Eur Radiol (2002) 12:1486–1496 DOI 10.1007/s00330-001-1211-3
Anastasia Oikonomou David M. Hansell
Received: 18 July 2001 / Accepted: 25 September 2001 / Published online: 13 November 2001 © Springer-Verlag 2001
A. Oikonomou · D.M. Hansell (✉) Department of Radiology, Royal Brompton Hospital, Sydney Street, London SW3 6NP, England e-mail:
[email protected] Tel.: +44-20-73518034 Fax: +44-20-73518098
CHEST
Organizing pneumonia: the many morphological faces
Abstract Organizing pneumonia is a non-specific response to various forms of lung injury and is the pathological hallmark of the distinct clinical entity termed cryptogenic organizing pneumonia. The typical imaging features of this syndrome have been widely documented and consist of patchy air-space consolidation, often subpleural, with or without ground-glass opacities. The purpose of this article is to highlight
Introduction Organizing pneumonia is one of the main reparative reactions to acute injury by the lung and reflects the incomplete resolution of inflammation within the alveoli, and to a lesser extent the distal bronchioles [1, 2, 3]. Although this pathological pattern is non-specific, given that it can be incited by many different types of “injury”, it is the particular hallmark of a more or less distinct clinicopathological syndrome which has been given the name cryptogenic organizing pneumonia (COP) [4]. Since the first description of COP in 1983 by Davison et al. [5], and the later report on bronchiolitis obliterans organizing pneumonia (BOOP) by Epler et al. [6], much has been written about the terminology. There have also been numerous reports about the typical radiographic findings that characterize this entity. The purpose of this article is to highlight the variable and sometimes idiosyncratic imaging appearances of organizing pneumonia.
Terminology The competing terms, i.e. COP vs BOOP, have generated much discussion over the years. “BOOP” was first
the less familiar imaging patterns of organizing pneumonia which include focal organizing pneumonia, a variety of nodular patterns, a bronchocentric distribution, band-like opacities, a perilobular pattern and a progressive fibrotic form of organizing pneumonia. Keywords Organizing pneumonia · Computed tomography · Patterns
coined as a term by Epler et al. [6] to emphasise to the pathological distribution of the pneumonic process in both alveoli and terminal bronchioles; however, the use of bronchiolitis obliterans in this term was a major source of confusion because of the semantic similarity that “BOOP” shared with bronchiolitis obliterans (obliterative bronchiolitis) which is a completely different entity [2, 3, 4, 7, 8]: obliterative bronchiolitis is an obstructive small airways disease with poor response to treatment, without intraluminal exudate, in which bronchioles are cicatrized and replaced by scanty fibrotic remnants. BOOP, on the other hand, is predominantly an air-space process in which terminal bronchioles may be filled with granulation tissue; but the airways are not obliterated in the true sense of the word. The cardinal component of “BOOP” is the organizing pneumonia, and this is reflected by a restrictive, not obstructive, functional deficit [3, 4, 8, 9, 10]. To overcome this confusion “COP” has been suggested as the preferred term for the clinicopathological syndrome as it conveys the essential features of the entity [2, 3, 4, 9, 10]. Although it seems likely that some authors will persist with the usage of BOOP, a working group sponsored by the American Thoracic Society and the European Respiratory Society has abandoned the term BOOP alto-
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Table 1 Causes of organizing pneumonia and associations with other conditions Infection Bacterial – Streptococcus pneumonia [15] – Legionella pneumophila [16] – Mycoplasma pneumonia [17] – Coxiella burnetti [18] – Nocardia asteroides [19] – Chlamydia pneumonia [20] Viral – Adenovirus [21] – Cytomegalovirus [14] – Influenza [22] and parainfluenza [3, 23] – Human immunodeficiency virus [24] Fig. 1 An open-lung biopsy specimen showing polypoidal masses of organized granulation tissue (Masson bodies) within the alveoli. The intervening alveolar walls show mild thickening by an inflammatory infiltrate, but the lung architecture is otherwise preserved. There are no features of established fibrosis. (Courtesy of A.G. Nicholson)
gether and has put its authority behind the terms organizing pneumonia and COP to describe the pathological and clinical entities, respectively [11].
Histology Histologically, organizing pneumonia is characterized by the presence of buds of granulation tissue in the distal air spaces comprising fibrin exudates and collagencontaining fibroblasts. The fibroblasts are embedded in a myxoid matrix with a variable infiltrate of lymphocytes, macrophages, plasma cells, neutrophils and eosinophils forming characteristic elongated polypoidal masses (Masson bodies or bourgeons conjonctifs; Fig. 1); these are located predominantly in the alveolar spaces but often extend into bronchiolar lumens. The buds of connective tissue frequently extend directly from one alveolus to the next, through the pores of Kohn, producing a characteristic “butterfly” pattern. There is no disturbance of the lung architecture. Other histological features include chronic inflammation in the walls of the surrounding alveoli with minor infiltration of the interstitium by mononuclear cells [1, 4, 6, 9, 10]. In a few cases the inflammatory infiltrate is more intense with the incorporation of fibrosis in the alveolar walls [2, 10, 12].
