Chest - Volume 139, Issue 4 (April 2011) - Copyright 2011 The American College of Chest Physicians

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1 Use of this content is subject to the Terms and Conditions Cryptogenic and Secondary Organizing Pneumonia Chest - Volume 139, Issue 4 (April 2011) - Copyright 2011 The American College of Chest Physicians MDC Extra Article: This additional article is not currently cited in MEDLINE, but was found in MD Consult's full-text literature database. Original Research Diffuse Lung Disease Cryptogenic and Secondary Organizing Pneumonia Clinical Presentation, Radiographic Findings, Treatment Response, and Prognosis Fotios Drakopanagiotakis, MD a Koralia Paschalaki, MD a Muhanned Abu-Hijleh, MD, FCCP b,* Bassam Aswad, MD c Napoleon Karagianidis, MD a Emmanouil Kastanakis, MD a Sidney S. Braman, MD, FCCP b Vlasis Polychronopoulos, MD, FCCP a a From the Third Pulmonary Medicine Department, Sismanoglion General Hospital, Maroussi, Greece b Department of Medicine, Division of Pulmonary, Critical Care, and Sleep Medicine, Brown University, Providence, RI c Department of Pathology, Rhode Island Hospital The Alpert Medical School of Brown University, Providence, RI * Correspondence to: Muhanned Abu-Hijleh, MD, FCCP, Division of Pulmonary, Critical Care and Sleep Medicine, Rhode Island Hospital The Alpert Medical School of Brown University, 593 Eddy St, APC Bldg, 7th Floor, Providence, RI address: Muhanned_Abu-Hijleh@Brown.edu Manuscript received April 15, 2010, accepted July 21, 2010 Drs Drakopanagiotakis, Paschalaki, and Abu-Hijleh contributed equally to this study.reproduction of this article is prohibited without written permission from the American College of Chest Physicians ( ). PII S (11)60192-X Background Organizing pneumonia (OP) is a distinct clinical and pathologic entity. This condition can be cryptogenic (COP) or secondary to other known causes (secondary OP). In the present study, we reviewed the features associated with COP and secondary OP in patients from two teaching hospitals. Methods The medical records of 61 patients with biopsy-proven OP were retrospectively reviewed. Forty patients were diagnosed with COP and 21 patients with secondary OP. The clinical presentation, radiographic studies, pulmonary function tests (PFTs), laboratory data, BAL findings, treatment, and outcome were analyzed. Results The mean age at presentation was ± years. Malaise, cough, fever, dyspnea, bilateral alveolar infiltrates, and a

2 restrictive pattern were the most common symptoms and findings. BAL lymphocytosis was observed in 43.8% of patients with OP. The relapse rate and mortality rate after 1 year of follow-up were 37.8% and 9.4%, respectively. The in-hospital mortality was 5.7%. The clinical presentation and radiographic findings did not differ significantly between patients with COP and secondary OP. A mixed PFT pattern (obstructive and restrictive physiology) and lower blood levels of serum sodium, serum potassium, platelets, albumin, protein, and ph were observed among patients with secondary OP. Higher blood levels of creatinine, bilirubin, PaCO 2, and BAL lymphocytes were also more common among patients with secondary OP. There were no differences in the relapse rate or mortality between patients with COP and secondary OP. The 1-year mortality correlated with an elevated erythrocyte sedimentation rate, low albumin, and low hemoglobin levels. Conclusions The clinical and radiographic findings in patients with COP and secondary OP are similar and nonspecific. Although certain laboratory abnormalities are more common in secondary OP and can be associated with worse prognosis, they are likely due to the underlying disease. COP and secondary OP have similar treatment response, relapse rates, and mortality. Abbreviations ANA antinuclear antibodies COP cryptogenic organizing pneumonia DLCO diffusion capacity for carbon monoxide ESR erythrocyte sedimentation rate ɣgt ɣ-glutamyl transpeptidase Hb hemoglobin HRCT high-resolution CT OP organizing pneumonia PFT pulmonary function test RF rheumatoid factor TBB transbronchial biopsy Organizing pneumonia (OP) is a clinical entity associated with nonspecific symptoms, radiographic findings, and pulmonary

