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Service de Pneumologie, Center des Maladies Orphelines Pulmonaires, Hôpital Cardiovasculaire et Pneumologique Louis Pradel, Lyon, France.
CORRESPONDENCE: J-F. Cordier, Dept of Respiratory Medicine, Reference Centre for Orphan Pulmonary Diseases, Louis Pradel University Hospital, 69677 Lyon (Bron), France. Fax: 33 472357653. E-mail: jean-francois.cordier{at}chu-lyon.fr
Keywords: Cryptogenic organising pneumonia
Received: February 8, 2005
Accepted November 22, 2005
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ABSTRACT |
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 TOP ABSTRACT PATHOGENESISA DISTINCT ENTITY AMONG...AETIOLOGY OF ORGANISING...SEVERE AND/OR OVERLAPPING COPTREATMENT OF COPACKNOWLEDGEMENTSREFERENCES |
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Although previous partial descriptions can be traced back to the latter half of the nineteenth century, as in the lectures given in 1877–1878 by J.M. Charcot in Paris, France 1, the concept of organising pneumonia (a term describing a histopathological pattern) emerged under various names at the beginning of the 20th century 2–9 (fig. 1
). For example, Milne 5 described a type of pneumonia "where the usual process of resolution has failed and organisation of the inflammatory exudate in the air alveoli of the lung by fibrous tissue has resulted" (resolution was the third stage in the course of pneumonia as described by Laennec, which followed the stages of congestion and hepatisation). These early observations were mostly made during the autopsy of patients who died due to nonresolving pneumococcal pneumonia before the era of antibiotherapy. These histopathological descriptions of organising pneumonia stated that the initial intra-alveolar material consisted of fibrin, further colonised by fibroblasts and replaced by "fibrillated connective tissue" 6. Intra-alveolar buds of granulation tissue consisting of intermixed myofibroblasts, fibroblasts, and connective matrix, especially consisting of collagens are the hallmark of organising pneumonia.
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PATHOGENESIS |
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TOPABSTRACTPATHOGENESISA DISTINCT ENTITY AMONG...AETIOLOGY OF ORGANISING...SEVERE AND/OR OVERLAPPING COPTREATMENT OF COPACKNOWLEDGEMENTSREFERENCES |
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The morphological sequential evolution of intra-alveolar fibrosis in human organising pneumonia has been established previously 23–26 (fig. 2). Alveolar epithelial injury is the first event, with necrosis and sloughing of pneumocytes resulting in the denudation of the epithelial basal laminae. Most basal laminae are not destroyed, although some gaps are present. The endothelial cells are only mildly damaged. In contrast with diffuse alveolar damage, no hyaline membranes are found. Inflammatory cells (lymphocytes, neutrophils, some eosinophils) infiltrate the alveolar interstitium. Fibroblasts present in the interstitium exhibit features of activation, such as conspicuous rough endoplasmic reticulum and Golgi apparatus, but these are not increased in number and there are no associated collagen deposits.
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The second stage is characterised by the formation of fibro-inflammatory buds. Fibrin is fragmented and inflammatory cells are present but less numerous. Fibroblasts migrating from the interstitium through gaps in the basal laminae colonise the fibrin remnants and proliferate, as demonstrated by the presence of mitotic figures. Fibroblasts undergo further phenotypic modulation, especially with the development of intracellular filaments (myofibroblasts). A reticulin framework takes place in the extracellular environment. A proliferation of alveolar cells progressively provides re-epithelialisation of the basal laminae, a crucial phenomenon for the preservation of the structural integrity of the alveolar unit.
The third and final stage of the process of organisation is defined by the characteristic "mature" fibrotic buds. Inflammatory cells have almost completely disappeared in most buds (although some may persist in the centre of some buds), and there is no longer any fibrin within the alveolar lumen. Concentric rings of fibroblasts alternate with layers of connective tissue (mainly collagen bundles). The fibroblasts are typical myofibroblasts with conspicuous filaments in their cytoplasm oriented along the axis of the cells, with an abundant endoplasmic reticulum.
The matrix pattern of the intra-alveolar buds is initially characterised by fibrillar material consisting of fibronectin, type III collagen and proteoglycans, among which the typical periodic (type I) collagen fibres represent a minority, leaving large empty areas of the extracellular space. The cellular rings of fibroblasts–myofibroblasts are then intercalated with connective matrix sheets, consisting of loose bundles of thin collagen type I fibres mixed with fibronectin, collagen and procollagen type III and proteoglycans. In the mature fibrotic buds, the connective network consists of thin collagen I fibres held together by thinner fibrils of collagen and procollagen type III, and fibrin to form bundles resulting in a loose connective network where fibronectin, type III procollagen and collagen are codistributed at a higher rate than type I collagen. This contrasts with the predominant deposition of type I collagen in UIP. A loose connective matrix with high type III collagen content is more susceptible to degradation and reversal of fibrosis 24, 27, 28. Glycoproteins, especially tenascin, are likely to play a role in loosening the adhesive interactions between cells and the pericellular matrix components in COP 29. Collagen VI, coexpressed with collagen III rather than collagen I, may also participate in the regulation of matrix deposition in COP 30.
