Idiopathic pulmonary fibrosis/cryptogenic fibrosing alveolitis

Abstract. Idiopathic pulmonary fibrosis (IPF), synonymous with cryptogenic fibrosing alveolitis (CFA), is a progressive and usually fatal disease of unknown cause characterized by sequential acute lung injury with subsequent scarring and end-stage lung disease. Historically, IPF/CFA encompassed a heterogeneous group of different histological and clinical entities arising in an idiopathic setting. Recently, the American Thoracic Society (ATS) and European Respiratory Society (ERS) core committee has redefined diagnostic criteria for both IPF/CFAand idiopathic interstitial pneumonias confining the term IPF/CFA to patients with a histological pattern of usual interstitial pneumonia on lung biopsy. This review attempts to refine the clinico-radiological-pathological features that together define IPF/CFA as it is understood today, and to summarize the rationale of new therapeutic approaches based on the current understanding of the pathogenetic mechanisms.     

Pathological differentiation of chronic hypersensitivity pneumonitis from idiopathic pulmonary fibrosis/usual interstitial pneumonia

Takemura T, Akashi T, Kamiya H, Ikushima S, Ando T, Oritsu M, Sawahata M & Ogura T
(2012) Histopathology
Pathological differentiation of chronic hypersensitivity pneumonitis from idiopathic pulmonary fibrosis/usual interstitial pneumonia Aims: To evaluate the histological characteristics differentiating chronic hypersensitivity pneumonitis (chronic HP) with a usual interstitial pneumonia (UIP)‐like pattern from idiopathic pulmonary fibrosis (IPF)/UIP. Methods and results: Surgical lung biopsy specimens from 22 patients with chronic HP diagnosed as having a UIP‐like pattern upon histological examination and 13 patients with IPF/UIP were examined and the incidences of bronchiolitis, perilobular fibrosis, centrilobular fibrosis, bridging fibrosis, organizing pneumonia, fibroblastic foci, honeycombing, granulomas, giant cells, lymphocytic alveolitis and lymphoid follicles were compared. Bronchiolitis, centrilobular fibrosis, bridging fibrosis, organizing pneumonia, granulomas, giant cells and lymphocytic alveolitis were significantly more frequent among patients with chronic HP than among patients with IPF (all P < 0.01). Conclusions: Centrilobular fibrosis, bridging fibrosis and organizing pneumonia, in addition to bronchiolitis, granulomas and giant cells, are characteristic features of chronic HP with a UIP‐like pattern. These features are therefore important in differentiating chronic HP from IPF/UIP, as management strategies differ for the two disorders.     

Nonspecific interstitial pneumonia: pathologic features and clinical implications

Nonspecific interstitial pneumonia (NSIP) is a form of chronic interstitial pneumonia that should be separated from the other idiopathic interstitial pneumonias, including most importantly, usual interstitial pneumonia (UIP). Diagnosis is predicated on identification of characteristic findings in a surgical lung biopsy in the appropriate clinical and radiological context. Affected patients may have a variety of underlying or associated conditions, although most have a form of idiopathic lung disease associated with a more favorable prognosis than UIP/idiopathic pulmonary fibrosis (IPF). Keys to distinguishing NSIP from UIP include absence of heterogeneous lung involvement, architectural distortion in the form of fibrotic scarring and/or honeycomb change, and fibroblast foci in NSIP.     

Collagen and elastic system in the remodelling process of major types of idiopathic interstitial pneumonias (IIP)

AIMS: Structural remodelling in acute and chronic idiopathic interstitial pneumonia (IIP) has been extensively investigated, but little attention has been directed to the elastic tissue in these situations. The aim of this study was to determine whether elastic deposition accompanies collagen deposition in the four major histological patterns of IIP: diffuse alveolar damage (DAD), organizing pneumonia (OP), non-specific interstitial pneumonia (NSIP) and usual interstitial pneumonia (UIP). METHODS AND RESULTS: We measured, by image analysis, the content of fibres of the collagenous and elastic systems of the alveolar septum in histological slides of open lung biopsies, using the picrosirius-polarization method and Weigert's resorcin-fuchsin stain, respectively. Five groups were studied: 10 cases of DAD; nine cases of OP; nine cases of NSIP; and 10 cases of UIP. Four normal lungs were used for comparison. The content of collagen fibres was significantly higher in UIP when compared to DAD, NSIP, OP and normal lung. The content of elastic fibres was increased in comparison with normal lungs but this was not significantly different among the histological patterns. CONCLUSION: Acute and chronic IIP cause a similar increase in the collagen and elastic contents of the lungs, representing a process of 'fibroelastosis' rather than an exclusive process of fibrosis. A profibrogenic mechanism is responsible for the unparallelled collagen augmentation observed in UIP subjects, the nature of which is yet to be determined.     

