Background: Organizing pneumonia is characterized by the presence of granulation tissue in the distal air spaces. When associated with granulation tissue in the bronchiolar lumen, organizing pneumonia is qualified by the term bronchiolitis obliterans (BO). Hence, the term bronchiolitis obliterans organizing pneumonia (BOOP) is used.
Organizing pneumonia may be classified according to whether (1) its cause is determined, (2) its cause is undetermined but occurring in a specific and relevant context, or (3) it is cryptogenic (idiopathic) organizing pneumonia (COP) (Cordier, 2000). Cryptogenic organizing pneumonia (COP) is often confused with BOOP. COP is a clinicopathologic syndrome characterized by rapid resolution with corticosteroids but frequent relapses when treatment is tapered or stopped.
Radiologically identical peripheral airspace consolidation can be seen in patients with chronic eosinophilic pneumonia (CEP) and BOOP. Whereas CEP has a predominant upper-lobe involvement, consolidation in BOOP involves the lower zones to a greater degree, though some patients have pathologic features of both CEP and BOOP.
Although the precise diagnosis depends on the analysis of a tissue biopsy specimen, clinicoradiologic features derived during biopsy-based studies may be sufficient. This article discusses BOOP in the general context of organizing pneumonia, combining data as necessary from studies in patients with BOOP or COP. No features distinguish organizing pneumonias of known cause from those of unknown cause (Lohr, 1997).
Pathophysiology: Approximately one half of cases of BOOP are idiopathic (Epler, 1985). A variety of conditions are associated with BOOP as follows:
- 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: Infection may be caused by Coxiella burnetii,
Pseudomonas aeruginosa, or Mycoplasma species. A
possible association exists with human herpesvirus 7 after lung
transplantation and with Pneumocystis carinii in patients
receiving tacrolimus after liver transplantation. Infection can be
caused by influenza A virus, measles virus, parvovirus B19, HIV, Chlamydia
species, Plasmodium vivax, or 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; 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 workers, silo-filler's disease, free-base cocaine use, and smoke inhalation.
- Radiation therapy: In patients treated with radiation therapy
for small cell bronchogenic carcinoma or breast cancer, BOOP may
affect the ipsilateral or contralateral lung.
- Associated pathologies
- Connective tissue disease - Rheumatoid arthritis, Sjögren
syndrome, ankylosing spondylitis, polymyositis-dermatomyositis,
cutaneous vasculitis, Behçet disease, Wegener granulomatosis,
ulcerative colitis, Crohn disease, systemic sclerosis, systemic
lupus erythematosus, systemic lupus erythematosus with
antiphospholipid syndrome, primary biliary cirrhosis, and
thyroiditis
- Immunosuppressed states - Hematopoietic stem cell
transplantation (HSCT), graft versus host disease of the liver
after allogenic 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 immune deficiency syndrome
- Miscellaneous conditions
- Sarcoidosis, lung cancer, lung atelectasis, asthma, cystic
fibrosis, secondary amyloidosis, Sweet syndrome, idiopathic
thrombocytopenic purpura, Evans syndrome, essential mixed
cryoglobulinemia, and chronic sinusitis
- A seasonal variety
- Menstrual- and pregnancy-related BOOP
- Sarcoidosis, lung cancer, lung atelectasis, asthma, cystic
fibrosis, secondary amyloidosis, Sweet syndrome, idiopathic
thrombocytopenic purpura, Evans syndrome, essential mixed
cryoglobulinemia, and chronic sinusitis
- Connective tissue disease - Rheumatoid arthritis, Sjögren
syndrome, ankylosing spondylitis, polymyositis-dermatomyositis,
cutaneous vasculitis, Behçet disease, Wegener granulomatosis,
ulcerative colitis, Crohn disease, systemic sclerosis, systemic
lupus erythematosus, systemic lupus erythematosus with
antiphospholipid syndrome, primary biliary cirrhosis, and
thyroiditis
Cytologic and immunocytologic profile of bronchoalveolar lavage in patients with BOOP:
- Cytologic examination reveals 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 as well.
- 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 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:
- In the US: BOOP is believed to represent 20-30% of all cases of chronic infiltrative lung disease.
- Internationally: No significant difference has been reported between the US rates and those in other countries.
Mortality/Morbidity: Overall mortality rate in patients with BOOP is 10%. Pulmonary complications occur in 30-60% of patients with HSCT. Complications include BOOP, BO, and idiopathic pneumonia syndrome (IPS). BO and BOOP occur exclusively in patients who have undergone allogenic HSCT, and BO and BOOP have 61% and 21% mortality rates, respectively. Patients with BOOP respond favorably to treatment with steroids, whereas patients with IPS have a 1-year survival rate of less than 15%.
Race: No racial predilection exists.
Sex: No sex predilection exists.
Age: Most patients present at age 40-70 years, but BOOP has been reported in children, particularly in children with underlying malignancy.
Clinical Details: Approximately one half of patients give a history of an influenzalike illness followed by a short illness of approximately 3 months' (1-4 mo) duration characterized by a persistent nonproductive cough, effort dyspnea, low-grade pyrexia, malaise, and weight loss. Less common symptoms include pleuritic chest pain and hemoptysis.
Symptoms do not respond to broad-spectrum antibiotics. A significant number of patients have associated collagen vascular disease (16%) and inhalation exposure to toxins (17%). BOOP may be the first manifestation of non-Hodgkin lymphoma and collagen vascular disease. Clinical examination of the thorax reveals fine, dry, lung crepitations in 70-90% of patients. Clubbing is unusual. The erythrocyte sedimentation rate is invariably increased and may be very high. Pulmonary function tests characteristically show a restrictive pattern. The diffusing capacity (DLCO) 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: Plain radiography is usually the initial examination, as in most cases of suspected pulmonary pathology. However, CT scans provide a better assessment of the disease pattern and distribution; therefore, CT is superior to chest radiography in determining the optimal biopsy site.
