INTRODUCTION:
"Diffuse interstitial lung disease" (ILD) is a generic term encompassing a broad range of largely unrelated conditions that share the propensity to cause breathlessness and/or cough associated with bilateral abnormal opacities of various types on conventional chest radiographs or computed tomography (CT) scans. The idiopathic interstitial pneumonias are a subset of diffuse interstitial lung diseases characterized by expansion of the interstitial compartment (i.e. that portion of the lung parenchyma sandwiched between 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 proliferation of fibroblasts capable of collagen synthesis.

Averill Liebow pioneered the notion that morphologic characteristics are useful in separating idiopathic interstitial pneumonias into clinically and histologically distinct groups. Dr. Liebow's categories of usual interstitial pneumonia (UIP) and desquamative interstitial pneumonia (DIP) have persisted as important histologic groups, while bronchiolitis obliterans with classical interstitial pneumonia (BIP) and giant cell interstitial pneumonia (GIP) have disappeared from more recent classification schemes (Table 1). Lymphoid interstitial pneumonia (LIP) remains controversial in terms of its relationship to other idiopathic interstitial pneumonias. Regardless of the classification scheme you prefer, the principles developed by Liebow remain relevant. He 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 etiology and to pathogenesis and certainly to natural history and prognosis". In other words, although histological patterns are not free-standing diagnostic entities, each significantly limits the differential diagnosis in terms of potential etiologies or clinical associations and each has specific implications concerning likely treatment response and outcome. In the specific clinical context of a patient with unexplained (i.e. idiopathic) interstitial lung disease, these histologically defined patterns are indeed specific diseases. In this clinical setting biopsy is usually 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 morphologic classification has proven to be a powerful tool in predicting prognosis.

Table 1: Classification of Idiopathic Interstitial Pneumonias

Katzenstein & Myers †	International Classification ‡
	Clinical diagnosis	Pathologic pattern
Usual interstitial pneumonia (UIP)	Idiopathic pulmonary fibrosis (IPF)	Usual interstitial pneumonia (UIP)
Desquamative interstitial pneumonia (DIP)/Respiratory bronchiolitis interstitial lung disease (RBILD)	Desquamative interstitial pneumonia (DIP) Respiratory bronchiolitis interstitial lung disease (RBILD)	Desquamative interstitial pneumonia (DIP) Respiratory bronchiolitis interstitial lung disease (RBILD)
Acute interstitial pneumonia (AIP)	Acute interstitial pneumonia (AIP)	Diffuse alveolar damage (DAD)
Nonspecific interstitial pneumonia (NSIP)	Nonspecific interstitial pneumonia (NSIP) Cryptogenic organizing pneumonia (COP) Lymphoid interstitial pneumonia (LIP)	Nonspecific interstitial pneumonia (NSIP) Organizing pneumonia Lymphoid interstitial pneumonia (LIP)

^†Katzenstein A-L and Myers J. Idiopathic pulmonary fibrosis: Clinical relevance of pathologic classification. Am J Resp Crit Care Med 1998; 157: 1301-15.

^‡ American Thoracic Society/European Respiratory Society internationl multidisciplinary consensus classification of the idiopathic interstitial pneumonias. Am J Respir Crit Care Med 2002; 165: 277-304.

Usual interstitial pneumonia
A recently published ATS consensus statement defines IPF as: a specific form of chronic fibrosing interstitial pneumonia limited to the lung and associated with histologic appearance of usual interstitial pneumonia (UIP) on surgical (thoracoscopic or open) lung biopsy.

Most cases are sporadic, occurring in patients who present in the 5th or 6th decade of life complaining of slowly progressive dyspnea and nonproductive cough. Men are affected more commonly than women by a ratio of nearly 2:1. Rare familial cases of IPF have been described. Pulmonary function studies show a restrictive pattern (i.e. reduced lung volumes with relative preservation of airflow) and chest roentgenograms show diffuse interstitial opacities associated with reduced lung volumes. High resolution CT (HRCT) scans show a characteristic pattern of peripheral (subpleural) and bibasilar reticulonodular opacities associated with architectural distortion including honeycomb change and traction bronchiectasis. Although this combination of radiologic findings is characteristic and relatively specific, it occurs in only about half of patients. IPF usually follows a relentlessly progressive course with most patients dying of respiratory failure within 2-5 years of diagnosis. Periodic exacerbations associated with accelerated decline in symptoms and pulmonary function are the rule and can be related to either variation in the tempo of the underlying lesion or superimposed complications of various types. Most patients succumb to respiratory failure, although other fatal complications such as bronchogenic carcinoma account for a significant minority of deaths.

