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non-specific interstitial pneumonia overlap is associated with unfavorable lung disease progression
Respiratory Medicine 109 (2015) 1460e1468
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Organizing pneumonia/non-specific interstitial pneumonia overlap is associated with unfavorable lung disease progression Nevins W. Todd a, b, *, Ellen T. Marciniak a, Ashutosh Sachdeva a, Seth J. Kligerman c, Jeffrey R. Galvin a, c, Irina G. Luzina a, b, Sergei P. Atamas a, b, Allen P. Burke d a
Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, USA Baltimore VA Medical Center, Baltimore, MD, USA Department of Diagnostic Radiology, University of Maryland School of Medicine, Baltimore, MD, USA d Department of Pathology, University of Maryland School of Medicine, Baltimore, MD, USA b c
a r t i c l e i n f o
a b s t r a c t
Article history: Received 30 June 2015 Received in revised form 24 September 2015 Accepted 28 September 2015 Available online 9 October 2015
Background: Overlapping forms of interstitial pneumonia have been recognized, but are likely underappreciated, and their clinical, radiologic, and histologic characteristics are not well-defined. Methods: We identified 38 patients with surgical lung biopsy demonstrating histologic organizing pneumonia (OP) or histologic organizing pneumonia/non-specific interstitial pneumonia overlap (OP/ NSIP) who met established multi-disciplinary clinical-radiologic-histologic criteria for OP. For each patient, radiologic and co-histologic findings were assessed, and clinical outcome was characterized as disease resolution (complete or near-complete resolution of radiologic opacities and absence of chronic respiratory symptoms) or unfavorable disease progression (death due to respiratory failure or forced vital capacity < 70% predicted > six months from diagnosis). Results: Seven of 38 patients had clinical-radiologic-histologic focal OP. Focal OP was associated with histologic OP (p ¼ 0.019), and all seven patients demonstrated disease resolution. In the remaining 31 patients with cryptogenic or autoimmune-associated OP, 21 patients had histologic OP/NSIP, and 10 had histologic OP. Histologic OP/NSIP was associated with ground glass opacity (GGO, p ¼ 0.012), reticulation (p ¼ 0.029), traction bronchiectasis (p ¼ 0.029), reactive pneumocytes (p ¼ 0.013), and unfavorable disease progression (p < 0.0001). Histologic OP was associated with consolidation (p ¼ 0.028) and disease resolution (p < 0.0001). Multivariate analysis demonstrated histologic OP/NSIP (p < 0.001) and radiologic GGO (p ¼ 0.041) to be independently associated with unfavorable disease progression. Conclusions: OP/NSIP overlap, either idiopathic or autoimmune-associated and identified by histologic and radiologic findings, was associated with unfavorable disease progression, and should therefore be recognized as a characteristic clinical-radiologic-histologic entity. Published by Elsevier Ltd.
Keywords: Organizing pneumonia Non-specific interstitial pneumonia Traction bronchiectasis Reticulation Ground glass opacity
1. Introduction Interstitial pneumonia encompasses a heterogeneous group of lung diseases characterized by varying amounts of inflammation and/or fibrosis throughout the lung parenchyma [1]. These diseases may be idiopathic, or may be secondary to a wide variety of identifiable etiologies. Interstitial pneumonia is generally classified into one of several precisely defined, non-overlapping disorders based predominantly on the histologic findings of lung biopsy. Despite
* Corresponding author. 110 South Paca Street, Baltimore, MD, 21201, USA. E-mail address: [email protected] (N.W. Todd). http://dx.doi.org/10.1016/j.rmed.2015.09.015 0954-6111/Published by Elsevier Ltd.
stringent classification categories, overlapping forms have been recognized, and have included combinations of acute interstitial pneumonia, usual interstitial pneumonia, non-specific interstitial pneumonia (NSIP), and organizing pneumonia (OP) [1e3]. OP has long been recognized as a histologic pattern occurring in response to lung injury in patients with focal or diffuse lung disease [4,5]. Histologically, foci of organization are characterized by basophilic-staining deposits of extracellular matrix which are usually round or oval in shape, and contain spindle-shaped fibroblasts or myofibroblasts. These deposits are located intraluminally within small airways or alveoli, or are located within the interstitium of the lung following septal incorporation [6e8]. Several different clinical terms and associated abbreviations
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related to the histology of OP have been used previously [9e11], but the term OP is currently preferred. The clinical-radiologichistologic entities of cryptogenic OP, secondary OP, or focal OP are diagnosed when histologic evaluation shows widespread foci of OP along with preservation of background lung architecture, and when compatible clinical and radiologic features are present [1,12,13]. NSIP is characterized histologically by diffuse interstitial inflammation and/or fibrosis that occur in a spatially uniform pattern throughout the lung parenchyma [1,14]. Background lung architecture is preserved, and areas of OP and areas of honeycombing are minimal or absent. NSIP is often characterized as cellular or fibrotic based upon the degree of cellular inflammation or fibrosis, respectively. The clinical-radiologic-histologic entities of idiopathic or secondary NSIP are diagnosed when NSIP is the predominant histologic finding, and when compatible clinical and radiologic features are present [1,14]. Of particular importance in interstitial pneumonia is recognition of prognosis and anticipated clinical outcome. Clinical outcomes in patients with distinct forms of interstitial pneumonia, particularly OP, are quite diverse, ranging from complete resolution of disease without sequela to severe, progressive pulmonary fibrosis [1,12,15]. One cause of such diverse clinical outcomes in individual patients may be overlapping forms of interstitial pneumonia, in which combinations of different histologic findings and patterns co-exist. However, clinical, radiologic, and histologic features of these overlapping forms have not been well characterized. We identified 38 patients who met current, established multidisciplinary clinical-radiologic-histologic criteria for OP. Further analysis of surgical lung biopsy (SLB) identified two histologic subsets of patients: histologic OP and histologic OP/NSIP overlap. Detailed quantitative and qualitative assessments were performed in each patient of clinical, physiologic, radiologic, and co-histologic findings, and overall clinical outcome was determined for each patient after appropriate follow-up. The purpose of this study was to determine whether overlapping forms of lung histology in clinical-radiologic-histologic OP were associated with particular demographic features, radiologic findings, histologic co-findings, or clinical outcomes. 2. Materials and methods 2.1. Patients This study was reviewed and approved by the University of Maryland Institutional Review Board (HP-00044077). From a group of 135 patients with foci of organization identified on SLB at the University of Maryland, we retrospectively identified 38 patients who met established multi-disciplinary clinical-radiologic-histologic criteria for OP [1,2,13]. These clinical, radiologic, and histologic criteria consisted of 1) subacute onset of dyspnea, cough, and/or fever (though patients with focal OP were asymptomatic), and absence of toxic occupational or environmental exposures, 2) combinations of consolidation, ground glass opacity, reticulation, solitary nodule, or traction bronchiectasis on imaging, and absence of a radiologic pattern consistent with idiopathic pulmonary fibrosis (IPF), and 3) multiple histologic foci of OP (at least > 10% of tissue section) as a predominant histologic finding, relatively preserved background lung architecture, and absence of an alternative histologic diagnosis such as usual interstitial pneumonia (UIP), diffuse alveolar damage (DAD), or hypersensitivity pneumonitis (HP) [1,2,13]. Thus, patients with histologic foci of organization and an alternative multi-disciplinary clinical-radiologic-histologic diagnosis, such as IPF/UIP, organizing DAD, or chronic HP, were excluded from analysis in this study.
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All clinical information, including demographics, pulmonary function tests, computed tomography (CT) of the chest, lung histology, pharmacologic treatment, date of SLB, etiology of OP (idiopathic or secondary), and clinical course was reviewed and documented for each patient. In conjunction with the above findings, patients were identified as having one of two clinical outcomes: 1) disease resolution, defined as complete or near-complete resolution of radiologic opacities and absence of chronic respiratory symptoms, or 2) unfavorable disease progression, defined as either death due to acute or progressive respiratory failure, or forced vital capacity <70% predicted at greater than six months from date of SLB. Since all patients (histologic OP and histologic OP/NSIP overlap) met established criteria for clinical-radiologic-histologic OP, a consensus diagnosis of cryptogenic OP, secondary OP, or focal OP was assigned for each patient according to established criteria [1,12,13]. 2.2. Pulmonary function tests All pulmonary function test (PFT) data available was recorded for each patient, including forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC), FEV1/FVC ratio, total lung capacity (TLC), functional residual capacity (FRC), residual volume (RV), and diffusing capacity for carbon monoxide (DLCO). For the purposes of this study, PFT data at > 6 months from time of SLB was used for analyses of clinical outcomes. 2.3. Computed tomography All patients had a computed tomography (CT) of the chest performed, and the chest CT closest to the date of SLB was used for initial analysis in this study. The chest CT images were reviewed by two thoracic radiologists (SJK, JRG) specifically for the purpose of this study in 35/38 patients; for the remaining three patients (two with focal OP, one with cryptogenic OP), the CT images were not obtainable, and we relied on the original CT interpretation for our analysis. For each patient, the radiologic findings of reticulation, traction bronchiectasis (TB), consolidation, and solitary nodules were identified as present or absent. Additionally, we used a semi-quantitative scoring system to assess the degree of ground glass opacity (GGO) present in each patient, similar to previously described [16]. A numerical score was assigned to each of the five lobes and the lingula based on the percentage of GGO present in each lobe: 0 (none), 1 (1e10%), 2 (10e25%), 3 (26e50%), 4 (51e75%), and 5 (>75%). A cumulative GGO score was then calculated for each patient by addition of each individual score. All patients had serial imaging studies performed subsequent to SLB, and these images were available for review in 34/38 patients. Serial imaging studies available consisted of serial chest CT (n ¼ 26) or conventional chest radiography (n ¼ 8, predominantly in patients with disease resolution). For the 26 patients with serial chest CT, the presence of GGO, consolidation, reticulation, and TB on the lattermost serial CT were reassessed and recorded. 2.4. Histologic evaluation A detailed histologic evaluation was performed in each sample by a clinical pathologist (APB) with experience in diffuse lung disease. To assist with analysis of tissue samples, sections were scanned into a digital pathology system (Aperio Technologies, Vista, CA) which allowed for analyzing slides at any magnification up to the highest magnification scanned. All patients met established multi-disciplinary clinical-radiologic-histologic criteria for OP. Additionally, two histologic
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subgroups were identified, histologic OP or histologic OP/NSIP overlap, and were identified based on established criteria for OP and NSIP [1,2,13,14]. Histologic OP was identified by the presence of widespread foci of OP, preservation of background lung architecture, and confinement of interstitial inflammation to areas of organization [1,2,13]. Diffuse interstitial inflammation and/or fibrosis in areas spatially distinct from foci of organization were minimal or absent. Histologic OP/NSIP overlap was identified by widespread foci of OP, relative preservation of background lung architecture, and the presence of diffuse interstitial inflammation and/or fibrosis in areas spatially distinct from foci of organization [1,13,14]. In addition to confirming histologic OP or histologic OP/NSIP, the following co-existing histologic findings were assessed: the predominant location of foci of organization (airway centered, interstitial, or both), presence or absence of reactive type II pneumocytes, and presence or absence of small airway disease (bronchiolitis or squamous metaplasia). Additionally, we semiquantitatively assessed the amount of fibrin and lymphocyte aggregates in each patient. The amount of fibrin was characterized as 1) low fibrin, identified by an absence of fibrin deposits or by small focal deposits <100 mm in greatest dimension and few in number (<5 per tissue section), or as 2) high fibrin, identified by multifocal deposits of fibrin >100 mm in greatest dimension and seen in high numbers on multiple tissue sections, similar to previously described [17]. Lymphocyte aggregates (100 mm in greatest dimension) were assessed by scoring absolute numerical counts observed in each lung tissue section, and then standardizing to numerical counts per tissue section, similar to previously described [18].
