Pulmonary Medicine

Bronchiolitis Obliterans Organizing Pneumonia/Cryptogenic Organizing Pneumonia

What every physician needs to know:

Cryptogenic organizing pneumonia (formerly known as bronchiolitis obliterans organizing pneumonia, or BOOP) is a form of idiopathic interstitial pneumonia. The typical clinical features of COP are subacute onset (typically weeks) of a mild, flu-like illness with cough, fever, malaise, and progressive dyspnea, frequently accompanied by weight loss. Patients are often initially diagnosed with bacterial pneumonia, and it is only when they are not responsive to antibiotic therapy that the possibility of COP is raised.

Typical radiographic features are peripheral, patchy ground-glass opacities and consolidation on chest radiograph or high-resolution chest CT (Figure 1) (Figure 2) (Figure 3) (Figure 4). Diagnosis is confirmed by the demonstration of organizing pneumonia on surgical lung biopsy. Treatment with corticosteroids leads to dramatic clinical improvement in the vast majority of cases, although relapse of disease with steroid taper is common. Patients tend to respond to retreatment with corticosteroids, and slower taper may be required.

Figure 1.

Cryptogenic organizing pneumonia on HRCT with peripheral, dense consolidation.

Figure 2.

Cryptogenic organizing pneumonia on HRCT.

Figure 3.

Cryptogenic organizing pneumonia on HRCT.

Figure 4.

Chest radiograph in cryptogenic organizing pneumonia.

One of the key points regarding the diagnosis of COP is the need to rule out an underlying infection, systemic illness, or exposure that might lead to the same clinical and pathological features of COP. In particular, atypical infections, drug and environmental exposures, and connective tissue diseases (particularly rheumatoid arthritis and polymyositis/dermatomyositis) should be sought. These cases are called secondary organizing pneumonia. When a diagnosis of secondary organizing pneumonia is found, prognosis and response to corticosteroids correlates more closely with the specific etiology. If the OP is due to an inhalational or medication exposure, removal of the triggering agent is essential.

Occasionally, the diagnosis of OP may be made by transbronchial biopsy in the context of typical clinical and radiographic features, but this pathologic finding is not completely specific; areas of OP may be seen in other forms of interstitial lung disease, such as usual interstitial pneumonia (UIP) and nonspecific pneumonia (NSIP), as well as in association with lung cancer, vasculitis, and infection. Surgical lung biopsy is often required for diagnosis.

Rarely, COP may present with fulminant respiratory failure similar to acute respiratory distress syndrome (ARDS). This is more common in cases associated with connective tissue disease, such as rheumatoid arthritis, polymyositis/dermatomyositis, and the anti-synthetase syndrome. These cases may be less responsive to corticosteroids alone and may require the addition of other immunosuppressive agents. This diagnosis should be considered in a patient who presents with diffuse ground-glass and alveolar opacities on radiograph without obvious etiology. Serological testing may be required, as pulmonary manifestations can be the initial presentation of connective tissue diseases in up to 10 percent of cases.

Classification:

The American Thoracic Society/European Respiratory Society (ATS/ERS) guidelines classify COP as one of the seven idiopathic interstitial pneumonias. While COP is primarily an intra-alveolar disorder histopathologically, it is classified as an interstitial lung disease rather than as an airways disease because of its clinical and radiographic findings.

To be categorized as idiopathic, COP must be distinguished from secondary forms of organizing pneumonia (OP), which are histopathologically indistinguishable from COP. OP can be seen in infection, chronic aspiration, connective tissue disease, hematologic disorders and malignancies, bone marrow and organ transplantation (including lung), inflammatory bowel disease, and immunological disorders. COP may also develop after a wide range of exposures, including exposure to drugs, radiation therapy, and environmental and occupational agents. Identification of a known association may allow a causative exposure to be avoided in the future.

Clinicians may receive radiographic or pathologic reports that describe organizing pneumonia (OP) in patients with features of the other idiopathic interstitial pneumonias. These reports should suggest one of several possibilities: First, OP may be the radiographic and histopathologic pattern observed in an acute exacerbation of idiopathic pulmonary fibrosis (defined as a sudden clinical decline with ground-glass opacities on HRCT without identified cause), suggesting that IPF is the primary diagnosis and the OP is a secondary feature.