Usual interstitial pneumonia is a specific morphologic entity. The histologic hallmark and chief diagnostic criterion is a heterogeneous appearance at low magnification with alternating areas of normal lung, interstitial inflammation, fibrosis, and honeycomb change. The histological changes correlate with findings on HRCT in that peripheral subpleural parenchyma is most severely affected, although a peripheral subpleural distribution may not be appreciable in surgical lung biopsies. The interstitial inflammation is usually patchy and consists of an alveolar septal infiltrate of lymphocytes, plasma cells, and histiocytes associated with hyperplasia of type 2 pneumocytes. The fibrotic zones are composed mainly of dense collagen, although scattered foci of fibroblast proliferation ("fibroblast foci") are a consistent finding. Areas of honeycomb change are composed of cystic fibrotic air spaces frequently lined by bronchiolar epithelium and filled with mucin. Smooth muscle hyperplasia is commonly seen in areas of fibrosis and honeycomb change. Fibrotic scars resulting in obliteration of the underlying lung architecture may also be present. Patients who are biopsied during a period of accelerated decline ("accelerated IPF") may show a combination of UIP and superimposed diffuse alveolar damage. There is no single histologic finding that has shown a consistent correlation with treatment response or prognosis in UIP. Recent studies indicates that the profusion of fibroblast foci may be linked to mortality and mean survival (i.e. more is worse).

Desquamative interstitial pneumonia (DIP)/RESPIRATORY
BRONCHIOLITIS-ASSOCIATED INTERSTITIAL LUNG DISEASE (RBILD)
DIP is a distinct clinicopathologic entity that differs substantially from UIP (see Table 2). It is relatively uncommon, comprising eight percent of biopsied Mayo Clinic patients suspected of having IPF and sixteen percent of patients in a series of patients from the Pulmonary Branch of the National Heart, Lung and Blood Institute. DIP typically affects cigarette smokers in their fourth or fifth decades of life. Physiologic testing usually shows mild reduction in lung volumes associated with a moderate decrease in DL _CO . The radiographic abnormalities tend to be less severe than those seen in UIP; indeed, chest roentgenograms are normal in as many as one fifth of patients. HRCT shows ground glass opacities without the peripheral reticular and reticulonodular opacities characteristic of UIP. In two separate studies of serial CT scans, no "progression" from DIP to UIP was documented further supporting the notion that DIP and UIP are separate and distinct entities. Corticosteroids are beneficial in the majority of patients, and the overall survival is 70% or better after 10 years. Indeed recent studies have demonstrated 100% survival rates for DIP, but to some extent this reflects a trend toward excluding patients with associated fibrosis.

TABLE 2: COMPARISON OF UIP AND DIP *

	UIP	DIP
mean age	50.9 yrs	42.3 yrs
cig smokers	71%	90%
abnormal CxR	92.4%	77.5%
¯volumes	45.0%	23.0%
HNCB	49.1%	12.5%
mean severity	2/3	1/2
mortality	66.0%	27.5%
mean survival	5.6 ± 3.7 yrs	12.2 ± 5.5 yrs

* data from Carrington C et al. N Engl J Med 1978; 298: 801-9.

Respiratory bronchiolitis was defined in 1974 by Niewoehner and colleagues as a distinct histopathologic entity characterized by the presence of pigmented intraluminal macrophages within first and second-order respiratory bronchioles. These investigators hypothesized that respiratory bronchiolitis might contribute to small airways dysfunction in cigarette smokers, and also suggested that respiratory bronchiolitis might be a precursor of centriacinar emphysema. More importantly, perhaps, respiratory bronchiolitis has been linked to a syndrome of diffuse interstitial lung disease (respiratory bronchiolitis interstitial lung disease or RBILD) that can mimic IPF. Like DIP, RBILD is an uncommon form of interstitial pneumonia, accounting for only two percent of biopsied Mayo Clinic patients who were suspected of having IPF. DIP and RBILD show significant clinical, radiologic and histologic overlap, and in some patients the distinction is arbitrary and of uncertain clinical significance. RBILD mainly affects current smokers in the fourth or fifth decade of life with average exposures of over 30 pack-years of cigarette smoking (see Table 3). Men are affected more often than women by a ratio of almost 2:1. Symptoms are usually mild and not disabling. Nearly all patients present with nonspecific respiratory complaints including insidious onset of dyspnea and a new or changed cough. Chest roentgenograms are abnormal in 80% of patients and typically show diffuse fine reticular or reticulonodular opacities in a bibasilar distribution. Patchy ground glass attenuation is the most frequently observed abnormality on CT scans. RBILD appears to be a relatively benign self-limited condition. Only three of the 34 reported patients for whom details are available suffered progression of their interstitial lung disease. One of the three patients with progressive disease had underlying scleroderma and another continued to smoke. None of the reported patients have died of their disease.