2.5. Statistical analyses Statistical analyses were performed using SAS statistical software (Cary, NC). For categorical variables, analyses were performed using Pierson's chi-square test, and for continuous variables, analyses were performed using the Wilcoxon rank-sum test. Multivariate analysis was performed of clinical, radiologic, and histologic variables related to clinical outcome. Differences at p < 0.05 were considered significant. 3. Results 3.1. Characteristics of all patients based on histologic OP or histologic OP/NSIP All patients (n ¼ 38) met established multi-disciplinary criteria for clinical-radiologic-histologic OP, and additionally were identified as having histologic OP or histologic OP/NSIP overlap. Table 1 compares the clinical, radiologic, and co-histologic findings between the two histologic groups. Twenty-two patients had histologic OP/NSIP, and 16 had histologic OP. Although patients with OP/NSIP were younger and had fewer smoking pack-years, there were no statistically significant differences in age, race, gender, or smoking history. Radiologic correlation demonstrated that histologic OP/NSIP was associated with the presence of GGO (p ¼ 0.001), reticulation (p ¼ 0.004), and TB (p ¼ 0.004), whereas histologic OP was associated with solitary nodules (p ¼ 0.012). Consolidation was observed equally between the groups. Fig. 1 demonstrates examples of the radiologic findings, and as demonstrated in Table 1, each individual radiologic finding was often observed co-existing with
Table 1 Characteristics of all patients (n ¼ 38) based on histologic finding of OP or OP/NSIP overlap. Variable
OP (n ¼ 16)
OP/NSIP (n ¼ 22)
Age, years, median [1st, 3rd] Gender Male, n Female, n Race Caucasian, n African-American, n Other, n Smoking Ever-smoker, n (%) Pack/years, median [1st, 3rd] Chest CT findings Consolidation (focal or multifocal), n (%) Ground glass opacity score, median [1st, 3rd] Reticulation, n (%) Solitary nodule, n (%) Traction bronchiectasis, n (%) Histology co-findings Fibrin deposits, n (%) OP location Airway-centered, n Interstitial, n Airway-centered and Interstitial, n Lymphocyte aggregates, median [1st, 3rd] Reactive type II pneumocytes, n (%) Small airway disease, n (%) Clinical-radiologic-pathologic diagnosis COP, n Autoimmune-associated OP, n Focal OP, n Clinical Outcome Disease resolution, n Unfavorable disease progression, n
62 [55,68]
55 [45,62]
0.09
8 8
12 10
0.78
13 3 0
14 6 2
0.54
11 (69) 22 [0,41]
14 (64) 6 [0,15]
0.74 0.10
7 0 2 6 2
6 (27) 8 [2,20] 13 (59) 1 (4) 13 (59)
0.29 0.001* 0.004* 0.012* 0.004*
5 (31)
5 (23)
0.56
3 8 5 2 [1,10] 10 (62) 10 (62)
1 19 2 2 [0,7] 21 (95) 16 (73)
0.05
9 1 6
15 6 1
0.019*
15 1
3 19
<0.0001*
(44) [0,2] (12) (38) (12)
P Value
0.41 0.009* 0.51
Definition of abbreviations: OP ¼ organizing pneumonia, NSIP ¼ non-specific interstitial pneumonia, COP ¼ cryptogenic organizing pneumonia. Analyses performed using Pierson's chi-square test or Wilcoxon rank sum test as appropriate. * indicates p < 0.05.
N.W. Todd et al. / Respiratory Medicine 109 (2015) 1460e1468
one or more of the other findings. Correlation of histologic co-findings demonstrated that histologic OP/NSIP was associated with the presence of reactive type II pneumocytes (p ¼ 0.009), but there were no differences in fibrin deposits, OP location, lymphocyte aggregates, or small airway disease. Fig. 2 demonstrates examples of the histologic findings of OP and OP/NSIP overlap. Since all patients (histologic OP and histologic OP/NSIP) met established criteria for clinical-radiologic-histologic OP, a consensus multi-disciplinary diagnosis of cryptogenic OP, secondary OP, or focal OP was assigned for each patient. Histologic OP/NSIP was associated with cryptogenic OP and autoimmune-associated OP, and histologic OP was associated with focal OP (p ¼ 0.019). In all patients (cryptogenic, secondary, or focal), histologic OP was associated with disease resolution, and histologic OP/NSIP was strongly associated with unfavorable disease progression (p < 0.0001). 3.2. Focal OP Seven of the 38 patients had clinical-radiologic-histologic focal
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OP, defined by the presence of a radiologic solitary nodule, absence of other radiologic co-findings (consolidation, GGO, reticulation, TB), and by histologic foci of OP within the solitary nodule. As seen in Table 1, focal OP was strongly associated with histologic OP (p ¼ 0.019). All seven patients with clinicalradiologic-histologic focal OP demonstrated complete disease resolution, manifested by absence of chronic pulmonary symptoms and by complete or near complete resolution of radiologic abnormalities on serial imaging studies. No patients with focal OP were treated with any type of anti-inflammatory or immunosuppressive medication. 3.3. Characteristics of patients with cryptogenic or autoimmuneassociated OP based on histologic OP or histologic OP/NSIP Since seven patients had focal OP with solitary nodules as the sole radiologic findings and had complete disease resolution, the remaining 31 patients with cryptogenic or autoimmune-associated OP were analyzed separately based on the presence of histologic OP or histologic OP/NSIP overlap. As seen in Table 2, 21 patients had
Fig. 1. Representative chest CT findings from six patients, with each panel obtained from a different patient. Reticulation (dashed arrows) was seen in a peripheral (A) or diffuse (B,D) pattern. Peripheral reticulation was often demonstrated to spare the extreme periphery of the lung (B), a pattern well-described in OP and NSIP [5,14]. Consolidation (triangle) was observed in a multifocal (B) or focal (E) pattern. Traction bronchiectasis (block arrows) and widespread GGO (asterisks) were well-demonstrated in many patients (C,D). As seen in this Figure and as noted in Table 1, the individual findings of consolidation, GGO, reticulation, and TB were most often observed co-existing with one or more of the other findings. Solitary nodules (F, arrowhead) were observed in isolation in our patients, without co-existing consolidation, GGO, reticulation, or TB.
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Fig. 2. Representative H&E SLB histology from four patients, with each horizontal pair of low and high magnification images obtained from a different patient. The length of the white bar in the left lower corner of each panel represents 2 mm (A), 3 mm (C,E), 4 mm (G), and 300 mm (B,D,F,H). Panels A,B and C,D demonstrate two patients with histologic OP/ NSIP overlap. Low magnification (A,C) shows abnormal background lung architecture, diffuse interstitial inflammation, and widespread thickening of intra-alveolar septae, consistent with NSIP. Well-formed foci of organizing pneumonia (block arrows) are seen on low and high magnification (B,D) images, and were abundant and widespread. Panels E,F and G,H demonstrate two patients with histologic OP. Low magnification (E,G) shows normal lung background architecture and normal intra-alveolar septae (asterisks) in areas distinct from OP. Cellular inflammation is confined to areas of OP, and thus histologic evidence of NSIP overlap is absent. Well-formed foci of OP (block arrows) are seen on low and high magnification (F,H) images.
histologic OP/NSIP overlap, and 10 had histologic OP. Although patients with OP/NSIP were younger and had fewer smoking packyears, there were no statistically significant differences in age, race, gender, or smoking history. There was a trend towards a higher percentage of patients in the OP/NSIP group being administered prednisone and other immunosuppressive therapies, but there
were no statistically significant differences between the groups. Radiologic correlation demonstrated that histologic OP/NSIP was associated with the presence of GGO (p ¼ 0.012), reticulation (p ¼ 0.029), and TB (p ¼ 0.029), whereas histologic OP was associated with the presence of consolidation (p ¼ 0.028). Fig. 1 again demonstrates examples of the radiologic findings.