A further characteristic of the intra-alveolar buds in COP is the prominent capillarisation, which is reminiscent of granulation tissue in wound healing, another type of a reversible fibro-inflammatory lesion 31. Vascular endothelial growth factor and basic fibroblast growth factor are widely expressed in intra-alveolar buds 32. Angiogenesis mediated by these growth factors could contribute to the reversal of buds in organising pneumonia.
Experimental models provide further information about the morphogenesis of intra-alveolar fibrosis. Paraquat in monkeys 33 or lobar instillation of CdCl2 in rats 34 results in intra-alveolar migration of interstitial cells through gaps in the epithelial basement membranes after lung injury. The early damage to type I pneumocytes progressing to necrosis, leaving areas of denuded alveolar membrane with abnormal alveolar repair, is associated with failure of resolution in experimental streptococcal pneumonia in rats 35. In intra-alveolar fibrosis produced by bleomycin in rats, alveolar structural remodelling is seen only when mural incorporation of intra-alveolar buds occurs 36.
An animal model of intraluminal fibrosis has been developed with intranasal inoculation of reovirus serotype 1 into CBA/J mice at a titre of 106 plaque-forming units (pfu) 37. In this model, severe pneumonia, characterised by a prominent peribronchiolar lymphocytic inflammation, further evolves with the formation of intraluminal fibroblastic lesions indistinguishable from organising pneumonia. Interestingly, these lesions develop in CBA/J, but not in other strains of mice, suggesting that genetic host factors are critical in the development of intra-alveolar fibrosis. A model of diffuse alveolar damage with typical hyaline membranes and high mortality has been obtained with the same animal model but using a higher titre (107 pfu) of reovirus 1 38, 39. Thus, the degree of severity of the initial injury seems to be a critical determinant in the progression towards either organising pneumonia or diffuse alveolar damage 38. Furthermore, whereas corticosteroids can both inhibit the development of fibrotic lesions and enhance the resolution of fibrotic lesions in the model of intraluminal fibrosis, in the diffuse alveolar damage model corticosteroids fail to modulate the development of the lesions at any stage 39. The role of T-cells has been explored in the reovirus 1-induced lung injury model, with neonatal thymectomy in mice demonstrating that T-cells are required for the development of organising pneumonia, but not for that of diffuse alveolar damage 40.
The pathohistophysiology recognised by the previous morphological studies in human and animal models offers some cornerstones for the understanding of the biopathology of intra-alveolar fibrosis. The pathogenesis of pulmonary fibrosis involves a complex network and interaction of cells 41–43, mediators 44–48 and extracellular matrix (ECM) components 49–52.
Some other limited information has been published on biopathological features in organising pneumonia. Platelet-derived growth factor 53 and interleukin (IL)-8 54 produced by macrophages are likely to play a role in the pathogenesis of intra-alveolar fibrosis in COP. Pulmonary tissue from rheumatoid arthritis patients with organising pneumonia contains many cells positive for S-100 protein 55. B7-2 and class II major histocompatibility complex molecule expression in alveolar macrophages of patients with organising pneumonia is decreased compared with control subjects 56. The soluble form of the Fas ligand (implicated in the system of apoptosis-signalling receptor molecules) is elevated in the bronchoalveolar lavage (BAL) fluid of patients with COP, which may abrogate the cytotoxicity of the Fas-ligand 57.
Mast cells and released tryptase are increased in the BAL fluid of patients with COP 58. The cytokine profile of BAL in COP is characterised by increased monocyte chemotactic protein-1, IL-10, IL-12 and IL-18 levels with respect to controls and UIP, consistent with a marked degree of macrophage and lymphocyte activation with an expansion of T-helper type-1 response in COP 59.
Some insights into the pathogenesis of organising pneumonia may further be extrapolated with acceptable likelihood from studies in the other infiltrative and fibrosing lung diseases, especially acute respiratory distress syndrome (ARDS; which is characterised by two successive stages of diffuse alveolar damage, namely acute exudative and chronic organising) 20, 21, 60, 61 and idiopathic pulmonary fibrosis (IPF) 62.
Clearly, epithelial alveolar damage with leakage of plasma proteins and further fibrin formation within the alveolar lumen is a crucial initial event, which has been especially studied in ARDS and further emphasised in pulmonary fibrosis 20, 21, 63–68. The formation of fibrin results from an imbalance in the alveolar lumen between the coagulation and fibrinolytic cascades, with a net result of clotting 69. Recently, increased levels of a potent inhibitor of fibrinolysis, thrombin activable fibrinolysis inhibitor, and of protein C inhibitor have been found in the BAL from patients with interstitial lung disease, especially COP 70. In addition to providing a provisional fibrin matrix for the migration of cells (including fibroblasts), the coagulation and fibrinolysis factors and inhibitors (especially plasminogen activator inhibitor-1) play a complex role in fibrogenesis 68. Interestingly, an animal model demonstrated prevention of bleomycin-induced lung fibrosis by aerosolisation of heparin or urokinase 71.