3 function test (PFT) abnormalities. The histopathologic pattern is characterized by patchy filling of the lung alveoli and respiratory bronchioles by loose plugs of granulation tissue (Masson bodies). [1] The predominant feature is that of an alveolar inflammatory and filling process rather than a small airway disease (bronchiolitis) (Fig 1). The presenting symptoms are usually nonspecific and include constitutional symptoms with flulike illness, cough, and dyspnea. The radiographic findings are also nonspecific and usually include a patchy bilateral alveolar filling process that can be recurrent and migratory in nature. Figure 1 A, Bronchoscopic transbronchial lung biopsy specimen in a patient with secondary organizing pneumonia (hemotoxylin and eosin stain, original magnification 100). B, Surgical thoracoscopic lung biopsy specimen in patient with secondary organizing pneumonia (hemotoxylin and eosin stain, original magnification 100). The biopsy specimens show evidence of proliferative bronchiolitis, with loose plugs of granulation tissue filling the alveoli (Masson bodies). The arrows point to the Masson bodies. OP can be primary (cryptogenic organizing pneumonia [COP]) or secondary (secondary OP). COP is classified as an idiopathic interstitial pneumonia, [2] whereas secondary OP is associated with a variety of diseases known to induce the OP clinical syndrome and the characteristic pathologic pattern. These entities include connective tissue diseases, infections, malignancies, drugs, radiation injury, organ transplantation, and aspiration, among others. COP is diagnosed in the appropriate clinical, radiographic, and pathologic setting after excluding diseases associated with secondary OP. [3] The significance of such distinction is important, as the management of secondary OP requires treatment of the underlying disease (eg, infection and connective tissue disease) or potential avoidance of the offending agent (eg, medication and radiation injury). Previous reports and clinical experience suggested that secondary OP could be associated with a worse prognosis and be less responsive to treatment when compared with COP. [4] The goal of this report is to review our experience with OP and highlight potential similarities and differences between COP and secondary OP. OP-specific diagnosis codes in two institutions (the Division of Pulmonary, Sleep and Critical Care Medicine, at Rhode Island Hospital, Providence, Rhode Island, and the Third Pulmonary Medicine Department of Sismanoglion General Hospital,

4 Maroussi, Greece) from January 2001 to June 2008 were reviewed. The study was approved by the institutional review boards of both institutions. If a patient was identified by lung biopsy results, the records were examined for information pertaining to OP. This included the clinical diagnosis prior to referral for biopsy, presence or absence of OP, extent of OP (OP as the predominant pattern or as a minor association with another predominant distinctive pattern), and the presence of other pathologic patterns. We reviewed patients' symptoms, duration of the disease, comorbidities, concomitant drug use, laboratory data, PFT, radiographic studies, and the response to treatment. Statistical Analysis SPSS, version 14 software (SPSS, Inc; Chicago, Illinois) was used for statistical analysis. Continuous data normal distribution is expressed as mean ± SD. We used Pearson χ 2 for nonparametric data, expressed as mean and interquartile range. Two-tailed Student t test (Mann-Whitney U test) was used for comparing continuous variables as appropriate. Clinical Presentation and Laboratory Data: All Patients We identified 61 patients with a biopsy-proven diagnosis of OP, 27 men and 34 