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Table 2 Characteristics of patients with cryptogenic or autoimmune-associated OP (n ¼ 31) based on histologic finding of OP or OP/NSIP overlap. Variable
OP (n ¼ 10)
OP/NSIP (n ¼ 21)
Age, years, median [1st, 3rd] Gender Male, n Female, n Race Caucasian, n African-American, n Other, n Smoking Ever-smoker, n (%) Pack/years, median [1st, 3rd] Medications Prednisone, n (%) Azathioprine, n (%) Mycophenolate, n (%) Cyclophosphamide, n (%) Methotrexate, n (%) Chest CT findings Consolidation (focal or multifocal), n (%) Ground glass opacity score, median [1st, 3rd] Reticulation, n (%) Traction bronchiectasis, n (%) Histology co-findings Fibrin deposits, n (%) OP location Airway-centered, n Interstitial, n Airway-centered and Interstitial, n Lymphocyte aggregates, median [1st, 3rd] Reactive type II pneumocytes, n (%) Small airway disease, n (%) Clinical-radiologic-pathologic diagnosis COP, n Autoimmune-associated OP, n Clinical Outcome Disease resolution, n Unfavorable disease progression, n Death, n FVC < 70% predicted > 6 months, n
65 [57,69]
55 [45,62]
0.14
5 5
11 10
0.91
7 3 0
13 6 2
0.79
7(70) 20 [3,40]
13 (62) 5 [0,14]
0.65 0.11
5 1 2 1 0
(50) (10) (20) (10) (0)
17 (81) 7 (33) 9 (43) 0 (0) 4 (19)
0.08 0.16 0.21 0.14 0.14
7 1 2 2
(70) [0,5] (20) (20)
6 (28) 8 [3,20] 13 (62) 13 (62)
0.028* 0.012* 0.029* 0.029*
3 (30)
5 (24)
0.71
3 6 1 2 [1,8] 6 (60) 7 (70)
0 19 2 3 [0,7] 20 (95) 15 (71)
0.029*
9 1
15 6
0.25
9 1 0 1
2 19 8 11
P Value
0.67 0.013* 0.93
<0.0001*
Definition of abbreviations: OP ¼ organizing pneumonia, NSIP ¼ non-specific interstitial pneumonia, COP ¼ cryptogenic organizing pneumonia. Analyses performed using Pierson's chi-square test or Wilcoxon rank sum test as appropriate. * indicates p < 0.05.
Correlation of histologic co-findings demonstrated that histologic OP/NSIP was associated with the presence of reactive type II pneumocytes (p ¼ 0.013) and an interstitial location of OP deposits (p ¼ 0.029). There were no differences in fibrin deposits, lymphocyte aggregates, or small airway disease. Fig. 2 again demonstrates examples of the histologic findings of OP and OP/ NSIP overlap. Histologic OP was associated with disease resolution, and histologic OP/NSIP was strongly associated with unfavorable disease progression (p < 0.0001). In patients with OP/NSIP and unfavorable disease progression (n ¼ 19, Table 2), 8 patients died due to acute or progressive respiratory failure (median time from SLB to death 3 [2,6] months) and 11 patients had FVC < 70% predicted (median 58 [44,65]) greater than six months from date of SLB, with a median follow-up of 26 months for these 11 patients. Five of these 11 patients with FVC <70% predicted at > 6 months additionally underwent lung transplantation due to end-stage lung disease.
patients demonstrated complete or near complete resolution of the initial radiologic opacities. In the single patient with histologic OP and unfavorable disease progression, serial CT imaging (over 19 months) demonstrated resolution of consolidation, but persistent GGO, reticulation, and TB. In the histologic OP/NSIP group (n ¼ 21), two patients demonstrated clinical disease resolution, which included complete or near complete resolution of radiologic opacities. In the remaining 19 patients with unfavorable disease progression, serial chest CT imaging was available in 15 patients. In these patients, chest CT at the time of diagnosis demonstrated GGO (n ¼ 13), consolidation (n ¼ 3), reticulation (n ¼ 11), and TB (n ¼ 10). On the lattermost serial CT, findings observed were GGO (n ¼ 12), consolidation (n ¼ 4), reticulation (n ¼ 11), and TB (n ¼ 11). These observations demonstrate persistence of GGO, reticulation, and TB in the unfavorable disease progression group. Median time interval from initial CT to lattermost serial CT was 11 [2,18] months.
3.4. Serial imaging studies in patients with cryptogenic or autoimmune-associated OP
3.5. Multivariate analysis of variables associated with clinical outcome
To assess changes in radiologic findings over the course of disease, serial imaging studies were analyzed in patients with cryptogenic or autoimmune-associated OP. In the histologic OP group (n ¼ 10), nine demonstrated clinical disease resolution, and these
Since histologic OP/NSIP overlap was associated with unfavorable disease progression, a multivariate analysis was performed in patients with clinical-radiologic-histologic cryptogenic or autoimmune-associated OP (n ¼ 31) to determine which clinical,
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Table 3 Multivariate analysis of variables associated with clinical outcome (disease resolution versus unfavorable disease progression) in patients with cryptogenic or autoimmuneassociated OP (n ¼ 31). Variable Clinical
Radiology
Histology
Combined
Age Gender Race Smoking, pack/years Autoimmune disease Consolidation Ground glass opacity score Reticulation Traction bronchiectasis Fibrin deposits Lymphocyte aggregates OP/NSIP overlap Reactive type II pneumocytes Small airway disease Ground glass opacity score OP/NSIP overlap
Chi-square
P Value
0.59 0.34 2.7 0.38 0.81 0.01 9.2 1.6 1.8 3.0 1.1 21.5 0.15 2.8 4.1 12.3
0.44 0.56 0.43 0.53 0.37 0.93 0.002* 0.20 0.18 0.08 0.30 <0.0001* 0.69 0.09 0.041* <0.001*
Definition of abbreviations: OP ¼ organizing pneumonia, NSIP ¼ non-specific interstitial pneumonia. * indicates p < 0.05.
radiologic, or histologic variables were independently associated with clinical outcomes. As seen in Table 3, multivariate analysis was performed using clinical, radiologic, and histologic variables within their respective groups. This analysis demonstrated that GGO score (p ¼ 0.002) and histologic OP/NSIP overlap (p < 0.0001) were independently associated with unfavorable disease progression within their respective groups, and this independent association remained when these two variables were subsequently combined (p ¼ 0.041 and p < 0.001, respectively). 4. Discussion In this study of 38 patients who met established multidisciplinary clinical-radiologic-histologic criteria for OP, two histologic subsets of patients were identified: histologic OP and histologic OP/NSIP. Histologic OP was associated with radiologic consolidation and clinical-radiologic-histologic focal OP, and was additionally strongly associated with disease resolution. Histologic OP/NSIP overlap was associated with GGO, reticulation, TB, and reactive pneumocytes, and was additionally strongly associated with unfavorable disease progression. The association of histologic OP/NSIP with unfavorable disease progression was observed in the entire group of patients, and also in the subgroup of 31 patients with cryptogenic or autoimmune-associated OP in which patients with focal OP were excluded. Multivariate analysis utilizing clinical, radiologic, and histologic findings indicated that histologic OP/NSIP was independently associated with unfavorable disease progression. The novelty of our study is the clinical and radiologic characterization of a group of patients with histologic OP/NSIP overlap, and the statistical correlation of histologic OP/NSIP with particular radiologic findings and with unfavorable lung disease progression. Only two previous studies to our knowledge have published findings correlating lung histology evidence of diffuse disease in OP with adverse clinical outcomes [15,19]. Both were performed prior to the more recent classifications of the interstitial pneumonias [1,13], which makes direct lung terminology comparisons to our study difficult. Our study does have a larger number of patients than either previous study, which allowed us to statistically correlate radiologic and histologic findings with clinical outcomes. The concept of OP and NSIP co-existing may seem puzzling or even improbable at first, as these are most often described and discussed as distinct clinical and histologic entities. However, the presence of both findings concurrently in SLB samples has been described, but is often likely considered of lesser importance, and the
precise terminology used has varied. In series of patients in which NSIP was the consensus diagnosis, OP was observed as a co-existing finding in some patients [5,14,20,21]. In series of patients in which OP was the consensus diagnosis, interstitial inflammation and interstitial fibrosis (NSIP pattern) were observed as co-existing findings in some patients [1,15,19]. Current nomenclature and criteria indicate that if significant amounts (>10e15%) of OP are present, the histologic diagnosis of OP is appropriate with or without co-existing interstitial inflammation or fibrosis [1,2,13]. Each patient in our study demonstrated widespread histologic foci of OP (at least > 10% of tissue section) as a predominant histologic finding, in conjunction with relative preservation of background lung architecture. Regarding NSIP, established criteria have stated that foci of OP should be inconspicuous or absent [1]. Therefore, if significant interstitial inflammation and/or interstitial fibrosis was present in our patients in areas spatially distinct from areas of organization, we identified this histologic pattern as OP/NSIP overlap, similar to previously used terms of NSIP/OP profile or NSIP/OP overlap [2,22]. Our OP/NSIP patients thus had findings most consistent with a true overlap syndrome, with widespread foci of OP and widespread areas of NSIP distinct from areas of organization. It is not surprising that reticulation and TB were associated with unfavorable disease progression, as these abnormalities have previously been associated with poor outcomes in OP and other forms of interstitial pneumonia [23e25]. GGO has been observed in OP, and has also been associated with persistent disease [23]. Our data complements these previous studies by demonstrating an association between a histologic OP/NSIP overlap pattern and these observed radiologic findings. Serial CT imaging findings in our patients with histologic OP/NSIP and unfavorable disease progression demonstrated persistence of GGO, reticulation, and TB. Ever since original descriptions of OP, a subgroup of patients have shown progression to fibrosis, which has often been termed a fibrosing variant of OP [1,26], and which has led to the concept that some patients diagnosed with fibrotic NSIP may have rather had a fibrosing variant of OP [1,2,5]. This phenotype appears very similar to the histologic OP/NSIP overlap group of patients in our study. Many previous studies have suggested that subgroups of patients with OP have markedly variable clinical outcomes [1,12,15,26]. The use of anti-inflammatory or immunosuppressive medications may potentially alter clinical outcomes, but in our study, all patients with focal OP who had complete disease resolution did not receive any type of anti-inflammatory or immunosuppressive therapy. In our patients with COP or autoimmune associated OP, there were no
