Cryptogenic organizing pneumonia

INTRODUCTION — Cryptogenic organizing pneumonia (COP), the idiopathic form of organizing pneumonia (formerly called bronchiolitis obliterans organizing pneumonia [BOOP]), is a diffuse interstitial lung disease arising from injury to the alveolar wall. It is typically characterized by peripheral lung infiltrates and responsiveness to systemic glucocorticoid therapy [1-8].

In addition to the cryptogenic form, secondary organizing pneumonia (OP) can be seen in association with connective tissue diseases, a variety of drugs, malignancy, and other interstitial pneumonias (table 1) [2,9].

COP will be reviewed here. The other idiopathic interstitial pneumonias (IIPs) and an approach to the evaluation and diagnosis of interstitial lung disease in adults are discussed separately. (See "Idiopathic interstitial pneumonias: Classification and pathology" and "Approach to the adult with interstitial lung disease: Clinical evaluation" and "Approach to the adult with interstitial lung disease: Diagnostic testing".)

The American Thoracic Society (ATS) and European Respiratory Society (ERS) joint statement on the classification of IIPs, as well as other ATS guidelines, can be accessed through the ATS website.

EPIDEMIOLOGY — The disease onset is typically in the fifth or sixth decades of life, with males and females affected equally [8,10-12]. COP is only rarely reported in children. Past or current smoking is not considered a precipitating factor [6,13-15].

COP is a rare disease, although exact incidence and prevalence are unknown. A cumulative incidence of 6 to 7 cases per 100,000 hospital admissions was found at a major teaching hospital in Canada [13], while in a 20-year review of national statistics for Iceland, the mean annual incidence was 1.1 per 100,000 [10]. Among patients with interstitial lung disease, registry studies have reported a 5 percent prevalence of COP in Greece [16] and 10 percent in Spain [17].

PATHOGENESIS — The pathogenesis of COP remains unknown. OP is a reversible inflammatory and fibroproliferative process that does not disrupt the underlying lung architecture like most other idiopathic interstitial pneumonias (IIPs). Inciting acute alveolar epithelial injury [1,8,18] is followed by leakage of plasma proteins, recruitment of fibroblasts, and formation of fibrin within the alveolar lumen. The process culminates in alveolar organization, characterized by recruitment and proliferation of fibroblasts and myofibroblasts within the alveolar lumen to form fibroinflammatory buds (Masson polyps) (picture 1).

Abnormal regulation of vascular endothelial growth factor and matrix metalloproteinase has been reported in association with COP [19,20]. However, dysregulation of these proteins has been observed in many other pulmonary diseases, and their precise role in the pathogenesis of COP remains speculative [21]. Regulation of angiogenesis and apoptosis may influence the reversibility of the fibrotic lesions in COP, compared with the irreversible lesions in usual interstitial pneumonia [8,19,20,22].

With treatment, the inflammatory cells and fibrin deposits disappear, and the intra-alveolar buds undergo remodeling into the interstitium, leading to the restoration of the integrity and function of the alveolar unit.

A potential link between OP and microaspiration of gastric secretions in patients with gastroesophageal reflux disease (GERD) has been suggested [23]. A link to environmental factors has also been suggested [24,25].

CLINICAL FEATURES — COP is generally suspected in patients with cough, dyspnea, and unresolving or recurrent pulmonary infiltrates that clinically mimic infectious pneumonia.

History — Patients with COP typically have symptoms of cough, dyspnea, fever, and malaise that are of relatively short duration (eg, weeks to months) [1,26]. In almost three-fourths of the patients, symptoms are present for less than two months (figure 1) [27]. In one-half, the onset is heralded by the acute onset of a flu-like illness with fever, malaise, fatigue, and cough, but in other patients, the onset of symptoms is less acute. A lack of response to empiric antibiotics for community-acquired pneumonia can be the initial clue to the presence of a noninfectious, inflammatory pneumonia.

The most common features of the history at presentation are [8,27]:

●Persistent nonproductive cough (71 percent)

●Dyspnea (62 percent)

●Fever (44 percent)

●Malaise (48 percent)

●Weight loss of greater than 10 pounds (57 percent)

As with all patients who present with potential interstitial lung disease, the history should include questions about any symptoms or history suggestive of connective tissue disease (eg, arthralgias, dry eyes, dry mouth, muscle weakness, numbness, tingling), current and recent medications, and history of exposure to therapeutic irradiation, fumes, or dusts. Many of these processes can also lead to secondary OP (table 1). (See "Approach to the adult with interstitial lung disease: Clinical evaluation", section on 'History'.)

Physical examination — In patients with COP, the physical examination often reveals inspiratory crackles (60 percent) [8]. Wheezing is rare and, when present, is heard in combination with crackles; clubbing is seen in less than 5 percent of cases [28]. A normal pulmonary examination is found in less than 5 percent of patients at diagnosis [8].

Given the association of OP with many connective tissue diseases (table 1), particularly dermatomyositis, polymyositis, and scleroderma, the patient should be examined for extrapulmonary manifestations of these diseases, such as alopecia, Gottron sign, heliotrope rash, muscle weakness or tenderness, sclerodactyly, and abnormal nailfold capillaroscopy. Identification of these features is described separately.

●(See "Approach to the adult with interstitial lung disease: Clinical evaluation", section on 'Physical examination'.)

●(See "Clinical manifestations of dermatomyositis and polymyositis in adults", section on 'Skin findings in dermatomyositis'.)

●(See "Clinical manifestations of rheumatoid arthritis", section on 'Symptoms and physical findings'.)

●(See "Clinical manifestations of dermatomyositis and polymyositis in adults", section on 'Muscle weakness'.)

●(See "Clinical manifestations and diagnosis of systemic sclerosis (scleroderma) in adults", section on 'Physical examination'.)

Chest imaging — Most patients with COP will have had chest imaging for their symptoms prior to evaluation for potential interstitial lung disease.

