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.

Figure 50-5 Reverse halo sign (atoll sign) on high-resolution computed tomography (HRCT) scan.

Another imaging pattern in COP is a solitary focal nodule or mass-like area of consolidation that may mimic lung carcinoma especially when associated with hypermetabolism on positron emission tomography. It commonly is located in the upper lobes and usually is asymptomatic. An air bronchogram may be present. Diagnosis often is obtained by surgical resection of the lesion in the suspicion of cancer. Solitary focal COP likely represents nonresolving infectious pneumonia in a number of cases.

The infiltrative (or progressive fibrotic) pattern of OP associates interstitial opacities, with small superimposed alveolar opacities on HRCT (with possible perilobular pattern consisting of bowed or polygonal opacities with poorly defined margins bordering the interlobular septa). Honeycombing is not present. Infiltrative or progressive COP may overlap on both histopathologic and imaging studies with idiopathic nonspecific interstitial pneumonia (NSIP), with uniform alveolar and interstitial cellular inflammation (with more or less fibrosis), with the possible presence of foci of organizing pneumonia. Such imaging presentation of OP seems to be particularly frequent in patients with idiopathic inflammatory myopathy (Figure 50-6).

Figure 50-6 High-resolution computed tomography (HRCT) features of progressive organizing pneumonia (OP). The patient had idiopathic inflammatory myopathy. Reticular, hazy, perilobular opacities are evident in the lower lobes.

Several less common imaging presentations of COP have been occasionally reported, including multiple nodules, cavitary opacities, perilobular opacities, centrilobular or peribronchovascular ill-defined nodules, bronchocentric areas of consolidation, and linear subpleural bands (Box 50-1). A few mediastinal lymphadenopathies are not rare in COP. Pleural effusion is uncommon.

Box 50-1

High-Resolution Computed Tomography Patterns in Organizing Pneumonia

• Multiple patchy alveolar opacities (classic COP pattern)

• Focal pattern

• Nodular pattern

• Bronchocentric pattern

• Linear and bandlike pattern

• Perilobular pattern

• Reverse halo pattern

• Progressive fibrosis pattern

COP, cryptogenic organizing pneumonia.

Modified from King TE: Organizing pneumonia. In Schwarz MI, King TE, editors: Interstitial lung disease, ed 5, Shelton, Conn, People’s Medical Publishing House, 2011, pp 981–984.

Whereas mimics of COP with typical imaging features are few, mimics of COP presenting as nodules, masses, or infiltrative lung diseases are many (Box 50-2).

Box 50-2

Mimics of Cryptogenic Organizing Pneumonia (COP) on Chest Imaging

Multiple patchy alveolar opacities (classic COP pattern)

Eosinophilic pneumonia (especially chronic idiopathic)

Pneumonic-type invasive mucinous adenocarcinoma of the lung

Primary pulmonary lymphoma (low-grade B cell lymphoma of mucosa-associated lymphoid tissue [MALT])

Others: infectious pneumonia, tuberculosis or nontuberculous mycobacterial infection, granulomatosis with polyangiitis (Wegener granulomatosis), diffuse alveolar hemorrhage, multiple-infarct lesions, aspiration pneumonia

Solitary focal nodule or mass (focal pattern)

Lung carcinoma

Round pneumonia or abscess

Inflammatory pseudotumors

Others: all causes of coin lesions or masses

Diffuse infiltrative opacities (progressive or fibrosis pattern)

Idiopathic interstitial pneumonias, especially nonspecific interstitial pneumonia and idiopathic pulmonary fibrosis (especially acute exacerbation)

Interstitial pneumonias overlapping with organizing pneumonia

Others: all causes of infiltrative opacities, especially of infectious or neoplastic origin

Diagnosis

A thorascopic lung biopsy is recommended for a definitive histopathologic diagnosis of OP, also ruling out other conditions that may mimic OP.