Second, a combination of histopathologic patterns is often seen in underlying connective tissue disease. This type of description should prompt a careful search for such a rheumatologic disorder. Third, an infiltrative form of COP has been described that may represent a hybrid form of OP superimposed upon a background of nonspecific interstitial pneumonia (NSIP). In this case, the presence of NSIP features may explain the more modest treatment response in these patients.

Are you sure your patient has cryptogenic organizing pneumonia? What should you expect to find?

COP patients' mean age tends to fall between age 50 and 60. Males and females are equally affected. Clinical features typically include flu-like symptoms, including nonproductive cough and mild dyspnea. Weight loss occurs in up to 50 percent of patients. While COP generally has a chronic or subacute course, a rapidly progressive, fulminant form has been described that is associated with a poor prognosis. In critically ill patients with diffuse alveolar infiltrates, COP should be considered an alternate cause of the acute respiratory distress syndrome (ARDS).

The diagnosis is often not suspected until the patient has failed to respond to antibiotic therapy, so the diagnosis may be delayed by weeks or months from the onset of symptoms. Before entertaining a diagnosis of COP, the physician must seek infectious etiologies aggressively since fever, nonproductive cough ,and multifocal lung opacities are non-specific. OP can also develop in the post-infectious stage of many bacterial, viral, parasitic, and fungal infections.

A meticulous history may implicate an alternate association or cause for patients with suspected OP. High fevers and arthralgias are more frequent in patients with connective-tissue-disease-associated organizing pneumonia. Other historical features suggestive of connective tissue disease should be sought, such as prior skin rashes, photosensitivity, Raynaud’s phenomenon, and myalgias or muscle weakness.

In addition, a variety of causative exposures may be discovered, including inhaled toxins among factory workers, illicit substances such as cocaine, and prescribed drugs, including nitrofurantoin and amiodarone. In patients with known malignancy, OP can occur in the context of chemotherapy or radiation treatment. In the case of breast cancer, OP may occur as long as six months after the completion of radiation therapy. OP, which has been described in association with underlying hematologic disorders like myelodysplastic syndrome, T-cell leukemias, and lymphoma, is seen following organ transplantation.

Physical examination findings in COP are non-specific. Lung examination reveals crackles in more than 70 percent of patients, but COP patients rarely demonstrate clubbing. Findings suggestive of underlying connective tissue disease include active synovitis; skin rashes like the heliotrope rash, malar rash, mechanic’s hands, and Gottron’s papules; and Raynaud’s phenomenon. Comprehensive laboratory and serologic testing may reveal previously undiagnosed or occult connective tissue disease or hematologic malignancies.

Typical radiographic findings include bilateral, patchy, often peripheral, ground-glass and alveolar opacities. Air bronchograms may be present. The opacities may be progressive and nonresolving, or they may migrate. Rarer presentations include a solitary nodular form and an infiltrative form consisting of interstitial changes with superimposed alveolar opacities.

Histologically, OP consists of patchy areas of consolidation characterized by polypoid plugs of inflammatory cells, debris, fibrin, myofibroblasts, and loose connective tissue that fill and obstruct the lumens of terminal and respiratory bronchioles, extending to the level of the alveoli (Figure 5). The main pattern should be comprised of these findings.

Figure 5.

Histopathology of cryptogenic organizing pneumonia (courtesy of Robert Homer, MD PHD, Yale University)

Beware: there are other diseases that can mimic cryptogenic organizing pneumonia:

After excluding infection, connective tissue disease, and drug and environmental exposures, the clinician should consider other forms of interstitial lung disease. In particular, chronic eosinophilic pneumonia is typically characterized by multiple areas of peripheral dense consolidation on chest radiograph and HRCT.

Chronic eosinophilic pneumonia is often associated with asthma-like symptoms and eosinophilia in peripheral blood and bronchoalveolar lavage fluid. Pulmonary lymphoma and bronchoalveolar carcinoma can also present with bilateral and peripheral airspace opacities. Low-grade lymphomas may partially respond to corticosteroid therapy, but bronchoalveolar carcinoma will not regress. Typical COP lesions may be migratory. The differential diagnosis for migratory airspace opacities includes recurrent aspiration and diffuse alveolar hemorrhage.

When patients with the rapidly progressive form of COP present in critical care settings, infectious pneumonia and acute respiratory distress syndrome are most often suspected. Other forms of interstitial lung disease, such as acute interstitial pneumonia and acute exacerbation of IPF, should be considered. Similarly, entities, such as diffuse alveolar hemorrhage, may present with respiratory failure and diffuse parenchymal opacities. The severe form of OP has been described in association with polymyositis/dermatomyositis and rheumatoid arthritis.