Heterogeneous proliferation of type II pneumocytes in usual interstitial pneumonia

AIMS: Heterogeneous alveolar fibrosis, the most specific pathological finding in idiopathic pulmonary fibrosis (IPF)/usual interstitial pneumonia (UIP), enables differentiation of UIP from other interstitial pneumonias. Heterogeneous and mild alveolar injury may occur, and this will be a clue to clarifying the pathogenesis of UIP. METHODS: We examined nine lung biopsy specimens obtained from patients with IPF and five control specimens. We semi-quantitatively examined alveolar injury by measuring the density of type II pneumocytes. Serial 3 microm sections were stained with anti-Thomsen-Friedenreich (TF) antibody. We divided each UIP lesion into three areas: area near fibrosis (fibrous area), area with an apparently normal alveolar structure (normal area), and area between the fibrous and normal areas (intervening area). RESULTS: Immunostaining with anti-TF antibody stained the apical surface of type II pneumocytes and enabled us to recognise and count type II pneumocytes. The density of type II pneumocytes was increased in the fibrous area, and gradually decreased away from the fibrous lesion. The densities of type II pneumocytes in the above three areas were, respectively: 13.9+/-2.0, 7.2+/-1.6, and 9.5+/-1.6/mm alveolar length. The densities in the fibrous and intervening areas were significantly greater than those in the normal area and in control specimens (6.6+/-0.7/mm). CONCLUSIONS: If the density of type II pneumocytes indicates their degree of regeneration after alveolar injury, it reflects the severity of the pre-existing injury. This study confirms that heterogeneous and mild alveolar injury occurs in UIP.     

Gremlin localization and expression levels partially differentiate idiopathic interstitial pneumonia severity and subtype

Idiopathic pulmonary fibrosis (IPF) (histopathology of usual interstitial pneumonia, UIP) and non-specific interstitial pneumonia (NSIP) are diseases characterized by loss of normal lung architecture and function. The differential diagnosis between IPF/UIP and NSIP may be difficult. The levels of bone morphogenetic protein (BMP)-4 antagonist gremlin are up-regulated in IPF/UIP. The present study was performed to clarify whether the localization or the mRNA expression of gremlin or BMP-4 could be used in the differential diagnosis or assessment of severity of IPF/UIP and NSIP. Gremlin and BMP-4 immunoreactivities were quantitated from 24 UIP and 12 NSIP lung specimens. Quantitative real-time polymerase chain reaction analyses were performed to compare gremlin and BMP-4 expression between UIP (n = 8) and NSIP (n = 5) biopsies. Immunohistochemical positivity and mRNA levels were correlated to lung function parameters. In IPF/UIP biopsies, gremlin was detected mainly in the thickened lung parenchyma, whereas in NSIP it was observed in the alveolar epithelium. BMP-4-positive (BMP-4+) cells were detected solely in the alveolar wall. The percentage of gremlin-positive area was higher in IPF/UIP (5.1 +/- 0.6) than in NSIP (1.8 +/- 0.7) (n = 36, p < 0.0001). Gremlin mRNA levels were higher in advanced UIP (p = 0.008) and NSIP (p = 0.007) biopsies than in the normal control lung. A negative correlation was found between the specific diffusion capacity corrected for alveolar volume (DLCO/VA) and gremlin mRNA levels (r = - 0.69, p = 0.007). The highest numbers of BMP-4+ cells were found in NSIP biopsies. BMP-4 mRNA levels correlated positively with forced vital capacity (r = 0.801, p < 0.0001) and diffusion capacity. Parenchymal gremlin immunoreactivity is thus suggestive of a UIP-type interstitial pneumonia. Gremlin expression levels correlating negatively and BMP-4 levels positively with disease severity support recent observations of a fibroprotective role for the BMPs.     

