Interstitial Lung Diseases That Are Difficult to Classify A Review of Bronchiolocentric Interstitial Lung Disease Renu K. Virk, MD; Armando E. Fraire, MD

 Context.—Idiopathic bronchiolocentric interstitial pneumonia, airway-centered interstitial fibrosis, centrilobular fibrosis, and bronchiolitis interstitial pneumonia are increasingly recognized histopathologic variants of idiopathic interstitial pneumonia that are difficult to fit within existing classification schemes. Objective.—To review and analyze the appropriate literature that describes the spectrum of histopathologic changes in these conditions, in an effort to ascertain similarities as well as their differences. In addition, we examined associations with hypersensitivity, cigarette smoking, and survival data. Data Sources.—Relevant and peer-reviewed literature

indexed in PubMed (National Library of Medicine) coupled with experience gained by review of personal cases with appropriate histopathology constitute the basis of this study. Conclusions.—As anticipated, the common link among the above-cited conditions is their bronchiolocentricity, with a predominance of either fibrosis or inflammation. Clear-cut associations with hypersensitivity or cigarette smoking are not evident in this study. The airway-centered interstitial fibrosis variant of bronchiolocentric interstitial lung disease appears to have a poor outcome. (Arch Pathol Lab Med. 2015;139:984–988; doi: 10.5858/ arpa.2013-0383-RA)

T

nia (NSIP), among others.3 There is, however, a number of chronic fibrosing ILDs that cannot readily be accommodated or fit into specific or well-known entities. For these ILDs the noncommittal term of chronic interstitial pneumonia has been advocated by some authors but not by others.4,5 Some of the difficult to classify ILDs include idiopathic pleuropulmonary fibroelastosis6 (not discussed here) and a group of ILDs that occur in association with small airway disease.7–11

he spectrum of disorders included in the category of idiopathic interstitial lung disease is vast and complex. How to separate and classify these disorders become a perplexing problem because the various disorders could be categorized in a variety of ways: diffuse or localized; predominant fibrosis or predominant inflammation; known versus unknown causes; and temporal features, such as acuteness, versus chronicity.1 There is a notion among some pathologists that the diagnosis of interstitial lung disease (ILD), particularly the idiopathic variants, is sometimes difficult to establish. This notion is enhanced by the multiplicity (and frequent overlapping) of histopathologic features that are seen in these diseases of the lung.2 Whether this notion is true or not, there appears to be a need for the establishment and dissemination of classification schemes that provide pathologists with useful and reproducible criteria for the diagnosis of ILD. Valuable and ongoing work by organizations such as the American Thoracic Society (ATS) and the European Respiratory Society (ERS) have already provided excellent criteria for the recognition of a variety of entities, such as usual interstitial pneumonia, desquamative interstitial pneumonia, respiratory bronchiolitis–ILD, cryptogenic organizing pneumonia, and idiopathic nonspecific interstitial pneumoAccepted for publication January 29, 2014. From the Department of Pathology, Yale School of Medicine, New Haven, Connecticut (Dr Virk); and the Department of Pathology, University of Massachusetts Medical School, Worcester (Dr Fraire). The authors have no relevant financial interest in the products or companies described in this article. Corresponding author: Renu Kaur Virk, MD, Department of Pathology, Yale School of Medicine, EP2, 20 York St, New Haven, CT 06520 (e-mail: [email protected]). 984 Arch Pathol Lab Med—Vol 139, August 2015

LITERATURE REVIEW In terms of idiopathic ILDs showing bronchiolocentricity, efforts to classify the unclassified began only in the early part of the 2000s, with a seminal paper by Yousem and Dacic7 calling attention to a distinctive form of idiopathic bronchiolocentric interstitial pneumonia (IBIP) that shared histologic similarities with hypersensitivity pneumonitis. In their series of 10 patients, the authors described a centrilobular inflammatory process with small airway fibrosis and inflammation that radiated into the interstitium in a patchy fashion. This constellation of features was named idiopathic bronchiolocentric interstitial pneumonia, or IBIP. Follow-up was available in 9 of the 10 patients, with a mean duration of 4.0 years. A total of 3 of the 9 patients died, and 6 had progressive disease.7 Subsequent to this report of IBIP, a number of small series and some singlecase reports appeared in the literature. From an initial pool of 112 patients, de Carvalho et al8 identified 49 patients with clinical and radiographic evidence of idiopathic interstitial pneumonia. All patients had open lung biopsies and were studied in detail according to architecture, temporal homogeneity, distribution of lesions, damage to bronchiolar epithelium, fibroblastic foci, and air space remodeling. Three groups emerged: usual interstitial Interstitial Lung Diseases That Defy Classification—Virk & Fraire