Association of OP with other conditions It is worth emphasizing that there can be overlap between organizing pneumonia and other pneumonic entities such as chronic eosinophilic pneumonia and extrinsic allergic alveolitis. In these conditions the presence of clusters of eosinophils or occasional granulomas, in what
Drugs Antibiotics – Amphotericin B [14] – Cephalosporins [25] – Minocycline [26] – Nitrofurantoin [27] Others – Sulfasalazine [28] – Bleomycin [29] – Amiodarone [30] – Acebutolol [31] – Busulfan [32] – Barbiturates [33] – Paraquat [34] – Cocaine [35] – Gold [36] – Phenytoin [37] Connective tissue disorders – Systemic lupus erythematosus [38] – Rheumatoid arthritis [39] – Sjogren syndrome [40] – Polymyositis [40] – Dermatomyositis [41] – Polymyalgia rheumatica [42] Immunological disorders – Common variable immunodeficiency syndrome [43] – Essential mixed cryoglobulinaemia [44] Organ transplantation – Bone marrow [45] – Lung [46] – Renal [47] Miscellaneous – Inflammatory bowel disease [48] – Primary biliary cirrhosis [49] – Polyarteritis nodosa [50] – Haematological malignancies – Myelodysplastic syndrome [51] – T-cell leukaemia [52] – Lymphoma [53] – Seasonal syndrome with cholestasis [54] – Radiotherapy [55, 56] – Environmental exposure (textile printing dye) [57] – Penicillium mould dust [58]
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would otherwise be regarded as organizing pneumonia, suggest the diagnosis of eosinophilic pneumonia or extrinsic allergic alveolitis, respectively [12]. Similarly, diffuse alveolar damage in the organizing phase is similar to OP in that there is extensive cellular fibroblastic proliferation associated with a myxoid-appearing matrix. Diffuse alveolar damage differs in that the changes tend to be more diffuse and uniform, with the characteristic formation of hyaline membranes [9]. An organizing pneumonia-like reaction can also be a major histological feature in Wegener’s or bronchocentric granulomatosis and other inflammatory lesions including lung abscesses, pulmonary infarcts and lung cancer [12, 13, 14]. Indeed, a component of organizing pneumonia is identifiable in a huge variety of different contexts, including resolving infection, as a drug reaction, in association with connective tissue disorders, and many other conditions. A sample of the many causes and association of organizing pneumonia are given in Table 1.
Fig. 2 A 58-year-old woman from Kuwait with a 6-month history of lethargy, night sweats and increasing breathlessness on exertion. A standard CT shows the typical CT features of cryptogenic organizing pneumonia. There are several basal and peripheral areas of air-space consolidation. A lung biopsy confirmed the diagnosis of organizing pneumonia
Classical COP: clinical and imaging presentation The “typical” COP syndrome is characterized by an indolent onset of a flu-like illness accompanied with fever, non-productive cough, malaise, anorexia and weight loss. Dyspnoea is common but usually mild and evident only on exertion. Less common symptoms are bronchorrhoea, haemoptysis (but severe haemoptysis is exceedingly rare), chest pain, arthralgia and night sweats. It affects men and women equally and occurs in middleaged adults with a peak incidence in the sixth decade. No cause has been identified, although there is the suspicion that infection, viral or otherwise, may be the trigger in some cases; in particular, COP is not related to smoking. The mean duration of symptoms at presentation varies, but in most cases it is less than 3 months. Patients are often prescribed antibiotics (without obvious effect) in the belief that the clinical picture is of a communityacquired pneumonia. Pulmonary function tests show a mild to moderate restrictive defect and the total gas transfer (Dlco) is reduced, although the Kco (gas transfer adjusted for alveolar volume) is preserved. Arterial hypoxaemia is occasionally severe and probably reflects right-to-left shunting through consolidated lung. Airflow obstruction is not a feature [4, 5, 6, 10, 59, 60]. The imaging in classical COP has been thoroughly described [4, 5, 6, 10, 59, 61, 62, 63, 64, 65, 66, 67, 68]. The most usual radiographic appearance is of bilateral patchy areas of air-space consolidation with a tendency to progress and change location over time. Spontaneous regression of some focal areas of consolidation is a striking feature. The CT findings mirror the radiographic appearances, but there is often associated ground-glass opacification, and the distribution of disease is predominantly peripheral and lower zone (Fig. 2). An air bron-
chogram and bronchial dilatation may be present in consolidated areas. Response to corticosteroid treatment is prompt in most cases and relapse does not occur if sufficient therapy is given. Serial radiographic and clinical features are regarded as sufficiently characteristic in some cases, as to obviate the need for biopsy confirmation. Nevertheless, there is increasing awareness that imaging patterns of OP may deviate from this typical picture. What follows is a description of the less commonly encountered and atypical CT manifestations of organizing pneumonia.
CT variants of organizing pneumonia Focal lesion Focal organizing pneumonia can closely resemble lung cancer on a chest radiograph and the exclusion of malignancy cannot be made on the basis of the radiographic appearances alone. In most cases resection or biopsy is mandatory. In a study by Cordier et al., COP was stratified into one of three clinical profiles with “focal COP” being one of them (Fig. 3) [69]. This category accounted for one-third of the study group and is noteworthy that the location in 4 of 5 patients was in the upper lobes, the commonest site for lung cancer. The patient’s symptoms may also suggest the diagnosis of lung cancer as focal organizing pneumonia may present with haemoptysis [70, 71, 72]. Occasional cavitation of focal organizing pneumonia raises the question of whether such lesions are in fact sterile post-infective or post-infarctive abscesses. The CT characteristics of 18 cases of focal solitary OP were eval-
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Focal OP can also present as multiple mass-like opacities (Fig. 4) [74, 75, 76]. This was the most frequent finding in one study in which the majority of cases were peripherally located and demonstrated a pulmonary vessel leading to a nodular opacity or a small bronchus entering the centre of the nodular opacity [77]. In a series of Akira et al., in which COP manifested as focal multiple large nodules or masses, the most prominent feature was the irregular and spiculated margin [78]. It is noteworthy that bleomycin-induced lung organizing pneumonia can present as pseudometastatic pulmonary nodules, occasionally with cavitation [29].