普通型间质性肺炎的临床病理特征及其与特发性非特异性间质性肺炎的鉴别诊断

目的 探讨普通型间质性肺炎(UIP)的临床病理特征以及与特发性非特异性间质性肺炎(INSIP)的鉴别诊断。方法 对15例经电视胸腔镜或小切口开胸肺活检诊断为UIP的病例进行光镜观察和临床病理资料回顾性分析,治疗后随访,与11例病理诊断的INSIP进行比较分析。结果UIP多见于50岁以上的男性,临床主要表现为活动后气促、咳嗽咳痰、双下肺闻及吸气相爆裂音;高分辨CT表现为以中下肺和胸膜下为主的片状和网状阴影,8例有蜂窝肺。UIP的病理特征为病变进展不一致,间质的炎症、纤维化和蜂窝变与正常肺组织呈交替分布,轻重不一。纤维母细胞灶、肌硬化、镜下蜂窝肺、弥漫胶原沉积和肺泡结构改建的检出情况在UIP和INSIP分别是15/15和3/11(P<0.001)、12/15和4/11(P<0.05)、13/15和3/11(P<0.01)、15/15和6/11(P<0.01)、15/15和5/11(P<0.01)。两者对糖皮质激素的反应率分别为3/15和8/11(P<0.05)。结论 UIP和INSIP的一般临床表现差异不明显,高分辨CT对疑难病例的鉴别诊断有帮助,明确诊断依赖肺活检病理诊断;纤维母细胞灶、伴胶原沉积的瘢痕化和蜂窝变组成不同时相的病变共同构成诊断UIP的形态特征。     

Aberrant Wnt/beta-catenin pathway activation in idiopathic pulmonary fibrosis

To investigate the molecular events that may underpin dysfunctional repair processes that characterize idiopathic pulmonary fibrosis/usual interstitial pneumonia (IPF/UIP), we analyzed the expression patterns of beta-catenin on 20 IPF/UIP lung samples, together with two downstream target genes of Wnt signaling, cyclin-D1, and matrilysin. In 18 of 20 cases of IPF/UIP investigated on serial sections, nuclear beta-catenin immunoreactivity and abnormal levels of cyclin-D1 and matrilysin were demonstrated in proliferative bronchiolar lesions (basal-cell hyperplasia, squamous metaplasia, bronchiolization, honeycombing). The nature of these lesions was precisely defined using specific markers (DeltaN-p63, surfactant-protein-A, cytokeratin-5). Interestingly, nuclear beta-catenin accumulation was also demonstrated in fibroblast foci in most (16 of 20) IPF/UIP samples, often associated with bronchiolar lesions. Similar features were not observed in normal lung and other fibrosing pulmonary diseases (diffuse alveolar damage, organizing pneumonia, nonspecific interstitial pneumonia, desquamative interstitial pneumonia). Sequence analysis performed on DNA extracted from three samples of IPF/UIP did not reveal abnormalities affecting the beta-catenin gene. On the basis of these findings new models for IPF/UIP pathogenesis can be hypothesized, centered on the aberrant activation of Wnt/beta-catenin signaling, with eventual triggering of divergent epithelial regeneration at bronchiolo-alveolar junctions and epithelial-mesenchymal-transitions, leading to severe and irreversible remodeling of the pulmonary tissue.     

Terminal diffuse alveolar damage in relation to interstitial pneumonias. An autopsy study

Acute exacerbations of idiopathic pulmonary fibrosis/cryptogenic fibrosing alveolitis (IPF/CFA) are rare and typically terminal events, but their relationship to underlying patterns of idiopathic interstitial pneumonias is unknown. We reviewed autopsy material from patients who died of diffuse alveolar damage in the clinical setting of pulmonary fibrosis, both idiopathic and with background fibrosing alveolitis with connective tissue disorders (FA-CTDs), and compared them with cases of acute interstitial pneumonia. Of 15 patients with acute exacerbations of IPF/CFA (n = 12) or FA-CTD (n = 3), 12 had a background pattern of usual interstitial pneumonia and 3 had fibrotic nonspecific interstitial pneumonia. All cases of fibrotic nonspecific interstitial pneumonia were seen in association with FA-CTD. The cause of acute exacerbations is unknown, but our data suggest that toxic effects of oxygen and triggering infection are unlikely causes. In patients with CTDs, it remains uncertain whether the acute exacerbation is related to the fibrosis, the associated CTD, or a combination of these factors. Acute exacerbations of IPF/CFA may be a more common terminal event than previously thought.     

