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AUTHOR AND EDITOR INFORMATION

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Author: Ali Nawaz Khan, MBBS, FRCS, FRCP, FRCR, LRCP, Chairman of Medical Imaging, Professor of Radiology, NGHA, King Fahad National Guard Hospital, King Abdulaziz Medical City, Riyadh, Saudi Arabia

Ali Nawaz Khan is a member of the following medical societies: American Institute of Ultrasound in Medicine, Radiological Society of North America, Royal College of Physicians, Royal College of Physicians and Surgeons of the USA, Royal College of Radiologists, and Royal College of Surgeons of England

Coauthor(s): Simon Hanley, MBBS, MRCP, FRCP, Consulting Staff, Department of Internal Medicine, North Manchester General Hospital; Sumaira MacDonald, MBChB, PhD, MRCP, FRCR, Lecturer, Sheffield University Medical School; Endovascular Fellow, Sheffield Vascular Institute; Muthusamy Chandramohan, MBBS, DMRD, FRCR, Special Registrar, Department of Radiology, Manchester Radiology; Sarah Al Ghanem, MBBS, Consulting Staff, Department of Medical Imaging, King Fahad National Guard Hospital, Riyadh, Saudi Arabia

Editors: Jeffrey A Miller, MD, Associate Professor of Clinical Radiology, University of Medicine and Dentistry of New Jersey; Associate Chief of Service, Department of Radiology, Veterans Affairs of New Jersey Health Care System; Bernard D Coombs, MB, ChB, PhD, Consulting Staff, Department of Specialist Rehabilitation Services, Hutt Valley District Health Board, New Zealand; John D Newell, Jr, MD, FACR, FCCP, FASER, Co-Director of Thoracic Imaging, UCDHSC; Director of Lung Imaging Center, Professor of Radiology and Professor of Medicine, Department of Radiology, University of Colorado Health Sciences Center, National Jewish Medical and Research Center; Univ. Colorado Hospital; Robert M Krasny, MD, Consulting Staff, Department of Radiology, The Angeles Clinic and Research Institute; Eugene C Lin, MD, Consulting Staff, Department of Radiology, Virginia Mason Medical Center

Author and Editor Disclosure

Synonyms and related keywords: BOOP, cryptogenic organizing pneumonia, COP, Ardystil syndrome, nonspecific interstitial pneumonia with fibrosis, proliferative bronchiolitis, pulmonary disease, pneumonia, organizing pneumonia, idiopathic organizing pneumonia

INTRODUCTION

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Background

Organizing pneumonia features granulation tissue in the distal air spaces. When organizing pneumonia is associated with granulation tissue in the bronchiolar lumen, the qualifying term bronchiolitis obliterans (BO) is added.

Organizing pneumonia may be classified according to the following criteria1:

  • The cause has been determined.
  • The cause remains undetermined but is occurring in a specific and relevant context.
  • The disease is cryptogenic (idiopathic) organizing pneumonia (COP).

Cryptogenic organizing pneumonia (COP) is often confused with bronchiolitis obliterans organizing pneumonia (BOOP). COP is a clinicopathologic syndrome that is rapidly resolved with corticosteroids but that is also marked by frequent relapses when treatment is tapered off or stopped.

Radiologically identical peripheral airspace consolidation occurs in patients with chronic eosinophilic pneumonia (CEP) and BOOP. CEP primarily involves the upper lobe, while in BOOP, consolidation is predominantly in the lower zones, although some patients have pathologic characteristics of CEP and BOOP.

A tissue biopsy specimen is needed for a precise diagnosis, but clinicoradiologic characteristics determined through biopsy-based studies may provide enough diagnostic information. This article discusses BOOP in the general context of organizing pneumonia; it combines data from BOOP and COP patient research. Organizing pneumonias that are of known cause are indistinguishable from those that are of unknown cause.2

Pathophysiology

About 50% of BOOP cases are idiopathic.3 The following conditions are associated with BOOP:

  • Conditions in which the cause is determined
    • Radiation therapy - In patients treated with radiation therapy for small-cell bronchogenic carcinoma or breast cancer, BOOP may affect the ipsilateral or contralateral lung.
    • Infections - BOOP can be caused by Coxiella burnetii and  Pseudomonas aeruginosa, as well as by Mycoplasma species. BOOP possibly may be associated with human herpesvirus 7 infection following lung transplantation and with Pneumocystis jiroveci (formerly, P. carinii) in patients receiving tacrolimus (after liver transplantation). Infection also can be caused by influenza A virus, measles virus, parvovirus B19, human immunodeficiency virus (HIV), Chlamydia species, Plasmodium vivax, and Plasmodium malariae.
    • Drugs and toxins - BOOP is associated with exposure to minocycline, gold, cephalosporin, acebutolol, sulfasalazine, mesalazine, bucillamine, interferon beta-1a, nitrofurantoin, amiodarone, ticlopidine, carbamazepine, phenytoin, sotalol, and rapid intravenous cyclophosphamide pulse therapy; a combination of cytosine arabinoside, anthracyclines, and massive L-tryptophan ingestion; Sauropus androgynus vegetable poisoning; exposure to paint aerosols in textile workers; nylon flock–related disease; silo-filler's disease; freebase cocaine use; and smoke inhalation.
  • Associated pathologies
    • Connective tissue diseases - Rheumatoid arthritis, Sjögren syndrome, ankylosing spondylitis, polymyositis-dermatomyositis, cutaneous vasculitis, Behçet syndrome, Wegener granulomatosis, ulcerative colitis, regional enteritis, systemic sclerosis, systemic lupus erythematosus, systemic lupus erythematosus with antiphospholipid-antibody syndrome, primary biliary cirrhosis, and thyroiditis
    • Immunosuppressed states - Hematopoietic stem cell transplantation (HSCT), graft versus host disease of the liver after allogeneic bone marrow transplantation, renal transplantation, coronary artery bypass graft surgery, kidney transplantation with Fabry disease, T-cell leukemia, primary non-Hodgkin lymphoma, malignancies in children, myelodysplastic syndrome, recent surgery, severe pneumonia, adult respiratory distress syndrome, and acquired immunodeficiency syndrome (AIDS)
    • Miscellaneous conditions
      • Sarcoidosis, lung cancer, lung atelectasis, asthma, cystic fibrosis, secondary amyloidosis, acute febrile neutrophilic dermatosis (Sweet disease), idiopathic thrombocytopenic purpura, Evans syndrome, essential mixed cryoglobulinemia, and chronic sinusitis
      • A seasonal variety
      • Menstrual- and pregnancy-related BOOP

Bronchoalveolar lavage reveals the following cytologic and immunocytologic characteristics in patients with BOOP4:

  • Cytologic examination demonstrates a mixed cell pattern, with an increase in lymphocytes (20-40%), neutrophils (10%), eosinophils (5%), mast cells, foamy macrophages, and occasional plasma cells.
  • An increase in the percentages of neutrophils and lymphocytes in patients with BOOP differentiates the condition from idiopathic pulmonary fibrosis.
  • Eosinophils are increased significantly in patients with CEP, with a small overlap with BOOP.
  • The CD4+/CD8+ ratio is decreased.
  • The percentage of CD57+ cells is within the reference range.
  • Activation of T cells is increased in terms of human leukocyte antigen-DR (HLA-DR) expression and, occasionally, interleukin-2 receptor (CD25+) expression.
  • All of the above findings are similar in extrinsic allergic alveolitis, except that CD25+ expression is always within the reference range in patients with BOOP and that levels of CD57+ cells are always increased in extrinsic allergic alveolitis.
  • In patients with BOOP, the ratio of lymphocytes to CD8+ cells is significantly increased, and the CD4+/CD8+ ratio is significantly lower than the ratios in patients with usual interstitial pneumonia.

Frequency

United States

It is believed that BOOP is the source of 20-30% of all cases of chronic infiltrative lung disease.5

International

No significant difference has been reported between US and international rates.

Mortality/Morbidity

The overall mortality rate in patients with BOOP is 10%. Pulmonary complications—including BOOP, BO, and idiopathic pneumonia syndrome (IPS)—develop in 30-60% of patients with HSCT. BO and BOOP, which have a 61% and 21% mortality rate, respectively, occur exclusively in patients who have undergone allogenic HSCT. Patients with BOOP respond favorably to treatment with steroids, whereas patients with IPS have a 1-year survival rate of less than 15%.2

Race

No racial predilection is reported.

Sex

No sex predilection is described.