Fig. 3a, b Two examples of focal organizing pneumonia. a The mass-like lesion in the lingula was thought, at radiographic presentation, to represent a lung cancer. Note ground-glass opacity in the contralateral right lower lobe. b Patient with ulcerative colitis and focal cavitating lesion in the right upper lobe, shown to be a focus of organizing pneumonia on surgical resection Fig. 4 A 59-year-old man with ulcerative colitis and insulin-dependent diabetes mellitus. The CT shows multiple focal mass-like lesions, some of which contain an air bronchogram. On biopsy these lesions proved to be areas of organizing pneumonia
uated and a trend towards location of the lesion in the lung periphery (outer third of the lung parenchyma) was reported [73]. Helpful, but not definitive, differentiating CT features from lung cancer include: 1. Location of the lesion in contact with the pleura (i.e. relatively broad pleural-based lesion) or along the bronchovascular bundle with some contraction and convergence of vessels 2. The presence of flat, oval or trapezoidal-shaped masses instead of a rounded lesion 3. The presence of satellite lesions [73]
Nodular pattern Organizing pneumonia can present as one of two nodular patterns: 1. A well-defined “acinar” pattern with nodules of approximately 8 mm in diameter (Fig. 5) 2. A more subtle poorly defined (micro)nodular pattern (Fig. 6). In two early CT series describing COP, nodules were reported to be one of the more prevalent features. In Müller et al.’s study, well-defined nodules of up to 5 mm diameter and situated predominantly along the bronchovascular bundles were described [65]. The authors also noted the presence of nodules up to 10 mm in diameter (“acinar” nodules). Pathological correlation showed that these represented focal areas of organizing pneumonia around plugged bronchioles. This type of lesion was separated from others by a zone of relatively normal aerated lung, which explained the nodular appearance. In the study by Lee et al., nodules were present in one-third of patients [66]. They were the sole finding in 9% of pa-
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Fig. 5 A CT of the right upper lobe of a patient with a 10-day history of dyspnoea and suspected community acquired pneumonia. Combined pattern of peripheral “acinar” nodules and smaller nodules, some of which resemble a tree-in-bud pattern. Biopsy-proven organizing pneumonia. (Courtesy of S. Diederich, Muenster)
tients and part of a mixed pattern in the remaining cases. Most of the nodules had well-defined margins and were randomly distributed. Nishimura and Itoh reported a nodular pattern (nodules of approximately 1 cm in diameter) superimposed on an overall increase in lung density or ground-glass opacification [67]. In a recent study the presence of parenchymal nodules with ill-defined margins and a predominantly peripheral distribution was the most important discriminating CT feature between organizing pneumonia and chronic eosinophilic pneumonia [79]. A micronodular pattern (nodules ≤4 mm) in which the micronodules are poorly defined and of relatively low attenuation is an uncommon CT appearance of organizing pneumonia (Fig. 6) [64, 80] and is more frequently encountered in subacute extrinisic allergic alveolitis. In a study of the CT and histopathological characteristics of bronchiolar diseases, the authors mention that in occasional cases of organizing pneumonia the CT appearances resemble an infectious bronchiolitis with a tree-in-bud pattern [81]. Cordier describes in a recent review article, a distinct bronchiolocentric distribution in which organizing pneumonia is limited to the alveoli immediately adjacent to the involved bronchioles, thus giving a miliary pattern [4]. Although organizing pneumonia is not mentioned as a differential diagnosis in a survey of cases characterized by tree-in-bud appearance [82], it is reasonable to assume that in order to have any kind of “nodular” pattern the affected bronchioles and adjacent alveoli occupied by OP must be surrounded by normally aerated parenchyma.
Fig. 6 a A 23-year-old bodybuilder gradually became severely dyspnoeic and ultimately required mechanical ventilation. The diagnosis of organizing pneumonia was confirmed on lung biopsy and he responded slowly to prolonged treatment with steroids (no specific cause was found). On CT there is a micronodular pattern characterized by small ill-defined centrilobular nodules of less than 5 mm. b Lung biopsy specimen showing discrete small foci of organizing pneumonia, surrounded by normal aerated lung
Bronchocentric pattern The bronchocentric pattern was first identified in the first two CT series by Müller et al. [65] and Lee et al. [66] (Figs. 7, 8). In Müller et al.’s study one-third of patients showed a combination of subpleural and peribronchovascular consolidation [65]. In Lee et al.’s study, approximately one-third of cases also had a predominantly peribronchovascular pattern [66]. There have been subsequent reports about pulmonary disease associated with polymyositis and dermatomyositis that have emphasized the association with predominantly bronchocentric organizing pneumonia. In a study of patients with poly- or dermatomyositis the consolidation on CT had a predominantly peribronchovascular distribution which corresponded pathologically to OP [83]. The authors concluded that although air-space consolidation is a nonspecific finding, in the context of
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Linear and band-like pattern
Fig. 7 Bronchocentric pattern of organizing pneumonia: areas of consolidation surround the bronchovascular bundles in a patient admitted to intensive care
A linear or band-like pattern of OP is unusual and striking and has been described in isolation or in combination with other patterns. It is seen on CT as lines or bands longer than 2 cm, smooth or irregular sometimes forming arcades and/or containing air bronchograms. These lines or bands are usually at least 8 mm in width (Fig. 9) [85]. Murphy et al. reported two distinct types of linear opacity [86]: (a) those extending in a radial manner along the line of the bronchi towards the pleura, usually intimately related to bronchi; and (b) those occurring in a peripheral location bearing no relationship to the bronchi [86] These linear opacities are usually associated with multifocal areas of consolidation, but in 2 of 11 patients they were the sole HRCT abnormality. Organizing pneumonia may present on CT with extraordinary crescentic and ring-shaped opacities surrounding areas of groundglass opacification (Fig. 10) [87]. These features may be accompanied by a more typical nodular or a consolidation pattern. The CT pathological correlation has shown that the central areas of ground-glass opacification in CT reflect alveolar septal inflammation and cellular debris. In an HRCT study of patients with polymyositis or dermatomyositis, subpleural band-like opacities have been described which lie in the lung periphery parallel to the chest wall [83]. This may be regarded as bronchocentric distribution of organizing pneumonia around adjacent subpleural bronchi that gives the impression of a band as bronchi are “joined” together by intervening organizing pneumonia (Fig. 11). Perilobular pattern
Fig. 8 Bronchocentric pattern of organizing pneumonia: a strikingly peribronchovascular distribution in a diabetic patient with biopsy proven organizing pneumonia. (Courtesy of A. Vathi, Bolatti, Milan)
known polymyositis/dermatomyositis, dense bronchocentric opacification on CT is likely to represent organizing pneumonia. In a study that assessed the diagnostic accuracy of thin-section CT in patients with idiopathic interstitial pneumonias, although a peripheral distribution was found in the majority of OP cases, 17% had a predominantly peribronchovascular pattern [80]. Furthermore, a bronchocentric location of air-space and ground-glass consolidation was found to be a more frequent feature in organizing pneumonia when compared with chronic eosinophilic pneumonia [79].
