Continuing Education Activity

Cryptogenic organizing pneumonia (COP) known formerly as bronchiolitis obliterans organizing pneumonia (BOOP) is a form of idiopathic diffuse interstitial lung disease. Davison et al. coined the term COP in 1983. This was followed by detailed descriptions of the disease under the term BOOP by Epler et al. in 1985. Cryptogenic organizing pneumonia is believed to be a consequence of alveolar injury and is characterized by the formation of organized buds of granulation tissue obstructing the alveolar lumen and bronchioles resulting in respiratory failure. This activity reviews the cause and presentation of cryptogenic organizing pneumonia and highlights the role of the interprofessional team in its management.

Objectives:

• Describe the pathophysiology of cryptogenic organizing pneumonia.
• Review the presentation of a patient with cryptogenic organizing pneumonia.
• Summarize the treatment options for cryptogenic organizing pneumonia.
• Outline the importance of improving care coordination among interprofessional team members to improve outcomes for patients affected by cryptogenic organizing pneumonia.

Introduction

Cryptogenic organizing pneumonia (COP), formerly bronchiolitis obliterans organizing pneumonia (BOOP), is a form of idiopathic diffuse interstitial lung disease. Davison et al. coined the term COP in 1983. This was followed by detailed descriptions of the disease under the term BOOP by Epler et al. in 1985. Cryptogenic organizing pneumonia is believed to be a consequence of alveolar injury. It is characterized by the formation of organized buds of granulation tissue obstructing the alveolar lumen and bronchioles, resulting in respiratory failure. Organizing pneumonia is a pathologic diagnosis and can be secondary to an identifiable etiology. Cryptogenic organizing pneumonia should be diagnosed only after excluding any other possible etiology.[1][2][3]

Etiology

The exact etiology of cryptogenic organizing pneumonia is unknown. It is thought to be secondary to alveolar epithelial injury due to an unknown insult. Various etiologic agents have been suggested to cause organizing pneumonia, including viral infections, toxic gases, medications, gastro-esophageal reflux, radiation therapy, and connective tissue disorders. Smoking is not considered a risk factor for the development of cryptogenic organizing pneumonia. Most patients with cryptogenic organizing pneumonia are non-smokers.

Epidemiology

Cryptogenic organizing pneumonia lacks precise prevalence data. Incidence is thought to be around 1 to 3 per 100,000 hospital admissions. Both genders are equally affected. Cryptogenic organizing pneumonia typically develops in the fifth to sixth decade of life.

Pathophysiology

Pathogenic mechanisms have not been clearly described, but alveolar epithelial injury due to an unknown provocative insult is thought to cause leakage of plasma proteins into the alveolar space, resulting in the recruitment of inflammatory cells. The subsequent process of organization occurs in 3 stages. The intra-alveolar stage comprises the formation of fibrin bands along with the infiltration of mononuclear inflammatory cells. The second stage is characterized by the proliferation of fibroblasts that lay down a reticulin framework. Meanwhile, the alveolar cells proliferate and re-epithelialize the basal lamina, restoring the alveolar basement membrane. The third stage is the organization of fibroblasts and connective tissue matrix. Vascular endothelial growth factor (VEGF) and basic fibroblast growth factor are central in organizing pneumonia. Matrix metalloproteinases are also up-regulated. In experimental models, glucocorticoids have been shown to inhibit the formation of granulation tissue plugs.[4][5][6][7]

Histopathology

The histopathological hallmark is an excessive proliferation of fibrous tissue within the alveolar sacs and alveolar ducts with extension into the bronchioles. Organized plugs of intraluminal granulation tissue are known as Masson bodies. The granulation tissue buds extend into the bronchiole and may obstruct the lumen, hence the previous bronchiolitis obliterans. The granulation tissue has a uniform appearance within the alveolar spaces with preservation of lung parenchymal architecture. Mild mononuclear cell interstitial inflammation and foamy macrophages can be seen in the lung immediately surrounding the lesion. Significant inflammatory cell infiltration diffusely in the lung should raise concern for alternative diagnoses such as Non-specific interstitial pneumonia (NSIP). Disruption of the normal lung architecture should also lead to consideration of an alternative diagnosis like Usual Interstitial Pneumonia (UIP) as seen in Idiopathic Pulmonary Fibrosis (IPF).

History and Physical

Patients typically present in the fifth or sixth decade of life with fever, malaise, cough, and shortness of breath. Cryptogenic organizing pneumonia is unique among interstitial lung diseases because symptoms are subacute (weeks in duration). Patients frequently fail empiric antibiotics for presumed bacterial pneumonia. Their cough may be dry or productive. Sputum may be clear or discolored. Rarely do patients develop a rapidly progressive disease with severe dyspnea and hypoxemia. Chest pain, night sweats, significant weight loss, and mild arthralgias are uncommon symptoms. Hemoptysis and pneumothorax have rarely been reported.