Figure 1. Bronchiolocentricity can be appreciated on subgross, glass-mounted tissue sections (hematoxylin-eosin, no magnification). Figure 2. Airway-centered fibrosis (ACIF) with extreme muscularization of peribronchiolar tissue. This closely approximates ACIF (hematoxylineosin, original magnification 340). Figure 3. Peribronchiolar metaplasia. Note extension of respiratory epithelium beyond small airways into adjacent alveoli, a process also known as bronchiolization (hematoxylin-eosin, original magnification 3100). Figure 4. Bronchiolitis with interstitial pneumonia (BIP). Note active inflammation with thickening of adjacent interalveolar septae. This closely approximates BIP (hematoxylin-eosin, original magnification 3100).

pneumonia (n ¼ 24), nonspecific interstitial pneumonia (n ¼ 13), and a group (n ¼ 12) that the authors named centrilobular fibrosis. Of much interest, all 12 patients—6 men and 6 women—in the centrilobular fibrosis group showed bronchiolocentricity, and most (11 of 12) showed histologic evidence of damage/regeneration of the bronchial respiratory epithelium. Given the predominance of bronchiolar damage (necrosis/regeneration), the authors hypothesized a possible relationship to chronic aspiration of gastric contents as a major causative factor in their series.8 The authors further called attention to the absence of any clinical evidence of inhalation injury in their patients, helping them to exclude a hypersensitivity type of reaction. Unfortunately, follow-up and survival data for the centrilobular fibrosis group and the other two groups were not provided.8 Churg and associates9 reported a cohort of 12 patients with a novel form of ILD characterized pathologically by small airway–centered interstitial fibrosis (ACIF) and metaArch Pathol Lab Med—Vol 139, August 2015

plastic bronchiolar epithelia extending around and often linking fibrotic and sometimes heavily muscularized bronchioles (Figures 1 and 2). The patients had chronic cough and progressive dyspnea. One patient was a current light smoker and two were ex-smokers. A total of 8 patients had a history of inhalational exposure to a variety of agents, including birds, cotton, chalk dust, and others. Follow-up was available in 10 of the 12 patients. A total of 5 patients had progressive disease, and 4 of the 5 died. A total of 3 patients improved and 2 remained stable.9 Fukuoka and associates10 studied 15 patients with ILD whose major histopathologic change included small airway disease characterized by PBM, or peribronchiolar metaplasia (Figure 3). A total of 13 patients were men and 2 were women. Among the patients, 3 were smokers, 2 were former smokers, and 7 were never-smokers. One had exposure to asbestos and one had exposure to avian antigens. Three patients had collagen vascular disease. Pulmonary function data were available in 10 patients. Of Interstitial Lung Diseases That Defy Classification—Virk & Fraire 985

Table 1. Interstitial Lung Disease With Bronchiolocentricity: Review of Literaturea Source, y

Case Load, No.

Terminology

Yousem and Dacic,7 2002 de Carvalho et al,8 2002 Churg et al,9 2004 Fukuoka et al,10 2005 Mark et al,11 2008

10 12 12 15 31

IBIP CLF ACIF PBM BIP

Abbreviations: ACIF, airway-centered interstitial fibrosis; BIP, bronchiolitis interstitial pneumonia; CLF, centrilobular fibrosis; IBIP, idiopathic bronchiolocentric interstitial pneumonia; PBM, peribronchiolar metaplasia. a Excludes individual case reports.