Chest radiograph — The chest radiograph manifestations of COP are diverse, but typically demonstrate bilateral, consolidative, or ground-glass opacities in either a patchy or diffuse distribution along with relatively normal-appearing lung volumes (image 1 and image 2) [29]. Other findings may include:

●A peripheral distribution of the opacities (greater than 50 percent), similar to that seen in chronic eosinophilic pneumonia (image 1) [5,30]. (See "Overview of pulmonary eosinophilia", section on 'Chronic eosinophilic pneumonia'.)

●Recurrent or migratory pulmonary opacities (25 to 50 percent) [30].

●Unilateral consolidative and ground-glass opacities (30 to 45 percent) [11].

●Irregular linear or nodular opacities as the only radiographic manifestation (4 to 6 percent) (image 3) [11,30].

●Pleural effusion (5 percent), usually small and unilateral [11].

Computed tomographic (CT) scanning — High-resolution CT (HRCT) lung scans are typically obtained to evaluate abnormalities seen on conventional chest radiographs. Rarely, a patient may have dyspnea and hypoxemia or a reduced diffusing capacity (DLCO) without a definite abnormality on chest radiograph, and an HRCT is obtained to evaluate the gas transfer abnormality.

HRCTs from patients with COP often reveal more extensive disease than expected from review of the plain chest radiograph. Radiographic patterns include patchy air-space consolidation, ground-glass opacities, small nodular opacities, and bronchial wall thickening with dilation (image 4) [31-37]. Patchy opacities occur more frequently in the periphery of the lung and are often in the lower lung zones.

Less common radiographic appearances include multiple nodules or masses that may cavitate, micronodules, irregular reticular opacities in a subpleural location, and crescentic or ring-shaped opacities [1,27,34,38-42]. In a case series, mediastinal lymphadenopathy (diameter ≥10 mm in short axis) was reported in 6 of 16 patients with COP [43]. Pleural effusion is uncommon [1].

Confident radiographic differentiation of COP from chronic eosinophilic pneumonia is frequently not possible, as both diseases have a predilection for the peripheral lung fields (image 5 and image 6) [44]. (See 'Differential diagnosis' below and "Overview of pulmonary eosinophilia", section on 'Chronic eosinophilic pneumonia'.)

Other typical work-up

Common laboratory tests — No laboratory findings are specific for COP [5,45,46]. However, in the evaluation of patients with dyspnea, cough, fever, and pulmonary radiographic opacities, the usual laboratory tests include a complete blood count and differential, blood urea nitrogen, creatinine, hepatic function tests, and urinalysis. (See "Approach to the adult with interstitial lung disease: Diagnostic testing", section on 'Laboratory tests'.)

Leukocytosis is present in approximately 50 percent of patients with COP [27,28]. An elevated initial erythrocyte sedimentation rate (ESR; frequently reaching or exceeding 100 mm) and an elevated C-reactive protein are each observed in 70 to 80 percent, although we do not routinely obtain these tests.

For hospitalized patients whose clinical presentations suggest community-acquired pneumonia, additional tests for pathogens are usually obtained, such as sputum Gram stain and culture, urinary studies for pneumococcal and legionella antigens, human immunodeficiency virus (HIV) testing, and assays for respiratory viruses (enzyme immunoassay, immunofluorescence, or polymerase chain reaction [PCR]) [47]. Although some infections may be associated with secondary OP (table 1), positive results on one or more of these studies would argue against the diagnosis of COP.

Pulmonary function testing — Pulmonary function tests (PFTs) are obtained in most ambulatory adults with dyspnea and cough to determine whether the symptoms are associated with an obstructive or restrictive impairment and whether a gas transfer defect is present. The severity of the impairment is one of the factors used to determine the need for invasive diagnostic testing. (See "Approach to the adult with interstitial lung disease: Diagnostic testing", section on 'Pulmonary function testing' and "Overview of pulmonary function testing in adults".)

A mild to moderate restrictive ventilatory defect is the most common finding in COP (algorithm 1) [7,13,48,49]. An obstructive deficit may also be seen, but this is most likely due to a separate process such as asthma or chronic obstructive pulmonary disease (COPD) and not a result of COP [48]. Lung volumes and flow measurements may also be normal in mild disease.

Gas exchange abnormalities are extremely common. The DLCO is reduced in most patients [6,13,28,48]. Resting and/or exercise arterial hypoxemia (each defined by an alveolar-arterial oxygen gradient greater than 20 mmHg) is present in more than 80 percent of subjects, although this test is not routinely performed [48]. Pulse oxygen saturation (SpO₂) may be normal or reduced at rest but commonly is decreased with exertion.

EVALUATION

When to suspect COP — COP is a rare disease that often mimics community-acquired pneumonia and less frequently appears clinically and radiographically similar to other idiopathic interstitial pneumonias (IIPs). The most salient features are subacute cough, dyspnea, and constitutional symptoms, chest imaging with patchy or diffuse ground-glass infiltrate or consolidation, and lack of response to (often multiple courses of) antibiotic therapy. Work-up for other causes, including immunocompromising conditions, atypical infections, and rheumatologic diseases, is unrevealing. (See 'Clinical features' above.)

The additional evaluation of patients with suspected COP usually begins with high-resolution chest CT imaging, if not already performed. Additional studies may be required to exclude atypical infections, malignancy, and systemic illnesses that might be associated with diffuse parenchymal lung disease. A definitive diagnosis of COP requires surgical lung biopsy. The evaluation of interstitial lung disease more generally is discussed separately. (See "Approach to the adult with interstitial lung disease: Clinical evaluation" and "Approach to the adult with interstitial lung disease: Diagnostic testing".)

Completion of noninvasive work-up — We recommend the following noninvasive evaluation:

●High-resolution chest CT (if not already performed) – High-resolution chest CT imaging better demonstrates the extent of disease, can provide clues to other processes in the differential diagnosis, and delineates areas of disease involvement as targets for more invasive testing. (See 'Computed tomographic (CT) scanning' above.)

●Pulmonary function testing, in selected patients – In the outpatient setting, spirometry with or without lung volumes and diffusion capacity can be useful as an additional marker of disease severity and as a baseline for longitudinal monitoring. Additional diagnostics should not be delayed in order to obtain this information.