Extracellular superoxide dismutase has a highly specific localization in idiopathic pulmonary fibrosis/usual interstitial pneumonia

Aims : Recent studies suggest the importance of oxidant stress in the progression of pulmonary fibrosis. The aim of this study was to investigate extracellular superoxide dismutase (ECSOD), the major antioxidant enzyme of the extracellular matrix of human lung, in biopsy - proven idiopathic pulmonary fibrosis (IPF) related to usual interstitial pneumonia (UIP).
Methods and results : Fibrotic areas and fibroblastic foci in UIP lungs were notable for absence of ECSOD by immunohistochemistry. Western blotting showed significantly lowered immunoreactivity of ECSOD in fibrotic compared with non-fibrotic areas of the diseased lung. The only cell type that showed intense ECSOD positivity in UIP was the interstitial mast cell. In order to investigate the mechanism for ECSOD depletion in fibrotic areas, alveolar epithelial cells were exposed to tumour necrosis factor-α and transforming growth factor (TGF)-β₁; TGF-β suggested a trend towards decreased synthesis. Patients with UIP were also assessed to determine whether this disease is associated with a naturally occurring mutation in ECSOD (Arg²¹³Gly) which leads to a loss of tissue binding of ECSOD. No significant differences could be found in the allele or genotype frequencies of this polymorphism between 63 UIP patients and 61 control subjects.
Conclusion : Overall, consistent with several other antioxidant enzymes, ECSOD is very low in fibrotic areas of UIP, which may further increase the oxidant burden in this disease.     

Classification of idiopathic interstitial pneumonias: what is new since 2002?

Since the introduction of the 2002 ATS/ERS consensus classification of interstitial lung disease, the body of literature has greatly expanded. As such, an updated classification is in the final review stages at the time of this writing. In addition, the clinical diagnosis of idiopathic pulmonary fibrosis has been refined, incorporating multidisciplinary guidelines. Similarly, the entity of clinically idiopathic non-specific interstitial pneumonia has been better defined. The issue of smoking-related interstitial fibrosis, while in some ways controversial, has also been better established. The aim of this article is to review updates in the major categories of interstitial lung disease since 2002 and discuss the concept of smoking-related interstitial fibrosis.     

Histopathologic findings of transbronchial biopsy in usual interstitial pneumonia

The role of transbronchial biopsy in diagnosis of usual interstitial pneumonia (UIP) is controversial. In this study, we retrospectively reviewed transbronchial biopsy specimens according to the similar criteria of previous studies, and evaluated whether diagnostic findings of UIP could be found in transbronchial biopsies. Thirty two patients with usual interstitial pneumonia, confirmed by surgical lung biopsy, were identified. In three cases (9.4%), there were combinations of interstitial fibrosis and fibroblast foci, and these findings were considered consistent with usual interstitial pneumonia. No patchwork fibrosis or honeycomb change was found. Diagnostic findings of usual interstitial pneumonia were not frequently manifested in transbronchial biopsy specimens in our study (3 out of 32 cases, 9.4%), compared with a previous report (9 out of 22 cases, 41%). In conclusion, it cannot be claimed that transbronchial biopsy is more useful in confirming usual interstitial pneumonia than previously recognized. The primary and main role of transbronchial biopsy in diagnosis of usual interstitial pneumonia is thought not to confirm a diagnosis, but to exclude other infiltrative diseases, such as malignancy, sarcoidosis or infections.     

COX-2 is widely expressed in metaplastic epithelium in pulmonary fibrous disorders

Idiopathic usual interstitial pneumonia/idiopathic pulmonary fibrosis (UIP/IPF) and asbestosis represent progressive and often fatal pulmonary fibrous disorders, whereas cryptogenic organizing pneumonia (COP), desquamative interstitial pneumonia (DIP), and respiratory bronchiolitis-interstitial lung disease (RB-ILD) usually are reversible or nonprogressive conditions. Prostaglandin E2 (PGE2) inhibits fibroblast proliferation and myofibroblast transition, its production depending on cyclooxygenase-2 (COX-2). In patients with UIP/IPF, levels of PGE2 and COX-2 are reduced in fibroblasts, and levels of PGE2 in bronchioalveolar lavage fluid may be lowered. We analyzed the immunohistochemical expression of COX-2 in UIP/IPF, asbestosis, COP, DIP, and RB-ILD. Our results show that the metaplastic epithelium in UIP/IPF, asbestosis, and COP is widely COX-2+, whereas COX-2 positivity is scant in DIP and RB-ILD. The mesenchymal cells remained negative. Our results suggest that irrespective of the underlying disease, lung injury that causes extensive fibrosis induces wide expression of COX-2 in the regenerating metaplastic epithelium.     