Age

Most patients present at age 40-70 years, but BOOP has been reported in children, particularly in those with underlying malignancy.6, 5

Clinical Details

Approximately half of all patients give a history of an influenzalike illness followed by a second illness that lasts about 3 months (1-4 mo) and features a persistent, nonproductive cough; effort dyspnea; low-grade pyrexia; malaise; and weight loss. Less common symptoms include pleuritic chest pain and hemoptysis.5 

Symptoms do not respond to broad-spectrum antibiotics. A significant number of patients have associated collagen disease (16%) and inhalation exposure to toxins (17%). BOOP may be the first manifestation of non-Hodgkin lymphoma and collagen disease.7 In most patients, clinical examination of the thorax demonstrates fine, dry lung crepitations. Clubbing is unusual. The erythrocyte sedimentation rate not only is invariably higher but may be greatly increased. Pulmonary function tests characteristically show a restrictive pattern. The diffusing capacity is reduced, the resting alveolar arterial oxygen gradient is widened, and exercise-related hypoxemia is present. By contrast, CEP involves an obstructive pattern of lung physiology.

Preferred Examination

As in most cases of suspected pulmonary pathology, plain radiography most often is used for the initial examination. However, computed tomography (CT) scans provide a better assessment of the disease pattern and distribution; therefore, CT scanning is superior to chest radiography in determining the optimal biopsy site.

Limitations of Techniques

Plain radiographic and CT-scan findings are nonspecific in patients with BOOP and may mimic findings from a variety of pulmonary fibrotic, inflammatory, and neoplastic processes.


DIFFERENTIALS

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Wegener Granulomatosis, Thoracic

Other Problems to Be Considered

Chronic interstitial pneumonia (organizing interstitial pneumonia, chronic diffuse sclerosing alveolitis)
Acute interstitial pneumonia (AIP)
Focal organizing pneumonia
Interstitial lung disease
Hypogammaglobulinemia
Pulmonary metastasis and primary adenocarcinoma
Pulmonary tuberculosis
Community-acquired pneumonia
Chronic eosinophilic pneumonia
Usual interstitial pneumonia
Bronchoalveolar carcinoma


RADIOGRAPH

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Findings

Plain radiographic findings include the following:

  • Bilateral or unilateral, patchy alveolar airspace consolidation is revealed, often subpleural and peribronchial in location and existing mainly in the lower zones.
  • Consolidation is nonsegmental and is commonly 2-6 cm in diameter.
  • An air bronchogram may be present.
  • Nodules 3-5 mm in diameter are seen in approximately 50% of patients.5
  • Ground-glass appearances are unusual on standard chest radiographs.
  • Basal, irregular linear opacities may be noted.
  • Unilateral focal or lobar consolidation may occur in 5-31% of patients.5
  • Miliary shadowing has been reported.
  • Cavitary BOOP that mimics tuberculosis and cavitating opacity after lung transplantation have been reported.
  • Pleural thickening occurs in 13% of patients.5 
  • Pleural effusions may be present.
  • Migratory opacities or areas of consolidation may be present.

Degree of Confidence

No radiographic features are diagnostic of BOOP.

False Positives/Negatives

Diseases that can mimic BOOP include collagen disease, usual interstitial pneumonia, lung metastases, Wegener granulomatosis, eosinophilic pneumonia, primary bronchogenic neoplasm, and tuberculosis. In 1 report, 2 patients with subacute symptoms and signs compatible with pulmonary tuberculosis had cavitary infiltrates in the right upper lobe, as demonstrated on chest radiographs. Histologic analysis of specimens from both patients yielded typical histologic features of BOOP.8


CT SCAN

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Findings

CT-scan and high-resolution CT-scan findings include the following5:

  • Patchy ground-glass opacities in a subpleural and/or peribronchovascular distribution (80%)
  • Bilateral basal airspace consolidation (71%)
  • Bronchial wall thickening and cylindrical bronchial dilatation in areas of air bronchogram (71%)
  • Centrilobular nodules 3-5 mm in diameter in approximately 50% of patients
  • Mediastinal lymphadenopathy (27%)
  • Small, nodular opacities measuring from 1 to 10 mm in diameter, typically ill defined (50%)
  • Cavitating lung mass (rare)
  • Pleural effusions in approximately one third of patients

Degree of Confidence

Plain radiographic and CT-scan findings are nonspecific in BOOP and may be seen in a variety of pulmonary infectious or inflammatory processes and neoplastic diseases. However, CT scanning is more sensitive than chest radiography is in assessing disease pattern and distribution. CT scanning is also superior in determining the biopsy site; therefore, high-resolution CT (HRCT) is usually performed prior to lung biopsy.

In the early stages, clinical and chest radiographic findings of acute AIP and BOOP may be similar; however, HRCT findings of AIP and BOOP may be different. Traction bronchiectasis, interlobular septal thickening, and intralobular septal thickening are significantly more prevalent in patients with AIP than in patients with BOOP, whereas parenchymal nodules and peripheral distribution are more prevalent in BOOP. Areas with ground-glass attenuation, airspace consolidation, and architectural distortion are common in AIP and BOOP.