●Rheumatologic testing – OP is frequently a presenting feature of dermatomyositis and polymyositis, and less frequently an early feature of rheumatoid arthritis, systemic lupus erythematosus, and scleroderma. Even in patients without overt symptoms or signs of rheumatologic disease, testing for antinuclear antibody, rheumatoid factor, creatine kinase, antitopoisomerase [anti-Scl70], anticentromere antibody, anti-double-stranded DNA [deoxyribonucleic acid], and anti-JO1 is appropriate. We also routinely send an extended myositis panel, including anti-PL-7, anti-PL-12, and anti-MDA5, to evaluate for antisynthetase syndrome, but we do not await these results before proceeding with further diagnostics. In patients with COP (ie, without concomitant connective tissue disease), autoantibodies are usually negative or present in very low titer [27]. Laboratory testing to identify underlying connective tissue disease in the setting of interstitial lung disease is discussed separately (algorithm 2). (See "Approach to the adult with interstitial lung disease: Diagnostic testing", section on 'Laboratory tests' and "Overview of and approach to the idiopathic inflammatory myopathies".)

Invasive testing to rule out alternative diagnoses

Suspected infection, eosinophilic pneumonia, hemorrhage or lymphangitic malignancy — The vast majority of patients with suspected COP will have clinical and radiographic disease features that are also suspicious for atypical infection or eosinophilic pneumonia. For these patients and those with possible hemorrhage or lymphangitic malignancy, we recommend bronchoscopic evaluation with bronchoalveolar lavage (BAL). The technique of BAL and the preparation of lavage samples are discussed separately. (See "Role of bronchoalveolar lavage in diagnosis of interstitial lung disease" and "Basic principles and technique of bronchoalveolar lavage".)

The location for BAL may be chosen based on examination of the chest high-resolution computed tomography (HRCT) to select an area with radiographic evidence of involvement. Recent scans are required given the frequently migratory nature of the infiltrates in COP and other diseases in the differential such as chronic eosinophilic pneumonia. Alternatively, in diffuse disease, the right middle lobe or lingula is lavaged most commonly to optimize fluid recovery. (See 'Chest imaging' above and "Basic principles and technique of bronchoalveolar lavage", section on 'Optimal site'.)

There are no findings on BAL that are sensitive or specific enough to aid in the diagnosis of COP. The typical cell differential seen on BAL is a "mixed pattern" that is lymphocytic predominant (20 to 50 percent) with eosinophils (5 to 25 percent) and a small proportion of neutrophils (5 to 10 percent) [1,12].

Other (nondiagnostic) BAL abnormalities that may be found in COP patients include foamy macrophages, mast cells, plasma cells, a decreased CD4/CD8 T cell ratio, and an increase in activated T lymphocytes based on HLA-DR or interleukin (IL)-2 receptor expression [11,50,51]. Increased levels of Th1-related cytokines, including interferon (IFN)-y, IL-12, and IL-18, have been reported, although these tests are not used clinically [52,53].

Suspected granulomatous diseases — In patients with suspected granulomatous diseases (ie, tuberculosis, nontuberculous mycobacterial infection, sarcoidosis, berylliosis, and hypersensitivity pneumonitis), we recommend a transbronchial or CT-guided biopsy as a less invasive approach compared with surgical biopsy for diagnosis of these conditions (algorithm 2). The small size of these biopsies is generally inadequate for definitive confirmation of COP and exclusion of other concomitant processes. In particular, the histologic features of OP can be seen as a minor finding in other interstitial lung diseases and malignancies, so reliance on small transbronchial biopsies increases the likelihood of missing the true causative disease process. The location for performing transbronchial or CT-guided biopsies is chosen based on examination of the chest HRCT, which allows selection of an area with radiographic evidence of involvement and ability to obtain samples based on the approach. Biopsy samples are sent for histopathologic analysis and microbiologic stains and cultures. (See "Role of lung biopsy in the diagnosis of interstitial lung disease", section on 'Transbronchial lung biopsy' and "Flexible bronchoscopy in adults: Overview" and "Flexible bronchoscopy in adults: Associated diagnostic and therapeutic procedures", section on 'Transbronchial biopsy'.)

DIAGNOSIS — A definitive diagnosis of COP depends upon demonstration of the typical histopathologic features in a patient with a compatible clinical and radiographic pattern in the absence of a contributing factor or disease process (table 1) [1,27,54].

When to biopsy — As in other interstitial lung diseases, multidisciplinary discussion combining clinical, radiographic, and pathologic expertise is recommended to improve diagnostic confidence and avoid morbidity from unnecessary procedures [55]. Once the evaluation for alternative diagnoses has been completed, the risks and benefits of obtaining lung tissue for definitive diagnosis should be discussed. For many patients with suspected COP, the risks involved in missing alternative diagnoses and in receiving prolonged, possibly unnecessary, systemic glucocorticoid treatments outweigh the benefit of avoiding a surgical lung biopsy.

Alternative approaches to tissue collection (including transbronchial cryobiopsy and transbronchial biopsy) are most appropriate for patients with prototypical clinical and radiographic features, severe disease or comorbidities (eg, severe physiologic restriction, hypoxemia, respiratory failure), patient refusal of surgical lung biopsy, or a combination of these factors.

If a presumptive diagnosis is made without biopsy, failure to respond appropriately to initial COP treatment (see 'Initial approach' below) necessitates re-evaluation of the diagnosis and strong consideration of obtaining lung tissue for histologic evaluation.

How to biopsy

Surgical lung biopsy — An open or thoracoscopic lung biopsy is strongly preferred to obtain an adequate sample of lung tissue (eg, >4 cm diameter in the greatest dimension when inflated) for definitive diagnosis of COP [27,54]. The location of the lung biopsy is typically chosen based on areas of abnormality identified on the high-resolution computed tomography (HRCT) scan and on the accessibility of these areas to the surgical approach. Samples are sent for histopathologic and microbiologic analysis. (See "Role of lung biopsy in the diagnosis of interstitial lung disease", section on 'Surgical lung biopsy'.)