Table 3: Clinical Findings In 34 Patients With RBILD*

Mean age @ diagnosis (range)	39.3 yrs (22-65 yrs)
Males:females	20:14
Mean pack-years cig smoking (range)	34.0 pk-yrs (0†-80 pk-yrs)
Symptoms
- dyspnea	70.6%
- cough	50.0%
- chest pain	14.7%
- asymptomatic	11.8%
Signs
- clubbing	5.9%
- rales	41.1%
Chest radiograph
- interstitial opacities (reticular/reticulonodular)	67.6%
- normal	20.6%

*data summarized from Myers et al. 1987; Yousem et al. 1989; and Moon et al. 1999.

^†single non-smoker was reported by Moon et al. as having occupational exposure to solder flux fumes

DIP differs histologically from UIP in that the changes tend to be much more uniform at low magnification and lack the variegated appearance typical of UIP. Alveolar septa are thickened by a sparse inflammatory infiltrate that often includes plasma cells and occasional eosinophils, and are lined by plump cuboidal pneumocytes. The most striking feature is the presence of numerous mononuclear cells within most of the distal air spaces. The macrophages are distinctive in that they tend to have abundant cytoplasm containing finely granular dusty brown pigment. The pigmented granules represent complex phagolysosomes that are highlighted in Prussian blue iron stains. As in DIP, the most striking feature of respiratory bronchiolitis is the presence of pigmented ("smokers'") macrophages. Respiratory bronchiolitis differs, however, in that the changes are patchy at low magnification and have a distinctly bronchiolocentric distribution. Intraluminal macrophages are accompanied by a patchy submucosal and peribronchiolar infiltrate of lymphocytes and histiocytes. The interstitial histiocytes may contain dusty brown cytoplasmic pigment identical to that seen within the intraluminal macrophages, or they may contain coarse black anthracotic pigment. Peribronchiolar fibrosis is also seen and expands contiguous alveolar septa that are lined by hyperplastic type 2 pneumocytes and cuboidal bronchiolar-type epithelium.

Neither RBILD nor DIP should be viewed as a free-standing histopathologic entity, since areas resembling both are common as incidental findings in cigarette smokers. Given the dangers of sampling bias, RBILD and DIP should be diagnosed only when other forms of interstitial lung disease have been vigorously excluded, a process that requires correlation of biopsy findings with clinical and radiographic features. In a recently published review Fraig and colleagues identified respiratory bronchiolitis in 109 of 156 consecutive surgical specimens. "DIP-like" areas were identified in 6. Only two (1.8%) patients were thought to have either RBILD (1) or DIP (2) after careful correlation with clinical, radiologic and pathologic findings.

Acute interstitial pneumonia
Most of the idiopathic interstitial pneumonias are chronic processes characterized by an insidious onset and a relentlessly progressive course. Less commonly they present with the explosive onset of respiratory symptoms and are characterized by rapidly progressive respiratory failure associated with diffuse infiltrates on chest roentgenograms. This acute variant is analogous to ARDS, differing only in that it is not preceded by a catastrophic event -- that is, the condition is idiopathic. It has the same poor prognosis as ARDS and the majority of patients die of respiratory failure. A recent report suggests that some patients may recover only to suffer multiple relapses, and others may develop chronic interstitial lung disease. Several terms have been proposed for this clinicopathological syndrome, including acute interstitial pneumonia (AIP) and Hamman-Rich syndrome. Regardless of the term you prefer, the important point is that AIP should be distinguished from the group of chronic interstitial pneumonias because of marked differences in natural history.

