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INTRODUCTION — Cryptogenic organizing pneumonia (COP), the idiopathic form of organizing pneumonia (formerly called idiopathic bronchiolitis obliterans organizing pneumonia or BOOP), is a distinct clinical entity with predominant features of pneumonia, rather than a primary airway disorder [1-7]. Organizing pneumonia can also be seen in association with connective tissue diseases, a variety of drugs, malignancy, and other interstitial pneumonias [2,8].
Cryptogenic organizing pneumonia will be discussed here. An overview of the idiopathic interstitial pneumonias is presented separately. (See "Idiopathic interstitial pneumonias: Clinical manifestations and pathology".)
The American Thoracic Society (ATS) and European Respiratory Society (ERS) statement on the classification of idiopathic interstitial pneumonias, as well as other ATS guidelines, can be accessed through the ATS web site at www.thoracic.org/statements.
PATHOLOGICAL CHANGES — The histopathologic lesions characteristic of COP include excessive proliferation of granulation tissue within small airways (proliferative bronchiolitis) and alveolar ducts, associated with chronic inflammation in the surrounding alveoli. This organizing pneumonia is the most important process underlying the clinical and radiographic manifestations of COP. There are, in addition, several other key features (table 1) :
- A uniform, temporally recent appearance to the changes, without severe disruption of the lung architecture
- A patchy and peribronchiolar distribution
- Localization of lesions within the airspaces (figure 1)
- Foamy macrophages are commonly seen in the alveolar spaces, presumably secondary to the bronchiolar occlusion
- Intraluminal buds of granulation tissue consist of loose collagen-embedding fibroblasts and myofibroblasts that extend from one alveolus to the adjacent one through the pores of Kohn, giving rise to the characteristic "butterfly" pattern (picture 1 and figure 2) .
- Bronchiolar lesions are secondary to intraluminal plugs of granulation tissue always in association with plugs in the alveolar ducts and alveolar spaces.
- Severe fibrotic changes, such as honeycombing, are unusual at the time of diagnosis.
- Giant cells are rare or absent, and no granulomas or vasculitic lesions are present.
The pathogenesis of these changes remains unknown. Abnormal vascular endothelial growth factor and matrix metalloproteinase regulation has been reported in association with COP [10,11]. However, dysregulation of these proteins has been observed in a large number of other pulmonary diseases, and their precise role in the pathogenesis of COP remains speculative . Regulation of angiogenesis appears to influence the reversibility of the fibrotic lesions in COP, compared to the irreversible lesions in usual interstitial pneumonia [10,11].
CLINICAL PRESENTATION — The incidence and prevalence of COP are unknown, though a cumulative incidence of six to seven per 100,000 hospital admissions was found at a major teaching hospital . The disease onset is typically in the fifth or sixth decades of life, with men and women affected equally . Almost three-fourths of the patients are symptomatic for less than two months before presentation (figure 3). Cigarette smoking is not a precipitating factor .
Symptoms and signs — The clinical presentation of COP often mimics that of community-acquired pneumonia. In one-half of cases, the onset is heralded by a flu-like illness with fever, malaise, fatigue, and cough. The most common features at presentation are:
- Persistent nonproductive cough
- Dyspnea with exertion
- Weight loss of greater than 10 pounds (57 percent of subjects).
Physical examination often reveals inspiratory crackles (74 percent). Wheezing is rare and is usually present with rales, while clubbing is seen in less than 5 percent of cases . A normal pulmonary examination is found in one-fourth of subjects .
Laboratory findings — Routine laboratory studies are nonspecific [5,17,18]. Leukocytosis is present in about 50 percent of patients, while an elevated initial ESR (frequently reaching or exceeding 100 mm) and a positive C-reactive protein are each observed in 70 to 80 percent [9,16]. Autoantibodies are usually negative or present in very low titer .
Chest imaging studies
Chest radiograph — The chest radiograph manifestations of COP are quite distinctive, with bilateral, diffuse opacities in the presence of normal lung volumes occurring in most patients (picture 2 and picture 3) . Other changes include:
- A peripheral distribution of the opacities, similar to that seen in chronic eosinophilic pneumonia, may also be found in COP [5,19].
- The consolidative and ground-glass opacities are rarely unilateral .
- Recurrent or migratory pulmonary opacities are common (up to 50 percent of subjects in some series) .
- Irregular linear or nodular opacities are rarely present as the only radiographic manifestation (picture 4).
- Honeycombing is rarely seen at presentation in patients with COP and occurs as a late manifestation in the few patients with progressive disease.