Limitations of Techniques: Plain radiographic and CT findings are nonspecific in patients with BOOP and may mimic those of a variety of pulmonary fibrotic, inflammatory, and neoplastic processes.
DIFFERENTIALS
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
X-RAY
Findings: Plain radiograph findings include the following:
- Bilateral or unilateral, patchy, alveolar, airspace consolidation is
revealed, often subpleural and peribronchial in location and mainly in
the lower zones.
- Consolidation is nonsegmental and commonly 2-6 cm in diameter.
- An air bronchogram may be present.
- Nodules 3-5 mm in diameter are seen in approximately one half of
patients.
- 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.
- 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.
- 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: Mimics of BOOP include collagen vascular disease, usual interstitial pneumonia, lung metastases, Wegener granulomatosis, eosinophilic pneumonia, primary bronchogenic neoplasm, and tuberculosis. In one 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.
CAT SCAN
Findings: CT and high-resolution CT findings include the following:
- 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 one half
of patients
- Mediastinal lymphadenopathy (27%)
- Small nodular opacities measuring 1-10 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 findings are nonspecific in BOOP and may be seen in a variety of pulmonary infectious or inflammatory processes and neoplastic diseases. However, CT is more sensitive than chest radiography in the assessment of disease pattern and distribution of disease. CT is superior in determining the biopsy site; therefore, high-resolution computed tomography (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 both AIP and BOOP.
False Positives/Negatives: False-positive diagnosis of BOOP may occur with a variety of pulmonary pathologies. Interstitial lung disease is clinically characterized by diffuse pulmonary infiltrates. The term interstitial is actually a misnomer because it implies that the disease process is confined to the area between the alveolar epithelium and the capillary endothelial basement membrane. In fact, the group of conditions termed interstitial frequently involves the alveolar epithelium, alveolar space, pulmonary microvasculature, respiratory bronchioles, larger airways, and even the pleura. These features add to the nonspecificity of the 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 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 has a predominant upper-lobe involvement, the consolidation in BOOP involves the lower zones to a greater degree, though some patients have pathologic features of both CEP and BOOP.
MRI
Findings: An early report of the value of gadolinium-enhanced MRI in the evaluation of disease activity in chronic infiltrative lung diseases showed promising results. The 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. Disease activity was assessed by using 1 or more of the following: bronchoalveolar lavage, gallium-67 citrate radionuclide scanning, serum angiotensin-converting enzyme assay, and open lung biopsy. T1-weighted breath-hold MRIs were obtained before and after the intravenous administration of gadolinium-based contrast agent. Of the 17 patients with active disease, 14 had enhancing lesions.
At present, MRI has no diagnostic role in BOOP, but it may have a role in the follow-up imaging in patients with BOOP to assess the treatment response or disease activity.
Bronchoalveolar carcinoma may mimic BOOP. The white lung sign is an uncommon finding in pulmonary consolidations evaluated with heavily T2-weighted sequences. However, the sign is usually negative in patients with BOOP, but it was found to be positive in 5 of 5 patients with bronchoalveolar carcinoma in one study. Thus, MRI has a potential role in the differential diagnosis of BOOP.
ULTRASOUND
Findings: Ultrasonography is useful in the detection and characterization of pleural effusion and in the guidance of pleural interventions.
INTERVENTION
Intervention: 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.
PICTURES
| Caption: Picture 1. Bronchiolitis obliterans organizing pneumonia. Chest radiograph in an 81-year-old woman with mitral and aortic valve stenosis, hiatus hernia, and iron-deficiency anemia of unknown cause (same patient as in Images 2-4). 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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| Picture Type: X-RAY | |
| Caption: Picture 2. Bronchiolitis obliterans organizing pneumonia. Chest radiograph in an 81-year-old woman with mitral and aortic valve stenosis, hiatus hernia, and iron-deficiency anemia of unknown cause (same patient as in Images 1 and 3-4). 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 has moved to the right upper zone and both mid zones. | |
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| Picture Type: X-RAY | |
| Caption: Picture 3. Bronchiolitis obliterans organizing pneumonia. Chest radiograph in an 81-year-old woman with mitral and aortic valve stenosis, hiatus hernia, and iron-deficiency anemia of unknown cause (same patient as in Images 1-2 and 4). 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 mid zones. | |
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| Picture Type: X-RAY | |
| Caption: Picture 4. Bronchiolitis obliterans organizing pneumonia. Photomicrograph of a transbronchial biopsy sample of the right upper lobe bronchus in an 81-year-old woman with mitral and aortic valve stenosis, hiatus hernia, and iron-deficiency anemia of unknown cause. 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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| Picture Type: Photo | |
| Caption: Picture 5. Bronchiolitis obliterans organizing pneumonia. A 54-year-old man with an 8- to 9-month history of left-sided chest pain, anorexia, weight loss, and increasing shortness of breath. The patient has asthma. He 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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| Picture Type: X-RAY | |
| Caption: Picture 6. Bronchiolitis obliterans organizing pneumonia. Chest radiograph in a 54-year-old man with 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 has asthma. He had an episode of pneumonia 6 months previously. 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. | |
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| Picture Type: X-RAY | |
| Caption: Picture 7. Bronchiolitis obliterans organizing pneumonia. 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 (same patient as in Image 8). | |
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| Picture Type: X-RAY | |
| Caption: Picture 8. Bronchiolitis obliterans organizing pneumonia. Standard nonenhanced axial thoracic 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. | |
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| Picture Type: CT | |