the patients, 1 had an obstructive pattern, 5 had restrictive patterns, 2 had mixed obstructive and restrictive patterns, and 2 had normal patterns. Computed chest tomography in 7 patients showed mosaic attenuation in 3 patients and air trapping in 1 patient. Follow-up (0.6–6.9 years) was available in 9 of 11 patients. At last follow-up, all patients were alive and 4 had experienced symptomatic improvement.10 Mark and Ruangchira-urai11 in 2008 described their experience with 31 patients who had respiratory difficulty leading to open lung biopsy. The biopsy showed a combination of both prominent bronchiolitis and prominent interstitial pneumonitis, which the authors termed BIP, or bronchiolitis interstitial pneumonia (Figure 4). Of interest, the authors found no evidence of hypersensitivity in their patients. Importantly, the authors called attention to the pneumonitis component having inflammation and fibrosis but little or no organizing pneumonia, helping to differentiate BIP from its very similar acronym, BOOP (bronchiolitis obliterans organizing pneumonia), which is now currently referred to as cryptogenic organizing pneumonia, or COP.11 Of the 31 patients in the series, 19 had follow-up and had received corticosteroid therapy. A total of 7 patients objectively improved, 5 patients had subjective improvement, and 1 patient showed no changes. Among the remaining 6 patients the disease worsened, and 4 of the 6 patients with worsening disease subsequently died.11 Table 1 summarizes data from case series published on bronchiolocentric ILD. The case of a 46-year-old woman who underwent lung transplantation for a fibrotic lung disorder that was clinically, functionally, and radiographically very similar to ACIF was reported by a French group.12 Notably, the patient had considerable exposure to avian (pigeon) antigens and was felt to have a variant of hypersensitivity pneumonitis. Table 2.

Histopathologically, the explanted lungs showed fibrosis surrounding both larger and smaller airways, and interstitial fibrosis extending onto the alveolar walls. This case was unique in that it afforded examination of the entire lung.12 Further individual case reports were provided by Serrano et al,13 Fenton et al,14 Yi et al,15 and Lohman et al.16 The tabulated findings of these reports are shown in Table 2. Review papers in 2006, 2007, and 2012 discussed clinicopathologic features of ILDs with airway involvement but provided no new cases of their own.17–19 Imaging and pulmonary function test results for both case series and individual case report patients are shown in Table 3. COMMENT Focusing on data provided by the above-cited series of 10 patients or more, it is apparent that although the terminology differs, a common histopathologic denominator emerges in the variable amount of bronchiolar and peribronchiolar fibrosis and inflammation (Table 4). Clinical and tobacco smoke associations, however, do not appear to have a common thread. As noted in Table 5, hypersensitivity was suspected in the Yousem and Dacic review7 and in the single-case report by Fenton et al.14 Further, 2 of 12 cases in the Churg series had exposure to avian antigens.9 The remainder of the reports, however, considered other possible associations, namely, aspiration and inhalation exposure.9 Notably, the 31 cases reported by Mark and Ruangchira-urai11 did not have clinical evidence of an association with hypersensitivity. Individual cases of chemical fume exposure, and cases associated with common variable immunodeficiency and transplantation are singlecase reports and appear to be sporadic associations.13,16 A similar lack of a definite association with cigarette smoking applies to the examined studies. As shown in Table 6, it is difficult to establish a strong association between these bronchiolocentric disorders and cigarette smoking. Overall, smoking is reported in less than 50% of the examined studies. In keeping with the interstitial nature of the disease, pulmonary function testing showed a predominantly restrictive disease pattern (Table 3). Imaging findings were more diverse, with many studies reporting reticulonodular infiltrates (Table 3). Next, we examined reported outcome and survival data (Table 7). The numbers are decidedly small and no strong pattern of survival emerges. However, patients with fibrosis appear to have a poorer outcome, with 40% of patients with available follow-up dying of the disease.9 At the opposite end of the spectrum, ILD with a predominance of peribronchiolar metaplasia had an excellent outcome, with

Individual Case Reports: Airway Involvement in Interstitial Lung Disease

Source, y

Patient Age, y/Sex

Colombat et al,12 2004

46/F

Serrano et al,13 2006 Yi et al,15 2007 Yi et al,15 2007 Fenton et al,14 2007 Lohman et al,16 2011

51/F 39/M 53/M 37/M 52/F

Association Heavy pigeon exposure Chemicalsa Idiopathic Idiopathic Hypersensitivityb CVID

Smoking Negative Ex-smoker Heavy smoker Heavy smoker No smoking history available Lifetime nonsmoker

Outcome No response to Rx, underwent bilateral lung transplantation Progressive disease, no response to Rx Progressive disease, died at 8 mo Progressive disease, died at 6 mo Little objective response to therapy No objective response to therapy, but now stable disease

Abbreviations: CVID, combined variable immunodeficiency; Rx, therapy. a Chemicals, cleansing agents. b Hypersensitivity, avian proteins. 986 Arch Pathol Lab Med—Vol 139, August 2015

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Table 3.