A “perilobular” distribution was a term first coined by Murata et al. in their description of the localization of parenchymal disease at the level of the secondary pulmonary lobule [88]. They reserved this term for lesions that mainly involved the structures bordering the lobule, notably the interlobular septa and the pleura. In a more recent study the authors added in the definition of the perilobular region the peribronchovascular interstitium of the larger bronchi and accompanying pulmonary arteries which are too large to be located within the centre of the secondary lobules and therefore are located in the periphery of the lobule [89]. In this context, interstitial and air-space disease involving these perilobular (paraseptal) alveoli may mimic abnormalities of the interlobular septa on HRCT. Accumulation of organizing exudate (i.e. organizing pneumonia) or the infiltration of the alveolar walls, even if they are not associated with thickening of the interlobular septa histologically, may be seen as “apparent” septal thickening contributing to a coarse reticular pattern on HRCT. In terms of anatomical distribution there is some congruence between the perilobular pattern
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Fig. 9 A 41-year-old man developed cryptogenic organizing pneumonia concurrent with an episode of pericarditis. On CT there are bilateral band-like opacities, both of which contain an air-bronchogram. Biopsy of one of these lesions confirmed organizing pneumonia Fig. 10a, b A CT scan of a 14-year-old boy not responding to treatment for suspected tuberculosis (later excluded). A striking pattern of ring-like opacities surrounding areas of ground-glass opacification is seen in the a upper and b lower lobes. Open-lung biopsy revealed organizing pneumonia Fig. 11 A bronchocentric distribution of organizing pneumonia around adjacent bronchi resembling a band as bronchi are “joined together” by the intervening organizing pneumonia
and the grosser distribution of “typical” OP: a subpleural distribution is the dominant feature in COP and, at a much smaller or microscopic level, a perilobular disposition of OP can also be regarded as “subpleural” (Fig. 12). One of the secondary changes that accompanies OP is a mild inflammatory infiltrate [9] which probably contributes to the perilobular disease. It can be speculated that this pattern of OP is responsible for the reported resolution of an apparently irreversible (fibrot-
Fig. 12 A perilobular pattern of organizing pneumonia. There is opacification around the periphery of individual secondary lobules resembling poorly defined thickened interlobular septa
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ic) pattern in nitrofurantoin-induced lung disease, in which there is an OP-like reaction [27, 90]. In some CT studies of OP, thickening of the interlobular septa is described and is usually associated with areas of consolidation or near nodules and masses [65, 78, 86, 91]; however, it remains uncertain how often this is “real” thickening of the interlobular septa, as opposed to “apparent” thickening caused by perilobular disease, as described above. Progressive fibrotic pattern A less distinct pattern (unlike the previous relatively well-defined morphological patterns) encompasses those cases of “aggressive” OP in which there is supervening irreversible fibrosis. This pattern, if it can be called that, was initially described as a separate clinical–radiologic profile of COP having an overlap with usual interstitial pneumonia and consequently a worse prognosis than typical COP [69]. In a recent study, 10 patients with an initial histological diagnosis of OP had a fulminant course leading to death. Post-mortem examination revealed OP associated with alveolar septal inflammation, established fibrosis and honeycombing [92]. The authors suggested that OP can, on occasion, be the precursor of interstitial fibrosis and end-stage honeycomb lung. One of the main objectives of the defining series by Epler et al. was the differentiation between UIP and OP, particularly given the much better prognosis of OP [6]. As background to this apparent overlap, it may be useful to consider the following histopathological concepts [93, 94, 95, 96, 97, 98, 99]. Alveolar epithelial damage is an early event in both UIP and OP. In OP the necrosis of bronchiolar and alveolar epithelium is followed by migration of fibroblasts from the interstitial compartment into the airways and air-spaces through gaps in the damaged basal membrane; organization begins with the formation of fibro-inflammatory buds with deposition of a loose connective tissue matrix (intraluminal organization) [4, 9, 10]. The alveolar architecture is remarkably preserved and there is a variable inflammatory cellular infiltration of the interstitium. On the other hand, when organization is predominantly interstitial the epithelial basal lamina is disrupted and fibrosis is incorporated within the alveolar interstitium [61, 93]. In UIP small fibroblastic foci are usually restricted to interstitium, and intraluminal fibrosis is much less extensive than in OP [9]. After a seemingly similar initial alveolar injury, it is not clear what determines whether organization will proceed intraluminally (OP) or in the interstitium (UIP) [61, 93, 94, 95]. One determinant may be that significant fibroblastic proliferation occurs where the continuity of basal lamina is disrupted [96, 97], whereas the integrity of the lung parenchyma can be restored after injury if basal lamina remains relatively intact [98, 99].