Histologically, AIP is identical to the organizing or proliferative stage of DAD. The main finding is extensive interstitial fibroblast proliferation within an edematous-appearing stroma. Alveolar septa are dramatically thickened and are lined by hyperplastic type II pneumocytes which are often cytologically atypical. Hyaline membrane remnants are inconspicuous but may be present within occasional air spaces or within alveolar walls. The main differential diagnosis in the setting of idiopathic interstitial lung disease in a non-immunocompromised patient is so-called accelerated IPF. The distinction depends not only on recognizing underlying UIP but also on correlation with the clinical and radiographic findings. In a comparison of patients with AIP and patients suffering acute exacerbation of IPF reported only in abstract form, patients with accelerated IPF were older, more likely to have digital clubbing, and had radiographic features of UIP on HRCT scans.

Nonspecific interstitial pneumonia/fibrosis
Occasionally lung biopsies show a chronic interstitial pneumonia that lacks the histopathologic features typical of UIP, DIP, RBILD or AIP. These lesions are often characterized by a relatively uniform appearance at low magnification due to a cellular interstitial infiltrate of mononuclear inflammatory cells associated with varying degrees of interstitial fibrosis. Examples of this condition have undoubtedly been included in studies of idiopathic pulmonary fibrosis as "early" or "cellular" UIP. This type of tissue response is relatively nonspecific and may be seen as a manifestation of collagen vascular disease, drug-induced lung disease, or as an idiopathic lesion. In 1994 Dr. Katzenstein proposed the term nonspecific interstitial pneumonia/fibrosis (NSIP) for this subset of patients and suggested that they enjoy a prognosis that is significantly better than UIP.

Multiple studies have now confirmed the survival advantage associated with a diagnosis of NSIP compared to UIP. In a review of Mayo Clinic patients suspected of having IPF, only 62% had classical UIP; NSIP was the second most common histologic category accounting for 14% of cases. As Katzenstein had predicted, patients with NSIP had a significantly better prognosis than patients with UIP. More recent studies from the NIH and the Brompton Hospital in London have demonstrated a more aggressive course in patients with associated fibrosis. These studies differ from Dr. Katzenstein's original report in that many patients with fibrotic disease had associated honeycomb change, something that occurred in fewer than 10 percent of Katzenstein's patients. These observations raise the possibility that some patients with fibrotic NSIP may in fact have UIP that is not fully represented in the lung biopsies.

As the term implies, the histological findings in patients with nonspecific interstitial pneumonia (NSIP) are variable. From the outset NSIP has been defined largely on the basis of exclusionary criteria (i.e. lung biopsies that fail to show features diagnostic of another form of diffuse interstitial lung disease such as UIP, DIP, acute interstitial pneumonia, sarcoidosis, etc.). It is likely that emphasis of these exclusionary criteria initially resulted in identification of a heterogeneous group of patients, many of whom had fundamentally non-diagnostic biopsies for which a label became available that sounded like a diagnosis! In her original definition Katzenstein emphasized not only exclusionary criteria but also a fundamentally important inclusionary criteria: "All cases were characterized by an interstitial inflammatory or fibrosing process or both . . . [that] appeared temporally uniform within each case." That is, NSIP is first and foremost a form of chronic interstitial pneumonia. Although her original series of 64 patients included some with likely etiologies (i.e. hypersensitivity pneumonia), the term is now generally restricted to a subset of patients with idiopathic interstitial pneumonia that is fundamentally different from UIP. Because this pattern of interstitial pneumonia is relatively nonspecific, however, it remains a diagnosis of exclusion. In this case exclusion implies careful correlation with clinical and radiographic data for reasons cited previously.

The fundamental feature that is required before a diagnosis of NSIP can be considered is the presence of an interstitial pneumonia in the absence of other more specific pathologic processes. Interstitial pneumonia refers to expansion of alveolar septa by a combination of inflammation and/or fibrosis. Alveolar septa comprise one of several continuous connective tissue compartments in the distal lung that also include bronchovascular bundles, interlobular septa, and visceral pleura. Alveolar septa may be affected in a diffuse or patchy fashion. Patchy involvement may be random or more discrete (e.g. affecting mainly peribronchiolar alveolar septa in bronchiolocentric forms of interstitial pneumonia). In some conditions interstitial pneumonia is a secondary phenomenon either resulting from some other primary insult (e.g. proximal large airway obstruction, viral infection), or accompanied by other more important pathologic changes that define the underlying condition (e.g. acute bronchopneumonia, hypersensitivity pneumonia). Thus the diagnosis of NSIP starts with

• the presence of a patchy or diffuse interstitial pneumonia without other primary pathologic processes,