Interstitial Lung Disease With Bronchiolocentricity: Imaging Findings and Pulmonary Functions Imaging Findings (Including Chest X-Ray and HRCT Findings)

Source, y 7

Yousem and Dacic, 2002

de Carvalho et al,8 2002a 15

Yi et al,

2002

Churg et al,9 2004 Colombat et al,12 2004 Serrano et al,13 2006 Fenton et al,14 2007 Mark et al,11 2008b Lohmann et al,16 2011 Fukuoka et al,10 2005

Pulmonary Functions

Bibasilar interstitial infiltrates (n ¼ 9) Alveolar infiltrates superimposed on interstitial reticular and reticulonodular disease (n ¼ 2) Normal (n ¼ 1) Small airway involvement with peribronchiolar consolidation and air trapping, more common in lower two-thirds of lungs Bronchovascular fibrosis and diffuse reticulonodular pattern in both patients Diffuse reticulonodular infiltrates with central predominance and peribronchovascular fibrosis and interstitial thickening Honeycombing in 3 patients Peribronchovascular fibrosis and traction bronchiectasis with bilateral involvement of upper lung zones Peribronchovascular fibrosis, bronchiolectasis, and patchy groundglass attenuation, predominantly in lower lungs Bilateral interstitial nodular infiltrates Interstitial infiltrates, diffuse ground-glass opacities Honeycombing (n ¼ 1) Normal (n ¼ 2) Tree-in-bud nodularity (centrilobular nodules with branching opacities) Imaging available (n ¼ 11) Diffuse mosaic attenuation and air trapping Normal (n ¼ 3)

Restrictive lung disease pattern

Restrictive lung disease pattern Restrictive lung disease pattern Restrictive lung disease pattern Restrictive lung disease pattern Restrictive lung disease pattern Restrictive lung disease pattern Restrictive pattern (n ¼ 8) Obstructive pattern (n ¼ 1) Combined pattern (n ¼ 4) Restrictive lung disease pattern Restrictive pattern (n ¼ 5) Obstructive pattern (n ¼ 1) Combined pattern (n ¼ 2) Normal (n ¼ 2)

Abbreviation: HRCT, high-resolution computed tomography. a Radiology findings not available in all patients. b Available in 18 of 31 patients.

all patients with available follow-up being alive over a mean period of 2.4 years.10 In between these two ends of the spectrum are patients with small airway disease characterized by inflammation showing low and high levels of intermediate survival, respectively (Table 7).7,11 Our analysis of single-case reports (shown in Table 2) further suggests poor outcome. Of 6 individually reported patients, 2 died, 1 required a lung transplant, and the remaining 3 showed no objective response to therapy. In this group of 6 patients, 3 were men and 3 were women. Three had exposure to organic antigens and one to chemicals. Two were smokers, one was an ex-smoker, two were nonsmokers, and a smoking history was not available for one patient. Given the small numbers in this group it is difficult to draw conclusions, except that, as noted above, the outcome appeared to be poor. Colby20 examined the subject of airway-centered ILD and reviewed the existing literature up to 2008. His approach was similar to the one used in this study, but the author reached somewhat different conclusions. In particular, Colby emphasized the role of hypersensitivity in these airway-centered ILDs, but the evidence for this is not firm. On the one hand, histologically, the classic poorly formed Table 4.

granulomas of hypersensitivity pneumonitis are not reported in the reviewed papers, and the role of hypersensitivity was dismissed in the largest series of 31 patients reported by Mark and Ruangchira-urai.11 We agree, however, that all of the reported series are small and follow-up is at best inconsistent.20 We also agree that no statistical significance exists among the various series. Clearly, major problems with these bronchiolocentric ILDs include their rarity and the current lack of adequate clinical follow-up. One major step forward is the recent recognition of these ILDs with bronchiolocentricity as a rare histologic pattern by the ATS/ ERS.21 In summary, this review supports the existing view that ACIF, BIP, IBIP, and PBM share a common link: bronchiolocentricity. This study further shows no clear association between these bronchiolocentric conditions and hypersensitivity or cigarette smoke. One subset of cases appears to have a background of environmental exposure.9 Airway-centered interstitial fibrosis appears to have a more severe prognosis compared with the other 3 variants of bronchiolocentric ILD. As noted, the caseload from the reported series and individual case reports is limited, and further studies

Histopathology of Idiopathic Bronchiolocentric Interstitial Pneumonia (IBIP), Airway-Centered Interstitial Fibrosis (ACIF), and Bronchiolitis Interstitial Pneumonia (BIP)

Parameter

IBIP

ACIF

BIP

Bronchiolocentricity Interstitial inflammation Extension to alveoli Subpleural space Peribronchiolar fibrosis Muscle hyperplasia

Yes Yes, chronic Yes Spared Yes ...