When nonspecific clinical manifestations associated with typical imaging features suggest the diagnosis of COP, fiberoptic bronchoscopy (which excludes any bronchial obstruction) with BAL is first necessary, and transbronchial biopsy may be contributive. The BAL fluid differential cell count in COP often shows a mixed pattern with increased levels of lymphocytes (20% to 40%), neutrophils (approximately 10%), and eosinophils (5%); some mast cells and plasma cells may be present. The transbronchial lung biopsy specimens may show typical buds of granulation tissue within alveoli. Infectious agents must be systematically searched for on BAL fluid preparations (and on transbronchial biopsy specimens by specific staining, if performed). The combination of a typical clinical-radiologic pattern and a mixed pattern on BAL fluid differential cell count is considered highly suggestive of OP (and of COP in the appropriate clinical context). A decreased ratio of CD4⁺ to CD8⁺ lymphocytes in BAL has been reported in COP.

OP is a nonspecific consequence of interstitial inflammation that may be present as an accessory finding in many disorders, including nonspecific interstitial pneumonia, organizing diffuse alveolar damage, aspiration pneumonia, vasculitides, distal obstruction of the airways, and occult aspiration pneumonia. Some histopathologic overlap may exist with chronic eosinophilic pneumonia or the OP-like variant of granulomatous polyangiitis (Wegener granulomatosis). Additional findings suggestive of another diagnosis in secondary OP include necrosis or microabscesses (seen in infectious processes and necrotizing vasculitis) and organic debris (as in occult aspiration pneumonia).

With transbronchial biopsy, the small size of specimens obtained by this method does not allow exclusion of other histopathologic patterns, so the findings should therefore be considered diagnostic of OP only in patients with a typical clinical-imaging profile. The sensitivity and specificity of transbronchial biopsy for the diagnosis of OP have not been rigorously evaluated. Core needle biopsy generally is safe and may be appropriate in a minority of patients with suspected OP, especially with focal consolidation at imaging. Videothorascopic lung biopsy remains the most appropriate procedure to obtain specimens of sufficient size both to make a definitive diagnosis of OP and to exclude other processes. When performed, the biopsy should be done before corticosteroids are initiated and should be planned in a preoperative discussion between the surgeon and the physician or a radiologist. Microbiologic analysis also may be performed on the lung specimen.

A reasonable alternative to lung biopsy is to proceed with appropriate management, to include presumptive treatment as indicated, in the absence of confirmation of the histopathologic pattern of OP. Although this approach commonly is used in clinical practice, it carries the risk of misdiagnosing alternative conditions that may mimic OP, including eosinophilic pneumonia, low-grade primary pulmonary lymphoma, and bronchioloalveolar carcinoma (see Box 50-2). Only patients in whom typical findings on imaging studies (e.g., multiple patchy consolidation) are associated with compatible clinical and BAL features should be treated without biopsy; particular attention must be paid to any clue to an alternative diagnosis (e.g., peripheral blood and/or BAL fluid eosinophilia, suggestive microbiologic findings in BAL fluid). When pathologic investigation is not available or consists of only transbronchial biopsy, the diagnosis should be reconsidered whenever the observed clinical response is unusual (especially in case of incomplete response to corticosteroids or relapse despite more than 20 mg/day of oral prednisone).

As in other conditions among the group of idiopathic interstitial pneumonias, the “gold standard” for diagnosis of OP is now the clinical-radiologic-pathologic approach, which effectively ensures that imaging and clinical data, as well as pathology data when available, are consistent with and specific for this entity. Although interobserver agreement for a clinically based diagnosis usually is fair to good, the multidisciplinary approach is particularly useful in cases with histopathologic features overlapping with those of eosinophilic pneumonia, nonspecific interstitial pneumonia, or diffuse alveolar damage. The clinical assessment must include a careful history and evaluation for the presence of comorbid diseases such as connective tissue disease (including formes frustes of connective tissue disease or undifferentiated connective tissue disease), cancer, thoracic radiotherapy for breast cancer, exposure to drugs, inflammatory bowel disease, aspiration, or less common conditions such as common variable immune deficiency (see Box 50-5). A final diagnosis of COP can be made only after all available data including findings on etiologic investigations have been reviewed in a dynamic process requiring close communication among the clinician, the radiologist, and the pathologist.