A detailed history and physical examination should be performed to rule out connective tissue diseases, as they can be associated with organizing pneumonia. A thorough medication and exposure history should also be obtained. The respiratory exam typically discloses inspiratory crackles, but the exam can be normal.

Evaluation

White cell count is typically elevated with neutrophilia. Inflammatory markers, erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP), are commonly elevated. When COP is suspected then testing for autoimmune diseases should be undertaken.

Radiography

The chest radiograph findings in COP include patchy diffuse consolidations, mostly involving bilateral lower zones. Other described findings include migratory, irregular, linear, or nodular opacities. Pleural effusions can also be seen.

High-Resolution Computed Tomography (HRCT)

HRCT of the lungs reveals bilateral patchy peripherally located consolidations or ground-glass opacities, which are often asymmetric. The classic HRCT sign described in COP is the atoll sign or the reverse halo sign. This sign is characterized by a dense outer rim of consolidation around a focal ground-glass opacity. This sign is seen in about 20% of patients with COP and is non-specific, as seen in other infectious and inflammatory conditions.

Other less common findings include irregular nodular opacities, cavitary lesions, and pleural effusions. Multiple nodules and cavitary lesions should raise suspicion for malignancy.

Pulmonary Function Testing (PFT)

PFTs typically reveal a restrictive defect with diffusion impairment. Desaturation with 6-minute walk testing is also commonly noted.

Bronchoscopy

Flexible bronchoscopy with bronchoalveolar lavage (BAL) is often performed to rule out infections, pulmonary hemorrhage, and malignancy. BAL fluid characteristically has mixed cellularity with neutrophils, lymphocytes, and eosinophils. Significant lymphocyte elevation (approximately 40%) is typical, and CD4/CD8 ratio reveals CD8 predominance. Lack of lymphocytosis on BAL portends a poor prognosis. Marked elevation of eosinophils (greater than 25%) suggests eosinophilic pneumonia or rarely an overlap phenomenon.

Lung Biopsy

Transbronchial lung biopsies may be attempted but are often inadequate to make a definitive diagnosis due to the small amount of lung tissue obtained and loss of tissue architecture from crushed artifacts. It can help rule out alternative diagnoses. A surgical lung biopsy is often required to make a definitive diagnosis. Wedge biopsies are preferably obtained from at least 2 lobes with distinct radiographic involvement. In patients with a convincing clinical and radiographic presentation, in whom the risks of an invasive procedure outweigh the benefits, treatment can be started without a lung biopsy after a discussion with the patient.

Treatment / Management

There have been no controlled trials comparing medications or duration of treatment in COP. Treatment regimens are based on consensus guidelines. The initial clinical presentation, severity of disease, and degree of responsiveness should be considered when deciding on an appropriate regimen and duration of therapy.[8][9][10][11]

Spontaneous remissions have been described for patients with mild symptoms and minimal radiographic and PFT abnormalities. The anti-inflammatory effect of macrolides, particularly clarithromycin, has been exploited in some reports to treat patients with mild symptoms.

Most patients with progressive symptoms and diffuse radiographic involvement are treated with oral glucocorticoids resulting in marked improvement in symptoms. British Thoracic Society guidelines recommend initiating prednisone at a dose of 0.75 to 1 mg/kg per day and weaning over 6 to 12 months. Alternative regimens include starting prednisolone at a dose of 1 to 1.5 mg/kg for 3 months and then tapering or starting methylprednisolone 0.5 to 1 g intravenously (IV) for the first 3 days, followed by prednisolone at 20 mg daily, then tapering based on clinical response. Some authors have tried shorter courses tapered over 3 to 6 months with similar relapse rates. Regardless of the regimen, the initial dose is typically maintained for 4 to 8 weeks. Patients should be followed closely with follow-up clinical examination, pulmonary function testing, and chest radiographs. Relapses are common when tapering steroids but do not seem to affect the outcome. Delayed onset of initial treatment and evidence of cholestasis on laboratory testing is shown to be associated with multiple relapses. The last effective dose of glucocorticoids should be reinstituted at the earliest sign of worsening disease. Other groups have attempted lower doses of glucocorticoids intending to reduce cumulative steroid exposure, with slightly higher relapse rates but overall no change in morbidity and mortality. Close monitoring for adverse effects of glucocorticoids is recommended. Surgical resection is not recommended as treatment.

Patients who are unable to taper off glucocorticoids or have significant side effects from glucocorticoids can be started on a steroid-sparing agent, although COP is an unapproved indication for all steroid-sparing medications. Azathioprine and mycophenolate mofetil, among others, have been reported in case series for successful management of COP.

In patients who fail to improve despite high-dose steroid therapy, alternative diagnoses or infections should be first ruled out. Second-line agents such as cyclophosphamide and cyclosporine A have produced good clinical responses in these steroid-non-responsive cases.