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significant differences in anti-inflammatory or immunosuppressive therapies between the histologic OP versus OP/NSIP group, but the OP/NSIP group had a much poorer overall prognosis. These observations suggest that factors responsible for clinical outcomes in patients with OP are likely complex. One likely factor is differences in etiology and/or degree of lung injury in individual patients, which are subsequently manifested by different radiologic or histologic patterns. Our data suggest that when histologic findings are taken into account, outcomes are much more predictable. Patients with histologic OP, which was associated with nodules, consolidation, and clinical disease resolution (with or without anti-inflammatory therapy), likely had localized and self-limited lung injury. Patients with histologic OP/NSIP, which was associated with GGO, reticulation, TB, and reactive pneumocytes, likely had widespread areas of diffuse and ongoing lung injury, resulting in clinical disease progression despite the use of aggressive anti-inflammatory or immunosuppressive therapy. Our study does have some limitations. First, its retrospective format does create some difficulty with identifying the precise time of disease onset, and thus presents inherent difficulty in correlating observed radiologic or histologic findings with ultimate disease prognosis. For consistency, we used the date of surgical lung biopsy as the date of disease onset, and used the radiologic findings closest to the time of biopsy to correlate histology findings with radiographic patterns. We fully acknowledge that this approach has limitations, but in the absence of a consistent viable alternative, we believe our methodology provided the most objective and consistent approach for correlative analyses. Second, there is the possibility of selection bias in our group if patients with only severe disease were referred to our tertiary center. Lastly, a potential critique could be directed towards the confidence of our histologic diagnosis, and whether some patients in the OP/NSIP overlap group, due to the severity of their disease progression, had alternative histologic diagnoses, such as organizing diffuse alveolar damage (DAD) or acute exacerbation of IPF/UIP. By detailed multidisciplinary review by clinicians, radiologists, and pathologists with experience in diffuse lung disease, we are confident that all patients met established histologic and multi-disciplinary clinicalradiologic-histologic criteria for OP, and confident that patients with alternative histologic diagnoses were appropriately excluded from analysis in this study. 5. Conclusions In this study of 38 patients who met established multidisciplinary clinical-radiologic-histologic criteria for OP, two histologic subsets of patients were identified: histologic OP and histologic OP/NSIP overlap. Histologic OP was associated with radiologic consolidation, clinical-radiologic-histologic focal OP, and disease resolution. Histologic OP/NSIP was associated with GGO, reticulation, TB, reactive pneumocytes, and unfavorable disease progression, characterized by death from respiratory failure or persistent impairment in FVC >6 months post SLB. Multivariate analysis of clinical, radiologic, and histologic findings indicated that histologic OP/NSIP was independently associated with unfavorable disease progression. OP/NSIP overlap, either idiopathic or autoimmune-associated and identified by histologic and radiologic findings, was associated with unfavorable disease progression, and due to its aggressive clinical course, should be recognized as a characteristic clinical-radiologic-histologic entity. Conflict of interest Nevins Todd has no financial or non-financial competing interests.
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Ellen Marciniak has no financial or non-financial competing interests. Ashutosh Sachdeva has no financial or non-financial competing interests. Seth Kligerman has no financial or non-financial competing interests. Jeffrey Galvin has no financial or non-financial competing interests. Irina G Luzina has no financial or non-financial competing interests. Sergei P Atamas has no financial or non-financial competing interests. Allen Burke has no financial or non-financial competing interests. Acknowledgments Nevins Todd and Ellen Marciniak conceived the study, collected all data, analyzed all data, performed all statistical analyses, and wrote the manuscript. Allen Burke reviewed all pathology slides, assisted with data and statistical analyses, and substantially contributed to the conceptual message of the manuscript. Jeffrey Galvin and Seth Kligerman reviewed all chest radiology studies, and assisted with data interpretation and conclusions. Sergei Atamas contributed substantially to data analysis, data interpretation, and conceptual message of the manuscript. Ashutosh Schedeva and Irina Luzina contributed substantially to data interpretation and conceptual message of the manuscript. References [1] W.D. Travis, U. Costabel, D.M. Hansell, et al., ATS/ERS committee on idiopathic interstitial pneumonias. an official american thoracic society/european respiratory society statement: update of the international multidisciplinary classification of the idiopathic interstitial pneumonias, Am. J. Respir. Crit. Care Med. 188 (6) (2013) 733e748. [2] B. Bradley, H.M. Branley, J.J. Egan, et al., British Thoracic Society, Interstitial lung disease guideline group, british thoracic society standards of care committee; thoracic society of Australia; New Zealand thoracic society; Irish thoracic society. Interstitial lung disease guideline: the British thoracic society in collaboration with the thoracic society of Australia and New Zealand and the Irish thoracic society, Thorax 5 (63 Suppl) (2008) 1e58. [3] S.L. Walsh, D.M. Hansell, Diffuse interstitial lung disease: overlaps and uncertainties, Eur. Radiol. 20 (8) (2010) 1859e1867. [4] R. Floyd, Organization of pneumonic exudates, Am. J. Med. Sci. 163 (1922) 527e548. [5] S.J. Kligerman, T.J. Franks, J.R. Galvin, From the radiologic pathology archives: organization and fibrosis as a response to lung injury in diffuse alveolar damage, organizing pneumonia, and acute fibrinous and organizing pneumonia, Radiographics 33 (7) (2013) 1951e1975. [6] J.L. Myers, A.L. Katzenstein, Ultrastructural evidence of alveolar epithelial injury in idiopathic bronchiolitis obliterans-organizing pneumonia, Am. J. Pathol. 132 (1) (1988) 102e109. [7] S. Peyrol, J.F. Cordier, J.A. Grimaud, Intra-alveolar fibrosis of idiopathic bronchiolitis obliterans-organizing pneumonia. Cell-matrix patterns, Am. J. Pathol. 137 (1) (1990) 155e170. [8] B.J. Roberton, D.M. Hansell, Organizing pneumonia: a kaleidoscope of concepts and morphologies, Eur. Radiol. 21 (11) (2011) 2244e2254. [9] A.A. Liebow, C.B. Carrington, The interstitial pneumonias, in: M. Simon, E.J. Potchen, M. LeMay (Eds.), Frontiers of Pulmonary Radiology, Grune and Stratton, New York, 1969, pp. 102e141. [10] A.G. Davison, B.E. Heard, W.A.C. McAllister, et al., Cryptogenic organizing pneumonitis, Q. J. Med. 52 (207) (1983) 382e394. [11] G.R. Epler, T.V. Colby, T.C. McLoud, et al., Bronchiolitis obliterans organizing pneumonia, N. Engl. J. Med. 312 (1985) 152e158. [12] F. Maldonado, C.E. Daniels, E.A. Hoffman, et al., Focal organizing pneumonia on surgical lung biopsy: causes, clinicoradiologic features, and outcomes, Chest 132 (5) (2007) 1579e1583. [13] American Thoracic Society/European Respiratory Society International multidisciplinary consensus classification of the idiopathic interstitial pneumonias, Am. J. Respir. Crit. Care Med. 165 (2) (2002), 277e3042001. [14] W.D. Travis, G. Hunninghake, T.E. King Jr., et al., Idiopathic nonspecific interstitial pneumonia: report of an American Thoracic Society project, Am. J. Respir. Crit. Care Med. 177 (12) (2008) 1338e1347. [15] J.F. Cordier, R. Loire, J. Brune, Idiopathic bronchiolitis obliterans organizing
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N.W. Todd et al. / Respiratory Medicine 109 (2015) 1460e1468 pneumonia. Definition of characteristic clinical profiles in a series of 16 patients, Chest 96 (5) (1989) 999e1004. D. Assayag, S. Kaduri, M. Hudson, et al., High resolution computed tomography scoring systems for evaluating interstitial lung disease in systemic sclerosis patients, Rheumatology (2012) S1eS003. M. Nishino, S.K. Mathai, D. Schoenfeld, et al., Clinicopathologic features associated with relapse in cryptogenic organizing pneumonia, Hum. Pathol. 45 (2) (2014) 342e351. N.W. Todd, R.G. Scheraga, J.R. Galvin, et al., Lymphocyte aggregates persist and accumulate in the lungs of patients with idiopathic pulmonary fibrosis, J. Inflamm. Res. 6 (2013) 63e70. S.A. Yousem, R.H. Lohr, T.V. Colby, Idiopathic bronchiolitis obliterans organizing pneumonia/cryptogenic organizing pneumonia with unfavorable outcome: pathologic predictors, Mod. Pathol. 10 (9) (1997) 864e871. S. Nagai, M. Kitaichi, H. Itoh, et al., Idiopathic nonspecific interstitial pneumonia/fibrosis: comparison with idiopathic pulmonary fibrosis and BOOP, Eur. Respir. J. 12 (5) (1998) 1010e1019.