In addition to an adequate sample of tissue, it is important that the pathologist be given adequate clinical information to guide the search for the specific lesions and patterns that support the diagnosis. (See 'Histopathologic diagnosis of organizing pneumonia' below and "Interpretation of lung biopsy results in interstitial lung disease", section on 'Multidisciplinary discussion'.)

Transbronchial biopsy — Despite the limitations in yield and risk of misdiagnosis with smaller sample sizes on transbronchial cryobiopsy or standard transbronchial biopsy, we prefer histologic evaluation of limited tissue samples to empiric therapy if there is significant diagnostic uncertainty. (See "Role of lung biopsy in the diagnosis of interstitial lung disease", section on 'Transbronchial lung biopsy' and "Role of lung biopsy in the diagnosis of interstitial lung disease", section on 'Transbronchial cryobiopsy'.)

●Standard transbronchial biopsy – In patients with stereotypical features of the disease, some case series and guidelines suggest that a diagnosis can be made on the basis of a transbronchial biopsy [46,51,54,56-59]. One concern about relying on this approach is reduced yield based on failure to sample diseased tissue. Of equal concern, however, is the possibility of sampling a local area of organizing pneumonia within an alternative disease process (such as a different idiopathic interstitial pneumonia, vasculitis, or malignancy). This can lead to a missed diagnosis of diseases that require different treatment regimens.

●Transbronchial cryobiopsy – In centers with expertise in the technique, transbronchial cryobiopsy may increase the volume of tissue sampled, improving diagnostic yield and confidence in the eventual diagnosis. This increased yield comes with modestly increased risk of significant bleeding and pneumothorax.

Histopathologic diagnosis of organizing pneumonia — When making a histopathologic diagnosis of COP, it is necessary to satisfy two key criteria:

●The presence of the characteristic histopathologic features of OP, including intraluminal plugs of inflammatory debris predominantly within small airways, alveolar ducts, and adjacent alveoli, and mild interstitial inflammation in the surrounding lung (table 2).

●The absence of histopathologic features suggestive of another process (eg, poorly formed granulomas suggestive of hypersensitivity pneumonitis, prominent eosinophilia suggestive of chronic eosinophilic pneumonia, temporal heterogeneity of the lesions, and fibroblast foci suggestive of usual interstitial pneumonitis) (table 1). (See 'Differential diagnosis' below.)

In order to have enough tissue for the pathologist to exclude other processes, such as nonspecific interstitial pneumonia or usual interstitial pneumonia, we prefer to obtain a lung biopsy via video-assisted thoracoscopic surgery (VATS) or open thoracotomy rather than transbronchial biopsy [54]. (See 'How to biopsy' above.)

The histopathologic lesions characteristic of COP demonstrate excessive proliferation of granulation tissue, which consists of loose collagen-embedded fibroblasts and myofibroblasts, involving alveolar ducts and alveoli, with or without bronchiolar intraluminal polyps. Intraluminal plugs of granulation tissue may extend from one alveolus to the adjacent one through the pores of Kohn, giving rise to the characteristic "butterfly" pattern (picture 1 and picture 2) [27]. Bronchiolar lesions likely reflect extension of intraluminal plugs of granulation tissue from alveolar sacs and ducts to the bronchioles. Other features include a uniform appearance within involved areas and a patchy distribution without severe disruption of the lung architecture. While the pathologic lesion is predominantly within the airspace, mild chronic inflammation (eg, lymphocytes and plasma cells) is present in the alveolar walls (picture 3).

Uncommonly, the lung parenchymal remodeling is characterized by residual interstitial inflammation and fibrosis throughout the alveolar wall in a pattern like nonspecific interstitial pneumonia (NSIP) [35,60,61]. Another reported variant, dubbed cicatricial OP, demonstrates organizing airspace and airway granulation tissue and a dense, mature eosinophilic scar tissue within the lumens of airways and airspaces (picture 4) [62,63].

Histologic features of OP can also be seen within specimens from other IIPs (table 3). OP is generally only seen in a small proportion (<10 percent) of the sample. (See "Interpretation of lung biopsy results in interstitial lung disease", section on 'Interstitial pneumonias'.)

Exclusion of other specific causes of organizing pneumonia — As part of the multidisciplinary discussion, we assess potential alternative etiologies of OP before conferring a diagnosis of COP. It is impossible to differentiate COP from secondary OP based on either radiologic or pathologic findings alone. Thus, a careful review of the patient’s history, physical examination, medication usage, potential exposures, and underlying diseases is needed to determine whether OP is indeed cryptogenic (table 1).

A more complete list of drugs associated with secondary OP is available at www.pneumotox.com.

DIFFERENTIAL DIAGNOSIS — The differential diagnosis of COP includes a broad spectrum of diseases that have similar clinical features, a similar radiographic appearance, similar histopathologic findings, or overlapping histopathologic features.

Diseases with similar clinical and radiographic features

●Community-acquired pneumonia – The onset of symptoms and radiographic appearance of COP often mimic community-acquired pneumonia, but the persistence of symptoms and lack of response to antibiotics suggest COP rather than bacterial or viral infection. As secondary OP can be a consequence of certain infections, positive culture results do not necessarily exclude this diagnosis (table 1). (See "Clinical evaluation and diagnostic testing for community-acquired pneumonia in adults".)

●Chronic eosinophilic pneumonia – Chronic eosinophilic pneumonia (CEP) can have a similar clinical presentation to COP, and the radiographic pattern of subpleural patchy areas of consolidation can be seen in both diseases. Furthermore, a mixed picture that includes features of OP and eosinophilic pneumonia may be seen, suggesting that CEP can transition to COP in some patients. The differentiation of these processes usually depends on the relative proportions of the histopathologic patterns and the response to systemic glucocorticoids. When bronchoalveolar lavage (BAL) is performed, greater than 25 percent eosinophilia on the cell differential is suggestive of CEP rather than COP. COP generally has a slower response over several days to a week, while CEP typically has a more rapid response (hours to a couple days). (See "Overview of pulmonary eosinophilia", section on 'Chronic eosinophilic pneumonia' and "Interpretation of lung biopsy results in interstitial lung disease", section on 'Eosinophilic pneumonia' and "Chronic eosinophilic pneumonia", section on 'Assessing the response to therapy'.)