Beyond a consensus classification for idiopathic interstitial pneumonias: progress and controversies

Histopathological classification schemes provide the underpinnings for separating idiopathic interstitial pneumonias into clinically meaningful groups. An interdisciplinary classification system based on a combination of evidence and expert opinion was published in 2002 and set the stage for controversy in several areas, including not only nomenclature but also the role of surgical lung biopsy and pathologists in diagnosis. We provide a brief overview of the clinical and histological features of the idiopathic interstitial pneumonias, and focus on selected topics of interest that have emerged in recent years.     

Lymphatic fluctuation in the parenchymal remodeling stage of acute interstitial pneumonia,organizing pneumonia,nonspecific interstitial pneumonia and idiopathic pulmonary fibrosis

Because the superficial lymphatics in the lungs are distributed in the subpleural, interlobular and peribroncovascular interstitium, lymphatic impairment may occur in the lungs of patients with idiopathic interstitial pneumonias (IIPs) and increase their severity. We investigated the distribution of lymphatics in different remodeling stages of IIPs by immunohistochemistry using the D2-40 antibody. Pulmonary tissue was obtained from 69 patients with acute interstitial pneumonia/diffuse alveolar damage (AIP/DAD, N = 24), cryptogenic organizing pneumonia/organizing pneumonia (COP/OP, N = 6), nonspecific interstitial pneumonia (NSIP/NSIP, N = 20), and idiopathic pulmonary fibrosis/usual interstitial pneumonia (IPF/UIP, N = 19). D2-40+ lymphatic in the lesions was quantitatively determined and associated with remodeling stage score. We observed an increase in the D2-40+ percent from DAD (6.66 ± 1.11) to UIP (23.45 ± 5.24, P = 0.008) with the advanced process of remodeling stage of the lesions. Kaplan-Meier survival curves showed a better survival for patients with higher lymphatic D2-40+ expression than 9.3%. Lymphatic impairment occurs in the lungs of IIPs and its severity increases according to remodeling stage. The results suggest that disruption of the superficial lymphatics may impair alveolar clearance, delay organ repair and cause severe disease progress mainly in patients with AIP/DAD. Therefore, lymphatic distribution may serve as a surrogate marker for the identification of patients at greatest risk for death due to IIPs.     

Variations in histological patterns of interstitial pneumonia between connective tissue disorders and their relationship to prognosis

Aims and methods: Pulmonary parenchymal disease is common in patients with connective tissue disorders (CTDs). However, most reports precede recognition of non‐specific interstitial pneumonia (NSIP). We have therefore reviewed 54 lung biopsies from 37 patients with polymyositis/dermatomyositis (PM/DM) (n = 13), Sjögren's syndrome (n = 5), rheumatoid arthritis (n = 17) and systemic lupus erythematosus (SLE) (n = 2) to assess the overall and relative frequencies of patterns of interstitial pneumonia and their impact on prognosis. Results and conclusions: NSIP was the most common pattern with an overall biopsy prevalence of 39% and patient prevalence of 41%. There was variation in prevalence between individual CTDs, with PM/DM commonly showing organizing pneumonia (n = 5), rheumatoid arthritis showing follicular bronchiolitis (n = 6) and Sjögren's syndrome showing chronic bronchiolitis (n = 4). These patterns presented either separately or in association with NSIP, occasionally with different patterns in biopsies from separate lobes. Only four patients showed a pattern of usual interstitial pneumonia (UIP): two with rheumatoid arthritis and one each with PM/DM and SLE. Overall mortality was 24%, the most frequently associated pattern being fibrotic NSIP (n = 5). In nine cases, pulmonary presentation preceded the systemic manifestation of the CTDs. When patients with CTDs present with chronic interstitial lung disease, the most common pattern is NSIP, although there is variation in pattern prevalence between individual disorders and patterns of interstitial pneumonia frequently overlap. These data suggest a different biology for intestitial pneumonias in CTDs when compared with the idiopathic interstitial pneumonias where UIP is the most common pattern. Mortality is similar to that seen in idiopathic NSIP and, coupled with pulmonary presentation occurring prior to the systemic manifestation of disease, this may have a bearing on the origin of some cases of putative idiopathic NSIP.     