[21] A.L. Katzenstein, R.F. Fiorelli, Nonspecific interstitial pneumonia/fibrosis. Histologic features and clinical significance, Am. J. Surg. Pathol. 18 (2) (1994) 136e147. [22] T.J. Corte, R. Ellis, E.A. Renzoni, et al., Use of intravenous cyclophosphamide in known or suspected, advanced non-specific interstitial pneumonia, Sarcoidosis Vasc. Diffuse Lung Dis. 26 (2) (2009) 132e138. [23] J.W. Lee, K.S. Lee, H.Y. Lee, et al., Cryptogenic organizing pneumonia: serial high-resolution CT findings in 22 patients, AJR Am. J. Roentgenol. 195 (4) (2010) 916e922. [24] S.L. Walsh, N. Sverzellati, A. Devaraj, et al., Chronic hypersensitivity pneumonitis: high resolution computed tomography patterns and pulmonary function indices as prognostic determinants, Eur. Radiol. 22 (8) (2012) 1672e1679. [25] D.A. Lynch, J.D. Godwin, S. Safrin, et al., Idiopathic Pulmonary Fibrosis Study Group. High-resolution computed tomography in idiopathic pulmonary fibrosis: diagnosis and prognosis, Am. J. Respir. Crit. Care Med. 172 (4) (2005) 488e493. [26] B. Beardsley, D. Rassl, Fibrosing organising pneumonia, J. Clin. Pathol. 66 (10) (2013) 875e881.
Contents lists available at ScienceDirect
Respiratory Medicine journal homepage: www.elsevier.com/locate/rmed
Organizing pneumonia/non-specific interstitial pneumonia overlap is associated with unfavorable lung disease progression Nevins W. Todd a, b, *, Ellen T. Marciniak a, Ashutosh Sachdeva a, Seth J. Kligerman c, Jeffrey R. Galvin a, c, Irina G. Luzina a, b, Sergei P. Atamas a, b, Allen P. Burke d a
Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, USA Baltimore VA Medical Center, Baltimore, MD, USA Department of Diagnostic Radiology, University of Maryland School of Medicine, Baltimore, MD, USA d Department of Pathology, University of Maryland School of Medicine, Baltimore, MD, USA b c
a r t i c l e i n f o
a b s t r a c t
Article history: Received 30 June 2015 Received in revised form 24 September 2015 Accepted 28 September 2015 Available online 9 October 2015
Background: Overlapping forms of interstitial pneumonia have been recognized, but are likely underappreciated, and their clinical, radiologic, and histologic characteristics are not well-defined. Methods: We identified 38 patients with surgical lung biopsy demonstrating histologic organizing pneumonia (OP) or histologic organizing pneumonia/non-specific interstitial pneumonia overlap (OP/ NSIP) who met established multi-disciplinary clinical-radiologic-histologic criteria for OP. For each patient, radiologic and co-histologic findings were assessed, and clinical outcome was characterized as disease resolution (complete or near-complete resolution of radiologic opacities and absence of chronic respiratory symptoms) or unfavorable disease progression (death due to respiratory failure or forced vital capacity < 70% predicted > six months from diagnosis). Results: Seven of 38 patients had clinical-radiologic-histologic focal OP. Focal OP was associated with histologic OP (p ¼ 0.019), and all seven patients demonstrated disease resolution. In the remaining 31 patients with cryptogenic or autoimmune-associated OP, 21 patients had histologic OP/NSIP, and 10 had histologic OP. Histologic OP/NSIP was associated with ground glass opacity (GGO, p ¼ 0.012), reticulation (p ¼ 0.029), traction bronchiectasis (p ¼ 0.029), reactive pneumocytes (p ¼ 0.013), and unfavorable disease progression (p < 0.0001). Histologic OP was associated with consolidation (p ¼ 0.028) and disease resolution (p < 0.0001). Multivariate analysis demonstrated histologic OP/NSIP (p < 0.001) and radiologic GGO (p ¼ 0.041) to be independently associated with unfavorable disease progression. Conclusions: OP/NSIP overlap, either idiopathic or autoimmune-associated and identified by histologic and radiologic findings, was associated with unfavorable disease progression, and should therefore be recognized as a characteristic clinical-radiologic-histologic entity. Published by Elsevier Ltd.
Keywords: Organizing pneumonia Non-specific interstitial pneumonia Traction bronchiectasis Reticulation Ground glass opacity
1. Introduction Interstitial pneumonia encompasses a heterogeneous group of lung diseases characterized by varying amounts of inflammation and/or fibrosis throughout the lung parenchyma [1]. These diseases may be idiopathic, or may be secondary to a wide variety of identifiable etiologies. Interstitial pneumonia is generally classified into one of several precisely defined, non-overlapping disorders based predominantly on the histologic findings of lung biopsy. Despite
* Corresponding author. 110 South Paca Street, Baltimore, MD, 21201, USA. E-mail address: [email protected] (N.W. Todd). http://dx.doi.org/10.1016/j.rmed.2015.09.015 0954-6111/Published by Elsevier Ltd.
stringent classification categories, overlapping forms have been recognized, and have included combinations of acute interstitial pneumonia, usual interstitial pneumonia, non-specific interstitial pneumonia (NSIP), and organizing pneumonia (OP) [1e3]. OP has long been recognized as a histologic pattern occurring in response to lung injury in patients with focal or diffuse lung disease [4,5]. Histologically, foci of organization are characterized by basophilic-staining deposits of extracellular matrix which are usually round or oval in shape, and contain spindle-shaped fibroblasts or myofibroblasts. These deposits are located intraluminally within small airways or alveoli, or are located within the interstitium of the lung following septal incorporation [6e8]. Several different clinical terms and associated abbreviations
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related to the histology of OP have been used previously [9e11], but the term OP is currently preferred. The clinical-radiologichistologic entities of cryptogenic OP, secondary OP, or focal OP are diagnosed when histologic evaluation shows widespread foci of OP along with preservation of background lung architecture, and when compatible clinical and radiologic features are present [1,12,13]. NSIP is characterized histologically by diffuse interstitial inflammation and/or fibrosis that occur in a spatially uniform pattern throughout the lung parenchyma [1,14]. Background lung architecture is preserved, and areas of OP and areas of honeycombing are minimal or absent. NSIP is often characterized as cellular or fibrotic based upon the degree of cellular inflammation or fibrosis, respectively. The clinical-radiologic-histologic entities of idiopathic or secondary NSIP are diagnosed when NSIP is the predominant histologic finding, and when compatible clinical and radiologic features are present [1,14]. Of particular importance in interstitial pneumonia is recognition of prognosis and anticipated clinical outcome. Clinical outcomes in patients with distinct forms of interstitial pneumonia, particularly OP, are quite diverse, ranging from complete resolution of disease without sequela to severe, progressive pulmonary fibrosis [1,12,15]. One cause of such diverse clinical outcomes in individual patients may be overlapping forms of interstitial pneumonia, in which combinations of different histologic findings and patterns co-exist. However, clinical, radiologic, and histologic features of these overlapping forms have not been well characterized. We identified 38 patients who met current, established multidisciplinary clinical-radiologic-histologic criteria for OP. Further analysis of surgical lung biopsy (SLB) identified two histologic subsets of patients: histologic OP and histologic OP/NSIP overlap. Detailed quantitative and qualitative assessments were performed in each patient of clinical, physiologic, radiologic, and co-histologic findings, and overall clinical outcome was determined for each patient after appropriate follow-up. The purpose of this study was to determine whether overlapping forms of lung histology in clinical-radiologic-histologic OP were associated with particular demographic features, radiologic findings, histologic co-findings, or clinical outcomes. 2. Materials and methods 2.1. Patients This study was reviewed and approved by the University of Maryland Institutional Review Board (HP-00044077). From a group of 135 patients with foci of organization identified on SLB at the University of Maryland, we retrospectively identified 38 patients who met established multi-disciplinary clinical-radiologic-histologic criteria for OP [1,2,13]. These clinical, radiologic, and histologic criteria consisted of 1) subacute onset of dyspnea, cough, and/or fever (though patients with focal OP were asymptomatic), and absence of toxic occupational or environmental exposures, 2) combinations of consolidation, ground glass opacity, reticulation, solitary nodule, or traction bronchiectasis on imaging, and absence of a radiologic pattern consistent with idiopathic pulmonary fibrosis (IPF), and 3) multiple histologic foci of OP (at least > 10% of tissue section) as a predominant histologic finding, relatively preserved background lung architecture, and absence of an alternative histologic diagnosis such as usual interstitial pneumonia (UIP), diffuse alveolar damage (DAD), or hypersensitivity pneumonitis (HP) [1,2,13]. Thus, patients with histologic foci of organization and an alternative multi-disciplinary clinical-radiologic-histologic diagnosis, such as IPF/UIP, organizing DAD, or chronic HP, were excluded from analysis in this study.
