Chapter 50 Organizing Pneumonia

Definition

Organizing pneumonia (OP) is a histopathologic diagnosis defined by a well-recognized pattern of changes underlying a characteristic clinical-pathologic entity. OP may occur in the absence of etiologic context, in which case it is known as cryptogenic organizing pneumonia (COP), or in association with a known causative agent or inflammatory disorder such as connective tissue disease, where it is called secondary organizing pneumonia.

Initially described as the specific histopathologic pattern resulting from organization of an inflammatory exudate in the lumen of alveoli of unresolved pneumonia, OP is characterized by intraalveolar buds of granulation tissue with fibroblasts and myofibroblasts intermixed with loose connective matrix (Figure 50-1). Similar lesions may be present within the lumen of the bronchioles—hence the formerly synonymous term bronchiolitis obliterans with organizing pneumonia (“BOOP”). The latter designation has been abandoned, however, because OP (rather than bronchiolitis) is clearly the major lesion, and furthermore, use of the older term was a potential source of confusion between this entity and bronchiolitis with airflow obstruction occurring, for example, after lung or hematopoietic stem cell transplantation. Although the condition is not strictly interstitial, COP is included in the American Thoracic Society/European Respiratory Society international consensus classification of the idiopathic interstitial pneumonias, because of its idiopathic nature and occasional similarities with interstitial pneumonias.

Figure 50-1 Buds of granulation tissue (arrows) in the lumen of alveoli.

(Courtesy F. Thivolet-Béjui, Lyon.)

Pathogenesis

OP is a unique condition characterized by intraalveolar accumulation of intermixed fibroblasts and connective matrix, especially collagen, that is reversible with corticosteroids, in contrast with other presentations of pulmonary fibrosis and especially that of usual interstitial pneumonia or idiopathic pulmonary fibrosis.

The first event of the sequence leading to the formation of intraalveolar buds is alveolar epithelial injury with necrosis of pneumocytes (especially type I) (Figure 50-2). The epithelial basal laminae are denuded and injured, resulting in formation of gaps. Capillary endothelial injury often is associated. The consequence of alveolar injury is flooding of the alveolar lumen by plasma proteins (permeability edema), including coagulation factors. The balance between coagulation and fibrinolysis is clearly tipped in favor of coagulation (especially because of decreased fibrinolysis), leading to accumulation of fibrin deposits that are soon populated by migratory inflammatory cells and fibroblasts.

Figure 50-2 Formation of the intraalveolar buds of granulation tissue characterizing organizing pneumonia. A, Structure of the normal alveolar space. AL, alveolar lumen; BL, basal laminae; CAP, capillaries; IC, interstitial cells; P1, type 1 pneumocytes; P2, type 2 pneumocytes. B, Alveolar injury with alteration and necrosis of alveolar epithelial cells (especially type 1 pneumocytes), denudation of basal laminae with formation of gaps, and leaking of plasma proteins, especially coagulation factors (arrows) with formation of fibrin (FIB) within the alveolar lumen. Some inflammatory cells and macrophages (M) are present. C, The intraluminal alveolar fibrin network has been colonized by mitotic fibroblasts (MitF), with some acquiring a myofibroblast (MF) phenotype characterized by presence of myofilaments beneath the cytoplasmic membrane. Fibroblasts and myofibroblasts have a developed rough endoplasmic reticulum and produce a loose connective matrix (composed of collagen types I and III, fibronectin, and proteoglycans) interspersed between the cells. Neoformed capillaries (NC) are present within this intraalveolar bud of granulation tissue, resembling those characteristic of the wound healing process.

Fibroblasts differentiate into myofibroblasts that organize and represent the predominant cell of fibroinflammatory buds. Inflammatory cells and fibrin are progressively replaced by aggregated fibroblasts/myofibroblasts intermixed with a loose connective matrix tissue rich in collagen (especially collagen III) and fibronectin. This process, resembling that of cutaneous wound healing, is similarly reversible, without significant sequelae. It is likely that the relative preservation of the alveolar basal laminae is crucial in determining the reversibility of the lesions. Although COP and secondary OP appear very similar, the microvascular density and the density of collagen fibers within intraalveolar air spaces may be higher in secondary OP than in COP.

Mouse models of intraluminal inflammation have been developed using reovirus infection to induce the histopathologic changes. Lesions similar to OP have been obtained by intranasal inoculation of moderate doses of virus only in a susceptible strain of mice (CBA/J), suggesting that genetic background may contribute to pathogenesis of the condition in mice. Alveolar macrophages and T lymphocytes were implicated in the disease process. Of interest, diffuse alveolar damage with hyaline membrane formation was obtained with the same animal model when higher doses of virus were used. These experimental studies suggest that the intensity of the initial epithelial injury and yet undetermined factors inherent to the host may influence the evolution to either OP or diffuse alveolar damage. Other animal models of OP have been developed in rats inoculated with bacteria and in pigs infected with a circovirus.