women. The diagnosis was made by surgical lung biopsy in 20 patients (32.8%) and by bronchoscopic transbronchial biopsy (TBB) in 41 patients (67.2%). The mean age of patients was ± years. Forty patients were diagnosed with COP and 21 patients with secondary OP. Causes of secondary OP in the patients are listed in Table 1. The mean duration of symptoms before diagnosis was 96 ± 93 days. Nineteen patients were active smokers and 14 patients were previous smokers (Table 2). Table 1 -- Diseases Associated With Secondary OP Associated Diseases No. (%) Drugs and substance abuse 6 (28.5) Amiodarone β-blockers Cocaine abuse Systemic inflammatory diseases 4 (19.8) Rheumatoid arthritis Polymyositis/dermatomyositis Polymyalgia rheumatica Solid tumors 5 (23.8) Colon Breast Hematologic malignancies 3 (14.2) Non-Hodgkin's lymphoma Renal transplantation 1 (4.7) Infections 2 (9.5) OP = organizing pneumonia. Table 2 -- Clinical Characteristics of Patients With COP and Secondary OP Variable OP COP Secondary OP Age ± SD ± ± ± Male (female) 27 (34) 19 (21) 8 (13) Smoking Active smokers 19 (32.8) 14 (35.9) 5 (26.3)

5 Variable OP COP Secondary OP Previous smokers 14 (24.1) 9 (23.1) 5 (26.3) Nonsmokers 25 (43.1) 16 (41.0) 9 (47.4) Cough 40 (67.8) 25 (65.8) 15 (71.4) Sputum 24 (40.0) 15 (38.5) 9 (42.9) Hemoptysis 4 (6.7) 1 (2.6) 3 (14.3) Dyspnea 38 (63.3) 22 (56.4) 16 (76.2) Fever 39 (65.0) 28 (71.8) 11 (52.4) Chest pain 18 (30.0) 10 (25.0) 8 (40.0) Malaise 44 (74.6) 28 (71.8) 16 (80.0) Arthralgias 15 (26.3) 12 (32.4) 3 (15.0) Weight loss 17 (27.9) 9 (23.0) 8 (38.0) Cyanosis 14 (43.7) 6 (15.8) 8 (38.1) Crackles 44 (75.9) 30 (78.9) 14 (70.0) Wheezing 8 (13.8) 4 (10.5) 4 (20.0) Values are presented as No. (%). P value was not significant for any variable. COP = crytogenic organizing pneumonia. See Table 1 legend for expansion of other abbreviation. The most common symptoms were cough (67.8%), fever (65.0%), and dyspnea (63.3%). Cough was usually nonproductive (60%). Malaise was reported by the majority of patients (74.6%), whereas arthralgias (26.3%) and weight loss > 3 kg (27.9% of patients) were less common. Thirty percent of patients presented with chest pain. Physical findings included cyanosis in 43.7%, crackles in 75.9%, and wheezing in 13.8% of patients (Table 2). The chest radiograph findings included consolidation in 50 patients (82%) that was bilateral in 68.6% and unilateral in 31.4% of patients. Migratory alveolar infiltrates were observed in seven patients (11.5%). A diffuse reticulonodular pattern was present in seven patients (11.5%) and masslike lesions in five patients (8.2%). Cavitation was present in only one case. Pleural effusion was identified in seven patients (11.5%) (Table 3). High-resolution CT (HRCT) scan findings included alveolar opacities, which proved to be bilateral in 73.5% of patients, diffuse reticulonodular pattern in 9.8%, and masslike lesions in 8.2% of patients. A mixed pattern was present in 15 patients (24.6%). Reverse halo sign was not identified in the patients. Table 3 -- Radiographic Findings in Patients With COP and Secondary OP Variable OP COP Secondary OP Chest radiograph Consolidation 50 (82.0) 33 (82.5) 17 (81.0) Bilateral 35 (68.6) 24 (72.7) 11 (61.1) Diffuse reticular 7 (11.5) 4 (10.0) 3 (14.3) Masslike lesion 5 (8.2) 4 (10.0) 1 (4.8) Pleural effusion 7 (11.5) 3 (7.5) 4 (19.0) Cavitation 1 (1.6) 1 (2.5) 0 (0) Migratory lesions 7 (11.5) 7 (17.5) 0 (0) CT scan Consolidation 49 (80.3) 31 (77.5) 18 (85.7) Bilateral 36 (73.5) 25 (80.6) 11 (61.1) Diffuse reticular 6 (9.8) 4 (10) 2 (9.5)