Systemic manifestations may be subtle, and the pulmonary disease may precede any skin, joint or muscle involvement. A comprehensive history, and physical and laboratory assessment are required. Surgical lung biopsy may be required to distinguish COP from other causes of acute interstitial lung disease.

How and/or why did the patient develop cryptogenic organizing pneumonia?

Similar to other interstitial lung diseases, organizing pneumonia develops as a response to alveolar epithelial injury. Inflammatory exudates organize into intra-alveolar fibrosis. In contrast to other idiopathic interstitial pneumonias, the fibrotic process in organizing pneumonia is strikingly reversible. The reversible nature of the disease process may be a consequence of the prominent vascularization mediated by growth factors like vascular endothelial growth factor and basic fibroblast growth factor.

Experimental animal models provide further insight into the pathogenesis of organizing pneumonia. Inhalational exposure to paraquat in monkeys or cadmium in rats creates gaps in the epithelial basement membrane that lead to intra-alveolar migration of interstitial cells, damage to type I pneumocytes, and the initiation of abnormal alveolar repair. Viral inoculations of animal models implicate T-cells in the pathogenesis of organizing pneumonia.

Wound-healing mechanisms like re-epithelialization and increased apoptotic activity in newly formed connective tissue may be found in organizing pneumonia specimens and may lead to appropriate matrix remodeling. Radiation therapy in breast cancer patients may lead to the release of autoantigens, causing an autoimmune reaction. Increased lymphocytes neutrophils and eosinophils with an increased CD4/CD8 ratio have been observed.

Which individuals are at greatest risk of developing cryptogenic organizing pneumonia?

There are no identified risk factors for COP. Smoking does not appear to be causative. Secondary causes or associations may account for up to 40 percent of OP cases. A number of bacterial (Chlamydia, Legionella), viral (parainfluenza, adenovirus), parasitic, and fungal infections have been reported to cause organizing pneumonia. Drug toxicity can produce an organizing pneumonia pattern. The long list of causative drugs includes illicit substances like cocaine, as well as prescribed medications like amiodarone, nitrofurantoin, and other antibiotics. The online resource pneumotox.com can be queried to adetermine whether OP has been reported in association with a suspect drug.

OP, which often occurs in the context of connective tissue diseases, is more responsive to corticosteroid therapy than nonspecific interstitial pneumonia is. In patients with underlying malignancy, treatments like radiation and chemotherapy have been reported to cause OP. OP has been reported to occur in 2.5 percent of breast cancer patients who are receiving radiation therapy, often many months after treatment. In fact, OP may be precipitated by courses of chemotherapy given years after the initial radiation treatment.

While bronchiolitis obliterans syndrome (a form of airways obstruction not to be confused with BOOP) is the most commonly identified post-lung-transplant complication, OP has been reported in 10%-28 percent of lung transplant patients and is generally associated with acute rejection.

What laboratory studies should you order to help make the diagnosis, and how should you interpret the results?

Blood tests are not diagnostic in COP. The white blood cell count, C-reactive protein level, and erythrocyte sedimentation rate are moderately elevated in most patients. When peripheral consolidation is present radiographically, chronic eosinophilic pneumonia should be considered in the differential diagnosis, and peripheral eosinophilia may be suggestive but not diagnostic of that entity. Infection should be excluded. In the febrile patient, the process of excluding infection will include routine blood, urine, and sputum cultures and may require other testing depending on the patient’s individual risk profile.

There are no standardized recommendations for screening for connective tissue disease in the setting of COP. Clinical features of connective tissue disease should be sought, including evidence of inflammatory arthritis, myositis or muscle weakness, symptoms of esophageal dysfunction, and skin rashes and other dermatological manifestations, such as Gottron’s papules, heliotrope rash, mechanic’s hands, and Raynaud’s phenomenon.

Serologic testing may be indicated, including anti-nuclear antibodies (ANA), rheumatoid factor (RF), anti-cyclic citrullinated peptide (CCP), anti-SSA, anti-SSB, anti-Scl-70, and anti-Jo1 and other anti-synthetase antibodies, which can be sent as a “myositis panel.” Because interstitial lung disease may be the presenting manifestation of connective tissue disease, serologic testing may unmask previously unsuspected connective tissue disease.

