Bronchiolitis Obliterans Organizing Pneumonia/Cryptogenic Organizing Pneumonia

What every physician needs to know:

Cryptogenic organizing pneumonia (COP) (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 over weeks to months of a mild, flu-like illness characterized by cough, fever, malaise, and progressive dyspnea, and frequently accompanied by weight loss. Patients are often initially diagnosed with community acquired pneumonia, and it is only when there is a lack of response or worsening with antibiotic therapy that the possibility of COP is raised.

Typical radiographic features include peripheral or peribronchovascular patchy, often migratory ground-glass opacities and consolidation on CXR 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 majority of cases. Relapse of disease with steroid taper is common with the initial course of therapy, however patients tend to respond to retreatment with corticosteroids, and slower tapers may be required.

Figure 1.

Figure 2.

Figure 3.

Figure 4.

COP is the idiopathic form of this disease. However, the majority of cases in which organizing pneumonia is found are non-cryptogenic. A key point in the evaluation of organizing pneumonia is that the clinician must search carefully for an underlying etiology that might lead to the same clinical and pathological features of COP. Specific causes for secondary organizing pneumonia (OP) include infections, drug and environmental exposures, and connective tissue diseases (particularly rheumatoid arthritis and polymyositis/dermatomyositis/anti-synthetase syndrome). When a diagnosis of secondary OP is made, prognosis and response to corticosteroids correlate more closely with the specific etiology. If the OP is due to an inhalational or medication exposure, removal of the inciting 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 (ILD), such as usual interstitial pneumonia (UIP) and nonspecific interstitial pneumonia (NSIP), as well as in association with lung cancer, vasculitis, and infection. Surgical lung biopsy may be required for diagnosis when the radiographic appearance is not typical.

Rarely, COP may present with fulminant respiratory failure, with a presentation 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 any patient who presents with diffuse ground-glass and alveolar opacities on imaging without an obvious etiology. Serological testing for autoantibodies should be performed in these cases, as lung disease can be the initial presentation of connective tissue diseases in up to 10% of cases.

Classification:

The American Thoracic Society/European Respiratory Society (ATS/ERS) guidelines classify COP as one of the major idiopathic interstitial pneumonias, distinct from the chronic fibrosing interstitial pneumonias. While COP is primarily an intra-alveolar disorder histopathologically, it is classified as an ILD 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 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. OP may also develop after a wide range of exposures, including medications, radiation therapy, environmental and occupational agents. Identification of a known association may allow a causative exposure to be removed or avoided in the future.

Clinicians may receive radiographic or pathologic reports that describe 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 (IPF) (defined as a sudden clinical decline with ground-glass opacities on CT without identified cause), suggesting that IPF is the primary diagnosis and 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 a rheumatologic disorder. Third, an infiltrative form of OP has been described that may represent a hybrid form of OP superimposed upon a background of 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?

The mean age of patients with COP is between 50 and 60. Males and females are equally affected. Clinical features typically include flu-like symptoms such as fever, non-productive cough and mild dyspnea. Weight loss occurs in up to 50% 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 ARDS.

COP is often not suspected until the patient has failed to respond to antibiotic therapy. Therefore, 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, non-productive 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. Post-infectious titers may be useful diagnostically in some cases.

A meticulous history may implicate an underlying systemic illness as the cause of OP. High fevers and arthralgias are more frequent in patients with connective tissue disease-associated OP. Other historical features suggestive of connective tissue disease should be sought, including 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 radiation or chemotherapy treatment. Recent immunotherapy additions in oncology, such as PD-1 inhibitors, are newly recognized offenders. In the case of breast cancer, OP may occur as long as six months after the completion of radiation therapy and reflects an inflammatory process separate from radiation pneumonitis. OP, which has been described in association with underlying hematologic disorders like myelodysplastic syndrome, T-cell leukemias, and lymphoma, is also seen following stem cell and solid organ transplantation.

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

Typical radiographic findings include multiple bilateral, patchy, often peripheral and peribronchovascular ground-glass and alveolar opacities. Air bronchograms may be present. The opacities may be progressive and nonresolving, or they may migrate. A less common but well-recognized presentation is that of a solitary nodular opacity which mimics primary lung cancer. Rarer radiographic patterns include the reverse-halo sign, multiple nodules, irregular lines/bands, 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.

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

After excluding infection, connective tissue disease, medications, and environmental exposures, the clinician should consider other forms of interstitial lung disease. In particular, chronic eosinophilic pneumonia is quite similar in radiographic appearance to OP, typically characterized by multiple areas of peripheral dense consolidation on chest radiograph and CT. Chronic eosinophilic pneumonia is often associated with asthma-like symptoms. Diagnosis may be made with the findings of peripheral blood and bronchoalveolar lavage fluid eosinophilia.