Fig. 13a, b A 36-year-old woman presented with the presumptive diagnosis of bronchopneumonia, with minor improvement on antibiotics; however, exertional dyspnoea and a restrictive ventilatory defect remained. a The initial CT showed patchy areas of consolidation concentrated in the lower lobes, but no obvious features established interstitial fibrosis. b The same patient 15 months later after prolonged steroid treatment. The areas of consolidation had largely resolved, but an extensive coarse reticular pattern, indicating supervening fibrosis, had developed
The radiographic pattern of organizing pneumonia admixed with interstitial fibrosis probably first appeared in the literature in 1973 when Gosink et al. [100] reported five patients with organizing pneumonia and linear/ reticular opacities on chest radiography; however, it was not until 1989 that Cordier et al. formally suggested a separate group, characterized by more interstitial involvement [69]. On CT a bibasal reticular pattern may be superimposed on a background of areas of frank consolidation or acinar nodules (Fig. 13) [10]. It is the relative paucity of consolidation and ground-glass opacification together with the predominance of reticular elements with architectural distortion that distinguishes this pattern from typical or “simple” OP. Other features of interstitial fibrosis, including traction bronchiectasis, honeycombing, with or without patchy areas of ground glass, may all be seen on CT in this “overlap” entity. This pattern is most frequently encountered in organizing pneu-
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monia associated with connective tissue diseases, particularly polymyositis/dermatomyositis, and has a poorer prognosis [84].
Conclusion In the 20 years since cryptogenic organizing pneumonia was first described, the terminology and pathological
concepts surrounding this entity have been clarified. The basic imaging pattern of changing multifocal air-space consolidation that characterizes cryptogenic organizing pneumonia is widely recognized but the increasing number of reported variant morphologies of organizing pneumonia, shown to advantage on CT, need to be borne in mind if the diagnosis is not to be overlooked.
References 1. Colby TV (1998) Bronchiolitis. Pathologic considerations. Am J Clin Pathol 109:101–109 2. Geddes DM (1991) BOOP and COP. Thorax 46:545–547 3. Hansell DM (1992) What are bronchiolitis obliterans organizing pneumonia (BOOP) and cryptogenic organizing pneumonia (COP)? Clin Radiol 45:369–370 4. Cordier JF (2000) Organizing pneumonia. Thorax 55:318–328 5. Davison AG, Heard BE, McAllister WA, Turner-Warwick ME (1983) Cryptogenic organizing pneumonitis. Q J Med 52:382–394 6. Epler GR, Colby TV, McLoud TC, Carrington CB, Gaensler EA (1985) Bronchiolitis obliterans organizing pneumonia. N Engl J Med 17:152–158 7. Du Bois RM, Geddes DM (1991) Obliterative bronchiolitis, cryptogenic organizing pneumonitis and bronchiolitis obliterans organizing pneumonia: three names for two different conditions. Eur Respir J 4:774–775 8. Woodhead MA, du Bois RM (1991) Bronchiolitis obliterans, cryptogenic organizing pneumonitis and BOOP. Respir Med 85:177–178 9. Myers JL, Colby TV (1993) Pathologic manifestations of bronchiolitis, constrictive bronchiolitis, cryptogenic organizing pneumonia, and diffuse panbronchiolitis. Clin Chest Med 14:611–622 10. Cordier JF (1993) Cryptogenic organizing pneumonitis. Bronchiolitis obliterans organizing pneumonia. Clin Chest Med 14:677–692 11. Travis WD, King TE, Bateman ED, Lynch DA, Capron F, Center D, Colby TV, Cordier JF, DuBois RM, Galvin J, Grenier P, Hansell DM, Hunninghake G, Kitaichi M, Myers JL, Muller NL, Nagai S, Nicholson A, Raghu G, Wallaert B ATS/ERS International consensus classification of idiopathic interstitial pneumonias (in preparation) 12. Colby TV (1992) Pathologic aspects of bronchiolitis obliterans organizing pneumonia. Chest 102 (Suppl 1):38–43
13. Uner AH, Rozum-Slota B, Katzenstein AL (1996) Bronchiolitis obliteransorganizing pneumonia (BOOP)-like variant of Wegener’s granulomatosis. A clinicopathologic study of 16 cases. Am J Surg Pathol 20:794–801 14. Epler GR (2001) Bronchiolitis obliterans organizing pneumonia. Arch Intern Med 22:158–164 15. Floyd R (1922) Organization of pneumonic exudates. Am J Med Sci 163:527–548 16. Chastre J, Raghu G, Soler P, Brun P, Basset F, Gibert C (1987) Pulmonary fibrosis following pneumonia due to acute Legionnaires’ disease. Clinical, ultrastructural, and immunofluorescent study. Chest 91:57–62 17. Prabhu MB, Barber D, Cockcroft DW (1991) Bronchiolitis obliterans and Mycoplasma pneumonia. Respir Med 