What imaging studies will be helpful in making or excluding the diagnosis of cryptogenic organizing pneumonia?

Chest Radiograph (CXR)

The first study typically obtained in the workup of COP is a chest radiograph, as many patients present with symptoms suggestive of infectious pneumonia. Typical findings include patchy, often peripheral, ground-glass and alveolar opacities. Air bronchograms may be present, and the radiographic appearance may be indistinguishable from infectious pneumonia. Migratory infiltrates should suggest the diagnosis, as should the presence of progressive opacity despite adequate therapy for community-acquired pneumonia.

High-resolution Chest CT (HRCT)

The abnormalities observed with high-resolution chest CT (HRCT) are similar to those seen on chest radiograph, but they are seen with greater sensitivity and resolution. In particular, the use of HRCT improves the ability to detect the presence of ground-glass opacities, and a greater extent of parenchymal disease may be observed. Typical COP, which may be unilateral or bilateral, is often diffuse. Findings include patchy ground-glass and alveolar opacities, which tend to have a peripheral distribution and may contain air bronchograms. Consolidation is present in 90 percent of patients with COP and is subpleural or peribronchial in nearly half. Ground-glass opacities are present in 60 percent of cases. Generally, radiographic evidence of fibrosis is absent.

Other, less common radiographic patterns include a solitary opacity or nodule (occasionally cavitary), which may suggest a primary lung cancer. “Infiltrative COP” has also been described, in which interstitial changes with concomitant alveolar opacities are present. If an appearance suggestive of underlying fibrotic lung disease is present, two major possibilities should be considered: 1) the primary diagnosis is an idiopathic interstitial pneumonia, such as idiopathic pulmonary fibrosis or nonspecific interstitial pneumonia, with superimposed acute exacerbation of disease; 2) the primary diagnosis is connective tissue disease, in which multiple radiographic and histopathologic patterns may coexist.

PET

Positron emission tomography is not useful in the evaluation of COP, which may cause hypermetabolism and may be difficult to distinguish from malignancy or infection.

What non-invasive pulmonary diagnostic studies will be helpful in making or excluding the diagnosis of cryptogenic organizing pneumonia?

Although the histopathologic changes are airway-centered, the respiratory physiology demonstrates restrictive physiology rather than an obstructive pattern. The abnormalities demonstrated on pulmonary function testing (PFT) in COP are more typical of interstitial lung disease than they are of obstructive airways disease. The forced vital capacity (FVC) and total lung capacity (TLC) are often decreased, and diffusion impairment (low DLCO) is present. Patients may demonstrate desaturation with exercise.

What diagnostic procedures will be helpful in making or excluding the diagnosis of cryptogenic organizing pneumonia?

Bronchoscopy

The most important function of bronchoscopy with bronchoalveolar lavage (BAL) is to exclude infection and other lung diseases. The BAL fluid characteristics, which are not specific for the diagnosis of COP, may demonstrate a mixture of cell types, including lymphocytes, neutrophils and eosinophils. BAL fluid characteristics may suggest alternate diagnoses. For example, the presence of high numbers of eosinophils (> 25%) makes the diagnosis of eosinophilic pneumonia more likely. The BAL fluid in diffuse alveolar hemorrhage has a progressively bloody appearance.

Transbronchial biopsy may help exclude malignancy, and it can aid in the diagnosis of certain fungal and atypical infections. OP may sometimes be found on transbronchial biopsy, although these results should be interpreted with caution, as areas of OP may be present in other forms of interstitial lung disease, such as usual interstitial pneumonia (UIP) and nonspecific pneumonia (NSIP). Such areas of OP can also be observed in association with lung cancer, obstructive pneumonia, Wegener’s granulomatosis, and infection/abscess.

VATS

Video-assisted thoracic surgical (VATS) lung biopsy, a safe and well-tolerated procedure, allows an adequate amount of tissue to be obtained. Typically, three wedge biopsies are taken from separate lobes. Any focal nodule that is present radiographically is targeted. The histopathology of OP consists of polypoid buds of connective tissue, called Masson bodies. These plugs are composed of inflammatory cells, debris, fibrin, myofibroblasts, and immature connective tissue, which fill and obstruct the lumens of terminal and respiratory bronchioles, extending to the level of the alveoli.

What pathology/cytology/genetic studies will be helpful in making or excluding the diagnosis of cryptogenic organizing pneumonia?