When patients with the rapidly progressive form of COP present in critical care settings, acute interstitial pneumonia (AIP) 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.

Pulmonary lymphoma and bronchoalveolar carcinoma can also present with bilateral 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.

Systemic manifestations may be subtle, and the pulmonary disease may precede any skin, joint or muscle involvement. A comprehensive history, 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?

Like other ILDs, OP 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 OP is strikingly reversible. This 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 OP. 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 OP.

Wound-healing mechanisms like re-epithelialization and increased apoptotic activity in newly formed connective tissue may be found in OP 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% of OP cases. A number of bacterial (Chlamydia, Legionella), viral (parainfluenza, adenovirus), parasitic, and fungal infections have been reported to cause OP. Drug toxicity can produce an OP pattern. The long list of causative drugs includes illicit substances like cocaine, as well as medications such as amiodarone, nitrofurantoin, and other antibiotics. The online resource pneumotox.com can be queried to determine whether OP has been reported in association with a suspect drug.

In patients with underlying malignancy, radiation and chemotherapy have been reported to cause OP. OP has been reported to occur in 2.5% of breast cancer patients receiving radiation therapy, often many months after treatment. This is thought to be a separate process from radiation pneumonitis. In fact, OP may be precipitated by courses of chemotherapy given years after the initial radiation treatment.

While bronchiolitis obliterans syndrome or BOS (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% 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, 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, anti-Jo1 and other anti-synthetase antibodies, which can be sent as a “myositis panel.” Muscle enzymes including creatine kinase and aldolase may be helpful as well. Because ILD 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 work-up of COP is a CXR, 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 opacities should suggest the diagnosis, as should the presence of progressive consolidation despite adequate therapy for community-acquired pneumonia.

High resolution Chest CT (HRCT)

The abnormalities observed with HRCT are similar to those seen on CXR, 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 or peribronchovascular distribution and may contain air bronchograms. Consolidation is present in 90% of patients with COP and is subpleural or peribronchial in nearly half. Ground-glass opacities are present in 60% 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 primary lung cancer. “Infiltrative COP” has also been described, in which interstitial changes with concomitant alveolar opacities are present. The “reverse halo” sign has also been described. 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 IPF or NSIP, 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 demonstrate FDG uptake due to inflammation 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 histopathologic changes are airway-centered, the respiratory physiology demonstrates restrictive physiology rather than an obstructive pattern. The abnormalities demonstrated on pulmonary function testing in COP are more typical of ILD than that of obstructive airways disease. The forced vital capacity and total lung capacity are often decreased, and diffusion impairment may be present. Patients may demonstrate oxygen 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. BAL fluid in diffuse alveolar hemorrhage has a progressively bloody appearance.

Transbronchial biopsy may help exclude malignancy, and 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 ILD. Areas of OP can also be observed in association with lung cancer, obstructive pneumonia, granulomatosis with polyangiitis, and infection/abscess. In some cases, with typical radiographic features, a provisional diagnosis may be made with transbronchial biopsies alone.

VATS

Video-assisted thoracic surgical (VATS) lung biopsy, a generally safe and well-tolerated procedure in appropriate candidates, 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 also targeted.

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 ILD, in which foci of OP may be present. In particular, UIP, NSIP, granulomatosis with polyangiitis, 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 OP 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, preferentially after biopsy tissue is obtained. Relapses commonly occur with tapering and are reported in 13-58% of cases. While some experts recommend prolonged courses of therapy (up to one year), more recent consensus is to recommend a shorter duration of therapy (five to six months) with rapid taper after the first month of treatment. 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 exist for most patients. In a small subset of asymptomatic patients and in patients with minimal disease, infiltrates may regress without treatment, and observation alone may be appropriate. In the case of critically ill patients, IV pulse-dose methylprednisolone (500-1000 mg per day) for three to five days may be indicated.

Macrolide therapy has been proposed as a therapeutic option because of its immunomodulatory effects, though data for this are at the level of case series. 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, mycophenolate mofetil, rituximab and cyclophosphamide have been used successfully to treat COP.

Corticosteroid therapy is also indicated for patients who have secondary causes of OP. 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 OP, and higher doses of corticosteroids 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 swallow 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 OP after radiation therapy may have been primed to experience “radiation recall” and may develop OP 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%, the prognosis for patients with COP remains excellent compared to that of other ILDs. Nearly 80% 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% to 27%. The mortality rates are higher with secondary forms of OP. Up to 80% 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 such as 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.

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