85:535–537 18. Seggev JS, Levin S, Schey G (1986) Unusual radiological manifestations of Q fever. Eur Respir Dis 69:120–122 19. Camp M, Mehta JB, Whitson M (1987) Bronchiolitis obliterans and Nocardia asteroides infection of the lung. Chest 92:1107–1108 20. Diehl JL, Gisselbrecht M, Meyer G, Israel-Biet D, Sors H (1996) Bronchiolitis obliterans organizing pneumonia associated with chlamydial infection. Eur Respir J 9:1320–1322 21. Jeon JS, Yi HA, Ki SY, Jeong SW, Uh ST, Jin SY, Park JS, Choi DL, Kang CH, Kim JS, Park CS (1997) A case of bronchiolitis obliterans organizing pneumonia associated with adenovirus. Korean J Intern Med 12:70–74 22. Winterbauer RH, Ludwig WR, Hammar SP (1977) Clinical course, management, and long-term sequelae of respiratory failure due to influenza viral pneumonia. Johns Hopkins Med J 141:148–155 23. Peramaki E, Salmi I, Kava T, Romppanen T, Hakkarainen T (1991) Unilateral bronchiolitis obliterans organizing pneumonia and bronchoalveolar lavage neutrophilia in a patient with parainfluenza 3 virus infection. Respir Med 85:159–161
24. Allen JN, Wewers MD (1989) HIV-associated bronchiolitis obliterans organizing pneumonia. Chest 96:197–198 25. Dreis DF, Winterbauer RH, Van Norman GA, Sullivan SL, Hammar SP (1984) Cephalosporin-induced interstitial pneumonitis. Chest 86:138–140 26. Piperno D, Donne C, Loire R, Cordier JF (1995) Bronchiolitis obliterans organizing pneumonia associated with minocycline therapy: a possible cause. Eur Respir J 8:1018–1020 27. Cameron RJ, Kolbe J, Wilsher ML, Lambie N (2000) Bronchiolitis obliterans organizing pneumonia associated with the use of nitrofurantoin. J Comput Assist Tomogr 24:259–261 28. Williams T, Eidus L, Thomas P (1998) Fibrosing alveolitis, bronchiolitis obliterans, and sulfasalazine therapy. Chest 81:766–768 29. Cohen MB, Austin JH, Smith-Vaniz A, Lutzky J, Grimes MM (1989) Nodular bleomycin toxicity. Am J Clin Pathol 92:101–104 30. Conte SC, Pagan V, Murer B (1997) Bronchiolitis obliterans organizing pneumonia secondary to amiodarone: clinical, radiological and histological pattern. Monaldi Arch Chest Dis 52:24–26 31. Camus P, Lombard JN, Perrichon M, Piard F, Guerin JC, Thivolet FB, Jeannin L (1989) Bronchiolitis obliterans organizing pneumonia in patients taking acebutolol or amiodarone. Thorax 44:711–715 32. Heard BE, Cooke RA (1968) Busulfan lung. Thorax 23:187–193 33. Bense L, Wiman LG, Steiner E, Hjerpe A (1986) Pulmonary side effects after treatment with barbiturates. Eur J Respir Dis 69:61–62 34. Copland GM, Kolin A, Shulman HS (1974) Fatal pulmonary intra-alveolar fibrosis after paraquat ingestion. N Engl J Med 8:290–292 35. Patel RC, Dutta D, Schonfeld SA (1987) Free-base cocaine use associated with bronchiolitis obliterans organizing pneumonia. Ann Intern Med 107:186–187
1495
36. Morley TF, Komansky HJ, Adelizzi RA, Giudice JC (1984) Pulmonary gold toxicity. Eur J Respir Dis 65:627–632 37. Angle P, Thomas P, Chiu B, Freedman J (1997) Bronchiolitis obliterans with organizing pneumonia and cold agglutinin disease associated with phenytoin hypersensitivity syndrome. Chest 112:1697–1699 38. Gammon RB, Bridges TA, al-Nezir H, Alexander CB, Kennedy JI Jr (1992) Bronchiolitis obliterans organizing pneumonia associated with systemic lupus erythematosus. Chest 102:1171–1174 39. Ippolito JA, Palmer L, Spector S, Kane PB, Gorevic PD (1993) Bronchiolitis obliterans organizing pneumonia and rheumatoid arthritis. Semin Arthritis Rheum 23:70–78 40. Imasaki T, Yoshii A, Tanaka S, Ogura T, Ishikawa A, Takahashi T (1996) Polymyositis and Sjogren’s syndrome associated with bronchiolitis obliterans organizing pneumonia. Intern Med 35:231–235 41. Knoell KA, Hook M, Grice DP, Hendrix JD Jr (1999) Dermatomyositis associated with bronchiolitis obliterans organizing pneumonia (BOOP). J Am Acad Dermatol 40:328–330 42. Stey C, Truninger K, Marti D, Vogt P, Medici TC (1999) Bronchiolitis obliterans organizing pneumonia associated with polymyalgia rheumatica. Eur Respir J 13:926–929 43. Kaufman J, Komorowski R (1991) Bronchiolitis obliterans organizing pneumonia in common variable immunodeficiency syndrome. Chest 100:552–553 44. Zackrison LH, Katz P (1993) Bronchiolitis obliterans organizing pneumonia associated with essential mixed cryoglobulinaemia. Arthritis Rheum 36:1627–1630 45. Kanda Y, Takahashi T, Imai Y, Miyagawa K, Ohishi N, Oka T, Chiba S, Hirai H, Yazaki Y (1997) Bronchiolitis obliterans organizing pneumonia after syngeneic bone marrow transplantation for acute lymphoblastic leukemia. Bone Marrow Transplant 19:1251–1253 46. Chaparro C, Chamberlain D, Maurer J, Winton T, Dehoyos A, Kesten S (1996) Bronchiolitis obliterans organizing pneumonia (BOOP) in lung transplant recipients. Chest 110:1150–1154 47. Verberckmoes R, Verbeken E, Verschakelen J, Vanrenterghem Y (1996) BOOP (bronchiolitis obliterans organizing pneumonia) after renal transplantation. Nephrol Dial Transplant 11:1862–1863