6 Variable OP COP Secondary OP Masslike lesion 5 (8.2) 4 (10) 1 (4.8) Pleural effusion 7 (11.5) 3 (7.5) 4 (19.0) Cavitation 1 (1.6) 1 (2.5) 0 (0) Migratory lesions 7 (11.5) 7 (17.5) 0 (0) Values are presented as No. (%). P value was not significant for any variable. See [Table 1], [Table 2] legends for expansion of abbreviations. Leukocytosis was present in 25 patients (40.9%) and leukopenia in one patient (1.6%). Peripheral eosinophilia was not identified in the patients. Six patients had anemia (hemoglobin [Hb] < 11 g/dl) and 21 patients had an erythrocyte sedimentation rate (ESR) > 60 mm/h. Antinuclear antibodies (ANA) were positive in 23.8% and rheumatoid factor (RF) in 8% of the patients (Table 4). BAL analysis was available for 32 patients with a mean neutrophil, eosinophil, and lymphocyte BAL% of 26.1%, 10.2%, and 18.8%, respectively. BAL lymphocytosis (> 20%) was present in 43.8% of patients (Table 5). Table 4 -- Laboratory Data in Patients With COP and Secondary OP Variable (No. COP/Secondary OP) OP ± SD COP ± SD Secondary OP ± SD P Value WBC (37/21), 10 3 /µl ± ± ± NS Neut (36/20), % ± ± ± NS Hb (37/21), g/dl ± ± ± 1.73 NS PLT (37/21), 10 3 /µl ± ± ± ESR (32/12), mm/h ± ± ± NS Na (36/19), meq/l ± ± ± K (36/19), meq/l 4.34 ± ± ± Ca (28/14), mg/dl 8.96 ± ± ± 0.98 NS BUN (37/21), mg/dl ± ± ± NS Creat (37/21), mg/dl 0.98 ± ± ± Gluc (37/21), mg/dl ± ± ± 41.9 NS Bili (31/15), mg/dl 0.73 ± ± ± SGOT (32/15), IU/L 32.4 ± ± ± 44.9 NS SGPT (32/15), IU/L 38.4 ± ± ± 66.9 NS LDH (29/9), IU/L 355 ± ± ± NS ALP (32/15), IU/L ± ± ± 97 NS ɣgt (27/5), IU/L 48.3 ± ± ± Protein (29/13), g/dl 6.87 ± ± ± Albumin (29/13), g/dl 3.51 ± ± ± ANA positivity [a] 10/42 (23.8%) 6/33 (18.2%) 4/9 (44.4%) NS RF positivity [a] 3/36 (8%) 3/29 (10.3%) 0/7 (0%) NS Values are presented as mean ± SD. ALP = serum alkaline phosphatase; ANA = antinuclear antibody; Bili = total serum bilirubin; Ca = serum calcium; Creat = serum creatinine; ESR = eryhtrocyte sedimentation rate; ɣgt = ɣ-glutamyl transpeptidase; Gluc = glucose; Hb = hemoglobin; K = serum potassium; LDH = lactate dehydrogenase; Na = serum sodium; Neut = neutrophils; NS = not significant; PLT = platelet count; RF = rheumatoid factor; SGOT = serum glutamic oxaloacetic transaminase; SGPT = serum glutamic pyruvic transaminase. See [Table 1], [Table 2] legends for expansion of other abbreviations. a ANA and RF were not associated with clinical connective tissue disease. Values are presented as absolute number of patients with positive ANA or

7 RF/total number of available patients with OP, COP, and secondary OP (%). Table 5 -- BAL Findings in COP and Secondary OP Variable (No. COP/Secondary OP) OP ± SD COP ± SD Secondary OP ± SD P Value Macrophages (27/5) ± ± ± NS Lymphocytes (27/5) ± ± ± Neutrophils (27/5) ± ± ± NS Eosinophils (27/5) ± ± ± 5.50 NS Mast cells (27/5) 2.28 ± ± ± 1.73 NS Lymphocytes > 20% 14 (43.8) 10 (37) 4 (80) NS Values are presented as mean ± SD or No. (%). See Table 1, 2, and 4 legends for expansion of abbreviations. PFT data were available for 36 patients. A reduced FVC was observed in 43% of patients, and a reduced diffusion capacity for carbon monoxide (DLCO) was observed in 42% of patients. Airflow obstructive pattern, restrictive pattern, and mixed patterns were observed in 25%, 41.7%, and 5.6% of patients, respectively. A total of 27.8% of the patients had normal PFT (Tables 6, 7). Table 6 -- PFTs and Arterial Blood Gases of Patients With COP and Secondary OP Variable (No. COP/Secondary OP) OP ± SD COP ± SD Secondary OP ± SD P Value PaO 2 (28/11) ± ± ± NS PaCO 2 (28/11) ± ± ± ph (28/11) 7.44 ± ± ± HCO 3 (23/13) ± ± ± 3.53 NS FEV 1 % (28/8) ± ± ± NS FVC % (28/7) ± ± ± NS DLCO % (16/3) ± ± ± NS SpO 2 (38/19) ± ± ± 6.77 NS Values are presented as mean ± SD. DLCO = diffusion capacity for carbon monoxide; HCO 3 = serum bicarbonate ion; PFT = pulmonary function test; SpO 2 = oxygen saturation. See Table 1, 2, and 4 legends for expansion of other abbreviations. Table 7 -- Specific Patterns of PFTs in Patients With COP and Secondary OP Variable OP COP Secondary OP P Value PFT pattern Restrictive 15 (41.7) 12 (42.9) 3 (37.5) NS Obstructive 9 (25) 9 (32.1) 0 (0) NS Normal 10 (27.8) 7 (25) 3 (37.5) NS Mixed 2 (5.6) 0 (0) 2 (25).044 DLCO < 60% 8 (42.1) 7 (43.8) 1 (33.1) NS PaO 2 < 80 mm Hg 28 (71.8) 21 (75) 7 (63.6) NS Values are presented as No. (%). See Table 1, 2, 4, and 6 legends for expansion of abbreviations.