Treatment of Cryptogenic Organizing Pneumonia

Corticosteroid treatment is standard therapy for COP and results in rapid clinical and imaging improvement in typical cases. With institution of therapy, consolidation evolves to ground glass opacities and reticulation and eventually regresses completely within a month; the less frequent linear or reticular opacities may not resolve. The optimal doses and duration of treatment have not been established, and treatment should aim at the best balance between disease control and side effects. We start with prednisone, 0.75 mg/kg per day for 4 weeks, and then continue with progressively decreasing doses for a total duration of treatment of 24 weeks (Table 50-1). This regimen limits intense and prolonged corticosteroid treatment with ensuing risk of iatrogenic complications. Other treatment protocols with slower tapering of dosage have been proposed. Parenteral corticosteroid therapy at higher doses often is used as the initial treatment in patients with the progressive or fibrotic variant of COP. Cyclophosphamide or azathioprine may be used in patients whose clinical condition deteriorates despite corticosteroid therapy. Of note, spontaneous improvement has been reported in some cases of COP. Macrolides have been suggested for their antiinflammatory properties as an alternative option in patients who are intolerant to corticosteroids or who experience frequent relapses; however, the benefit initially observed in case reports is not confirmed with empirical routine use of these drugs. Secondary OP requires treatment of the underlying condition (connective tissue disease, infection) or withdrawal of the causative drug or exposure. Focal COP does not require corticosteroid therapy after surgical resection (performed for suspected lung cancer).

Table 50-1 Proposed Therapeutic Regimen for Typical Cryptogenic Organizing Pneumonia

Most cases of typical COP with alveolar consolidation have a rapid and sometimes dramatic improvement with initiation of corticosteroid therapy, but a minority of patients will have persistent disease, especially those with reticulation on HRCT. Relapses are common (occurring in up to 60% of cases) on decreasing or after stopping treatment and may be treated with prednisone in doses of 20 mg per day given for 2 weeks and then progressively decreased. Relapses of the disease should prompt a search for a persisting cause of OP, especially drug intake. Relapses occurring with daily doses of more than 15 to 30 mg of prednisone (depending on body weight) should prompt extensive reappraisal of the diagnosis and further clinical-radiologic-pathologic consultation, especially when a large sample is not available for histopathologic analysis. The overall prognosis with typical COP is excellent.

Severe Organizing Pneumonia

Cases of severe COP have been reported, with potentially severe respiratory failure necessitating mechanical ventilation. Such cases only occasionally are found to be associated with “pure OP” histopathologic lesions. They usually represent overlap of COP with one of the following disorders: acute respiratory distress syndrome (ARDS) with pathologic features of diffuse alveolar damage undergoing organization, acute fibrinous and organizing pneumonia (AFOP), or usual interstitial pneumonia exacerbation. In patients with acute exacerbation of idiopathic pulmonary fibrosis, features of diffuse alveolar damage and/or of OP are found in association with preexisting usual interstitial pneumonia. In such cases, the response to corticosteroids is not as favorable as in classic COP. Immunosuppressive agents (especially cyclophosphamide) usually are added to corticosteroids (often used at a higher dose, starting with 1 to 2 mg/kg per day of intravenous methylprednisolone), with variable outcome.

Acute Fibrinous and Organizing Pneumonia

AFOP is a histopathologic pattern first reported in patients with acute respiratory failure, with predominantly basal and bilateral areas of consolidation at imaging. It is characterized by abundant fibrin deposition within the alveolar air spaces, with hyperplasia of type II pneumocytes, associated organizing-type pneumonia, and absence of hyaline membranes (which constitute the hallmark of diffuse alveolar damage). AFOP currently is considered to be a histopathologic variant of OP that may be associated with more rapid progression of disease. As with OP, AFOP may be encountered in the context of various underlying conditions, including infection.

Controversies and Pitfalls