Yes Yes, sparse Yes Not spared Yes Yes

Yes Yes, mild Yes ... Yes ...

Ellipses indicate data not available. Arch Pathol Lab Med—Vol 139, August 2015

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Table 5. Interstitial Lung Disease With Bronchiolocentricity: Clinical Associations Source, y

Associations

Yousem and Dacic,7 2002 de Carvalho et al,8 2002 Yi et al,15 2002 Churg et al,9 2004 Colombat et al,12 2004 Serrano et al,13 2006 Fenton et al,14 2007 Mark et al,11 2008 Lohmann et al,16 2011

HSP suspected Aspiration Idiopathic 8/12 inhalation, 2 avian exposure Organ transplant Chemical fumes HSP No HSP clinically CVID

Abbreviations: CVID, common variable immunodeficiency; HSP, hypersensitivity pneumonitis.

Table 6. Interstitial Lung Disease With Bronchiolocentricity: Smoking Histories Source, y

Smoking Data 7

Yousem and Dacic, 2002 de Carvalho et al,8 2002 Churg et al,9 2004 Yi et al,15 2007 Fenton et al,14 2007 Mark et al,11 2008

Table 7.

4/10 smokers 4/10 smokers 1 light smoker (of 12) 2 ex-smokers 2 patients, both heavy smokers Not stated Not stated

Prognosis of Interstitial Lung Disease With Bronchiolocentricity

PBM Favorable, follow-up available in 11 of 25 patients, mean 2.4 y 11 of 11 alive, 4 improved BIP Low intermediate, follow-up available in 19 of 31 patients 12 improved, 6 worsened, and 4 of the 6 died IBIP High intermediate, follow-up available in 9 of 10 patients, mean 4.0 y 3 of 9 patients died, 6 had progressive disease ACIF Poor, follow-up available in 10 of 12 patients 5 patients had progressive disease and 4 of the 5 died 3 patients improved and 2 remained stable Abbreviations: ACIF, airway-centered interstitial fibrosis; BIP, bronchiolitis interstitial pneumonia; IBIP, idiopathic bronchiolocentric interstitial pneumonia; PBM, peribronchiolar metaplasia.

encompassing a greater number of patients are needed in order to gain further understanding of these disorders. In 2008, the ATS/ERS convened in order to address concerns experienced by the pathology community that idiopathic NSIP was a wastebasket category of ILD, difficult to distinguish from other idiopathic ILDs.22 To address the concerns, 67 cases were studied, focusing on demographics, smoking status, symptomatology, radiographic features, histopathology, and survival at 5 years. The study was successful and reaffirmed the existence of idiopathic NSIP as a valid clinicopathologic entity primarily affecting women who are never-smokers, with excellent prognosis and a survival of 82.3% at 5 years.22 We would like to suggest that a collaborative study similar to the NSIP study be carried out 988 Arch Pathol Lab Med—Vol 139, August 2015