- Other rare radiographic abnormalities include pleural effusion, pleural thickening, hyperinflation, and cavities.
The severity of the radiographic abnormalities correlates with the extent of histologic involvement of the respiratory bronchioles and alveolar ducts, but not the larger terminal bronchioles.
Computed tomographic scanning — Computed tomographic (CT) lung scans 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 (picture 5) [22-25]. Patchy opacities occur more frequently in the periphery of the lung and are often in the lower lung zone.
Confident radiographic differentiation of COP from chronic eosinophilic pneumonia is frequently not possible, as both diseases have a predilection for the peripheral lung fields (picture 6 and picture 7) . Rarely, a single nodule is the only manifestation of organizing pneumonia; this is termed focal organizing pneumonia .
Pulmonary function tests — A mild to moderate restrictive ventilatory defect is most common. In contrast, an obstructive defect (FEV1/FVC ratio less than 70 percent) was found in only 20 percent of patients in one report, all of whom were current or former smokers. Lung function is occasionally normal.
The pressure-volume curve is shifted downward and to the right, consistent with a stiff, noncompliant lung. The maximal transpulmonary pressure and the coefficient of elastic recoil (maximum transpulmonary pressure/total lung capacity) are increased.
Gas exchange abnormalities are extremely common. The diffusing capacity (DLCO) is reduced in the majority of patients. Resting and/or exercise arterial hypoxemia (each defined by an alveolar-arterial oxygen gradient greater than 20 mmHg) are present in more than 80 percent of subjects .
Bronchoalveolar lavage — The percentage of the volume of bronchoalveolar lavage (BAL) fluid recovered from patients with COP is less than that recovered from healthy volunteers, but the total number of cells recovered is greater from patients with COP . In general, the BAL findings are most similar to those in hypersensitivity pneumonitis. The proportion of macrophages is lower in COP than in normals, whereas the proportions of lymphocytes, neutrophils, and eosinophils are higher . Patients with COP tend to have higher lymphocyte counts than do those with idiopathic pulmonary fibrosis, with expansion of CD8 cells and increased levels of Th1 related cytokines, including IFN-y, IL-12 and IL-18 [29,30].
Other BAL abnormalities found in COP patients include [20,31]:
- Foamy macrophages
- Occasionally, mast cells and plasma cells
- Decreased CD4/CD8 cell ratio, while the percentage of CD57+ cells is normal
- An increase in activated T-cells, in terms of HLA-DR expression and occasionally interleukin-2 receptor (CD25) expression
The "mixed pattern" of increased cellularity is thought to be characteristic of COP, especially in the proper clinical setting, eg, when associated with multiple alveolar opacities on chest radiograph .
DIAGNOSIS — The diagnosis of COP depends on finding the characteristic pathological features of the disease in the proper clinical setting, and the absence of features suggestive of another process (table 2) . The differential diagnosis often includes:
- Bacterial pneumonia
- Diffuse alveolar damage (acute respiratory distress syndrome)
- Hypersensitivity pneumonitis
- Chronic eosinophilic pneumonia
- Pulmonary drug reaction
- Pulmonary disease associated with a connective tissue disorder
Lung biopsy — An open or thoracoscopic lung biopsy is suggested to confirm the diagnosis. Ample lung tissue must be obtained and carefully reviewed to rule out other diseases. Step sectioning of transbronchial biopsies may be useful in identifying the lesions of COP , but transbronchial biopsies generally do not provide an adequate sample to definitively confirm COP and rule out other disorders. Because the histologic features of bronchiolitis obliterans associated with areas of organizing pneumonia can be seen in a number of settings, reliance on small transbronchial biopsies increases the chance of missing the central diagnosis.
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. Once the characteristic histologic lesions of proliferative bronchiolitis are confirmed, the clinician must ensure that a thorough search has been performed to rule out the many possible processes that induce similar pathological findings (table 2). (See 'Pathological changes' above.)
The clinicopathological syndrome of COP is a diagnosis of exclusion. (See "Role of lung biopsy in the diagnosis of interstitial lung disease".)
TREATMENT — In cryptogenic organizing pneumonia, spontaneous improvement is rare; most patients will need therapy with glucocorticoids, although resection may be adequate initial therapy for focal organizing pneumonia [6,14,17].
Glucocorticoids — Therapy is usually initiated with prednisone at 1.0 to 1.5 mg/kg per day (using ideal body weight) to a maximum of 100 mg/day given as a single oral dose in the morning.
