NSIP, UIP, and the ABCs of idiopathic interstitial pneumonias.

Diffuse interstitial lung disease (ILD) is a general term encompassing a broad range of largely unrelated conditions which share the propensity to cause breathlessness and/or cough, while resulting in bilateral abnormal opacities of various types on conventional chest radiographs or computed tomography (CT) scans. The idiopathic interstitial pneumonias are a subset of diffuse ILDs characterized by an expansion of the interstitial compartment (i.e. that portion of the lung parenchyma sandwiched between the epithelial and endothelial basement membranes) by an infiltrate of inflammatory cells. The inflammatory infiltrate is sometimes accompanied by fibrosis, either in the form of abnormal collagen deposition or a proliferation of fibroblasts capable of collagen synthesis. Our understanding of the idiopathic interstitial pneumonias has been plagued by our inability to clearly define the extent to which these represent distinct nosological entities as opposed to variations on the same fundamental theme. "Lumpers" would argue that all are appropriately covered under the venerable umbrellas of idiopathic pulmonary fibrosis (IPF), also referred to as cryptogenic fibrosing alveolitis (CFA), and that morphological separations are misguided attempts to segregate what are in fact highly related points on the same mysterious continuum of fibrosing lung disease. "Splitters" would respond that failure to control for histological subtypes has impeded our efforts to explain or predict the seemingly capricious behaviour of a family of similar but separable ILDs. LIEBOW [1] pioneered the notion that morphological characteristics are useful in separating idiopathic interstitial pneumonias into clinically and histologically distinct groups (table 1). Liebow's categories of usual interstitial pneumonia (UIP) and desquamative interstitial pneumonia (DIP) have persisted as important histological groups, while bronchiolitis obliterans with classical interstitial pneumonia (BIP), lymphoid interstitial pneumonia (LIP) and giant cell interstitial pneumonia (GIP) have disappeared from more recent classification schemes (table 2) [2]. Liebow was careful to say that these were histological patterns rather than free-standing diagnostic entities, and that each could occur in a variety of clinical contexts. Regardless of the clinical context, however, he maintained that precise histological classification of interstitial pneumonias provides "clues both to aetiology and to pathogenesis and certainly to natural history and prognosis" [1]. In other words, although histological patterns are not free-standing diagnostic entities, each significantly limits the differential diagnosis in terms of potential aetiologies or clinical associations and each has specific implications concerning the likely treatment response and outcome. From a practical standpoint the majority of patients in whom open or thoracoscopically guided lung wedge biopsies show the histological patterns encompassed under the heading of idiopathic interstitial pneumonias are suspected of having IPF/CFA, and the biopsy is intended not only to confirm the suspicion of an interstitial pneumonia but also to exclude various IPF mimics such as sarcoidosis, hypersensitivity pneumonitis and pulmonary eosinophilic granuloma. It is in this very context that morphological classification has proven to be a powerful tool in predicting prognosis. KATZENSTEIN and FIORELLI [3] coined the term nonspecific interstitial pneumonia (NSIP) to formalize the long held suspicion that not all histologically documented int-erstitial pneumonias could be classified using the cate-gories prescribed by Liebow. NSIP was defined more in terms of what it is not rather than what it is. NSIP is defined as those chronic interstitial pneumonias that lack the heterogeneity and variegated pattern of UIP while also lacking the extensive accumulation of pigmented alveolar histiocytes that distinguish DIP. Sixteen per cent of the 64 original patients in KATZENSTEIN and FIORELLI [3] had und-erlying collagen vascular disease of various sorts, while an equal number had potential organic antigen exposures that may have explained their lung disease. Five additional patients had histories suggesting antecedent acute lung injury, raising the possibility that NSIP may represent a resolving phase of diffuse alveolar damage (DAD) in some patients. A substantial number of patients remained, however, in whom NSIP was present in the context of susp-ected IPF/ CFA. Of the patients in whom follow-up was available, nearly half were alive and well, just under 40% had stable disease, and only approximately 10% had died. Interestingly, patients with fibrosis seemed to be at greater risk of dying than those with cellular, non-fibrotic lesions. KATZENSTEIN and FIORELLI [3] concluded that a pathological diagnosis of NSIP predicted greater likelihood of steroid responsiveness and a better outcome than classical UIP. BJORAKER et al. [4] subsequently provided additional evidence that there is a significant survival advantage in pa-tients with NSIP compared to patients with UIP. Table 1. – Classification of idiopathic interstitial pneumonias in LIEBOW [1]