Bronchiolitis obliterans organizing pneumonia: Pathogenesis, clinical features, imaging and therapy review

Bronchiolitis obliterans organizing pneumonia (BOOP) was first described in the early 1980s as a clinicopathologic syndrome characterized symptomatically by subacute or chronic respiratory illness and histopathologically by the presence of granulation tissue in the bronchiolar lumen, alveolar ducts and some alveoli, associated with a variable degree of interstitial and airspace infiltration by mononuclear cells and foamy macrophages. Persons of all ages can be affected. Dry cough and shortness of breath of 2 weeks to 2 months in duration usually characterizes BOOP. Symptoms persist despite antibiotic therapy. On imaging, air space consolidation can be indistinguishable from chronic eosinophilic pneumonia (CEP), interstitial pneumonitis (acute, nonspecific and usual interstitial pneumonitis, neoplasm, inflammation and infection). The definitive diagnosis is achieved by tissue biopsy. Patients with BOOP respond favorably to treatment with steroids.

3][4][5][6] BOOP is characterized by the presence of granulation tissue in the bronchiolar lumen, alveolar ducts and some alveoli, associated with a variable degree of interstitial and airspace infiltration by mononuclear cells and foamy macrophages.BOOP is differentiated from organizing pneumonia, which is defi ned by the presence of granulation tissue in the distal air spaces; but when associated with granulation tissue in the bronchiolar lumen, organizing pneumonia is qualifi ed by the term bronchiolitis obliterans (BO).

Pathogenesis of BOOP
Cytological profi le of bronchoalveolar lavage in BOOP reveals a mixed cell pattern with an increase in lymphocytes (20-40%), and lymphocytes in patients with BOOP help differentiate the condition from parenchymal pulmonary disease.Neutrophils (10%), eosinophils (5%), mast cells, foamy macrophages and occasional plasma cells increase in patients with IPF.The number of eosinophils is increased signifi cantly in patients with CEP, with a small overlap with BOOP.The CD4/CD8 ratio is decreased, but the percentage of CD57 + cells is within the reference range. [7]ctivation of T cells is increased in terms of human leukocyte antigen-DR expression; and occasionally, interleukin-2 receptor (CD25) is also expressed.These fi ndings are similar to those 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. [7]Other features include central clusters of mononuclear infl ammatory cells, possibly found in the intraluminal polyps; chronic infl ammation in the walls of the surrounding alveoli with reactive type II cells; increased foamy macrophages in the alveoli; and preserved lung architecture. [5]Several causes of BOOP have been recorded but most cases are idiopathic.BOOP has also been reported as a secondary phenomenon in several other clinical settings.Many lung pathologies are associated with BOOP, the BOOP process is histological and clinical course is that of the underlying primary pathology [Figures 1 and 2].
The pathogenesis of BOOP is that of an infl ammatory lung disease rather than a fi brosing process such as in UIP/IPF.However, the inflammatory response in BOOP appears to be different from that in other pulmonary infl ammatory disorders such as COPD, asthma and granulomatous lung disease.These differences are important because treatment directed towards one type of inflammatory response might not be effective against another type. [8]BOOP responds well to corticosteroid therapy, while UIP/IPF usually does not.There is a new fi bromyxoid connective formation in BOOP, as well as in UIP/IPF; but this process can be fully reversed with corticosteroid therapy in BOOP but not in UIP/IPF [Figures 1 and 2].This phenomenon is not completely understood.However, it is known that the newly formed fi bromyxoid connective tissue causes destruction of the lung interstitium in UIP/IPF.There is extensive capillarization of the airway fi bromyxoid tissue in BOOP but not in UIP/IPF.1]

