual interstitial pneumonia; nonspecific interstitial pneumonia; desquamative interstitial pneumonia/respiratory bronchiolitis-associated interstitial lung disease; acute interstitial pneumonia (formerly Hamman-Rich syndrome); cryptogenic organizing pneumonia; and lymphoid interstitial pneumonia (4, 5). This scheme incorporated the idea that identification of histologic subtypes might provide clues to the etiology, pathogenesis, and the natural history and prognosis of the idiopathic interstitial pneumonias. Particularly important distinguishing histopathologic features include: the presence or absence of temporal heterogeneity of inflammation and fibrosis, the extent of inflammation, the extent of accumulation of intra-alveolar macrophages, and the presence of honeycombing or hyaline membranes. It has also been concluded that the diagnosis of idiopathic pulmonary fibrosis should be confined to those cases with the histologic features of usual interstitial pneumonia, thus making the group more homogeneous (6). Given these changes in the classification of the idiopathic interstitial pneumonias, there has been an interest in determining which of these patterns are found in patients with interstitial pneumonia, with and without a connective tissue disease. Several groups have reassessed the cases previously called idiopathic pulmonary fibrosis and found that the usual interstitial pneumonia pattern (found in up to 50% of the cases) and the nonspecific interstitial pneumonia pattern (particularly fibrotic nonspecific interstitial pneumonia) were the most common patterns (7, 8). Desquamative interstitial pneumonia, respiratory bronchiolitis-associated interstitial lung disease, acute interstitial pneumonia, lymphoid interstitial pneumonia, and cryptogenic organizing pneumonia were uncommon. Similarly, investigators have reviewed the pathologic features found in connective tissue disease and surprisingly found that nonspecific interstitial pneumonia is by far the most common pattern (9, 10). In this issue of AJRCCM (pp. 1581–1586) Bouros and coworkers (11) report the histologic patterns found in surgical lung biopsies of 80 patients with systemic sclerosis seen over a 12-year period. Several histologic patterns were found: 62 patients (77.5%) had nonspecific interstitial pneumonia; 6 had usual interstitial pneumonia; 6 had unclassifiable end-stage fibrosis; 4 had respiratory bronchiolitis-associated interstitial lung disease; and 1 had organizing pneumonia. There were 22 deaths: 16 in the nonspecific interstitial pneumonia group and 6 in the usual interstitial pneumonia/end-stage fibrosis group. Given the small sample size of the usual interstitial pneumonia group, it could not be determined whether survival differed in the two groups, although 69% of the patients with nonspecific interstitial pneumonia were alive at 10 years compared with only 29% with usual interstitial pneumonia. These data confirm that the 5-year survival in systemic sclerosis is considerably longer than that previously shown by this group and others for idiopathic pulmonary fibrosis/usual interstitial pneumonia. They identified several features that predict poorer survival in the nonspecific interstitial pneumonia subset: lower baseline diffusing capacity for carbon monoxide; higher eosinophil levels on bronchoalveolar lavage; and deterioration in diffusing capacity during the first 3 years of follow-up. Although we have yet to adequately define nonspecific interstitial pneumonia, it is increasingly clear that separation of patients with usual interstitial pneumonia from patients with nonspecific interstitial pneumonia has significant implications concerning treatment and prognosis. There are no recognized and distinctive clinical descriptions of patients presenting with nonspecific interstitial pneumonia, and to date this condition has been largely " ... defined more in terms of what it is not rather than what it is" (12). However, the term "nonspecific interstitial pneumonia" has evolved from its original use, which was intended to indicate a histologic pattern with a variety of etiologies (e.g., hypersensitivity pneumonitis, or drug reaction, associated with connective tissue diseases and survivors of acute respiratory distress syndrome), to now being used to identify a specific form of idiopathic interstitial pneumonitis (4, 5). Nonspecific interstitial pneumonia is characterized by varying degrees of inflammation and fibrosis, with some forms being primarily inflammatory ("cellular nonspecific interstitial pneumonia") and the most prevalent being primarily fibrotic ("fibrotic nonspecific interstitial pneumonia") (5). While nonspecific interstitial pneumonia may have significant fibrosis, it usually does not have the temporal heterogeneity of usual interstitial pneumonia (i.e., it lacks fibroblastic foci and honeycombing). Unfortunately, fibrotic nonspecific interstitial pneumonia can be difficult to distinguish reliably from usual interstitial pneumonia, and it remains unknown if nonspecific interstitial pneumonia represents an early form of usual interstitial pneumonia. Both patterns can be seen in multiple biopsies from the same patient, even in multiple biopsies from the same lobe (13), and there is significant interobserver variability even among expert histopathologists in the recognition of these entities (5). Another intriguing finding in this study is that several patients had end-stage lung disease that could not be classified as either usual interstitial pneumonia or nonspecific interstitial pneumonia. This brings up a problem that still exists in the classification of the idiopathic interstitial pneumonias: the need to accept that a small subset of patients with interstitial lung disease remains unclassifiable even after extensive clinical, radiologic, and/or pathologic examination. Clinicians should acknowledge that uncertainty remains in individual cases and these unresolved cases should be called "unclassifiable interstitial pneumonia" and should not be lumped with another idiopathic interstitial pneumonia (5). Finally, this study adds useful information about the response to treatment and prognosis of interstitial lung disease in systemic sclerosis. There has been growing interest in the aggressive, early treatment of interstitial lung disease in systemic sclerosis. Several uncontrolled and retrospective studies suggest that if you eliminate pulmonary vascular disease and malignancy, treatment of interstitial lung disease in systemic sclerosis with cyclophosphamide (with or without prednisone) improves long-term morbidity and mortality in systemic sclerosis. Controlled clinical trials are needed to confirm these findings. REFERENCES
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