The cellular origin of fibroblasts that populate the distal air spaces is unclear. The respective contribution of proliferating lung fibroblasts, fibrocytes or bone marrow–derived fibroblasts, and epithelial-mesenchymal transition has not been evaluated in OP. The mechanism by which corticosteroids facilitate the rapid resolution of OP also is unclear. Several studies have highlighted some characteristics that distinguish the reversible fibrotic budding characteristic of OP from the uncontrolled process of accumulation of fibroblastic foci and collagen deposition seen in usual interstitial pneumonia, including a distinct pattern of expression of metalloproteases, the increased vascularity of fibrotic buds, and a lower apoptotic activity in granulation tissue. In addition, the expression of tumor necrosis factor-α receptor-1 and Fas by alveolar macrophages is higher in patients with OP than in control subjects or patients with idiopathic pulmonary fibrosis. Overall, OP may be considered as a model of normal wound repair, contrasted with the uncontrolled aberrant repair and fibrosing process observed in usual interstitial pneumonia of idiopathic pulmonary fibrosis.

Clinical and Imaging Features

Cryptogenic Organizing Pneumonia

Clinical Features

The mean age at onset of COP is approximately 50 to 60 years, with no gender predilection. It is more common in nonsmokers or former smokers. The initial manifestations are fever, cough, malaise, anorexia, and progressive weight loss, with a subacute onset over a few weeks. The median duration of the clinical syndrome is less than 3 months. Dyspnea usually is mild. Hemoptysis, chest pain, and severe dyspnea are rare. Crackles may be heard at pulmonary auscultation over involved areas, with clinical features of consolidation in rare instances. Finger clubbing is absent. In many patients, the diagnosis is considered after they have received antibiotics for presumed infectious pneumonia without improvement.

Lung function tests in COP show a mild to moderate restrictive ventilatory pattern and may occasionally yield normal results. The carbon monoxide transfer factor is reduced in most patients, whereas the carbon monoxide transfer coefficient (KCO) is within normal limits. Hypoxemia usually is mild. When present, severe hypoxemia may be associated with diffuse infiltrative opacities or right-to-left shunting in perfused areas of lung consolidation.

Blood tests often show moderate leukocytosis and increased C-reactive protein but no significant peripheral blood eosinophilia.

Imaging Features

The imaging features of COP may consist of a variety of high-resolution computed tomography (HRCT) findings, some of which are highly suggestive of the diagnosis. The most typical imaging pattern in COP consists of multiple patchy alveolar opacities (Figures 50-3 and 50-4). These usually are bilateral, with a subpleural distribution, and sometimes migratory (with attenuation or clearing in some areas and appearance of new opacities in others), ranging in density from ground glass to consolidation with air bronchogram, with no predominance in cranial versus caudal distribution. The size of the opacities may vary, ranging from 1 to 2 cm to involvement of an entire lobe. Consolidation at imaging corresponds pathologically with intraalveolar buds of granulation tissue within the distal air spaces, whereas areas of ground glass opacity reflect the cell infiltration of alveolar wall by inflammatory cells, with some OP changes in the distal air spaces. This imaging pattern with multiple patchy alveolar opacities, especially those of a migratory nature, is so characteristic of typical COP that it should immediately suggest the diagnosis. The main other consideration in the differential diagnosis at this stage is idiopathic chronic eosinophilic pneumonia (in the latter, blood eosinophilia with cell counts usually greater than 1500/µL is present; conversely, nodules may be found more frequently in COP than in chronic eosinophilic pneumonia).

Figure 50-3 Chest radiographs showing the typical imaging pattern in cryptogenic organizing pneumonia. A, Patchy alveolar opacity. B, Six days later, the distribution of the right lower lobe opacity has changed, with appearance of a new contralateral basal opacity.

Figure 50-4 High-resolution computed tomography (HRCT) features of typical cryptogenic organizing pneumonia (COP). Patchy bilateral consolidation with peripheral predominance and air bronchogram, associated with ground glass opacities in the right lower lobe, are evident.

Patchy ground glass opacities frequently are observed, usually associated with consolidation. The reverse halo sign or atoll sign (Figure 50-5), consisting of a circular consolidation pattern (corresponding histopathologically to organizing pneumonia in the distal air spaces) surrounding an area of ground glass opacities (corresponding to alveolar wall inflammation), also is highly suggestive of the diagnosis, although not specific.