False Positives/Negatives

A number of pulmonary pathologies may lead to a false-positive diagnosis of BOOP. Interstitial lung disease is clinically characterized by diffuse pulmonary infiltrates. The term interstitial is a misnomer because it suggests that the disease process is limited to the region between the alveolar epithelium and the capillary endothelial basement membrane. In fact, the conditions termed interstitial often involve the alveolar epithelium, alveolar space, pulmonary microvasculature, respiratory bronchioles, larger airways, and pleura, increasing the nonspecificity of radiographic findings.

The enormous list of interstitial lung diseases may be made manageable by reviewing the patient's history, by testing for specific serologic measures, and by performing bronchoalveolar lavage, transbronchial biopsy, biopsy of extrathoracic tissues, or open lung biopsy. Radiographic findings serve as a guide for further investigation. The lack of honeycombing or an irregular reticular pattern in BOOP may help to differentiate BOOP from other interstitial lung disease. Unilobar consolidation may be mistaken for lung malignancy. Identical peripheral airspace consolidation can be seen in CEP and BOOP. Whereas CEP primarily involves the lung's upper lobe, BOOP's consolidation predominantly involves the lower zones, although some patients have pathologic features of CEP and BOOP.


MRI

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Findings

An early report of the value of gadolinium-enhanced magnetic resonance imaging (MRI) in the evaluation of disease activity in chronic infiltrative lung diseases showed promising results. A cohort of 25 patients included patients with sarcoidosis, BOOP, usual interstitial pneumonia, radiation pneumonitis, desquamative interstitial pneumonia, rheumatoid lung, vasculitis, alveolar proteinosis, bronchoalveolar carcinoma, and/or CEP. One or more studies—bronchoalveolar lavage, gallium-67 citrate radionuclide scanning, serum angiotensin-converting enzyme assay, and open lung biopsy—were employed to assess disease activity. T1-weighted breath-hold magnetic resonance images were obtained prior to and following the intravenous administration of gadolinium-based contrast agent. Fourteen out of the 17 patients with active disease  were  found  to  have  enhanced  lesions.9

At present, MRI has no diagnostic role in BOOP, but it may have a role in the follow-up imaging of patients with the disease, in order to assess treatment response or disease activity.

Bronchoalveolar carcinoma may mimic BOOP. The white lung sign is not commonly found in pulmonary consolidations that have been assessed with heavily T2-weighted sequences. However, although the sign is usually negative in patients with BOOP, 1 study found the sign to be positive in 5 out of 5 patients with bronchoalveolar carcinoma. Thus, MRI has a potential role in the differential diagnosis of BOOP.10 

Gadolinium-based contrast agents (gadopentetate dimeglumine [Magnevist], gadobenate dimeglumine [MultiHance], gadodiamide [Omniscan], gadoversetamide [OptiMARK], gadoteridol [ProHance]) have recently been linked to the development of nephrogenic systemic fibrosis (NSF) or nephrogenic fibrosing dermopathy (NFD). For more information, see the eMedicine topic Nephrogenic Fibrosing Dermopathy. The disease has occurred in patients with moderate to end-stage renal disease after being given a gadolinium-based contrast agent to enhance MRI or magnetic resonance angiography scans. As of late December 2006, the Food and Drug Administration (FDA) had received reports of 90 such cases. Worldwide, over 200 cases have been reported, according to the FDA. NSF/NFD is a debilitating and sometimes fatal disease. Characteristics include red or dark patches on the skin; burning, itching, swelling, hardening, and tightening of  the  skin;  yellow  spots  on  the  whites  of  the  eyes;  joint  stiffness  with  trouble  moving  or  straightening  the  arms,  hands,  legs,  or  feet;  pain  deep  in  the  hip bones or ribs; and muscle weakness. For more information, see the FDA Public Health Advisory or Medscape.


ULTRASOUND

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Findings

Ultrasonography is useful in the detection and characterization of pleural effusion and in the guidance of pleural interventions.


NUCLEAR MEDICINE

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Findings

A study has shown that the degree of BOOP disease activity can be reflected in an enhanced accumulation of 18F-fluorodeoxyglucose (FDG) in patients.11


INTERVENTION

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Most patients with BOOP require open lung biopsy for diagnosis. However, some evidence suggests that combining the cytologic bronchoalveolar lavage and histologic transbronchial lung biopsy data obtained during a fiberoptic procedure appears to be an effective method for initially investigating BOOP that presents with patchy radiographic shadows. Percutaneous lung biopsy has been used in a few patients, but on the whole, it appears to be inadequate.