●Hypersensitivity pneumonitis – The clinical presentation of COP resembles that of subacute hypersensitivity pneumonitis (cough, dyspnea, fatigue, anorexia, and weight loss). The radiographic findings typical of subacute hypersensitivity pneumonitis (eg, diffuse micronodules, ground-glass attenuation) are also sometimes seen in some patients with COP. A known exposure to an etiologic agent, a higher percentage of lymphocytes on BAL, and the presence of poorly formed granulomas on lung biopsy all favor hypersensitivity pneumonitis. However, small areas of OP can be seen in hypersensitivity pneumonitis, so differentiation of these diseases requires clinicopathologic collaboration (table 1) [64,65]. (See "Hypersensitivity pneumonitis (extrinsic allergic alveolitis): Clinical manifestations and diagnosis", section on 'Histopathology' and "Interpretation of lung biopsy results in interstitial lung disease", section on 'Multidisciplinary discussion'.)

●Pulmonary lymphoma and lymphomatoid granulomatosis – The radiographic appearance of pulmonary lymphoma can resemble COP with patchy, nodular areas of consolidation and an air bronchogram. A single area of consolidation is more common in lymphoma than in COP, although focal COP can be seen. The diseases are differentiated by the histopathologic and immunohistochemical appearance. (See "Clinical manifestations, pathologic features, and diagnosis of extranodal marginal zone lymphoma of mucosa associated lymphoid tissue (MALT)".)

Pulmonary lymphomatoid granulomatosis (PLG) is a form of lymphoproliferative disease that looks like multifocal COP. In PLG, multiple poorly defined nodules are typically present on chest CT, and lung biopsy shows the triad of polymorphic lymphoid infiltrates, transmural infiltration of arteries and veins by lymphoid cells ("angiitis"), and focal areas of necrosis within the lymphoid infiltrates. (See "Pulmonary lymphomatoid granulomatosis", section on 'Pathology'.)

Organizing pneumonia in other lung diseases

●Idiopathic interstitial pneumonias – COP is one type of idiopathic interstitial pneumonia (IIP) (table 3). Sometimes, small areas (<10 percent) of OP are seen within a broader appearance of another IIP, such as nonspecific interstitial pneumonia (NSIP) or idiopathic pulmonary fibrosis (table 1). Clinicopathologic collaboration is needed to determine the correct diagnosis. (See 'Histopathologic diagnosis of organizing pneumonia' above and "Interpretation of lung biopsy results in interstitial lung disease", section on 'Multidisciplinary discussion' and "Interpretation of lung biopsy results in interstitial lung disease", section on 'Interstitial pneumonias' and "Idiopathic interstitial pneumonias: Classification and pathology".)

●Diffuse alveolar damage – Diffuse alveolar damage (DAD) is a nonspecific histopathologic reaction to lung injury most seen in patients with acute respiratory distress syndrome (ARDS). Occasional cases of COP have a fulminant onset and progress rapidly to respiratory failure [54]. In these patients, COP is the dominant pattern with areas of DAD. Conversely, a component of OP may be seen on lung biopsy specimens obtained during the proliferative phase of ARDS due to other causes (eg, acute interstitial pneumonia). Careful review of the histopathologic findings is needed to differentiate these processes. (See "Acute interstitial pneumonia (Hamman-Rich syndrome)", section on 'Pathology' and "Acute respiratory distress syndrome: Epidemiology, pathophysiology, pathology, and etiology in adults", section on 'Pathologic stages'.)

Histopathologic variants

●Granulomatous organizing pneumonia – Granulomatous organizing pneumonia (GOP) is a newly described variant of COP, characterized by a histopathologic pattern of OP in close association with small poorly formed non-necrotizing granulomas [66]. These non-necrotizing granulomas must be confined to the same peribronchiolar location and within the OP pattern. The cause of this pattern is not known, but it is thought to be an allergic or immunologic response [66].

●Acute fibrinous and organizing pneumonia – Acute fibrinous and organizing pneumonia (AFOP) is associated with a clinical picture of acute lung injury and can be idiopathic or associated with other processes, such as hypersensitivity pneumonitis, infection, drug toxicity, eosinophilic pneumonia, and rheumatic disease [67]. The histopathology is characterized by intra-alveolar fibrin deposition (fibrin "balls") and associated OP but without hyaline membranes (picture 5). Although also treated with systemic glucocorticoids, patients with this variant experience a much higher rate of OP relapse compared with patients with COP [68]. (See "Interpretation of lung biopsy results in interstitial lung disease", section on 'Rare histopathologic interstitial pneumonia patterns'.)

●Focal organizing pneumonia – Rarely, a single nodule is the only manifestation of OP; this is termed focal OP (image 7) [38,39,69].

Resection of a solitary lung nodule containing focal OP is adequate initial therapy for most patients. In three retrospective studies of patients undergoing resection for focal OP, only 2 out of a total of 80 patients required glucocorticoid therapy for local recurrence [38,39,70].

TREATMENT — The treatment of COP has not been studied in randomized trials, so treatment decisions are based on practice guidelines, observations from case series, and our clinical experience [6,12,27,45,54,71]. The decision to initiate therapy and the choice of initial therapy depend on the severity of symptoms and pulmonary function impairment at presentation, the radiographic extent of disease, and the rapidity of progression [27,54].

Initial approach

Patients with minimal symptoms and mild radiographic involvement — For patients with minimal symptoms and mild radiographic involvement, it is reasonable to monitor without therapy pending any worsening of symptoms or pulmonary function (algorithm 3). Among such patients with mild disease, spontaneous remission may rarely occur (in <10 percent of patients) [8,54]. We reassess patients at 8- to 12-week intervals for any increase in symptoms or interval worsening of performance on pulmonary function testing.

Occasional patients with mild but bothersome disease who prefer to avoid systemic glucocorticoid therapy may be trialed on long-term macrolide antibiotics if they have not already failed courses of macrolide therapy during their initial work-up. The benefit of macrolide therapy is likely related to anti-inflammatory rather than antimicrobial effects [72]. Macrolide treatment appears less effective than initiation of glucocorticoids [73].