BAL in the diagnosis of smoking-related interstitial lung diseases: review of literature and analysis of our experience

The group of interstitial lung diseases (ILDs) is formed by respiratory tract disorders, whose aetiology is unknown in the majority of cases, the clinical course differs and the prognosis is generally serious. Some of the ILDs have a potential relation to tobacco smoking and are known as smoking-related ILDs (sr-ILD). Bronchoalveolar lavage fluid (BALF) examination is one of the initial procedures in the diagnosis of ILD. Despite the fact that histological confirmation is the gold standard in ILD diagnosis in many studies, the number of reported biopsies was low. In this review we present the results of BALF examinations of patients with sr-ILD and discuss their value in the differential diagnosis with other types of ILD. An extremely high total cell count (about 50 x 10(6) cells) with significant predominance of pigmented alveolar macrophages is a characteristic pattern of BALF in sr-ILD. The greatest challenge in BALF cytology interpretation is to distinguish sr-ILD and idiopathic pulmonary fibrosis (IPF). IPF is characterised by an elevated proportion and absolute count of lymphocytes and neutrophils; in addition, BALF lymphocytosis is higher in non-specific interstitial pneumonia than in usual interstitial pneumonia (UIP). The population of alveolar macrophage of patients with sr-ILD differs markedly from the foamy and vacuolated cells that predominate in IPF/UIP. Thus, the absence of pigmented cells rather excludes sr-ILD and indicates other types of ILD. To summarise, the place of BALF in the diagnosis of sr-ILD seems to be established.     

Interstitial lung diseases

Interstitial lung diseases comprise a heterogeneous group of about 200 entities. In the classification of these diseases, diffuse parenchymal lung diseases with known cause, granulomatous diseases, and other specific interstitial lung diseases are separated from the important group of idiopathic interstitial pneumonias, which are classified according to the 2002 ATS/ERS consensus classification. Concerning the histological pattern, this classification differentiates between "usual interstitial pneumonia" (UIP), "nonspecific interstitial pneumonia" (NSIP), "organising pneumonia" (COP), "diffuse alveolar damage" (DAD), "respiratory bronchiolitis" (RB), "desquamative interstitial pneumonia" (DIP), "lymphocytic interstitial pneumonia" (LIP) and "unclassifiable interstitial pneumonias". A key message of this classification is that the pathologist will give the diagnosis of a histological pattern, whereas the final clinicopathologic diagnosis can be made only by the clinical pulmonologist after careful correlation with the clinical and radiologic features, which is essential in the diagnosis of interstitial lung diseases.     

Histopathological classification of idiopathic interstitial pneumonias

The classification scheme of interstitial lung diseases has undergone numerous revisions. The criteria for distinguishing seven distinct subtypes of idiopathic interstitial pneumonias are now well defined by consensus in the recently published ATS/ERS classification of these lung diseases. In our present review the histological patterns of the different types are described and the differential diagnosis of idiopathic interstitial pneumonias is discussed. Surgical lung biopsy remains the gold standard for the diagnosis of interstitial pneumonias, and sampling from at least 2 sites is recommended. Video-assisted thoracoscopic surgical biopsy is the preferred method for obtaining lung tissue as this procedure offers a similar yield as an open thoracotomy The most common histological subtype of chronic interstitial lung disease is the usual interstitial pneumonia [UIP] which makes up 47-71% of cases. The key histologic features include patchy subpleural and paraseptal distribution of remodeling lung architecture with dense fibrosis, frequent honeycombing, and large fibroblastic foci. Temporal and spatial heterogeneity are the hallmarks. Nonspecific interstitial pneumonia [NSIP] occurs primarily in middle-aged women who have never smoked, with more than 5-years survival rate in 80% of patients. The major feature of NSIP is a uniform interstitial thickening of alveolar septa by a fibrosing or cellular process. The cardinal histological feature in respiratory bronchiolitis and desquamative pneumonia is an excess of intraalveolar histiocytes. In both patterns, there is variable interstitial fibrosis and chronic inflammation, and a strong association with a history of smoking. Organizing pneumonia (idiopathic bronchiolitis obliterans-organizing pneumonia [BOOP]) is not strictly an interstitial process, because the alveoli and bronchioles are filled by intraluminal polyps of fibroblastic tissue and the expansion of the interstitium is mild. Lymphocytic interstitial pneumonia [LIP] is currently viewed as a pattern of diffuse reactive pulmonary hyperplasia associated in most cases with EB virus, immunosuppression, or a connective tissue disorder. Malignant transformation may rarely occur. A dense mixed interstitial lymphoid infiltrate is a typical histological finding. Diffuse alveolar damage [DAD] from unknown causes is termed acute interstitial pneumonia [AIP], and is synonymous with cases of Hamman-Rich disease. Hyaline membranes in the exsudative phase and marked expansion of the interstitium later are present.