Differential Diagnosis

Variants of COP

Secondary Organizing Pneumonia

Organizing pneumonia (OP) due to a secondary cause has similar clinical, radiological, and histological features as COP; hence, these causes have to be rigorously excluded before diagnosing COP. Secondary OP is associated with autoimmune diseases such as rheumatoid arthritis, granulomatosis with polyangiitis, and polymyositis/dermatomyositis or after radiation exposure to the lung or associated with hematological malignancies or secondary to drug exposures. It is important to distinguish from COP because treatment varies, and a secondary OP has a worse prognosis.

Acute Fulminant COP

Fulminant COP is suspected when patients present with rapidly worsening respiratory failure and hypoxemia, often requiring invasive mechanical ventilation. The clinical presentation resembles adult respiratory distress syndrome (ARDS) but histologically resembles OP without overt fibrosis. Clinically and radiographically, it cannot be distinguished from acute interstitial pneumonia (AIP). Patients progress to worsening respiratory failure and have high mortality. Reports have shown a rapid response to glucocorticoids if the diagnosis is made.

Acute Fibrinous and Organizing Pneumonia (AFOP)

This rare entity presents as an acute respiratory failure but radiographically and histopathologically appears similar to organizing pneumonia. It is typically idiopathic but may be associated with collagen vascular disease, hypersensitivity pneumonitis, or drug reaction.

Fibrosing COP

Fibrosing COP is a rare entity with a similar clinical and histological appearance to COP but with variable amounts of fibrosis. The fibrosis may or may not be evident radiographically but is seen on pathologic examination. These patients have a poor response to glucocorticoids or other agents. Patients often succumb to progressive respiratory failure. These cases may represent overlap with other idiopathic interstitial pneumonia.

Unifocal COP

Unifocal COP is typically diagnosed during the evaluation of a solitary pulmonary nodule for lung malignancy. No relapses have been reported.

Other Causes

Infectious Causes

Bacterial, fungal, or viral pneumonia is appropriately the first diagnosis considered in a patient with fever, cough, shortness of breath, and radiographic findings.

Inflammatory Causes

Other interstitial lung diseases, including idiopathic interstitial pneumonia, such as NSIP and UIP, could give a similar radiographic appearance. Hypersensitivity pneumonitis could have a similar clinical presentation, but radiographic changes are usually in the predominant upper lobe, and there is an identifiable exposure history. Hypersensitivity pneumonitis and COP share a lymphocyte-predominant BAL, but histopathology reveals chronic inflammation with poorly formed granulomas in hypersensitivity pneumonitis. Chronic eosinophilic pneumonia has a similar clinical and radiologic presentation but is differentiated by BAL fluid or peripheral eosinophilia and histology.

Malignancy

Radiographically, pulmonary malignancies such as primary pulmonary lymphoma or adenocarcinoma in situ could have an appearance similar to a focal area of COP. The diseases can be typically differentiated based on the clinical presentation and histopathologic examination. Low-grade primary pulmonary lymphoma may have some response to glucocorticoids, thus mimicking COP. Adenocarcinoma-in-situ tends to have associated nodules and does not respond to glucocorticoids.

Prognosis

COP is associated with excellent, long-term outcomes when treated. Spontaneous remissions are seen in about 50% of mild cases. Patients demonstrate a rapid symptomatic response to treatment, and up to 80% achieve a complete cure. Relapses are common but do not seem to affect long-term outcomes regarding morbidity and mortality.

Pearls and Other Issues

Persistent pulmonary opacities with symptoms of pneumonia not improving despite antibiotic therapy should prompt suspicion of COP. A rigorous search for secondary causes should be done before diagnosing COP. Glucocorticoid therapy produces a dramatic response, and up to 80% of individuals achieve a complete cure.

Enhancing Healthcare Team Outcomes

The diagnosis and management of COP requires an interprofessional team that includes a pulmonologist, infectious disease expert, thoracic surgeon, internist, pathologist, and radiologist. Once the diagnosis is made, the treatment is complex as there are no controlled trials comparing medications or duration of treatment in COP. Treatment regimens are based on consensus guidelines. The initial clinical presentation, severity of disease, and degree of responsiveness should be considered when deciding on an appropriate regimen and duration of therapy.

Spontaneous remissions have been described for patients with mild symptoms and minimal radiographic and PFT abnormalities. The anti-inflammatory effect of macrolides, particularly clarithromycin, has been exploited in some reports to treat patients with mild symptoms.

Most patients with progressive symptoms and diffuse radiographic involvement are treated with oral glucocorticoids resulting in marked improvement in symptoms. Close monitoring for adverse effects of glucocorticoids is recommended. Patients who are unable to taper off glucocorticoids or have significant side effects from glucocorticoids can be started on a steroid-sparing agent, although COP is an unapproved indication for all steroid-sparing medications. 

COP is associated with excellent, long-term outcomes when treated. Spontaneous remissions are seen in about 50% of mild cases. Patients demonstrate a rapid symptomatic response to treatment, and up to 80% achieve a complete cure. Relapses are common but do not seem to affect long-term outcomes regarding morbidity and mortality.[12]