8 Clinical Presentation and Laboratory Data: COP vs Secondary OP The age, sex, and smoking distribution among patients with COP or secondary OP were not significantly different. The duration of symptoms was slightly longer in secondary OP, although not statistically significant (P =.724). Diagnosis by bronchoscopic TBB (67.2%) was equally distributed among patients. The symptoms and physical findings in patients with OP were nonspecific, and did not differentiate COP from secondary OP. Cyanosis was more common among patients with secondary OP (38.1% vs 15.8%) but did not reach statistical significance (Table 2). Laboratory data demonstrated lower serum sodium levels (P =.022), potassium levels (P =.016), and platelet counts (P =.001), with higher blood creatinine (P =.014) and bilirubin (P =.001) levels in patients with secondary OP. The total protein (P =.027) and albumin levels (P =.042) were also lower in patients with secondary OP. Severe anemia (Hb < 7 g/dl), leukocytosis (WBC > /µl), ESR elevation (> 60 mm/h), and ANA or RF positivity (not associated with clinical connective tissue disease) were equally present among patients with COP and secondary OP (Table 4). BAL mean lymphocyte count was significantly higher in patients with secondary OP (P =.002). The majority of cases with COP (54%) did not have lymphocytosis (> 20%) in the BAL (Table 5). There was no difference in lung volumes, DLCO, or PaO2 among the two groups, but a mixed PFT pattern was more common in patients with secondary OP (P =.044). Patients with COP had a significantly higher ph (P =.007) and lower PaCO2 (P =.023) (Tables 6, 7). Treatment and Prognosis Specific treatment and prognosis data were available for 53 patients with OP. The majority of the patients were treated with systemic steroids, three patients were treated with macrolide antibiotics, nine patients were not treated because of the lack of specific symptoms or physical limitations, and three patients underwent surgery for removal of a solitary pulmonary nodule that was proven to be unexpected OP on the biopsy specimens. Patients with COP were treated similar to those with secondary OP (Table 8). Table 8 -- Treatment and Prognosis in Patients With COP and Secondary OP Treatment OP COP Secondary OP Corticosteroids 41 (77.4) 30 (81.1) 11 (68.8) Macrolides 3 (5.7) 2 (5.4) 1 (6.3) No treatment 9 (17) 5 (13.5) 4 (25.0) Relapse 17 (37.8) 13 (38.2) 4 (36.4) 1-y mortality 5 (9.4) 2 (5.3) 3 (20) In-hospital mortality 3 (5.7) 1 (2.6) 2 (13.3) Values are presented as No. (%). P value was not significant for any variable. See [Table 1], [Table 2] legends for expansion of abbreviations. Mortality data were available for 53 of the hospitalized patients at the time of discharge, and 45 patients were followed 1 year after the initial diagnosis. In-hospital mortality and 1-year mortality in patients with OP were 5.7% and 9.4%, respectively. There was no difference between COP and secondary OP regarding in-hospital mortality (P =.190) or mortality at 1 year after discharge (P =.131) (Table 8). Death 1 year after hospitalization correlated with low Hb (Hb < 11 g/dl, P =.002), an ESR > 60 mm/h (P =.048), and serum albumin < 3.5 g/dl (P =.017) at the time of diagnosis. Mortality did not correlate with BAL lymphocytosis, a reticulonodular pattern on HRCT scan, or hypoxemia (PaO2 < 80 mm Hg) (Table 9). The relapse rate within 1 year was 37.8%. We found no difference in the number of patients with COP or secondary OP who relapsed within 1 year after diagnosis (P =.602) or in the number of patients who relapsed while on active treatment (P =.682). Furthermore, the relapse rate did not correlate with low PaO2, low albumin level, BAL lymphocytosis (> 20%), or the presence of a reticulonodular pattern on HRCT imaging (Table 10). Table 9 -- One-Year All-Cause Mortality Variable Deceased Alive P Value Hb < 11 g/dl 4 (80) 1 (20).02 WBC > /µl 3 (60) 2 (40) NS