The matrix metalloproteinases (MMPs) that cleave protein components of the ECM play a central role in tissue remodelling 72. Two collagenolytic metalloproteinases are involved in the destruction of subepithelial basement membranes, MMP-2 (preferentially secreted by fibroblasts and epithelial cells) and MMP-9 (preferentially produced by inflammatory cells). In organising pneumonia, MMP-2 is expressed in BAL fluid and by regenerated type II cells, in contrast with UIP where MMP-9 is preferentially expressed 73. In another study, the concentration of MMP-9 and tissue inhibitors of metalloproteinases (TIMP) was increased more in the BAL fluid of patients with COP compared with UIP 74. Although these studies are somewhat contradictory, they suggest that an imbalance between MMP and TIMP may play a role in the remodelling of connective tissue in COP. Interestingly, laminin-5 (a glycoprotein involved in cell attachment, migration, proliferation, differentiation and apoptosis), expressed in epithelial cells of wound healing, is also expressed in regenerating epithelial cells in COP, as well as in UIP 75. However, re-epithelialisation is disturbed in UIP, which may contribute to the progression of fibrosis.
The role of the myofibroblast in wound healing and fibrosis is critical 76, 77. The origin of fibroblasts–myofibroblasts involved in organising pneumonia is not known. Several recent papers have demonstrated that myofibroblasts involved in pulmonary fibrosis in animal models (fibrosis induced by bleomycin or irradiation) are of bone marrow origin and not derived from resident fibroblasts in the pulmonary interstitium 78–80. Whether intra-alveolar myofibroblasts in organising pneumonia could also originate from bone marrow and not from resident interstitial cells is presently unknown. Furthermore, epithelial to mesenchymal transition has been recently emphasised 81.
The disappearance of myofibroblasts and fibroblasts in fibrosis may occur by apoptosis, possibly through loss of transforming growth factor-ß signalling 82, 83. Apoptotic activity is increased in the newly formed connective tissue in organising pneumonia 84.
Although several rather similar factors of matrix remodelling are present in both COP and UIP, the reasons for the opposing mechanisms of reversibility of fibrosis in COP and ongoing fibrosis in UIP are not yet established.
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A DISTINCT ENTITY AMONG THE IDIOPATHIC INTERSTITIAL PNEUMONIAS |
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TOPABSTRACTPATHOGENESISA DISTINCT ENTITY AMONG...AETIOLOGY OF ORGANISING...SEVERE AND/OR OVERLAPPING COPTREATMENT OF COPACKNOWLEDGEMENTSREFERENCES |
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), especially when the imaging pattern is infiltrative; and 3) histopathological features of interstitial inflammation in the involved areas. The previous terminology of BOOP was abandoned because the major process is organising pneumonia, with bronchiolitis obliterans being only a minor and accessory finding (which may even be absent).
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50–60 yrs. A few rare cases have been reported in children 102. Nonsmokers or ex-smokers are affected approximately twice as often as smokers, but the proportion of nonsmokers may be higher among females 89, a finding which needs to be confronted with the prevalence of smoking in the different countries. However, COP is clearly a disorder not related to smoking. A seasonal (early spring) occurrence of COP with relapse every year at the same period has been reported 103. Recurrent catamenial COP has also been mentioned 104. Clinical manifestations begin with a mild flu-like illness with fever, cough, malaise and progressively mild dyspnoea, anorexia and weight loss. Dyspnoea may occasionally be severe, especially in the eventuality of rapidly progressive disease. Haemoptysis is uncommon and seldom severe 105. Other uncommon manifestations include chest pain, night sweats and mild arthralgia (when arthralgia is prominent and/or associated with myalgia an underlying connective tissue disease should be suspected). Air leak (pneumothorax, pneumomediastinum) may be a rare presenting feature 106, 107. Since the most common manifestations are nonspecific, diagnosis is often delayed (6–13 weeks). Physical examination usually discloses focal sparse crackles, but may be almost normal. There is no finger clubbing.
Imaging features
For more information about the imaging features of COP refer to 15–18, 90, 95, 96, 98, 100, 108–133. The three main characteristic imaging patterns of COP consist of multiple alveolar opacities (typical COP), solitary opacity (focal COP), and infiltrative opacities (infiltrative COP) 17. In a study of diagnostic accuracy of thin-section computed tomography (CT) in a series of patients with idiopathic interstitial pneumonias, the correct diagnosis of COP was the highest, in 79% of cases 134, suggesting that the CT imaging features are characteristic.
Typical COP
Multiple alveolar opacities on imaging represent the most frequent and typical imaging features of COP (figures 3 and 4). These are usually bilateral and peripheral, and are often migratory. Their size varies from a few centimetres to a whole lobe, and an air bronchogram is often present in consolidated opacities. On a high-resolution computed tomography (HRCT) scan, the density of opacities ranges from ground glass to consolidation and more opacities are detected than on chest radiographs. This imaging pattern narrows the differential diagnosis, which mainly comprises the idiopathic chronic eosinophilic pneumonias, low-grade pulmonary lymphomas, and bronchioloalveolar lung carcinoma. Idiopathic chronic eosinophilic pneumonia is often associated with asthma and increased blood eosinophil level is present. However, it may overlap with COP, as in the figures of histopathological features reported in the series by Carrington et al. 135, where typical buds of granulation tissue in addition to eosinophilic pneumonia are seen. Other cases of overlap of organising pneumonia and chronic eosinophilic pneumonia (idiopathic or not) have been reported 136–140. Furthermore, increased level of eosinophils in BAL may be found in some patients with COP. In both disorders, relapses are common. The primary pulmonary lymphomas of low grade are also relatively responsive to corticosteroids (but not as rapidly as in COP). In bronchioloalveolar carcinoma, associated nodules are common and there is no regression with corticosteroids.