Histologically, OP demonstrates patchy areas of consolidation characterized by polypoid plugs of inflammatory cells, debris, fibrin, myofibroblasts, and loose connective tissue. These plugs, called Masson bodies, fill and obstruct the lumens of terminal and respiratory bronchioles, extending to the level of the alveoli. The connective tissue is immature and temporally homogeneous. Mild to moderate inflammation and endobronchiolar polyps may be present, but the architecture of the lung is preserved.

The pathologist must be careful to look for evidence of other underlying interstitial lung disease, in which foci of OP may be present. In particular UIP, NSIP, Wegener’s granulomatosis, hypersensitivity pneumonitis, and organizing diffuse alveolar damage should be excluded. Tissue should also be sent for microbiologic stains and cultures to exclude infection.

If you decide the patient has cryptogenic organizing pneumonia, how should the patient be managed?

The cornerstone of treatment for organizing pneumonia is corticosteroid therapy. The swift response to therapy within the first few days to weeks is well described. Doses of 0.75-1.0 mg/kg/day should be initiated once the diagnosis is established. Relapses commonly occur with tapering and are reported in 13-58 percent of cases. While some experts recommend prolonged courses of therapy (up to one year), other experts recommend a shorter duration of therapy (five to six months).

Since relapse does not increase mortality, clinicians may elect to accept the risk of relapse in favor of a shorter treatment course and decreasing the risk of steroid-related complications that exists for most patients. In the case of critically ill patients, intravenous pulse-dose methylprednisolone (500-1000 mg per day) for three to five days may be indicated.

Recently, macrolide therapy has been proposed as a therapeutic option because of its immunomodulatory effects. A three-to-six-month course of macrolide therapy may be attempted for patients with mild disease and for those who are unable to tolerate steroids.

Because of the corticosteroid responsiveness of COP, the role of other immunosuppressive or cytotoxic agents has generally been less well described, but these may be considered in patients with COP refractory to corticosteroid therapy or in those who are troubled by severe side effects. Azathioprine and cyclophosphamide have been used successfully to treat COP. In a small subset of asymptomatic patients and in patients with minimal disease, infiltrates may regress without treatment, so observation alone may be appropriate.

Corticosteroid therapy is also indicated for patients who have secondary causes of organizing pneumonia. Complete recovery is less common among patients with connective tissue disease (20%) than among patients with COP, and recurrence rates may be higher (40%). In patients with connective tissue disease, immunosuppression with other medications may be indicated earlier in the course of disease, and higher doses of corticosteroid may be required.

The secondary causes and conditions identified in the diagnostic assessment should be addressed aggressively. For example, patients with chronic aspiration should undergo a thorough swallowing evaluation and gastrointestinal motility studies. Surgical intervention may be necessary in some patients. Causative agents, such as medications and occupational exposures, should be eliminated whenever possible.

The assessment of lung disease may be complicated by the fact that OP can be associated with both the underlying systemic illness and with the drugs used to treat it; for example, such is the case in connective tissue disease, inflammatory bowel disease, and hematologic disorders. When caring for patients with breast cancer, oncologists should be aware that patients who initially developed organizing pneumonia after radiation therapy may have been primed to experience “radiation recall” and may develop organizing pneumonia when treated with chemotherapy years after the inciting event.

What is the prognosis for patients managed in the recommended ways?

While relapse rates may be as high as 40 percent, the prognosis for patients with COP remains excellent compared to the prognosis for other interstitial lung diseases. Nearly 80 percent of patients achieve complete recovery within the first weeks of corticosteroid treatment. When relapse occurs, multiple courses and slow tapers of corticosteroids may be required. Patients with connective tissue disease-associated OP appear to have higher relapse rates and less chance for complete recovery than do those with COP, as overall mortality has been reported to vary from 5 percent to 27 percent. The mortality rates are higher with secondary forms of OP. Up to 80 percent of patients with the rapidly progressive form of OP may succumb to the disease.

What other considerations exist for patients with cryptogenic organizing pneumonia?

Treatment benefit comes at the cost of the short- and long-term side effects of systemic corticosteroid therapy. Mood changes, sleep disturbance, increased appetite, and weight gain are almost universal. Underlying medical conditions like diabetes, glaucoma, and congestive heart failure are often exacerbated. The long-term side effects of systemic therapy include acid reflux, obesity, heart disease, myopathy, and osteoporosis.