9 Variable Deceased Alive P Value ESR > 60 mm/h 4 (100) 0 (0).048 Albumin < 3.5 g/dl 4 (100) 0 (0).017 PaO 2 < 80 mm Hg 3 (75) 1 (25) NS BAL lymphocytes > 20% 1 (100) 0 (0) NS HRCT scan reticular 0 (0) 5 (100) NS Values are presented as No. (%). HRCT = high-resolution CT. See Table 4 for expansion of other abbreviations. Table Relapse Rate in Patients With OP Variable Relapse No Relapse Hb < 11 g/dl 2 (33.3) 4 (66.7) WBC > /µl 7 (46.7) 8 (53.3) ESR > 60 9 (50) 9 (50) Albumin < 3.5 g/dl 5 (45.5) 6 (54.5) PaO 2 < 80 mm Hg 10 (41.7) 14 (58.3) BAL lymphocytes > 20% 6 (42.9) 8 (57.1) HRCT scan reticular 0 (0) 4 (100) Values are presented as No. (%). P value was not significant for any variable. See Tables 1, 4, and 9 legends for expansion of abbreviations. The term organizing pneumonia has replaced the previously used term bronchiolitis obliterans with organizing pneumonia. The nonspecific clinical, radiographic and pathologic pattern of OP may be associated with a variety of other conditions, such as malignancy, interstitial lung disease, and Wegener granulomatosis. [1] This suggests that OP may represent a nonspecific repair process in response to local or distant injury. OP can also present as a distinct clinical and pathologic entity, unrelated to any other condition. When a patient presents with the clinical syndrome of OP and a condition known to be associated with the pathologic pattern of OP, the term secondary OP is applied. [2] COP is the term used in the absence of such known associated conditions. The classification of OP into COP and secondary OP is clinically important, as the management of patients with secondary OP includes not only the treatment of OP but also the management of underlying disease and avoidance of any known offending agents. To date, it remains unclear if COP and secondary OP represent two distinctive clinical entities or if they are a common entity of nonspecific lung injury and repair. Previous studies have reported conflicting results. To address this question, we reviewed our experience with OP. We did not identify significant differences between the clinical characteristics of patients with COP and secondary OP. Patients with COP and secondary OP present during the fifth or sixth decade of life, [5], [6] without sex differences. The association of OP with current or previous smoking has been a controversial issue. [7], [8] In our study, 56% of the patients with OP had a smoking history and there was no difference between the COP and secondary OP groups. OP typically presents as a flulike illness followed by a nonresolving pneumonia despite adequate treatment. [9] The mean duration of symptoms prior to diagnosis in our series was approximately 3 months, compared with the 2 months reported by King and Mortenson. [7] The delay in the diagnosis of OP is likely because of its rarity and because it is underrecognized by physicians. [10] The nonspecific symptoms of malaise, cough, fever, and dyspnea occurred in more than two-thirds of the patients. Hemoptysis as previously described [7], [11] was uncommon, and chest pain, reported to be rare, [12], [13] was present in 30% of the patients. This is similar to a report by Lohr et al. [14] We and others have found that peripheral bilateral consolidation is the most common radiographic finding. [15], [16] Migratory pulmonary infiltrates, considered by some a classic radiographic presentation, were only present in 11.5% of the patients. This is significantly lower than previous reports. [5], [17] Our study confirmed that pleural effusions (11.5%) are not common in OP, [7], [18] and contrary to the findings by Vasu et al, [5] the prevalence was similar among patients with COP and

10 secondary OP. Other roentgenographic findings in our study included: a diffuse reticular pattern (11.5%), a mixed pattern of alveolar opacities and interstitial infiltrates (24.6%), and masslike lesions (8.2%). We did not identify any patient with the reversed halo sign (central ground glass opacities surrounded by crescentic or ring-shaped consolidation). [19] Analysis of the laboratory data showed subtle but statistically significant findings. Mild leukocytosis (10.44 ± 4.31) and elevated ESR (61.61 ± 39.56) were common findings in the patients. ANA and RF positivity, previously reported in OP, [20], [21] were found in some of the patients, similar to the report by Basarakodu et al. [10] The significance of the lower levels of serum sodium, serum potassium, platelet count, total serum protein, and serum albumin, and higher levels of creatinine, bilirubin, and ɣ-glutamyl transferase (ɣgt) in the patients with secondary OP is not completely clear. This may be a reflection of the severity of secondary OP and/or the associated underlying disease. A low serum albumin level has been reported in patients with secondary OP [22] and may be a risk factor for relapse. A low serum albumin