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Solitary focal opacity
This pattern is not characteristic and the diagnosis of COP is often made from histopathology of a nodule or a mass excised on suspicion of bronchogenic carcinoma 141 (fig. 5). However, organising pneumonia is distinct from round pneumonia improving with antibiotics 142–144. Neutrophilic inflammation or microabscesses may be associated with the typical features of organising pneumonia 145, 146. The lesions are often located in the upper lobes, and may be cavitary. The clinical presentation may be that of COP as described above, but focal organising pneumonia may be totally asymptomatic and discovered by routine chest radiographs (some patients may recall that they had a previous history of pneumonia) 17, 90, 145. The suspicion of carcinoma may be increased by false-positive fluorodeoxyglucose positron emission uptake 147, 148. Solitary focal organising pneumonia usually does not relapse after surgical excision. Possible spontaneous regression of solitary nodular organising pneumonia has been reported previously 149.
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). Some cases overlap with other types of idiopathic interstitial pneumonias, especially IPF and nonspecific interstitial pneumonia (NSIP). In the latter, focal areas of organising pneumonia are often encountered at histopathology 150, 151. However, these are scattered foci, which are small and compose <10% of lesions, with interstitial pneumonia being the main lesion, whereas in organising pneumonia interstitial inflammation does not extend beyond the area of intra-alveolar fibrosis. The infiltrative pattern may consist of a poorly defined arcade-like or polygonal appearance defining a perilobular pattern 152, which is often associated with other opacities, especially consolidation.
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8 mm in diameter, or of a more subtle poorly defined (micro)nodular pattern. Multiple nodules of organising pneumonia may suggest metastatic lesions 153, especially in patients with a history of cancer. Some reported cases of cavitary COP correspond to consolidation superimposed on emphysema 154. The bronchocentric pattern of COP is defined by areas of consolidation surrounding the bronchovascular bundles. The linear and band-like pattern consists of opacities extending radially to the pleura; some band-like opacities lie in the periphery of the lung parallel to the chest wall (the latter may be observed especially during the resolution of peripheral alveolar opacities). The halo sign 155, or particularly a reversed halo sign, of lung opacities have been reported 156. Other imaging features consist of multiple masses or nodules (possibly excavated), and pneumatocele 132. A diffuse micronodular pattern with histopathological features of bronchiolitis with peribronchiolar organising pneumonia has been reported 157. Pleural effusion is seldom seen in COP, although it was present in 22% of cases in a previous series 90.
Lung function tests
For more information about lung function tests in COP refer to 15–19, 95, 96, 98, 103, 114, 158, 159. A mild or moderate restrictive ventilatory defect is the most common abnormality at spirometry. Airflow obstruction may be present in patients with a history of smoking and underlying chronic obstructive pulmonary disease. The transfer factor of the lung for carbon monoxide is reduced in proportion to restriction, but the transfer coefficient is usually normal. Hypoxaemia at rest and/or during exercise is usually mild. More severe hypoxaemia may be present in patients with widespread lung lesions and rapidly progressive disease. However, some patients have marked hypoxaemia (usually well tolerated) with possible orthodeoxia because of alveolar right to left shunting, as demonstrated by increased alveolar–arterial oxygen difference on breathing 100% oxygen and negative contrast echocardiography 160, 161. This is likely to result from defective vasoconstriction in areas of nonventilated alveoli because of intra-alveolar buds occupying the entire lumen of alveoli.
Biological features
BAL is indicated in all cases where COP is suspected. First, it helps in excluding other diagnoses or determining a cause of organising pneumonia. Thus, it may disclose active infection or neoplastic disorders especially lymphoma and bronchioloalveolar carcinoma (immunocytological analysis may establish the monotype of lymphocytes characteristic of lymphoma). In COP, a mixed pattern at differential cell count may orientate towards the diagnosis. It consists of an increase in lymphocytes (20–40%), neutrophils (10%) and eosinophils (5%) with the level of lymphocytes higher than that of eosinophils 17, 94, 97, 110, 162–164. A markedly elevated percentage of eosinophils (>25%) may suggest an overlap with idiopathic chronic eosinophilic pneumonia 18, 96, 99, 109, 138. The finding of a few plasma cells and/or mast cells is remarkable in COP. The lymphocytes are activated and the CD4/CD8 ratio is usually decreased 162, 165, 166.
Blood tests do not make a significant contribution to the diagnosis of COP. A moderate leukocytosis is usual with an increase in neutrophils. There is no eosinophilia and the C-reactive protein level and erythrocyte sedimentation rate are increased.