Clinical Findings
Persons of all ages can be affected.Approximately 50% of patients present with infl uenza-like illness followed by a short illness of approximately few months' duration characterized by a persistent nonproductive cough, effort dyspnea, lowgrade pyrexia, malaise and weight loss.In one series 94% had symptoms of cough, fever or dyspnea.Less common symptoms include pleuritic chest pain and hemoptysis.Associated collagen vascular disorder is found in 16% and inhalation exposure to toxins in 17%. [12,13]Clinical examination of the thorax reveals fi ne, dry lung crepitations in the majority of patients.Clubbing is unusual.The ESR is usually elevated, and pulmonary function tests show a restrictive pattern.The diffusing capacity is reduced, the resting alveolar arterial oxygen gradient is widened and exercise-related hypoxemia is present.Conventional chest radiographs revealed that bilateral patchy infi ltrates were seen most frequently in 68%, followed by small linear opacities in 15%, both patchy infi ltrates and reticulonodular opacities in 12% and reticulonodular opacities in 6%. [14]third of patients with BOOP treated for less than a year may have recurrence of the disease.Nevertheless, BOOP can be effectively treated a second and third time with the previously effective dosage level of prednisone. [1]Nonresponsive BOOP may be secondary or may be associated with other pathology; or may represent a combination of BOOP and UIP/IPF, where the associated fi brotic process does not respond to corticosteroids.
This form can occur in a previously healthy individual or can be associated with other systemic illness.The course of the disease can be galloping, with 1 to 3 days of symptoms and acute respiratory failure. [22]In fatal cases, an underlying fi brotic process has been implicated.Most fatal cases have a secondary form of BOOP.[25] Urgent tissue sampling may lead to urgent introduction of corticosteroids for primary BOOP, which might improve survival. [21]][28][29] Some focal nodular lesions may progress to the typical bilateral process of idiopathic BOOP but most do not.Surgical resection may result in a cure. Thus BOOP should be considered when multiple large nodular lesions have chest CT fi ndings of air bronchogram, irregular margins, broad pleural tags, parenchymal bands or subpleural lines.In patients with multiple BOOP nodules, the mode of presentation is pleuritic type chest pain in approximately 50% patients.The nodular type of BOOP may be related to reports of spontaneous resolution of lung metastases. [30]It has been suggested that reports of spontaneous regression of lung metastases have decreased in recent years with increasing reliance on tissue diagnosis and with confi rmation of the fact that the nodular lesions indeed represent nodular BOOP.
BOOP can follow all types of pneumonias when symptoms and radiographic changes persist despite an initial improvement.Thus the pneumonic process organizes into BOOP. A case of ticlopidine-associated BOOP resolved following the withdrawal of the offending agent. [42]45][46][47][48][49][50][51][52][53][54] However, a case of corticosteroid-resistant BOOP in association with dermatomyositis has been reported that improved when cyclophosphamide was added to the patient's regimen. [47]55] BOOP lesions respond well to treatment if the underlying acute rejection is successfully treated.CMV pneumoniaassociated BOOP can occur with lung transplantation, which usually responds well to corticosteroids. [55]BOOP associated with renal transplantation has been described in only one patient, which responded quickly with an increase in dose of corticosteroids. [12]OP associated with radiotherapy usually occurs in patients receiving radiotherapy for breast cancer.7][58][59][60][61].
1][62][63] BOOP is associated with a variety of unrelated miscellaneous c o n d i t i o n s [ T a b l e 1 ] , i n c l u d i n g : e s s e n t i a l m i x e d cryoglobulinemia, myelodysplastic syndrome, interstitial cystitis, chronic thyroiditis, sarcoidosis, alcoholic cirrhosis and, in England, seasonal syndrome with cholestasis.There has been one report of BOOP during menstrual and pregnancyrelated infl ammatory bowel disease.The BOOP lesion might be associated with lymphoma/leukemia and other neoplastic processes.BOOP has also been reported in primary biliary cirrhosis and after coronary artery bypass graft surgery, Evans syndrome and chronic sinusitis, lung cancer, lung atelectasis, asthma, cystic fi brosis, secondary amyloidosis, Sweet syndrome, idiopathic thrombocytopenic purpura and Fabry disease.A case report of ITP-associated BOOP spontaneously resolved after suppression of cyclosporine and positive serology for Epstein-Barr virus. [13, The Mie Eastern Experience To compare clinico-radiological features and outcomes in Saudi Arabia with international experience in patients with BOOP, a retrospective study was carried out in three large hospitals in Riyadh.The clinical profi le in 20 Saudi patients was similar to that described in the world literature.The outcomes were favorable except in patients with underlying systemic disease. [104]aging Findings Plain radiograph fi ndings include the following: [7,26,32,[105][106][107][108] • Bilateral or unilateral patchy alveolar airspace consolidation is revealed, often subpleural and peribronchial in location and mainly in the lower zones.• Generally, the infiltrates gradually enlarge from their original size or new infi ltrates appear.• Consolidation is often nonsegmental and varies from 2 to 6 cm in diameter.• Cavitary BOOP that mimics tuberculosis and cavitating opacity after lung transplantation has been reported.• An air bronchogram may be present.• Nodules 3-5 mm in diameter are seen in approximately one half of patients; nodules may be migratory.• Basal linear opacities are linked to a poorer prognosis.
• Pleural thickening occurs but pleural effusions are rare.