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All clinical information, including demographics, pulmonary function tests, computed tomography (CT) of the chest, lung histology, pharmacologic treatment, date of SLB, etiology of OP (idiopathic or secondary), and clinical course was reviewed and documented for each patient. In conjunction with the above findings, patients were identified as having one of two clinical outcomes: 1) disease resolution, defined as complete or near-complete resolution of radiologic opacities and absence of chronic respiratory symptoms, or 2) unfavorable disease progression, defined as either death due to acute or progressive respiratory failure, or forced vital capacity <70% predicted at greater than six months from date of SLB. Since all patients (histologic OP and histologic OP/NSIP overlap) met established criteria for clinical-radiologic-histologic OP, a consensus diagnosis of cryptogenic OP, secondary OP, or focal OP was assigned for each patient according to established criteria [1,12,13]. 2.2. Pulmonary function tests All pulmonary function test (PFT) data available was recorded for each patient, including forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC), FEV1/FVC ratio, total lung capacity (TLC), functional residual capacity (FRC), residual volume (RV), and diffusing capacity for carbon monoxide (DLCO). For the purposes of this study, PFT data at > 6 months from time of SLB was used for analyses of clinical outcomes. 2.3. Computed tomography All patients had a computed tomography (CT) of the chest performed, and the chest CT closest to the date of SLB was used for initial analysis in this study. The chest CT images were reviewed by two thoracic radiologists (SJK, JRG) specifically for the purpose of this study in 35/38 patients; for the remaining three patients (two with focal OP, one with cryptogenic OP), the CT images were not obtainable, and we relied on the original CT interpretation for our analysis. For each patient, the radiologic findings of reticulation, traction bronchiectasis (TB), consolidation, and solitary nodules were identified as present or absent. Additionally, we used a semi-quantitative scoring system to assess the degree of ground glass opacity (GGO) present in each patient, similar to previously described [16]. A numerical score was assigned to each of the five lobes and the lingula based on the percentage of GGO present in each lobe: 0 (none), 1 (1e10%), 2 (10e25%), 3 (26e50%), 4 (51e75%), and 5 (>75%). A cumulative GGO score was then calculated for each patient by addition of each individual score. All patients had serial imaging studies performed subsequent to SLB, and these images were available for review in 34/38 patients. Serial imaging studies available consisted of serial chest CT (n ¼ 26) or conventional chest radiography (n ¼ 8, predominantly in patients with disease resolution). For the 26 patients with serial chest CT, the presence of GGO, consolidation, reticulation, and TB on the lattermost serial CT were reassessed and recorded. 2.4. Histologic evaluation A detailed histologic evaluation was performed in each sample by a clinical pathologist (APB) with experience in diffuse lung disease. To assist with analysis of tissue samples, sections were scanned into a digital pathology system (Aperio Technologies, Vista, CA) which allowed for analyzing slides at any magnification up to the highest magnification scanned. All patients met established multi-disciplinary clinical-radiologic-histologic criteria for OP. Additionally, two histologic
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subgroups were identified, histologic OP or histologic OP/NSIP overlap, and were identified based on established criteria for OP and NSIP [1,2,13,14]. Histologic OP was identified by the presence of widespread foci of OP, preservation of background lung architecture, and confinement of interstitial inflammation to areas of organization [1,2,13]. Diffuse interstitial inflammation and/or fibrosis in areas spatially distinct from foci of organization were minimal or absent. Histologic OP/NSIP overlap was identified by widespread foci of OP, relative preservation of background lung architecture, and the presence of diffuse interstitial inflammation and/or fibrosis in areas spatially distinct from foci of organization [1,13,14]. In addition to confirming histologic OP or histologic OP/NSIP, the following co-existing histologic findings were assessed: the predominant location of foci of organization (airway centered, interstitial, or both), presence or absence of reactive type II pneumocytes, and presence or absence of small airway disease (bronchiolitis or squamous metaplasia). Additionally, we semiquantitatively assessed the amount of fibrin and lymphocyte aggregates in each patient. The amount of fibrin was characterized as 1) low fibrin, identified by an absence of fibrin deposits or by small focal deposits <100 mm in greatest dimension and few in number (<5 per tissue section), or as 2) high fibrin, identified by multifocal deposits of fibrin >100 mm in greatest dimension and seen in high numbers on multiple tissue sections, similar to previously described [17]. Lymphocyte aggregates (100 mm in greatest dimension) were assessed by scoring absolute numerical counts observed in each lung tissue section, and then standardizing to numerical counts per tissue section, similar to previously described [18].
2.5. Statistical analyses Statistical analyses were performed using SAS statistical software (Cary, NC). For categorical variables, analyses were performed using Pierson's chi-square test, and for continuous variables, analyses were performed using the Wilcoxon rank-sum test. Multivariate analysis was performed of clinical, radiologic, and histologic variables related to clinical outcome. Differences at p < 0.05 were considered significant. 3. Results 3.1. Characteristics of all patients based on histologic OP or histologic OP/NSIP All patients (n ¼ 38) met established multi-disciplinary criteria for clinical-radiologic-histologic OP, and additionally were identified as having histologic OP or histologic OP/NSIP overlap. Table 1 compares the clinical, radiologic, and co-histologic findings between the two histologic groups. Twenty-two patients had histologic OP/NSIP, and 16 had histologic OP. Although patients with OP/NSIP were younger and had fewer smoking pack-years, there were no statistically significant differences in age, race, gender, or smoking history. Radiologic correlation demonstrated that histologic OP/NSIP was associated with the presence of GGO (p ¼ 0.001), reticulation (p ¼ 0.004), and TB (p ¼ 0.004), whereas histologic OP was associated with solitary nodules (p ¼ 0.012). Consolidation was observed equally between the groups. Fig. 1 demonstrates examples of the radiologic findings, and as demonstrated in Table 1, each individual radiologic finding was often observed co-existing with
Table 1 Characteristics of all patients (n ¼ 38) based on histologic finding of OP or OP/NSIP overlap. Variable
OP (n ¼ 16)
OP/NSIP (n ¼ 22)
Age, years, median [1st, 3rd] Gender Male, n Female, n Race Caucasian, n African-American, n Other, n Smoking Ever-smoker, n (%) Pack/years, median [1st, 3rd] Chest CT findings Consolidation (focal or multifocal), n (%) Ground glass opacity score, median [1st, 3rd] Reticulation, n (%) Solitary nodule, n (%) Traction bronchiectasis, n (%) Histology co-findings Fibrin deposits, n (%) OP location Airway-centered, n Interstitial, n Airway-centered and Interstitial, n Lymphocyte aggregates, median [1st, 3rd] Reactive type II pneumocytes, n (%) Small airway disease, n (%) Clinical-radiologic-pathologic diagnosis COP, n Autoimmune-associated OP, n Focal OP, n Clinical Outcome Disease resolution, n Unfavorable disease progression, n
62 [55,68]
55 [45,62]
0.09
8 8
12 10
0.78
13 3 0
14 6 2
0.54
11 (69) 22 [0,41]
14 (64) 6 [0,15]
0.74 0.10
7 0 2 6 2
6 (27) 8 [2,20] 13 (59) 1 (4) 13 (59)
0.29 0.001* 0.004* 0.012* 0.004*
5 (31)
5 (23)
0.56
3 8 5 2 [1,10] 10 (62) 10 (62)
1 19 2 2 [0,7] 21 (95) 16 (73)
0.05
9 1 6
15 6 1
0.019*
15 1
3 19
<0.0001*
(44) [0,2] (12) (38) (12)
P Value
0.41 0.009* 0.51
Definition of abbreviations: OP ¼ organizing pneumonia, NSIP ¼ non-specific interstitial pneumonia, COP ¼ cryptogenic organizing pneumonia. Analyses performed using Pierson's chi-square test or Wilcoxon rank sum test as appropriate. * indicates p < 0.05.
N.W. Todd et al. / Respiratory Medicine 109 (2015) 1460e1468
one or more of the other findings. Correlation of histologic co-findings demonstrated that histologic OP/NSIP was associated with the presence of reactive type II pneumocytes (p ¼ 0.009), but there were no differences in fibrin deposits, OP location, lymphocyte aggregates, or small airway disease. Fig. 2 demonstrates examples of the histologic findings of OP and OP/NSIP overlap. Since all patients (histologic OP and histologic OP/NSIP) met established criteria for clinical-radiologic-histologic OP, a consensus multi-disciplinary diagnosis of cryptogenic OP, secondary OP, or focal OP was assigned for each patient. Histologic OP/NSIP was associated with cryptogenic OP and autoimmune-associated OP, and histologic OP was associated with focal OP (p ¼ 0.019). In all patients (cryptogenic, secondary, or focal), histologic OP was associated with disease resolution, and histologic OP/NSIP was strongly associated with unfavorable disease progression (p < 0.0001). 3.2. Focal OP Seven of the 38 patients had clinical-radiologic-histologic focal
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OP, defined by the presence of a radiologic solitary nodule, absence of other radiologic co-findings (consolidation, GGO, reticulation, TB), and by histologic foci of OP within the solitary nodule. As seen in Table 1, focal OP was strongly associated with histologic OP (p ¼ 0.019). All seven patients with clinicalradiologic-histologic focal OP demonstrated complete disease resolution, manifested by absence of chronic pulmonary symptoms and by complete or near complete resolution of radiologic abnormalities on serial imaging studies. No patients with focal OP were treated with any type of anti-inflammatory or immunosuppressive medication. 3.3. Characteristics of patients with cryptogenic or autoimmuneassociated OP based on histologic OP or histologic OP/NSIP Since seven patients had focal OP with solitary nodules as the sole radiologic findings and had complete disease resolution, the remaining 31 patients with cryptogenic or autoimmune-associated OP were analyzed separately based on the presence of histologic OP or histologic OP/NSIP overlap. As seen in Table 2, 21 patients had
Fig. 1. Representative chest CT findings from six patients, with each panel obtained from a different patient. Reticulation (dashed arrows) was seen in a peripheral (A) or diffuse (B,D) pattern. Peripheral reticulation was often demonstrated to spare the extreme periphery of the lung (B), a pattern well-described in OP and NSIP [5,14]. Consolidation (triangle) was observed in a multifocal (B) or focal (E) pattern. Traction bronchiectasis (block arrows) and widespread GGO (asterisks) were well-demonstrated in many patients (C,D). As seen in this Figure and as noted in Table 1, the individual findings of consolidation, GGO, reticulation, and TB were most often observed co-existing with one or more of the other findings. Solitary nodules (F, arrowhead) were observed in isolation in our patients, without co-existing consolidation, GGO, reticulation, or TB.