48. Camus P, Piard F, Ashcroft T, Gal AA, Colby TV (1993) The lung in inflammatory bowel disease. Medicine (Baltimore) 72:151–183 49. Strobel ES, Bonnet RB, Werner P, Schaefer HE, Peter HH (1998) Bronchiolitis obliterans organizing pneumonia and primary biliary cirrhosis-like lung involvement in a patient with primary biliary cirrhosis. Clin Rheumatol 17:246–249 50. Robinson BW, Sterrett G (1992) Bronchiolitis obliterans associated with polyarteritis nodosa. Chest 102:309–311 51. Tenholder MF, Becker GL, Cervoni MI (1990) The myelodysplastic syndrome and bronchiolitis obliterans. Ann Intern Med 1:714–715 52. Vaiman E, Odeh M, Attias D, Ben-Arie Y, Oliven A (1999) T-cell chronic lymphocytic leukaemia with pulmonary involvement and relapsing BOOP. Eur Respir J 14:471–474 53. Safadi R, Berkman N, Haviv YS, Ben-Yehuda A, Amir G, Naparstek Y (1997) Primary non-Hodgkin’s lymphoma of the lung presenting as bronchiolitis obliterans organizing pneumonia. Leuk Lymphoma 28:209–213 54. Spiteri MA, Klenerman P, Sheppard MN, Padley S, Clark TJ, NewmanTaylor A (1992) Seasonal cryptogenic organizing pneumonia with biochemical cholestasis: a new clinical entity. Lancet 1:281–284 55. Crestani B, Valeyre D, Roden S, Wallaert B, Dalphin JC, Cordier JF (1998) Bronchiolitis obliterans organizing pneumonia syndrome primed by radiation therapy to the breast. Am J Respir Crit Care Med 158:1929–1935 56. Arbetter KR, Prakash UB, Tazelaar HD, Douglas WW (1999) Radiationinduced pneumonitis in the “nonirradiated” lung. Mayo Clin Proc 74:27–36 57. Camus P, Nemery B (1998) A novel cause for bronchiolitis obliterans organizing pneumonia: exposure to paint aerosols in textile workshops. Eur Respir J 11:259–262 58. Bates C, Read RC, Morice AH (1997) A malicious mould. Lancet 31:1598 59. Epler GR (1992) Bronchiolitis obliterans organizing pneumonia: definition and clinical features. Chest 102 (Suppl 1):2–6 60. Epler GR (1998) Heterogeneity of bronchiolitis obliterans organizing pneumonia. Curr Opin Pulm Med 4:93–97 61. Guerry-Force ML, Müller NL, Wright JL, Wiggs B, Coppin C, Pare PD, Hogg JC (1987) A comparison of bronchiolitis obliterans with organizing pneumonia, usual interstitial pneumonia, and small airways disease. Am Rev Respir Dis 135:705–712
62. Müller NL, Guerry-Force ML, Staples CA, Wright JL, Wiggs B, Coppin C, Pare P, Hogg JC (1987) Differential diagnosis of bronchiolitis obliterans with organizing pneumonia and usual interstitial pneumonia: clinical, functional, and radiologic findings. Radiology 162:151–156 63. Chandler PW, Shin MS, Friedman SE, Myers JL, Katzenstein AL (1986) Radiographic manifestations of bronchiolitis obliterans with organizing pneumonia vs usual interstitial pneumonia. Am J Roentgenol 147:899–906 64. Haddock JA, Hansell DM (1992) The radiology and terminology of cryptogenic organizing pneumonia. Br J Radiol 65:674–680 65. Müller NL, Staples CA, Miller RR (1990) Bronchiolitis obliterans organizing pneumonia: CT features in 14 patients. Am J Roentgenol 154:983–987 66. Lee KS, Kullnig P, Hartman TE, Müller NL (1994) Cryptogenic organizing pneumonia: CT findings in 43 patients. Am J Roentgenol 162:543–546 67. Nishimura K, Itoh H (1992) High-resolution computed tomographic features of bronchiolitis obliterans organizing pneumonia. Chest 102 (Suppl 1):26–31 68. Flowers JR, Clunie G, Burke M, Constant O (1992) Bronchiolitis obliterans organizing pneumonia: the clinical and radiological features of seven cases and a review of the literature. Clin Radiol 45:371–377 69. Cordier JF, Loire R, Brune J (1989) Idiopathic bronchiolitis obliterans organizing pneumonia. Definition of characteristic clinical profiles in a series of 16 patients. Chest 96:999–1004 70. Lohr RH, Boland BJ, Douglas WW, Dockrell DH, Colby TV, Swensen SJ, Wollan PC, Silverstein MD (1997) Organizing pneumonia. Features and prognosis of cryptogenic, secondary, and focal variants. Arch Intern Med 23:1323–1329 71. Kohno N, Ikezoe J, Johkoh T, Takeuchi N, Tomiyama N, Kido S, Kondoh H, Arisawa J, Kozuka T (1993) Focal organizing pneumonia: CT appearance. Radiology 189:119–123 72. Murphy J, Schnyder P, Herold C, Flower C (1998) Bronchiolitis obliterans organising pneumonia simulating bronchial carcinoma. Eur Radiol 8:1165–1169 73. Domingo JA, Perez-Calvo JI, Carretero JA, Ferrando J, Cay A, Civeira F (1993) Bronchiolitis obliterans organizing pneumonia. An unusual cause of solitary pulmonary nodule. Chest 103:1621–1623