for ILDs whose common link is bronchiolocentricity. It is possible that such centralized, collaborative study with contributors from various centers may result in the formulation and validation of guidelines for the diagnosis of airway-centered ILD. Until such study is conducted and completed, we feel that similarities among these disorders are greater than the observed differences. In our opinion, perhaps the noncommittal term of airway-centered interstitial lung disease could be used by pathologists as a broad topline diagnosis for these cases, with supplemental comments calling attention to predominance of either fibrosis or inflammation in and around bronchioles, in a manner akin to the separation of idiopathic NSIP into its two well-known variants (cellular and fibrotic). References 1. Colby TV, Carrington CB. Interstitial lung disease. In: Thurlbeck WM and Churg AM, eds. Pathology of the Lung. 2nd ed. New York, NY: Thieme Medical Publishers Inc; 1995:589–737. 2. Katzenstein AL, Mukhopadhyay S, Myers JL. Diagnosis of usual interstitial pneumonia and distinction from other fibrosing interstitial lung diseases. Hum Pathol. 2008;39:1562–1581. 3. Travis WD, King TE, Bateman ED, et al. ATS/ERS international multidisciplinary consensus classification of idiopathic interstitial pneumonias: general principles and recommendations. Am J Respir Crit Care Med. 2002;165:277–304. 4. Katzensteina AA, Askin FB. Idiopathic interstitial pneumonia/idiopathic pulmonary fibrosis. In: Katzensteina AA, Askin FB, eds. Surgical Pathology of Non-Neoplastic Lung Disease. Philadelphia, PA: WB Saunders Co.; 1990:58–96. 5. Hasleton PS. Fibrosing alveolitis In: Hasleton PS, ed. Spencer’s Pathology of the Lung. 5th Ed. New York, NY: McGraw-Hill; 1996:401–432. 6. Kusagaya H, Nakamura Y, Kono M, et al. Idiopathic pleuroparenchymal fibroelastosis: consideration of a clinicopathological entity in a series of Japanese patients. BMC Pulm Med. 2012;12:72. 7. Yousem SA, Dacic S. Idiopathic bronchiolocentric interstitial pneumonia. Mod Pathol. 2002;15(11):1148–1153. 8. de Carvalho ME, Kairalla RA, Capelozzi VL, et al. Centrilobular fibrosis: a novel histological pattern of idiopathic interstitial pneumonia. Pathol Res Pract. 2002;198(9):577–583. 9. Churg A, Myers J, Suarez T, et al. Airway-centered interstitial fibrosis: a distinct form of aggressive diffuse lung disease. Am J Surg Pathol. 2004;28(1):62– 68. 10. Fukuoka J, Franks TJ, Colby TV, et al. Peribronchiolar metaplasia: a common histologic lesion in diffuse lung disease and a rare cause of interstitial lung disease: clinicopathologic features of 15 cases. Am J Surg Pathol. 2005; 29(7):948–954. 11. Mark EJ, Ruangchira-urai R. Bronchiolitis interstitial pneumonitis: a pathologic study of 31 lung biopsies with features intermediate between bronchiolitis obliterans organizing pneumonia and usual interstitial pneumonitis, with clinical correlation. Ann Diagn Pathol. 2008;12(3):171–180. 12. Colombat M, Groussard O, Taill´e C, et al. Lung transplantation in a patient with airway-centered fibrosis. Am J Surg Pathol. 2004;28(11):1540–1542. 13. Serrano M, Molina-Molina M, Ram´ırez J, et al. Airway-centered interstitial fibrosis related to exposure to fumes from cleaning products. Arch Bronconeumol. 2006;42(10):557–559. 14. Fenton ME, Cockcroft DW, Wright JL, et al. Hypersensitivity pneumonitis as a cause of airway-centered interstitial fibrosis. Ann Allergy Asthma Immunol. 2007;99(5):465–466. 15. Yi XH, Chu HQ, Chen XM, et al. Idiopathic airway-centered interstitial fibrosis: report of two cases. Chinese Med J. 2007;120(9):847–850. 16. Lohman T, Chan J, Kelly M. Airway-centered interstitial fibrosis in a patient with common variable immunodeficiency. Chest J. 2011:140 (4_MeetingAbstracts):68A. doi:10.1378/chest.1108837. 17. Cordeiro CR. Airway involvement in interstitial lung disease. Cur Opin Pulm Med. 2006;12(5):333–341. 18. Cordier JF. Challenges in pulmonary fibrosis, II: bronchiolocentric fibrosis. Thorax. 2007;62(7):638–649. 19. Virk RK, Fraire AE. Pathology of airway-centered idiopathic interstitial pneumonia. Medscape. http://emedicine.medscape.com/article/ 2078390-overview. Accessed January 24, 2014. 20. Colby TV. Unclassifiable and newly described interstitial pneumonias. Paper presented at: 97th Annual Meeting of the Pulmonary Pathology Society (PPS); March 2008; Denver, CO. 21. Travis WD, Costabel U, Hansell DM, et al. An official American Thoracic Society/European Respiratory Statement: update of the international multidisciplinary classification of the idiopathic interstitial pneumonias. Am J Respir Crit Care Med. 2013;188(6):773–748. 22. Travis WD, Hunninghake G, King TE Jr, et al. Idiopathic nonspecific interstitial pneumonia: report of an American Thoracic Society Project. Am J Respir Crit Care Med. 2008;177(12):1338–1347.

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