Diagnosis of COP
The diagnosis of COP requires the establishment of a diagnosis of organising pneumonia, then the exclusion of any possible cause (which may be relatively evident or require more laborious aetiological inquiry).
Histopathological diagnosis of organising pneumonia
Histopathological diagnosis of organising pneumonia has been discussed previously elsewhere 167, 168. Once a diagnosis of COP is suspected, obtaining lung tissue for histopathological study is necessary. The hallmark of organising pneumonia is the presence of buds of granulation tissue consisting of fibroblasts–myofibroblasts embedded in connective tissue (fig. 7). These may extend from one alveolus to the next through the interalveolar pores as described in a case of "fibrinous pneumonia" by Kohn 169, thus giving a characteristic "butterfly pattern". These buds often extend into the bronchioles and may obstruct the lumen (bronchiolitis obliterans of the proliferative type). Mild interstitial inflammation is present in areas of organising pneumonia, and foamy alveolar macrophages are present in those alveoli that are not filled by buds. It must be emphasised that the mere presence of some buds is not sufficient to make a diagnosis of organising pneumonia as the organisation of intra-alveolar exudates is a nonspecific process that may occur in a variety of inflammatory lung diseases 170. This is why pathologists must search carefully for other lesions that could represent the main inflammatory process associated with foci of intra-alveolar fibrosis.
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Video-assisted thoracoscopy (VAT) allows biopsy of the lung in good conditions of security and allows pieces of tissue of sufficient size to be obtained from several lobes (especially when all lesions do not appear of the same type on HRCT) to exclude associated conditions or different patterns of interstitial pneumonia. Currently, VAT is a safe procedure that may be used in most patients.
However, before proposing VAT, transbronchial biopsies are recommended, since the finding of characteristic intra-alveolar buds at histopathological examination is sufficient in most cases to make a provisional diagnosis of organising pneumonia 181, 182, thus allowing treatment in patients with typical imaging features and presumed good compliance for follow-up (hence allowing reconsideration of the diagnosis in the eventuality of unfavourable or atypical evolution under corticosteroid treatment). However, it must be remembered that the amount of lung tissue is relatively small and that the collapse and pinch artefacts induced by the forceps do not usually allow exclusion of other histopathological processes coexisting with foci of organising pneumonia. Therefore, atypical cases of COP diagnosed only on the basis of transbronchial biopsies need to be interpreted with caution, especially when imaging features are more suggestive of NSIP or IPF.
Whether a diagnosis of organising pneumonia may be accepted or not without histopathology and based only on clinical and imaging findings requires consideration, especially because it is increasingly frequent in clinical practice 86. In patients too frail and/or too old to undergo lung biopsy, or refusing lung biopsy, corticosteroid treatment can be started provided patients have been informed that diagnosis is only probable and that a careful follow-up is programmed. Often rapid clinical and imaging improvement reinforces the probability of organising pneumonia. However, since long-term corticosteroid treatment often results in significant side-effects, some patients treated without histopathological confirmation sometimes question the diagnosis, eventually leading to later biopsy, especially on relapse.
Aetiological diagnosis: cryptogenic or not?
Organising pneumonia may be considered cryptogenic, a term used synonymously to idiopathic, although etymologically cryptogenic means of hidden cause and idiopathic means a self-governing disease; the disorder described is both cryptogenic and idiopathic. It is only considered to be cryptogenic when a definite cause or characteristic associated context is not present. Therefore, the aetiological diagnosis is of major importance before accepting the diagnosis of COP.
In non-COP, although some cases present with imaging and histopathological features quite similar to COP, other cases are more atypical especially as associated to histopathological features with more interstitial inflammation and/or fibrosis, and diffuse alveolar damage.
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AETIOLOGY OF ORGANISING PNEUMONIA |
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TOPABSTRACTPATHOGENESISA DISTINCT ENTITY AMONG...AETIOLOGY OF ORGANISING...SEVERE AND/OR OVERLAPPING COPTREATMENT OF COPACKNOWLEDGEMENTSREFERENCES |
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Determined causes of organising pneumonia
There are many determined causes of organising pneumonia. In addition to pneumococcal pneumonia, several other infectious agents (including bacteria, viruses, parasites and fungi) have been reported to cause organising pneumonia resulting from nonresolving pneumonia (table 2). Organising pneumonia, which improved with corticosteroids, was reported in a pregnant patient with HIV infection treated with lamivudine and zidovudine 205. In clinical practice, the search for infection is not always exhaustive (sometimes because laboratory diagnostic tools such as serological tests or antigenuria are not available in all infectious disorders). Furthermore, some infections may initiate an uncontrolled inflammatory organising pneumonia process that persists after the aetiological agent has disappeared. An infectious agent may also induce a secondary noxious immunopathological process; a convincing example is rheumatic pneumonia 224, 225 where, in addition to the well known cardiac complications, typical organising pneumonia has been described 225–227, especially by Masson et al. 227, who called the intra-alveolar buds "bourgeons conjonctifs" (connective tissue buds), terminology still used by some pathologists 228. The clinical descriptions of rheumatic organising pneumonia have mentioned the "fleeting nature" of lung pneumonic opacities, improvement with adrenocorticotropin (ACTH), and even cited a case of "rebound phenomenon after small doses of ACTH were discontinued" 224.