A few case reports have described responses to a macrolide antibiotic (eg, clarithromycin 250 to 500 mg twice a day, azithromycin 250 mg daily, or azithromycin 500 mg three times a week) in patients with mild symptoms [6,72,74-76]. In these cases, a prolonged course of three to six months was needed; tapering of the macrolide to a once-daily dose was successful in some patients, but early discontinuation often led to recurrent disease. In a long-term retrospective study of 87 patients with biopsy-proven COP, 11 patients received macrolides (average duration 4.2 months, range 3 to 12 months); seven of them achieved remission without relapse, while four did not achieve remission [26].

Patients with a single resected area of OP (ie, focal OP) generally do not require further treatment. (See 'Histopathologic variants' above.)

Symptomatic patients without respiratory failure or rapidly progressive disease — The majority of patients with COP have persistent, bothersome, and progressive symptoms associated with moderate pulmonary function test (PFT) impairment and diffuse radiographic changes (algorithm 3). For these patients, we recommend initial therapy with systemic glucocorticoids, which are usually associated with rapid improvement. We typically use an initial dose of prednisone of 0.5 to 1 mg/kg per day, using ideal body weight (calculator 1), up to a maximum of 60 mg/day. We give this as a single oral dose in the morning as it tends to reduce insomnia [6,14,54]. In patients with a relative contraindication to glucocorticoid therapy, we would use azathioprine or mycophenolate mofetil, preferably in combination with a lower dose of prednisone. (See 'Glucocorticoid-sparing agents for recurrent relapses or glucocorticoid intolerance' below.)

In 12 studies with a total of 160 patients, a complete response to prednisone was seen in 60 percent, partial response in 27 percent, nonresponse in 14 percent, and a fatal outcome in 6 percent [54]. Many patients will begin to respond clinically within the first several days of treatment with glucocorticoids, and robust responses are typically seen after several weeks [6,9,11,14,24,48,77,78]. For example, one early report noted that 24 of 37 patients (65 percent) achieved improvement in symptoms within several days and complete clearance of their chest radiograph within several weeks [6]. In a later series, initial glucocorticoid therapy resulted in complete resolution of opacities on chest radiograph in 38 out of 48 (79 percent) treated patients [14]. Although spontaneous remission does occur in mild cases, frequent relapses with glucocorticoid tapering and occasional deaths after delayed diagnosis or relapse suggest that the natural history of COP without glucocorticoids is not benign.

We suggest maintaining the initial oral dose of prednisone for approximately four weeks unless there is severe glucocorticoid intolerance. The management of patients who fail to respond is discussed below. (See 'Treatment of patients who fail to respond to glucocorticoids' below.)

If the patient improves with prednisone therapy after four to six weeks of initial treatment, the dose is gradually tapered in two 4-week steps to 0.25 mg/kg per day (using ideal body weight), which we continue for four to six months. Radiologic findings typically improve or resolve over three to four months. After four to six months of oral prednisone, the dose is gradually tapered over the next six weeks to zero if the patient remains stable or improved. We recommend Pneumocystis jirovecii prophylaxis for all patients on doses of prednisone higher than 20 mg per day.

An alternative approach in patients who have improved rapidly or are having adverse effects from systemic glucocorticoids is to continue tapering slowly over three to four months after changing to the 0.25 mg/kg dosing [14]. This will modestly shorten the time on systemic glucocorticoids in patients who do not relapse but may increase the relapse risk. The management of patients who relapse during glucocorticoid taper is presented below. (See 'Treatment of relapses during glucocorticoid taper' below and 'Glucocorticoid-sparing agents for recurrent relapses or glucocorticoid intolerance' below.)

In addition to clinical assessment, the patient should be routinely followed with a conventional chest radiograph and pulmonary function testing every two to three months while on systemic glucocorticoid therapy. At the first sign of worsening or recurrent disease, the prednisone dose should be increased to the prior dose or reinstituted. Importantly, the chest radiograph may change before the patient develops significant symptoms. After cessation of glucocorticoids, we follow the patient clinically for the next year and repeat the chest radiograph approximately every three months.

Glucocorticoid treatment is associated with a variety of side effects. Thus, there needs to be a careful and ongoing assessment of risks and benefits. Steps to minimize the adverse effects (eg, infection, osteoporosis, myopathy, adrenal suppression) of systemic glucocorticoids are discussed separately. (See "Major adverse effects of systemic glucocorticoids" and "Prevention and treatment of glucocorticoid-induced osteoporosis" and "Pharmacologic use of glucocorticoids" and "Glucocorticoid withdrawal", section on 'Recommended tapering regimen'.)

Patients with rapidly progressive disease or respiratory failure — For the minority of patients who present with rapidly progressive and extensive disease, our approach depends on whether the patient requires mechanical ventilation for respiratory failure (algorithm 4).

●Patients who do not require mechanical ventilation – For these patients, we suggest initial therapy with intravenous (IV) glucocorticoids (eg, methylprednisolone 125 to 250 mg every six hours or a pulse of 750 to 1000 mg given once daily for three to five days) [54,79,80]. Once the patient shows signs of improvement (usually within five days), glucocorticoid therapy is transitioned to oral prednisone at a dose of 0.5 to 1 mg/kg per day (using ideal body weight) up to a maximum of 60 mg/day. Subsequent tapering and prevention of long-term adverse effects of glucocorticoid therapy are described above. (See 'Symptomatic patients without respiratory failure or rapidly progressive disease' above.)

If the patient fails to respond to IV glucocorticoids within five to seven days, we will add a second agent, typically azathioprine 1 to 2 mg/kg per day, although there are no published data to guide this approach. Azathioprine can be converted to mycophenolate mofetil at 1000 to 1500 mg twice daily if needed after six months. Prednisone is generally tapered to less than 20 mg daily before attempting withdrawal of the second immunosuppressing agent unless the patient is having adverse effects.