level was one of the predictors of 1-year mortality (but not relapse) in our series. A higher ɣgt level, another risk factor for relapse, [8] was also observed in the patients with secondary OP. Patients with OP usually present with a restrictive pattern on PFT. [7], [15] Our results confirm this finding (40% of the patients). An obstructive pattern and normal PFT were also common findings in the patients (Tables 6, 7). There was no difference in the smoking history of the patients with COP and secondary OP, whereas the finding of a mixed obstructiverestrictive PFT pattern was more common in patients with secondary OP. The significance of the lower PaCO2 and higher ph levels in patients with COP is unclear but could reflect a somewhat higher degree of ventilatory drive. BAL is an important tool in the evaluation of patients with OP. [23] It typically shows expansion of all cell lines (lymphocytes, neutrophils, eosinophils, and mast cells). Foamy macrophages, plasma cells, and a CD4/CD8 ratio of < 0.9 are other potential supportive findings. [23], [24] Paucity of lymphocytes has been suggested as a risk factor for relapse. A significant portion of the patients with secondary OP had BAL lymphocytosis. We did not find a significant correlation between BAL lymphocyte levels and relapse rates. Two-thirds of the patients had a pathologic diagnosis of OP by bronchoscopic TBB. Surgical lung biopsy (by thoracoscopic approach or open thoracotomy) remains the gold standard for optimal pathologic diagnosis of OP, as it is more able to rule out other predominant pathologic features or specific diseases with adjacent OP features. However, in the proper clinical and radiographic setting, TBB and BAL can confirm the clinical diagnosis of OP. [4], [23], [24] Our current practice and experience is to reserve surgical biopsies for patients with high clinical suspicion for a finding other than OP, unusual clinical or radiographic features (eg, nodules), or rapidly progressive disease, and when there is a lack of response to treatment. The majority of the patients were treated with systemic corticosteroids. Only three patients received macrolide antibiotics for their antiinflammatory properties. The relapse rate in our series (37.8% after 1 year of follow-up) was similar to other reports. Contrary to previous studies, we did not find correlation of the relapse rate with low albumin, low or high percentage of BAL lymphocytes, specific pattern on CT scan (reticulonodular pattern), or low PaO2. [12], [22] In-hospital mortality (5.7%) was similar to other studies. [5], [10], [11] The 1-year all-cause mortality (9.4%) was similar among patients with COP and secondary OP, and showed a correlation with anemia (Hb < 11 g/dl), ESR (> 60 mm/h), and a lower albumin level (< 3.5 g/dl) at the time of diagnosis. This correlation was not previously reported and is probably a reflection of the severity of the OP and underlying disease. In conclusion, this report highlights many similarities and minor differences between COP and secondary OP. The clinical features of OP are nonspecific and do not differ between COP and secondary OP. Laboratory abnormalities, such as severe anemia, high ESR, and low serum albumin, are more common in patients with secondary OP and can be associated with worse prognosis. The relapse rates and 1-year all-cause mortality are similar for both groups. Our findings suggest that the pathologic and clinical features of both COP and secondary OP are caused by common lung injury and repair mechanisms. The cryptogenic nature of COP could be related to our limited knowledge about all the entities that can lead to secondary OP. This report adds to our knowledge about OP, recognizing the limitations of this retrospective review of patients with OP in two different institutions. Acknowledgments Author contributions: Dr Abu-Hijleh had access to and takes responsibility for the integrity of the data and the accuracy of the data analysis. Dr Drakopanagiotakis: contributed to data collection, organization, analysis, preparation, review, and submission of this manuscript. Dr Paschalaki: contributed to data collection, organization, analysis, preparation, review, and submission of this manuscript. Dr Abu-Hijleh: contributed to data collection, organization, analysis, preparation, review, and submission of this manuscript.

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