Other imaging fi ndings
An early report of the value of gadolinium-enhanced MRI in the  In this report, 14 out of 17 patients with active disease showed enhancing lesions on T1-weighted breath-hold gadoliniumenhanced MRI.The white lung sign is an uncommon fi nding 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. 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.Ultrasonography is useful in the detection and characterization of pleural effusion and in the guidance of pleural interventions.A recent study has shown that patients with an enhanced 18F-FDG accumulation refl ect the degree of disease activity in BOOP. [128]agnosing BOOP Lung biopsy continues to be the preferred method for establishing the diagnosis.The multitude of interstitial lung diseases pose a diagnostic dilemma; however, the process may be made simpler by reviewing the patient's history, through specifi c serologic tests, by bronchoalveolar lavage, transbronchial biopsy, biopsy of extrathoracic tissues or openlung biopsy.Conventional radiography and HRCT serve as a guide for further investigation and the site of lung biopsy.
The lack of honeycombing or an irregular reticular pattern in BOOP may help to differentiate BOOP from other interstitial lung diseases.Lobar consolidation may be mistaken for lung malignancy, while 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.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 fi beroptic 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.The video-assisted thoracoscopic procedure has become the established technique.

Differential Diagnosis
Mimics of BOOP include collagen vascular disease, lung metastases [Figure 6], infective pneumonias, Wegener granulomatosis, eosinophilic pneumonia, primary bronchogenic neoplasm and tuberculosis.In one report, two patients with subacute symptoms and signs compatible with pulmonary tuberculosis had cavitary infi ltrates in the right upper lobe, as demonstrated on chest radiographs.Histologic analysis of specimens from both patients yielded typical histologic features of BOOP. [108]ur children following chemotherapy for malignant disease developed pulmonary infi ltrates, and solitary nodules on imaging led to open-lung biopsy.Histologic diagnosis was that of BOOP. [98] vs. BOOP The early clinical and radiographic fi ndings of IP are often similar to those of BOOP.Differentiation is important as IP carries a poor prognosis.Analysis of certain HRCT fi ndings has shown that traction bronchiectasis, interlobular septal thickening and intralobular reticular proliferation are more prevalent in UIP than in BOOP.Lung parenchymal nodules and peripheral distribution are more prevalent in BOOP than in IP.Areas with ground-glass attenuation, airspace consolidation and architectural distortion were common in both IP and BOOP.o assess the role of chest radiography in the differential diagnosis of BOOP and UIP, Muller NL et al. chest radiography, clinical information and pulmonary function data were reviewed, without knowledge of the pathologic diagnosis.The clinical symptoms of BOOP were similar to those of UIP, although the duration of symptoms was longer in UIP and the prevalence of systemic symptoms was higher in BOOP.The physical fi ndings were similar except that fi nger clubbing was more common in patients with UIP than in those with BOOP.No signifi cant difference in lung volumes, fl ows or diffusing capacity was recorded.The chest radiograph showed distinguishing features between UIP and BOOP in the majority of patients.The most characteristic radiologic fi nding in BOOP was the presence of patchy areas of airspace consolidation. [132]eatment of BOOP BOOP may resolve spontaneously; however, corticosteroids are the current standard treatment.The majority of patients with BOOP recover with treatment, symptoms resolving within days or weeks.Similarly the radiographic fi ndings show improvement in 50-86% of patients; however, in a minority of patients, the disease may persist.Approximately 30% of the patients experience relapse upon withdrawal of treatment.
Patients with asymptomatic mass lesions or nonprogressive disease can be observed and treated at a later time if needed.
There is no consensus regarding the optimal doses of prednisone and optimal treatment duration.The dosage is generally 0.75 mg/kg/day for 1 to 3 months, then 0.50 mg/kg mg/day for 3 months, then 10 to 20 mg/day or every other day for a total of 1 year.Every-other-day scheduling can be successfully used for this disorder.A shorter 6-month course may be suffi cient in certain situations.However, this duration can extend up to 12 months or even longer due to relapses.A total and permanent recovery is seen in most patients, but it is also dependent on the cause or associated systemic disorders.1]

Conclusion
BOOP is an important treatable infl ammatory lung disease.Idiopathic BOOP has become an important differential of focal lung nodular lesions.Postpneumonia BOOP remains a treatable process.BOOP occurs in virtually all of the connective tissue disorders and generally responds to corticosteroids.In the setting of malignancy, it is vital to differentiate lung metastases from BOOP.Lung biopsy continues to be the preferred method for establishing a diagnosis.

Figure 3 :
Figure 3: BOOP presenting as airspace and nodular opacities (L).Typical picture of BOOP with peripheral bilateral airspace opacities, predominantly at the bases (R).

Figure 5 :Figure 6 :
Figure 5: Left: endobronchial and acinar fi lling with tree-in-bud appearance with mild interstitial thickening.Right: Interstitial thickening and airspace opacities as a presentation of BOOP