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) have been reported to cause iatrogenic organising pneumonia, with relatively convincing histopathological features. Causality has not been firmly established for many drugs, mainly because only isolated case reports have been published. A further difficulty results from the association of several possible causes related to the disorder for which the drug has been prescribed; for example, in patients after bone marrow graft for haematological malignancy, it is often difficult to know from among the drug(s) received, infection(s) induced by iatrogenic aplasia, and immunological and inflammatory processes associated with graft versus host disease, which of these actually caused organising pneumonia.
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A peculiar iatrogenic organising pneumonia is one that is "primed" by radiation therapy to the breast (tangential field radiotherapy) 109, 290–300. It closely resembles COP and clearly differs from radiation pneumonitis, especially because it may involve nonirradiated areas of the lung and possibly be migratory. Therefore, it differs from organising pneumonia in radiation pneumonitis limited to the radiation field 299, 301. Organising pneumonia primed by radiation therapy had an incidence of 2.5% in a series of 157 patients with breast cancer who underwent radiotherapy after breast-conservative surgery 292, and a 2.4% incidence in another series of 206 patients 300. It usually develops within 9–16 months after radiation therapy 291, 296, 301, with the mean age of affected patients being 60 yrs. As in COP, the patients present with fever, nonproductive cough, mild dyspnoea and peripheral alveolar opacities on chest imaging with a pattern of consolidation and further ground-glass opacities. Often initially unilateral and located in the irradiated lung, these are migratory in many patients. In BAL, a "mixed pattern" is present at differential cell count with a marked increase in lymphocytes (40%), and a mild increase in neutrophils (4–10%) and eosinophils (3%). Mast cells are often present (1–2%) 291, 293 and the CD4/CD8 ratio of lymphocytes is decreased 293. Corticosteroid treatment results in rapid clinical improvement with clearing of the pulmonary opacities on imaging without significant sequelae, in contrast with radiation pneumonitis resulting in retractile consolidation with traction bronchiectasis. However, as in COP, relapses are frequent upon reducing (to daily doses of 5–10 mg prednisone) or stopping corticosteroids, with opacities in the same or other locations. Radiation-primed organising pneumonia is thus quite similar to COP. Interestingly, this peculiar iatrogenic organising pneumonia provides some insight into the pathogenesis of COP. Patients receiving radiation therapy to the breast develop bilateral alveolar lymphocytosis of similar intensity in both lungs within 15 days after completion of radiotherapy, regardless of whether the patients later develop pneumonitis or not 303–305. This suggests that after lymphocytic alveolitis has been "primed" by radiation therapy, a second trigger or individual characteristics (either genetic or acquired) may be required for organising pneumonia to develop. Most patients receive concomitant medical treatment (especially chemotherapy and/or tamoxifen), but no definite role of the drugs used has been identified as increasing the risk of organising pneumonia. However, fever and cough developed in one patient who received radiation therapy to the breast while receiving transtuzumab, with alveolar opacities in both lungs on imaging. A biopsy of an alveolar opacity in the nonirradiated lung found a histopathological pattern of organising pneumonia 287. The patient improved once transtuzumab was discontinued without adding corticosteroids. A patient who had received radiation therapy to the breast 10 yrs earlier developed severe organising pneumonia while receiving single-agent chemotherapy with doxorubicin 260, which might correspond to the phenomenon of "radiation recall" described with doxorubicin. The latter two cases represent examples of possible triggers for radiation-primed organising pneumonia. However, more common agents, such as respiratory infections, could also play a triggering role.
Some other causes of organising pneumonia have been reported. An epidemic of organising pneumonia due to the aerosolised textile dye Acramin FWN has been reported 306–309. However, a number of patients were characterised by severe progressive disease (especially those with an infiltrative pattern on imaging) with irreversible fibrosis and ensuing death. These patients had a histopathological pattern including hyaline membranes and mural incorporation of intra-alveolar fibrosis, suggesting the organising stage of diffuse alveolar damage rather than typical organising pneumonia 306, 308. Paraquat ingestion usually results in diffuse alveolar damage, but hyaline membranes were not present in a fatal case with intra-alveolar fibrosis 310. Organising pneumonia has been reported in association with cocaine use 311, including a case of a pregnant female with HIV infection 205.
Cavitating organising pneumonia was reported in a floor cleaner with an incidental heavy exposure to benzalkonium compounds; in addition, this patient had myeloperoxidase deficiency 312. A spice process technician developed organising pneumonia of presumed occupational origin 313.
An aetiological role for gastro-oesophageal reflux with occult aspiration has been suggested in several cases 314, 315, but has not been convincingly demonstrated as a common cause of organising pneumonia when histopathological criteria of aspiration pneumonia (exogeneous lipid pneumonia with multinucleated foreign-body giant cells) are not present 175, 316. Patchy organising pneumonia is a feature of middle lobe syndrome 317.