●Patients who require mechanical ventilation – For these patients, we also suggest initial therapy with high-dose IV glucocorticoids (generally methylprednisolone 250 mg every six hours or 1000 mg once daily for three to five days) [54,79,80]. Lack of response by 72 hours should prompt the addition of a second agent; typically, IV cyclophosphamide 500 to 750 mg/m² is chosen as it is felt to act most rapidly. This treatment approach is based on clinical experience, as there are no published data.

Patients requiring only steroids should transition to oral prednisone after their initial pulse at a dose of 0.5 to 1 mg/kg per day (using ideal body weight), with a maximum of 60 mg/day. Subsequent tapering and prevention of long-term adverse effects of glucocorticoid therapy are described above. (See 'Symptomatic patients without respiratory failure or rapidly progressive disease' above.)

Patients who required IV cyclophosphamide should decrease methylprednisolone dosing to 1 mg/kg per day (using ideal body weight) after three to five days, with subsequent taper guided by clinical improvement. After four weeks, cyclophosphamide should be transitioned to oral azathioprine 1 to 2 mg/kg per day, with a change to mycophenolate mofetil at 1000 to 1500 mg twice daily if needed after six months. Systemic glucocorticoids are generally tapered to less than 20 mg of prednisone daily before attempting withdrawal of the second immunosuppressing agent unless the patient is having adverse effects. (See 'Treatment of patients who fail to respond to glucocorticoids' below and "General principles of the use of cyclophosphamide in rheumatic diseases".)

Treatment of patients who fail to respond to glucocorticoids — For patients who have stable disease but fail to improve with systemic glucocorticoids, we review the initial diagnostic testing results to be sure that the patient does not have an alternate diagnosis. (See 'Differential diagnosis' above.)

Superimposed infection should also be excluded, particularly if deterioration has followed an initial improvement. In this setting, we generally repeat bronchoscopy with bronchoalveolar lavage (BAL) to detect occult infections.

●Preferred agents − After reconfirming the diagnosis of COP, a cytotoxic agent is usually started while maintaining oral prednisone. We typically use azathioprine, although data in support of this choice are limited. Due to the toxicity of cyclophosphamide, it is rarely used as an alternative in this setting. For patients with normal kidney function, we usually start azathioprine at 50 mg daily and slowly increase the dose over two to four weeks. The initial target azathioprine dose is 1 to 2 mg/kg per day (given as a single daily dose) up to a maximum of 150 mg/day, although the optimal dose in COP is unknown. A trial of at least three months is needed to ensure an adequate opportunity for clinical response. We discontinue cytotoxic agents after six months, with conversion to mycophenolate mofetil 1000 to 1500 mg twice daily, if necessary, for disease control. Glucocorticoids are generally tapered slowly once the patient has improved on an alternative agent.

Toxicity of azathioprine is partly related to deficiency in the enzyme thiopurine methyltransferase (TPMT), and analysis of the TPMT gene prior to the administration of azathioprine may help predict those individuals at risk for severe toxicity. The pharmacology and adverse effects of azathioprine are discussed separately. (See "Pharmacology and side effects of azathioprine when used in rheumatic diseases".)

●Other agents – In a few case reports, cyclosporine was used in combination with glucocorticoids to treat rapidly progressive disease [81,82]. A case series described four patients who had failed to respond to glucocorticoids but experienced at least some improvement with rituximab added to glucocorticoids; one patient had a complete response [83]. IV immunoglobulins have also been used in steroid-resistant OP [84].

Treatment of relapses during glucocorticoid taper — Relapses are common and usually occur when the glucocorticoids are tapered, most frequently when the dose is reduced to 15 mg or less. In some series, over one-half of patients experience at least one clinical relapse during their disease [9,14,35]. We suggest reinstatement of the last well-tolerated dose of glucocorticoids at the first sign of relapse, as this strategy avoids large up-titration of glucocorticoids and results in lower cumulative doses.

Some case reports and case series have also suggested benefit from the addition of a macrolide antibiotic in the setting of relapse [72,74-76,85,86].

Delayed diagnosis, delayed initiation of treatment, severe disease, and evidence of lung scarring or remodeling are associated with increased risk of relapse [9,14,87,88]. Most of these patients will improve when retreated with glucocorticoids, and the occurrence of relapses generally does not appear to affect the overall long-term prognosis [14].

Glucocorticoid-sparing agents for recurrent relapses or glucocorticoid intolerance — Patients with persistent or frequently recurrent (more than three) relapses may require long-term treatment with prednisone and a glucocorticoid-sparing agent. We typically use azathioprine as a glucocorticoid-sparing agent in patients who have responded to glucocorticoid therapy but require a high dose to control their disease, as well as in those who are intolerant of glucocorticoid adverse effects. After testing for TPMT deficiency, we initiate nondeficient patients on azathioprine at 25 to 50 mg daily, with up-titration over two to four weeks to a target dose of 1 to 2 mg/kg per day. Dose adjustment is necessary in kidney function impairment. We begin tapering prednisone only after three to four weeks on target dosing.

Data in support of glucocorticoid-sparing agents for COP are limited. A few case reports have described a favorable outcome with a combination of azathioprine and low-dose prednisone [89-91].

Use of oral mycophenolate mofetil, an inhibitor of proliferating lymphocytes, may be used as an alternative steroid-sparing agent in the treatment of COP [92,93]. Treatment with at least 2 g per day (and preferably 3 g per day) of mycophenolate mofetil is typically required to achieve a significant steroid-sparing effect. If possible, we prefer to avoid tapering prednisone until effective doses have been maintained for at least four weeks.

PROGNOSIS — Recovery, usually with complete clinical and physiologic improvement and normalization of the chest film, occurs in two-thirds of patients treated with glucocorticoids (figure 2) [1]. Symptomatic improvement is occasionally quite dramatic, occurring in one to two weeks, although many patients improve more gradually over several weeks to a few months. Serial high-resolution computed tomography (HRCT) scans may reveal persistent abnormalities despite clinical improvement [35]. Patients with airspace opacities on chest radiograph have a much better outcome than those with reticular opacities [46,94]. Approximately one-third of patients experience persistent symptoms, abnormalities on pulmonary function testing, and radiographic disease. In general, the severity of illness at presentation is related to potential for subsequent relapse. Risk factors for relapse include severity of hypoxemia, extent of radiographic abnormalities, severity of the decline in lung function, presence of an underlying illness, and length of delay before beginning treatment [9,14,87,88].