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Fig. 2. Representative H&E SLB histology from four patients, with each horizontal pair of low and high magnification images obtained from a different patient. The length of the white bar in the left lower corner of each panel represents 2 mm (A), 3 mm (C,E), 4 mm (G), and 300 mm (B,D,F,H). Panels A,B and C,D demonstrate two patients with histologic OP/ NSIP overlap. Low magnification (A,C) shows abnormal background lung architecture, diffuse interstitial inflammation, and widespread thickening of intra-alveolar septae, consistent with NSIP. Well-formed foci of organizing pneumonia (block arrows) are seen on low and high magnification (B,D) images, and were abundant and widespread. Panels E,F and G,H demonstrate two patients with histologic OP. Low magnification (E,G) shows normal lung background architecture and normal intra-alveolar septae (asterisks) in areas distinct from OP. Cellular inflammation is confined to areas of OP, and thus histologic evidence of NSIP overlap is absent. Well-formed foci of OP (block arrows) are seen on low and high magnification (F,H) images.
histologic OP/NSIP overlap, and 10 had histologic OP. Although patients with OP/NSIP were younger and had fewer smoking packyears, there were no statistically significant differences in age, race, gender, or smoking history. There was a trend towards a higher percentage of patients in the OP/NSIP group being administered prednisone and other immunosuppressive therapies, but there
were no statistically significant differences between the groups. Radiologic correlation demonstrated that histologic OP/NSIP was associated with the presence of GGO (p ¼ 0.012), reticulation (p ¼ 0.029), and TB (p ¼ 0.029), whereas histologic OP was associated with the presence of consolidation (p ¼ 0.028). Fig. 1 again demonstrates examples of the radiologic findings.
N.W. Todd et al. / Respiratory Medicine 109 (2015) 1460e1468
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Table 2 Characteristics of patients with cryptogenic or autoimmune-associated OP (n ¼ 31) based on histologic finding of OP or OP/NSIP overlap. Variable
OP (n ¼ 10)
OP/NSIP (n ¼ 21)
Age, years, median [1st, 3rd] Gender Male, n Female, n Race Caucasian, n African-American, n Other, n Smoking Ever-smoker, n (%) Pack/years, median [1st, 3rd] Medications Prednisone, n (%) Azathioprine, n (%) Mycophenolate, n (%) Cyclophosphamide, n (%) Methotrexate, n (%) Chest CT findings Consolidation (focal or multifocal), n (%) Ground glass opacity score, median [1st, 3rd] Reticulation, n (%) Traction bronchiectasis, n (%) Histology co-findings Fibrin deposits, n (%) OP location Airway-centered, n Interstitial, n Airway-centered and Interstitial, n Lymphocyte aggregates, median [1st, 3rd] Reactive type II pneumocytes, n (%) Small airway disease, n (%) Clinical-radiologic-pathologic diagnosis COP, n Autoimmune-associated OP, n Clinical Outcome Disease resolution, n Unfavorable disease progression, n Death, n FVC < 70% predicted > 6 months, n
65 [57,69]
55 [45,62]
0.14
5 5
11 10
0.91
7 3 0
13 6 2
0.79
7(70) 20 [3,40]
13 (62) 5 [0,14]
0.65 0.11
5 1 2 1 0
(50) (10) (20) (10) (0)
17 (81) 7 (33) 9 (43) 0 (0) 4 (19)
0.08 0.16 0.21 0.14 0.14
7 1 2 2
(70) [0,5] (20) (20)
6 (28) 8 [3,20] 13 (62) 13 (62)
0.028* 0.012* 0.029* 0.029*
3 (30)
5 (24)
0.71
3 6 1 2 [1,8] 6 (60) 7 (70)
0 19 2 3 [0,7] 20 (95) 15 (71)
0.029*
9 1
15 6
0.25
9 1 0 1
2 19 8 11
P Value
0.67 0.013* 0.93
<0.0001*
Definition of abbreviations: OP ¼ organizing pneumonia, NSIP ¼ non-specific interstitial pneumonia, COP ¼ cryptogenic organizing pneumonia. Analyses performed using Pierson's chi-square test or Wilcoxon rank sum test as appropriate. * indicates p < 0.05.
Correlation of histologic co-findings demonstrated that histologic OP/NSIP was associated with the presence of reactive type II pneumocytes (p ¼ 0.013) and an interstitial location of OP deposits (p ¼ 0.029). There were no differences in fibrin deposits, lymphocyte aggregates, or small airway disease. Fig. 2 again demonstrates examples of the histologic findings of OP and OP/ NSIP overlap. Histologic OP was associated with disease resolution, and histologic OP/NSIP was strongly associated with unfavorable disease progression (p < 0.0001). In patients with OP/NSIP and unfavorable disease progression (n ¼ 19, Table 2), 8 patients died due to acute or progressive respiratory failure (median time from SLB to death 3 [2,6] months) and 11 patients had FVC < 70% predicted (median 58 [44,65]) greater than six months from date of SLB, with a median follow-up of 26 months for these 11 patients. Five of these 11 patients with FVC <70% predicted at > 6 months additionally underwent lung transplantation due to end-stage lung disease.
patients demonstrated complete or near complete resolution of the initial radiologic opacities. In the single patient with histologic OP and unfavorable disease progression, serial CT imaging (over 19 months) demonstrated resolution of consolidation, but persistent GGO, reticulation, and TB. In the histologic OP/NSIP group (n ¼ 21), two patients demonstrated clinical disease resolution, which included complete or near complete resolution of radiologic opacities. In the remaining 19 patients with unfavorable disease progression, serial chest CT imaging was available in 15 patients. In these patients, chest CT at the time of diagnosis demonstrated GGO (n ¼ 13), consolidation (n ¼ 3), reticulation (n ¼ 11), and TB (n ¼ 10). On the lattermost serial CT, findings observed were GGO (n ¼ 12), consolidation (n ¼ 4), reticulation (n ¼ 11), and TB (n ¼ 11). These observations demonstrate persistence of GGO, reticulation, and TB in the unfavorable disease progression group. Median time interval from initial CT to lattermost serial CT was 11 [2,18] months.
3.4. Serial imaging studies in patients with cryptogenic or autoimmune-associated OP
3.5. Multivariate analysis of variables associated with clinical outcome
To assess changes in radiologic findings over the course of disease, serial imaging studies were analyzed in patients with cryptogenic or autoimmune-associated OP. In the histologic OP group (n ¼ 10), nine demonstrated clinical disease resolution, and these
Since histologic OP/NSIP overlap was associated with unfavorable disease progression, a multivariate analysis was performed in patients with clinical-radiologic-histologic cryptogenic or autoimmune-associated OP (n ¼ 31) to determine which clinical,
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Table 3 Multivariate analysis of variables associated with clinical outcome (disease resolution versus unfavorable disease progression) in patients with cryptogenic or autoimmuneassociated OP (n ¼ 31). Variable Clinical
Radiology
Histology
Combined
Age Gender Race Smoking, pack/years Autoimmune disease Consolidation Ground glass opacity score Reticulation Traction bronchiectasis Fibrin deposits Lymphocyte aggregates OP/NSIP overlap Reactive type II pneumocytes Small airway disease Ground glass opacity score OP/NSIP overlap
Chi-square
P Value
0.59 0.34 2.7 0.38 0.81 0.01 9.2 1.6 1.8 3.0 1.1 21.5 0.15 2.8 4.1 12.3
0.44 0.56 0.43 0.53 0.37 0.93 0.002* 0.20 0.18 0.08 0.30 <0.0001* 0.69 0.09 0.041* <0.001*
Definition of abbreviations: OP ¼ organizing pneumonia, NSIP ¼ non-specific interstitial pneumonia. * indicates p < 0.05.