Organising pneumonia within a specific context
Organising pneumonia may develop in patients with a well characterised disorder of unknown cause, such as connective tissue disease. It may also occur secondary to lung transplantation or bone marrow grafting. In such situations, organising pneumonia is considered as a pulmonary manifestation of the inflammatory and/or immune process associated with the underlying condition, but the synergistic role of iatrogenic or infectious agents must be systematically evaluated. The aetiology of organising pneumonia in such conditions is likely to be plurifactorial.
Connective tissue disorders may comprise lung involvement of various types, especially interstitial lung disease, which usually develops during the course of disease, but which may also precede its recognition. In clinical practice, many patients with connective tissue disease and interstitial lung disease do not undergo lung biopsy. In patients with lung biopsy, NSIP is the most common histopathological pattern associated with scleroderma, dermatomyositis–polymyositis and rheumatoid arthritis. Organising pneumonia occurs particularly in patients with dermatomyositis–polymyositis 318–331, where it may be the presenting manifestation 212, 332. In some patients it is associated with anti-JO-1 auto-antibodies 324, 326, 333. Organising pneumonia has also been reported in rheumatoid arthritis 158, 334–337, and more occasionally in systemic lupus erythematosus 338–341, scleroderma 342, 343, CREST (calcinosis, Raynaud's phenomenon, oesophageal dysmotility, sclerodactyly, telangiectasia) syndrome with primary biliary cirrhosis 15, 344, and Sjögren syndrome 345, 346. Abundant buds of organising pneumonia have been reported in association with NSIP in a patient with scleroderma 347.
In the connective tissue diseases, organising pneumonia may be the main histopathological feature, but a minor component of organising pneumonia may be associated with another histopathological pattern of interstitial pneumonia, especially NSIP. Overlap between organising pneumonia and eosinophilic pneumonia has also been reported 140, 319.
Organising pneumonia has increasingly been reported in patients after lung transplantation or bone marrow graft. The former terminology of COP (i.e. idiopathic bronchiolitis with organising pneumonia) was a source of confusion with bronchiolitis obliterans with airflow obstruction (obliterative bronchiolitis), which is the major cause of lung transplant failure and also a severe complication after allogenic bone marrow graft resulting from immune processes (namely transplant rejection and graft versus host disease, respectively). Several cases of organising pneumonia have been reported after lung transplantation 183, 200, 203, 348–351. In this context, when not explained by a determined cause (such as infection, which is common in this immunosuppressed population), organising pneumonia may be considered as an associated or predominant pattern of acute lung rejection with or without concomitant "pure" bronchiolitis obliterans 200, 183, 200, 352, 353. Furthermore, it is a risk factor for the bronchiolitis obliterans syndrome 350. Organising pneumonia has also been reported after bone marrow graft 93, 354–366, where it is strongly associated with prior acute and chronic graft versus host disease 93, 357. Some cases of organising pneumonia have also been reported after liver transplantation 367–369.
Organising pneumonia may occur in association with various haematological disorders or malignancies 90, 93 including: acute myelomonocytic leukaemia with inversion of chromosome 16 370; acute lymphoblastic leukaemia 371; chronic myelomonocytic leukaemia 372; myelodysplastic syndrome 354, 373, 374; T-cell adult leukaemia 375, 376; Evans syndrome 377; Ewing sarcoma 371; Hodgkin disease 371; and various cancers with or without radiation therapy to the chest 378. In patients with treated haematological malignancies and suspected invasive pulmonary aspergillosis, open lung biopsy may provide a diagnosis of organising pneumonia in up to 20% of cases 379. Organising pneumonia is frequently found in the vicinity of lung cancer 380, whether obstructive pneumonia is present or not. Obstructive pneumonia whatever its cause (e.g. foreign body inhalation) may comprise features of lipid pneumonia, chronic abscess and organising pneumonia. Coexistence of organising pneumonia with bronchioloalveolar carcinoma has been reported 381.
Although the most prevalent and distinctive pattern of respiratory involvement in inflammatory bowel disease (i.e. Crohn's disease and ulcerative colitis) is airway inflammation with ensuing bronchiectasis and/or obliterative bronchiolitis 382, organising pneumonia (focal or diffuse) is a well established manifestation of those disorders 231, 382–385. Interestingly, the mononuclear cell infiltration in the pulmonary interstitium is denser and more uniform than in COP, suggesting a possible overlap with NSIP 231. In contrast to patients with large airway disease, organising pneumonia does not manifest post-colectomy 231. Since drugs used to treat these conditions may themselves cause organising pneumonia, the issue remains complex.
Ulcerative colitis suspected to have been transmitted from donor to recipient after allogeneic bone marrow transplantation in a patient with acute myeloblastic leukaemia developed concomitantly with organising pneumonia 361.
Other disorders with associated organising pneumonia include: common variable hypogammaglobulinaemia and other immunoglobulin deficiencies 386–388; polyarteritis nodosa 389; Sweet syndrome 390–392; polymyalgia rheumatica 393, 394; Behçet disease 395; thyroid disease (including cancer, Basedow disease, thyroiditis, hypothyroidism) 396; and sarcoidosis (with organising pneumonia at the periphery of granulomatous lesions) 397. It was also reported after coronary artery bypass graft surgery 398 or in association with localised giant inflammatory polyposis of the caecum and distal ulcerative colitis 399.