We recommend maintaining this dose for four to eight weeks. If the patient is stable or improved, the prednisone dose is gradually tapered to 0.5 to 1.0 mg/kg per day (using ideal body weight) for the ensuing four to six weeks. High-dose parenteral glucocorticoid therapy (methylprednisolone 125 to 250 mg every six hours intravenously for three to five days) has been recommended as the initial treatment in patients with rapidly progressive severe disease.
Prednisone is gradually tapered to zero if the patient remains stable or improved after three to six months. The patient should be routinely followed with plain chest radiograph and pulmonary function testing every six to eight weeks during the first year, and therapy should be reinstituted aggressively at the sign of any recurrence. Importantly, the chest radiograph may change before the patient develops significant symptoms.
Other immunosuppressive drugs — If the patient has deteriorated despite, or cannot tolerate adequate glucocorticoid therapy, a cytotoxic agent should be started while generally maintaining low-dose (0.25 mg/kg per day) oral prednisone, if tolerated. We most often use cyclophosphamide in this setting. The recommended dose is one to two mg/kg per day (given as a single daily dose), although the optimal dose in COP is unknown. We usually start at 50 mg daily and slowly increase the dose over two to four weeks. We do not recommend exceeding 150 mg/day. A trial of at least three to six months is needed to ensure an adequate opportunity for clinical response.
Hematologic alterations are common side effects of cyclophosphamide therapy and frequently necessitate dose adjustment — the total white blood cell count should be maintained above 4000/mm3. Leukopenia is the most common manifestation of hematologic toxicity, with anemia and thrombocytopenia occurring less often. (See "General toxicity of cyclophosphamide and chlorambucil in inflammatory diseases".)
Macrolide antibiotics — A few case reports have described responses to a macrolide antibiotic (eg, clarithromycin 250-500 mg twice a day) in patients with mild symptoms [6,33,34]. 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 led to recurrent disease. It is thought that the benefit of the macrolide was related to anti-inflammatory rather than antimicrobial effects . More commonly, the diagnosis of COP is made after a patient has failed one or more courses of antibiotics. Macrolides are not indicated for the vast majority of patients, but may be a second line option for patients with mild disease who are intolerant of glucocorticoids.
Focal organizing pneumonia — Resection is adequate initial therapy for most patients with focal organizing pneumonia. In two retrospective studies of a combined total of 43 patients, focal organizing pneumonia was found in resected solitary pulmonary nodules [27,35]. No further therapy was given and there was no recurrence in 41 patients; the two patients with local recurrences were treated successfully with glucocorticoids.
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 4) . Approximately one-third of patients demonstrate persistent disease. Improvement is occasionally quite dramatic, occurring in one to two weeks. Serial HRCT scans may reveal persistent abnormalities despite clinical improvement . However, most patients improve within several weeks to three months.
Relapses are common and may occur when the glucocorticoids are withdrawn after one to three months of treatment. In some series, over one-half of patients experience at least one clinical relapse during the course of their disease [8,25,36]. 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.
Those patients with persistent or frequently recurrent (>3 episodes) may require continuous treatment with prednisone, cyclophosphamide, or both. Patients with airspace opacities on chest radiograph have a much better outcome than those with interstitial opacities [18,37].
The overall prognosis of COP is much better than that of other interstitial lung disease, such as idiopathic pulmonary fibrosis. Rapidly fatal COP is uncommon .
SUMMARY AND RECOMMENDATIONS
- Cryptogenic organizing pneumonia (COP) is a distinct clinical entity with predominant features of pneumonia, rather than those of a primary airway disorder. (See 'Introduction' above.)
- Disease onset is typically in the fifth or sixth decades of life, with men and women affected equally. Most patients are symptomatic for less than two months, with 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 'Clinical presentation' above.)
- Multiple ground-glass or consolidative opacities are the most frequent and typical features of COP identified by chest imaging. (See 'Chest imaging studies' above.)
- Histopathologic lesions characteristic of COP include excessive proliferation of granulation tissue within small airways (proliferative bronchiolitis) and alveolar ducts, associated with chronic inflammation in the surrounding alveoli. (See 'Pathological changes' above.)
- The diagnosis of COP requires histopathologic identification of organizing pneumonia and the exclusion of any possible cause, which may be relatively evident or may require a laborious search. (See 'Diagnosis' above.)
- An open or thoracoscopic lung biopsy is recommended to confirm the diagnosis. (See 'Diagnosis' above.)
- Glucocorticoid therapy induces rapid clinical improvement and clearing of the opacities on chest imaging, usually without significant sequelae. Relapses are common upon stopping or reduction of glucocorticoids, often leading to prolonged treatment. (See 'Treatment' above.)