radiologic, or histologic variables were independently associated with clinical outcomes. As seen in Table 3, multivariate analysis was performed using clinical, radiologic, and histologic variables within their respective groups. This analysis demonstrated that GGO score (p ¼ 0.002) and histologic OP/NSIP overlap (p < 0.0001) were independently associated with unfavorable disease progression within their respective groups, and this independent association remained when these two variables were subsequently combined (p ¼ 0.041 and p < 0.001, respectively). 4. Discussion In this study of 38 patients who met established multidisciplinary clinical-radiologic-histologic criteria for OP, two histologic subsets of patients were identified: histologic OP and histologic OP/NSIP. Histologic OP was associated with radiologic consolidation and clinical-radiologic-histologic focal OP, and was additionally strongly associated with disease resolution. Histologic OP/NSIP overlap was associated with GGO, reticulation, TB, and reactive pneumocytes, and was additionally strongly associated with unfavorable disease progression. The association of histologic OP/NSIP with unfavorable disease progression was observed in the entire group of patients, and also in the subgroup of 31 patients with cryptogenic or autoimmune-associated OP in which patients with focal OP were excluded. Multivariate analysis utilizing clinical, radiologic, and histologic findings indicated that histologic OP/NSIP was independently associated with unfavorable disease progression. The novelty of our study is the clinical and radiologic characterization of a group of patients with histologic OP/NSIP overlap, and the statistical correlation of histologic OP/NSIP with particular radiologic findings and with unfavorable lung disease progression. Only two previous studies to our knowledge have published findings correlating lung histology evidence of diffuse disease in OP with adverse clinical outcomes [15,19]. Both were performed prior to the more recent classifications of the interstitial pneumonias [1,13], which makes direct lung terminology comparisons to our study difficult. Our study does have a larger number of patients than either previous study, which allowed us to statistically correlate radiologic and histologic findings with clinical outcomes. The concept of OP and NSIP co-existing may seem puzzling or even improbable at first, as these are most often described and discussed as distinct clinical and histologic entities. However, the presence of both findings concurrently in SLB samples has been described, but is often likely considered of lesser importance, and the
precise terminology used has varied. In series of patients in which NSIP was the consensus diagnosis, OP was observed as a co-existing finding in some patients [5,14,20,21]. In series of patients in which OP was the consensus diagnosis, interstitial inflammation and interstitial fibrosis (NSIP pattern) were observed as co-existing findings in some patients [1,15,19]. Current nomenclature and criteria indicate that if significant amounts (>10e15%) of OP are present, the histologic diagnosis of OP is appropriate with or without co-existing interstitial inflammation or fibrosis [1,2,13]. Each patient in our study demonstrated widespread histologic foci of OP (at least > 10% of tissue section) as a predominant histologic finding, in conjunction with relative preservation of background lung architecture. Regarding NSIP, established criteria have stated that foci of OP should be inconspicuous or absent [1]. Therefore, if significant interstitial inflammation and/or interstitial fibrosis was present in our patients in areas spatially distinct from areas of organization, we identified this histologic pattern as OP/NSIP overlap, similar to previously used terms of NSIP/OP profile or NSIP/OP overlap [2,22]. Our OP/NSIP patients thus had findings most consistent with a true overlap syndrome, with widespread foci of OP and widespread areas of NSIP distinct from areas of organization. It is not surprising that reticulation and TB were associated with unfavorable disease progression, as these abnormalities have previously been associated with poor outcomes in OP and other forms of interstitial pneumonia [23e25]. GGO has been observed in OP, and has also been associated with persistent disease [23]. Our data complements these previous studies by demonstrating an association between a histologic OP/NSIP overlap pattern and these observed radiologic findings. Serial CT imaging findings in our patients with histologic OP/NSIP and unfavorable disease progression demonstrated persistence of GGO, reticulation, and TB. Ever since original descriptions of OP, a subgroup of patients have shown progression to fibrosis, which has often been termed a fibrosing variant of OP [1,26], and which has led to the concept that some patients diagnosed with fibrotic NSIP may have rather had a fibrosing variant of OP [1,2,5]. This phenotype appears very similar to the histologic OP/NSIP overlap group of patients in our study. Many previous studies have suggested that subgroups of patients with OP have markedly variable clinical outcomes [1,12,15,26]. The use of anti-inflammatory or immunosuppressive medications may potentially alter clinical outcomes, but in our study, all patients with focal OP who had complete disease resolution did not receive any type of anti-inflammatory or immunosuppressive therapy. In our patients with COP or autoimmune associated OP, there were no
N.W. Todd et al. / Respiratory Medicine 109 (2015) 1460e1468
significant differences in anti-inflammatory or immunosuppressive therapies between the histologic OP versus OP/NSIP group, but the OP/NSIP group had a much poorer overall prognosis. These observations suggest that factors responsible for clinical outcomes in patients with OP are likely complex. One likely factor is differences in etiology and/or degree of lung injury in individual patients, which are subsequently manifested by different radiologic or histologic patterns. Our data suggest that when histologic findings are taken into account, outcomes are much more predictable. Patients with histologic OP, which was associated with nodules, consolidation, and clinical disease resolution (with or without anti-inflammatory therapy), likely had localized and self-limited lung injury. Patients with histologic OP/NSIP, which was associated with GGO, reticulation, TB, and reactive pneumocytes, likely had widespread areas of diffuse and ongoing lung injury, resulting in clinical disease progression despite the use of aggressive anti-inflammatory or immunosuppressive therapy. Our study does have some limitations. First, its retrospective format does create some difficulty with identifying the precise time of disease onset, and thus presents inherent difficulty in correlating observed radiologic or histologic findings with ultimate disease prognosis. For consistency, we used the date of surgical lung biopsy as the date of disease onset, and used the radiologic findings closest to the time of biopsy to correlate histology findings with radiographic patterns. We fully acknowledge that this approach has limitations, but in the absence of a consistent viable alternative, we believe our methodology provided the most objective and consistent approach for correlative analyses. Second, there is the possibility of selection bias in our group if patients with only severe disease were referred to our tertiary center. Lastly, a potential critique could be directed towards the confidence of our histologic diagnosis, and whether some patients in the OP/NSIP overlap group, due to the severity of their disease progression, had alternative histologic diagnoses, such as organizing diffuse alveolar damage (DAD) or acute exacerbation of IPF/UIP. By detailed multidisciplinary review by clinicians, radiologists, and pathologists with experience in diffuse lung disease, we are confident that all patients met established histologic and multi-disciplinary clinicalradiologic-histologic criteria for OP, and confident that patients with alternative histologic diagnoses were appropriately excluded from analysis in this study. 5. Conclusions In this study of 38 patients who met established multidisciplinary clinical-radiologic-histologic criteria for OP, two histologic subsets of patients were identified: histologic OP and histologic OP/NSIP overlap. Histologic OP was associated with radiologic consolidation, clinical-radiologic-histologic focal OP, and disease resolution. Histologic OP/NSIP was associated with GGO, reticulation, TB, reactive pneumocytes, and unfavorable disease progression, characterized by death from respiratory failure or persistent impairment in FVC >6 months post SLB. Multivariate analysis of clinical, radiologic, and histologic findings indicated that histologic OP/NSIP was independently associated with unfavorable disease progression. OP/NSIP overlap, either idiopathic or autoimmune-associated and identified by histologic and radiologic findings, was associated with unfavorable disease progression, and due to its aggressive clinical course, should be recognized as a characteristic clinical-radiologic-histologic entity. Conflict of interest Nevins Todd has no financial or non-financial competing interests.
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Ellen Marciniak has no financial or non-financial competing interests. Ashutosh Sachdeva has no financial or non-financial competing interests. Seth Kligerman has no financial or non-financial competing interests. Jeffrey Galvin has no financial or non-financial competing interests. Irina G Luzina has no financial or non-financial competing interests. Sergei P Atamas has no financial or non-financial competing interests. Allen Burke has no financial or non-financial competing interests. Acknowledgments Nevins Todd and Ellen Marciniak conceived the study, collected all data, analyzed all data, performed all statistical analyses, and wrote the manuscript. Allen Burke reviewed all pathology slides, assisted with data and statistical analyses, and substantially contributed to the conceptual message of the manuscript. Jeffrey Galvin and Seth Kligerman reviewed all chest radiology studies, and assisted with data interpretation and conclusions. Sergei Atamas contributed substantially to data analysis, data interpretation, and conceptual message of the manuscript. Ashutosh Schedeva and Irina Luzina contributed substantially to data interpretation and conceptual message of the manuscript. References [1] W.D. Travis, U. Costabel, D.M. Hansell, et al., ATS/ERS committee on idiopathic interstitial pneumonias. an official american thoracic society/european respiratory society statement: update of the international multidisciplinary classification of the idiopathic interstitial pneumonias, Am. J. Respir. Crit. Care Med. 188 (6) (2013) 733e748. [2] B. Bradley, H.M. Branley, J.J. Egan, et al., British Thoracic Society, Interstitial lung disease guideline group, british thoracic society standards of care committee; thoracic society of Australia; New Zealand thoracic society; Irish thoracic society. Interstitial lung disease guideline: the British thoracic society in collaboration with the thoracic society of Australia and New Zealand and the Irish thoracic society, Thorax 5 (63 Suppl) (2008) 1e58. [3] S.L. Walsh, D.M. Hansell, Diffuse interstitial lung disease: overlaps and uncertainties, Eur. Radiol. 20 (8) (2010) 1859e1867. [4] R. Floyd, Organization of pneumonic exudates, Am. J. Med. Sci. 163 (1922) 527e548. [5] S.J. Kligerman, T.J. Franks, J.R. Galvin, From the radiologic pathology archives: organization and fibrosis as a response to lung injury in diffuse alveolar damage, organizing pneumonia, and acute fibrinous and organizing pneumonia, Radiographics 33 (7) (2013) 1951e1975. [6] J.L. Myers, A.L. Katzenstein, Ultrastructural evidence of alveolar epithelial injury in idiopathic bronchiolitis obliterans-organizing pneumonia, Am. J. Pathol. 132 (1) (1988) 102e109. [7] S. Peyrol, J.F. Cordier, J.A. Grimaud, Intra-alveolar fibrosis of idiopathic bronchiolitis obliterans-organizing pneumonia. Cell-matrix patterns, Am. J. Pathol. 137 (1) (1990) 155e170. [8] B.J. Roberton, D.M. Hansell, Organizing pneumonia: a kaleidoscope of concepts and morphologies, Eur. Radiol. 21 (11) (2011) 2244e2254. [9] A.A. Liebow, C.B. Carrington, The interstitial pneumonias, in: M. Simon, E.J. Potchen, M. LeMay (Eds.), Frontiers of Pulmonary Radiology, Grune and Stratton, New York, 1969, pp. 102e141. [10] A.G. Davison, B.E. Heard, W.A.C. McAllister, et al., Cryptogenic organizing pneumonitis, Q. J. Med. 52 (207) (1983) 382e394. [11] G.R. Epler, T.V. Colby, T.C. McLoud, et al., Bronchiolitis obliterans organizing pneumonia, N. Engl. J. Med. 312 (1985) 152e158. [12] F. Maldonado, C.E. Daniels, E.A. Hoffman, et al., Focal organizing pneumonia on surgical lung biopsy: causes, clinicoradiologic features, and outcomes, Chest 132 (5) (2007) 1579e1583. [13] American Thoracic Society/European Respiratory Society International multidisciplinary consensus classification of the idiopathic interstitial pneumonias, Am. J. Respir. Crit. Care Med. 165 (2) (2002), 277e3042001. [14] W.D. Travis, G. Hunninghake, T.E. King Jr., et al., Idiopathic nonspecific interstitial pneumonia: report of an American Thoracic Society project, Am. J. Respir. Crit. Care Med. 177 (12) (2008) 1338e1347. [15] J.F. Cordier, R. Loire, J. Brune, Idiopathic bronchiolitis obliterans organizing
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