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SEVERE AND/OR OVERLAPPING COP |
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COP may present with widespread opacities on imaging and hypoxaemia, corresponding to the criteria for acute lung injury or the ARDS. Although hypoxaemia with alveolar right-to-left shunt may be well tolerated as mentioned previously, other patients may require mechanical ventilation (noninvasive or with tracheal intubation) or progress to death, especially when corticosteroid treatment is delayed 400, 401. This occurs particularly in patients with delayed diagnosis who may improve once corticosteroid treatment is given (sometimes in association with immunosuppressive agents when corticosteroid resistance is suspected) 248, 402–407. In some patients, underlying conditions or exposure (connective tissue disease, drugs, infection) are associated 248, 408.
Some patients, who may have underlying conditions or exposure, present with acute fibrinous and organising pneumonia, a recently described condition overlapping with ARDS both clinically and pathologically 409. The onset is acute and progression may be fulminating or subacute. The dominant finding at lung biopsy is the presence of intra-alveolar fibrin in the form of "fibrin balls" without classic hyaline membranes. Some patients recover with treatment including corticosteroids, whereas other patients die.
This pathological pattern has also been reported upon autopsy of patients with severe acute respiratory syndrome 410 and in dermatomyositis 411. The presence of fibrin in the organising lesions at lung biopsy of patients with COP has been associated with less complete recovery under corticosteroids 412.
Overlap with acute interstitial pneumonia (idiopathic) or ARDS (when a cause is present) is likely to explain the majority of cases of severe acute organising pneumonia with poor outcome. In such cases, the organising stage of diffuse alveolar damage may overlap with the histopathological features of organising pneumonia on lung biopsy 405, 413–419.
Rare cases of progression of COP to fibrosis and honeycombing have been reported, especially in patients with the infiltrative imaging pattern of organising pneumonia, and particularly when associated histopathological and imaging features of UIP are present 138, 248, 417, 420. In some patients, acute exacerbation of idiopathic interstitial pneumonia may comprise organising pneumonia at lung biopsy 421. Superimposed organising pneumonia was found on explant specimens from a patient with UIP who underwent lung transplantation 422. Intra-alveolar organising lesions are common in the early fibrotic lesions in UIP 423. Pathological predictors of unfavourable outcome in COP include scarring and remodelling of the background lung parenchyma, suggesting that some cases might fall into a category of subacute injury in UIP 424.
All of the previous situations correspond to cases of COP that are somewhat atypical, clinically and/or histopathologically. In such an eventuality, corticosteroid treatment should be instituted, but the outcome is uncertain.
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TREATMENT OF COP |
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Initial doses vary from 0.75–1.5 mg·kg-1·day-1, with further boluses of methylprednisolone on the first few days and a progressive decrease of dosage over the following weeks 89, 97, 425, 426. The duration of treatment is not established, but 1 yr is often proposed.
Relapses are common, but their reported frequency depends on several parameters including the existence of underlying conditions or exposures in the published series, and the duration of treatment. It varies from 13% 90 to 58% of cases 89. The current author's policy is to propose low doses of corticosteroids and a short duration of treatment, in order to avoid the side-effects of corticosteroids and treatment for long periods without necessity in patients who would not relapse 89. Since relapses are not associated with increased mortality nor long-term functional morbidity, most informed patients accept an increased risk of relapse rather than having high doses of corticosteroids for up to 1 yr.
In a study of relapses in COP 89, the initial dose of corticosteroid to treat the first episode was 50±17 mg. Relapses (2.4±2.2) occurred in 58% of patients, with 19% having multiple (three or more) relapses. In total, 32% of patients had stopped treatment for a mean (median) delay of 9±20 (2) months when the first relapse occurred. During the first relapse in the 68% of patients still receiving corticosteroids, the mean (median) dose was 12±7 mg, with only one (4%) patient receiving >20 mg. The predictors of relapse included delayed treatment and mildly increased gammaglutamyltransferase and alkaline phosphatase levels. A standardised treatment proposed by the Groupe d'Etudes et de Recherche sur les Maladies "Orphelines" Pulmonaires allowed a reduction in steroid doses; patients received 0.75 mg·kg-1 prednisone daily during 4 weeks, followed by 0.5 mg·kg-1 for 4 weeks, then 20 mg for 4 weeks, 10 mg for 6 weeks, and then 5 mg for 6 weeks before they were stopped. In severe cases, initial treatment consisted of i.v. boluses of prednisolone (2 mg·kg-1·day-1 for the first 3–5 days). Relapses while receiving prednisone at 
20 mg daily were treated by increasing prednisone to 20 mg only, then decreasing as above. The severity of hypoxaemia as a determinant for the subsequent relapse 427 was not confirmed in the present series.
Occasional spontaneous improvement of crytogenic organising pneumonia, or response to treatment with antibiotics (especially macrolides) has been reported 16.
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ACKNOWLEDGEMENTS |
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FOOTNOTES |
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REFERENCES |
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