Early prevention and surveillance of fracture risk should be consistently performed. Calcium and vitamin D supplementation are routinely utilized. In the setting of high fracture risk, prevention with bisphosphonate therapy should be considered. In addition, clinicians should consider prophylaxis for Pneumocystis jiroveci pneumonia in patients who receive prednisone at a dosage greater than or equal to 20 mg per day.

What’s the evidence?

Cordier, JF. "Cryptogenic organising pneumonia". Eur Respir J. vol. 28. 2006. pp. 422-46.

This and the next two references are excellent reviews of cryptogenic organizing pneumonia. The first is a thorough review of the available literature while the others focus on radiographic and histopathologic findings.

Lynch, DA. "Idiopathic interstitial pneumonias: CT features". Radiology. vol. 236. 2005. pp. 10-21.

Visscher, DW, Myers, JL. "Histologic spectrum of idiopathic interstitial pneumonias". Proc Am Thorac Soc. vol. 3. 2006. pp. 322-9.

Davison, AG. "Cryptogenic organizing pneumonitis". Q J Med. vol. 52. 1983. pp. 382-94.

Cordier, JF, Loire, R, Brune, J. "Idiopathic bronchiolitis obliterans organizing pneumonia. Definition of characteristic clinical profiles in a series of 16 patients". Chest. vol. 96. 1989. pp. 999-1004.

This and the next reference are early case series that describe the key clinical, radiographic and histopathologic features of COP.

Epler, GR. "Bronchiolitis obliterans organizing pneumonia". N Engl J Med. vol. 312. 1985. pp. 152-8.

Epler, GR. "Bronchiolitis obliterans organizing pneumonia". N Engl J Med. vol. 312. 1985. pp. 152-8.

American Thoracic Society/European Respiratory Society International Multidisciplinary Consensus Classification of the Idiopathic Interstitial Pneumonias.

"Joint statement of the American Thoracic Society (ATS), and the European Respiratory Society (ERS), adopted by the ATS board of directors, June 2001 and the ERS Executive Committee, June 2001". Am J Respir Crit Care Med. vol. 165. 2002. pp. 277-304.

The ATS/ERS consensus classification includes COP as an idiopathic interstitial pneumonia and describes its distinguishing features.

Lazor, R. "Cryptogenic organizing pneumonia. Characteristics of relapses in a series of 48 patients. The Groupe d'Etudes et de Recherche sur les Maladles "Orphelines" Pulmonaires (GERM"O"P)". Am J Respir Crit Care Med. vol. 162. 2000. pp. 571-7.

This article contributes to our understanding of current treatment strategies for COP. These observations help us understand that relapses are common and do not affect mortality or the chance of subsequent cure.

Shinohara, T, Hidaka, T, Matsuki, Y, Ishizuka, T, Taakamizawa, M, Kawakami, M. "Rapidly progressive interstitial lung disease associated with dermatomyositis responding to intravenous cyclophosphamide pulse therapy.". Intern Med. vol. 38. 1997. pp. 519-523.

This and the next six articles offer clinical experience with the natural history of COP and other forms of OP.

Cohen, AJ, King, TE, Downey, GP. "Rapidly progressive bronchiolitis obliterans with organizing pneumonia". Am J Respir Crit Care Med. vol. 149. 1994. pp. 1670-5.

King, TE, Mortenson, RL. "Cryptogenic organizing pneumonitis. The North American experience". Chest. vol. 102. 1992. pp. 8S-13S.

Yoo, JW, Song, JW, Jang, SJ, Lee, CK, Kim, MY, Lee, HK. "Comparison between cryptogenic organizing pneumonia and connective tissue disease related organizing pneumonia". Rheumatology. vol. 50. 2011. pp. 932-938.

Crestani, B, Valeyre, D, Roden, S. "Bronchiolitis obliterans organizing pneumonia syndrome primed by radiation therapy to the breast: the Groupe d’Etudes et de Recherche sur les Maladies Orphelines Pulmonaires (GERM“O”P)". Am J Respir Crit Care Med. vol. 158. 1998. pp. 1929-1935.

Daniels, CE, Myers, JL, Utz, JP. "Organizing pneumonia in patients with hematologic malignancies: a steroid responsive lesion". Respir Med. vol. 101. 2007. pp. 162-168.

Stover, DE, Mangino, D. "Macrolides: a treatment alternative for bronchiolitis obliterans organizing pneumonia". Chest. vol. 128. 2005. pp. 3611-3617.

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