1496
74. Haro M, Vizcaya M, Texido A, Aguilar X, Arevalo M (1995) Idiopathic bronchiolitis obliterans organizing pneumonia with multiple cavitary lung nodules. Eur Respir J 8:1975–1977 75. Froudarakis M, Bouros D, Loire R, Valasiadou K, Tsiftsis D, Siafakas NM (1995) BOOP presenting with haemoptysis and multiple cavitary nodules. Eur Respir J 8:1972–1974 76. Cordier JF (1995) Cavitary bronchiolitis obliterans organizing pneumonia. Eur Respir J 8:1822–1823 77. Bouchardy LM, Kuhlman JE, Ball WC Jr, Hruban RH, Askin FB, Siegelman SS (1993) CT findings in bronchiolitis obliterans organizing pneumonia (BOOP) with radiographic, clinical, and histologic correlation. J Comput Assist Tomogr 17:352–357 78. Akira M, Yamamoto S, Sakatani M (1998) Bronchiolitis obliterans organizing pneumonia manifesting as multiple large nodules or masses. Am J Roentgenol 170:291–295 79. Arakawa H, Kurihara Y, Niimi H, Nakajima Y, Johkoh T, Nakamura H (2001) Bronchiolitis obliterans with organizing pneumonia versus chronic eosinophilic pneumonia: high-resolution CT findings in 81 patients. Am J Roentgenol 176:1053–1058 80. Johkoh T, Muller NL, Cartier Y, Kavanagh PV, Hartman TE, Akira M, Ichikado K, Ando M, Nakamura H (1999) Idiopathic interstitial pneumonias: diagnostic accuracy of thin-section CT in 129 patients. Radiology 211:555–560 81. Müller NL, Miller R (1995) Diseases of the bronchioles: CT and histopathologic findings. Radiology 196:3–12 82. Aquino SL, Gamsu G, Webb WR, Kee ST (1996) Tree-in-bud pattern: frequency and significance on thin section CT. J Comput Assist Tomogr 20:594–599
83. Ikezoe J, Johkoh T, Kohno N, Takeuchi N, Ichikado K, Nakamura H (1996) High-resolution CT findings of lung disease in patients with polymyositis and dermatomyositis. J Thorac Imaging 11:250–259 84. Akira M, Hara H, Sakatani M (1999) Interstitial lung disease in association with polymyositis-dermatomyositis: long-term follow-up CT evaluation in seven patients. Radiology 210:333– 338 85. Austin JH, Müller NL, Friedman PJ, Hansell DM, Naidich DP, Remy-Jardin M, Webb WR, Zerhouni EA (1996) Glossary of terms for CT of the lungs: recommendations of the Nomenclature Committee of the Fleischner Society. Radiology 200:327–331 86. Murphy JM, Schnyder P, Verschakelen J, Leuenberger P, Flower CD (1999) Linear opacities on HRCT in bronchiolitis obliterans organising pneumonia. Eur Radiol 9:1813–1817 87. Voloudaki AE, Bouros DE, Froudarakis ME, Datseris GE, Apostolaki EG, Gourtsoyiannis NC (1996) Crescentic and ring-shaped opacities. CT features in two cases of bronchiolitis obliterans organizing pneumonia (BOOP). Acta Radiol 37:889–892 88. Murata K, Khan A, Herman PG (1989) Pulmonary parenchymal disease: evaluation with high-resolution CT. Radiology 170:629–635 89. Johkoh T, Muller NL, Ichikado K, Nakamura H, Itoh H, Nagareda T (1999) Perilobular pulmonary opacities: high-resolution CT findings and pathologic correlation. J Thorac Imaging 14:172–177 90. Sheehan RE, Wells AU, Milne DG, Hansell DM (2000) Nitrofurantoin-induced lung disease: two cases demonstrating resolution of apparently irreversible CT abnormalities. J Comput Assist Tomogr 24:259–261
91. Preidler KW, Szolar DM, Moelleken S, Tripp R, Schreyer H (1996) Distribution pattern of computed tomography findings in patients with bronchiolitis obliterans organizing pneumonia. Invest Radiol 31:251–255 92. Cohen AJ, King TE Jr, Downey GP (1994) Rapidly progressive bronchiolitis obliterans with organizing pneumonia. Am J Respir Crit Care Med 149:1670–1675 93. Sulavik SB (1989) The concept of “organizing pneumonia”. Chest 96:967–969 94. Katzenstein AL, Myers JL, Prophet WD, Corley LS III, Shin MS (1986) Bronchiolitis obliterans and usual interstitial pneumonia. A comparative clinicopathologic study. Am J Surg Pathol 10:373–381 95. Myers JL, Katzenstein AL (1988) Ultrastructural evidence of alveolar epithelial injury in idiopathic bronchiolitis obliterans-organizing pneumonia. Am J Pathol 132:102–109 96. Katzenstein AL (1988) Pathogenesis of “fibrosis” in interstitial pneumonia: an electron microscopic study. Hum Pathol 16:1015–1024 97. Myers JL, Katzenstein AL (1988) Epithelial necrosis and alveolar collapse in the pathogenesis of usual interstitial pneumonia. Chest 94:1309–1311 98. Vracko R (1972) Significance of basal lamina for regeneration of injured lung. Virchows Arch A Pathol Pathol Anat 355:264–274 99. Battersby S, Anderson TJ (1985) Myofibroblast activity of radial scars. J Pathol 147:33–40 100. Gosink BB, Friedman PJ, Liebow AA (1973) Bronchiolitis obliterans. Roentgenologic–pathologic correlation. Am J Roentgenol Radium Ther Nucl Med 117:816–832