BOOP may resolve spontaneously; however, patients usually require treatment with steroids. Most patients recover with treatment, and symptoms resolve within days or weeks. Radiographic findings reportedly demonstrate improvement in 50-86% of patients; however, in a minority of patients, the disease may persist. Approximately 30% of patients experience relapse upon withdrawal of treatment. Patients with BOOP respond favorably to treatment with steroids.


MULTIMEDIA

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Media file 1:  Chest radiograph in an 81-year-old woman with mitral- and aortic-valve stenosis, hiatal hernia, and iron-deficiency anemia of unknown cause. The patient had undergone right-sided mastectomy for a carcinoma of the breast 20 years earlier. She presented with migratory lung opacities and areas of consolidation. Radiograph shows areas of consolidation at the lung base, with an air bronchogram at the right lung base. A wedge-shaped, pleural-based opacity is demonstrated astride the lateral part of the lesser fissure.
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Media type:  X-RAY

Media file 2:  Chest radiograph in an 81-year-old woman with mitral- and aortic-valve stenosis, hiatal hernia, and iron-deficiency anemia of unknown cause (same patient as in Image 1). The patient had undergone right-sided mastectomy for a carcinoma of the breast 20 years earlier. Radiograph obtained 2 months after Image 1 shows that the consolidation had moved to the right upper zone and both midzones.
Click to see larger pictureClick to see detailView Full Size Image
Media type:  X-RAY

Media file 3:  Chest radiograph in an 81-year-old woman with mitral- and aortic-valve stenosis, hiatal hernia, and iron-deficiency anemia of unknown cause (same patient as in Images 1-2). The patient had undergone right-sided mastectomy for a carcinoma of the breast 20 years earlier. Radiograph obtained 2 months after Image 2 shows changing consolidation located in both midzones.
Click to see larger pictureClick to see detailView Full Size Image
Media type:  X-RAY

Media file 4:  Photomicrograph of a transbronchial biopsy sample of the right–upper-lobe bronchus of an 81-year-old woman with mitral- and aortic-valve stenosis, hiatal hernia, and iron-deficiency anemia of unknown cause (same patient as in Images 1-3). The patient had undergone right-sided mastectomy for a carcinoma of the breast 20 years earlier. The slide was a part of a series of sections that showed granulation tissue polyps within the lumina of the bronchioles and alveolar ducts. These were associated with patchy areas of organizing pneumonia consisting largely of mononuclear cells and foamy macrophages in the surrounding lung. Plugs of immature fibroblasts covered by cuboidal cells were seen, as was a variable degree of infiltration of interstitium and alveoli.
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Media type:  Photo

Media file 5:  A 54-year-old man with asthma and an 8- to 9-month history of left-sided chest pain, anorexia, weight loss, and increasing shortness of breath. The patient had an episode of pneumonia 6 months previously, when a chest radiograph showed a right-sided, apical, segmental consolidation, which improved with antimicrobial therapy. This radiograph shows opacity in the left upper zone, with tethering to the pleural space.
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Media type:  X-RAY

Media file 6:  Chest radiograph in a 54-year-old man with asthma and an 8- to 9-month history of left-sided chest pain, anorexia, weight loss, and increasing shortness of breath (same patient as in Image 5). The patient had an episode of pneumonia 6 months previously. A computed tomography (CT) scan obtained 3 weeks after Image 5 shows enlargement of the left–upper-zone opacity. An open lung biopsy was performed and showed microscopic changes characteristic of bronchiolitis obliterans organizing pneumonia.
Click to see larger pictureClick to see detailView Full Size Image
Media type:  X-RAY

Media file 7:  Chest radiograph in a 56-year-old woman with systemic lupus erythematosus shows a left-sided unilateral focal/lobar consolidation associated with some loss of volume.
Click to see larger pictureClick to see detailView Full Size Image
Media type:  X-RAY

Media file 8:  Standard nonenhanced axial thoracic computed tomography (CT) scan in a 56-year-old woman with systemic lupus erythematosus (same patient as in Image 7) shows left–lower-lobe consolidation with some loss of volume and an air bronchogram. Transbronchial lung biopsy confirmed the diagnosis of bronchiolitis obliterans organizing pneumonia.
Click to see larger pictureClick to see detailView Full Size Image
Media type:  CT


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Bronchiolitis Obliterans Organizing Pneumonia excerpt

Article Last Updated: Aug 2, 2007