The overall prognosis of COP is much better than that of other interstitial lung diseases, such as idiopathic pulmonary fibrosis, fibrosis nonspecific interstitial pneumonia (NSIP), and acute interstitial pneumonia. Rapidly fatal COP is uncommon [60].

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Interstitial lung disease".)

SUMMARY AND RECOMMENDATIONS

●Classification – COP is one of the idiopathic interstitial pneumonias (IIPs) (algorithm 5). When organizing pneumonia (OP) is seen in association with other processes, such as connective tissue diseases, a variety of drugs, malignancy, or other interstitial pneumonias, it is called secondary OP. (See 'Introduction' above.)

●Clinical presentation – Disease onset is typically in the fifth or sixth decades of life with males and females affected equally. Most patients are symptomatic for less than two months and have a clinical presentation that mimics community-acquired pneumonia (eg, cough, dyspnea with exertion, weight loss). Approximately half of cases are heralded by a flu-like illness. (See 'Epidemiology' above and 'History' above.)

●Evaluation

•Imaging – The most common chest imaging features of COP are multiple ground-glass or consolidative opacities that tend to be at the lung periphery (image 4 and image 5 and image 8). Pulmonary function tests (PFTs) usually show a restrictive pattern with an associated gas transfer defect. (See 'Chest imaging' above and 'Pulmonary function testing' above.)

•Bronchoscopy – We typically perform flexible bronchoscopy to obtain bronchoalveolar lavage (BAL) samples for the evaluation of infection, eosinophilic pneumonia, hemorrhage, and malignancy. A transbronchial biopsy is sometimes performed during the procedure to obtain tissue for histopathologic and microbiologic studies. (See 'Invasive testing to rule out alternative diagnoses' above.)

•Lung biopsy – A surgical lung biopsy (thoracoscopic or open) is generally needed to obtain an adequate sample of lung tissue for definitive diagnosis of COP. (See 'Surgical lung biopsy' above.)

●Diagnosis – The diagnosis of COP requires histopathologic identification of a predominant pattern of OP and the exclusion of possible secondary causes (table 1). In addition, several diseases are in the differential diagnosis of COP and need to be excluded. (See 'Diagnosis' above and 'Differential diagnosis' above.)

●Initial therapy

•Choice of therapy – The decision to initiate therapy and the choice of initial therapy for COP depend on the severity of symptoms and degree of pulmonary function impairment at presentation, the radiographic extent of disease, and the rapidity of progression. (See 'Initial approach' above.)

•Minimally symptomatic patients with mild radiographic disease – For patients with COP who are minimally symptomatic and have absent or only mild abnormalities on PFTs, it is reasonable to monitor without therapy pending any worsening of symptoms or pulmonary function (algorithm 3). Patients are reassessed at 8- to 12-week intervals regarding any increase in symptoms, worsening of pulmonary function, or progression of the radiographic opacities. (See 'Patients with minimal symptoms and mild radiographic involvement' above.)

•Symptomatic patients without rapid progression or respiratory failure – For most symptomatic patients, we recommend initiation of systemic glucocorticoid therapy (Grade 1B) (algorithm 3). The usual dose is the equivalent of prednisone 0.5 to 1 mg/kg per day (using ideal body weight) up to a maximum of 60 mg/day given as a single oral dose in the morning. (See 'Symptomatic patients without respiratory failure or rapidly progressive disease' above.)

•Patients with rapid progression or respiratory failure – For patients with rapidly progressive disease or actual/impending respiratory failure, we suggest initial high-dose intravenous (IV) glucocorticoid therapy rather than a lower oral dose (Grade 2C) (algorithm 4). We use methylprednisolone 500 to 1000 mg intravenously each day for three to five days. For patients on mechanical ventilatory support or who fail to respond quickly to IV glucocorticoids, we suggest the addition of a second immunosuppressive agent (Grade 2C). We typically use IV cyclophosphamide, with dosing described above. (See 'Patients with rapidly progressive disease or respiratory failure' above.)

●Subsequent therapy

•Good response to glucocorticoids – Glucocorticoid therapy usually induces clinical improvement within several days and clearing of the opacities on chest imaging within a few weeks. Oral glucocorticoid therapy is transitioned to 0.25 mg/kg ideal body weight per day after four weeks and continued for four to six months. Prednisone is then gradually tapered as tolerated over 6 to 12 months. Relapses are common upon stopping or reduction of glucocorticoids, which requires interruptions of the taper and reinitiation of the last well-tolerated prednisone dose. (See 'Symptomatic patients without respiratory failure or rapidly progressive disease' above and 'Treatment of relapses during glucocorticoid taper' above and 'Prognosis' above.)

•Poor response to glucocorticoids – For patients who have stable disease but fail to improve with systemic glucocorticoids, we review the initial diagnostic testing results to be sure that the patient does not have an alternate diagnosis. After reconfirming the diagnosis of COP, we suggest starting a cytotoxic agent (Grade 2C).We typically use azathioprine, while maintaining oral prednisone. After response, azathioprine should be tapered or converted to mycophenolate mofetil. (See 'Treatment of patients who fail to respond to glucocorticoids' above.)

•Recurrent relapses or inability to taper glucocorticoids – For patients who are unable to taper glucocorticoids to a level that does not cause intolerable adverse effects, we suggest adding a second immunosuppressive agent (Grade 2C); azathioprine and mycophenolate mofetil are reasonable choices, although data are limited. (See 'Glucocorticoid-sparing agents for recurrent relapses or glucocorticoid intolerance' above.)

●Mitigating adverse effects of therapy – Glucocorticoid treatment is associated with a variety of side effects. Steps to minimize the adverse effects (eg, infection, osteoporosis, myopathy, adrenal suppression) of systemic glucocorticoids are discussed separately. (See "Major adverse effects of systemic glucocorticoids".)