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INVITED REVIEW SERIES: IDIOPATHIC INTERSTITIAL PNEUMONIA PART 2: SPECIFIC DISEASE ENTITIES SERIES EDITORS: TAMERA J CORTE, ATHOL U WELLS AND HAROLD R COLLARD

Idiopathic non-specific interstitial pneumonia ELIZABETH A. BELLOLI, ROSEMARIE BECKFORD, RYAN HADLEY AND KEVIN R. FLAHERTY Division of Pulmonary and Critical Care Medicine, University of Michigan Health System, Ann Arbor, Michigan, USA

ABSTRACT Non-specific interstitial pneumonia (NSIP) is an interstitial lung disease that may be idiopathic or secondary to connective tissue disease, toxins or numerous other causes. Idiopathic NSIP is a rare diagnosis and requires exclusion of these other possible causes. Patients typically present in mid-adulthood with dyspnoea, cough and often constitutional symptoms including fever and fatigue. The disease has a female predominance, and more than 50% of patients have never smoked. Physical exam features mild hypoxaemia and inspiratory rales. Pulmonary function tests demonstrate restriction and a low diffusing capacity for carbon monoxide. High-resolution computed tomography abnormalities include predominantly lower lobe subpleural reticular changes, traction bronchiectasis and ground-glass opacities; honeycombing is rarely seen. An evaluation of the underlying pathology is necessary for a firm diagnosis. Histologically, alveolar and interstitial mononuclear cell inflammation and fibrosis are seen in a temporally uniform pattern with preserved underlying alveolar architecture. NSIP must be differentiated Correspondence: Elizabeth A. Belloli, Division of Pulmonary and Critical Care Medicine, University of Michigan Health System, 3916 Taubman Center, 1500 East Medical Center Drive, SPC 5360, Ann Arbor, MI 48109, USA. Email: bellolie@ med.umich.edu The Authors: Elizabeth A. Belloli is a senior pulmonary and critical care medicine fellow with research interests in lung transplantation and interstitial lung disease. Rosemarie Beckford is a senior pulmonary and critical care medicine fellow with research interests in interstitial lung disease and sarcoidosis. Ryan Hadley is a clinical assistant professor and physician in the Division of Pulmonary and Critical Care Medicine at the University of Michigan and has research interests in interstitial lung disease. Kevin R. Flaherty is a professor and physician at the University of Michigan and has research interests in interstitial lung disease. He is the Steering Committee Chairman for the Pulmonary Fibrosis Foundation Care Center Network and Patient Registry. His research has been well funded by the National Institute of Health throughout his career, and he has published well more than 100 primary manuscripts, review articles and book chapters. Received 25 February 2015; invited to revise 6 May 2015; revised 10 July 2015; accepted 6 September 2015.

Article first published online: 13 November 2015 © 2015 Asian Pacific Society of Respirology

from other parenchymal lung diseases including idiopathic pulmonary fibrosis and hypersensitivity pneumonitis. A thorough exposure history and assessment for underlying connective tissue diseases are highly important, as positive findings in these categories would likely denote a case of secondary NSIP. A multidisciplinary discussion that includes pulmonologist(s), radiologist(s) and pathologist(s) assists in reaching a consensus diagnosis and improves diagnostic accuracy. Treatment of idiopathic NSIP, although not well proven, is generally instituted in the form of immunosuppression. Prognosis is favourable compared with idiopathic pulmonary fibrosis, although the diagnosis still carries an attributable mortality. Herein we will summarize the clinical characteristics and management of idiopathic NSIP. Key words: connective tissue disease; idiopathic interstitial pneumonia, interstitial lung disease, non-specific interstitial pneumonia. Abbreviations: ANCA, anti-neutrophil cytoplasmic antibody; ATS, American Thoracic Society; CCP, cyclic citrullinated peptide; CK, creatine kinase; cHP, chronic hypersensitivity pneumonitis; CT, computed tomography; CTD, connective tissue disease; CTDILD, connective tissue disease-related ILD; COP, cryptogenicorganizing pneumonia; DLCO, diffusing capacity of the lung for carbon monoxide (e.g., exempli gratia); ERS, European Respiratory Society; FVC, forced vital capacity; GAP, Gender–Age– Physiology; GER, gastro-oesophageal reflux; HIV, human immunodeficiency virus; HRCT, high-resolution computed tomography; HP, hypersensitivity pneumonitis; IgG4, Immunoglobulin G subclass 4; IIP, idiopathic interstitial pneumonia; ILD, interstitial lung disease; iNSIP, idiopathic NSIP; IPF, idiopathic pulmonary fibrosis; MDD, multi-disciplinary discussion; NSIP, non-specific interstitial pneumonia; OP, organizing pneumonia; PFT, pulmonary function test; RB, respiratory bronchiolitis; RNP, ribonucleoprotein; SLB, surgical lung biopsy; TNF, tumour necrosis factor; UCTD, undifferentiated connective tissue disease; UIP, usual interstitial pneumonia.

INTRODUCTION Non-specific interstitial pneumonia (NSIP), when first introduced, was defined by its ambiguity; namely, it was simply not one of the well-defined Respirology (2016) 21, 259–268 doi: 10.1111/resp.12674

260 histopathologic patterns of interstitial lung disease (ILD).1 Initially a non-specific finding or histologic ‘catch-all’ for patterns that did not neatly fit into other diagnostic categories, it has over the past two decades become solidified as a unique pathologic pattern.2 As an independent idiopathic interstitial pneumonia (IIP) diagnosis, idiopathic NSIP (iNSIP) was also once considered controversial. Initial controversy may have been bolstered by the fact that NSIP is the most common histologic finding in some forms of connective tissue disease-related ILD (CTD-ILD).3–5 In 2002, in an American Thoracic Society/European Respiratory Society (ATS/ERS) summary statement of IIP, iNSIP was given provisional status with suggestions for further research.6 From this, a panel of experts was convened by ATS with a detailed report of iNSIP published in 2008.7 The provisional status was removed in 2013, and iNSIP was determined to be an official IIP. Herein, we discuss the epidemiology, clinical presentation, evaluation, histology, radiology, prognosis and treatment of patients with iNSIP.

EPIDEMIOLOGY Given the recent institution of iNSIP as a diagnosis, prevalence and incidence are unknown. Based on retrospective data from mixed cohorts of idiopathic pulmonary fibrosis (IPF) and iNSIP, some have estimated the prevalence to be 1 to 9/100 000 for iNSIP compared with 2 to 20/100 000 for IPF.8 Determination of true incidence and prevalence was set forth as a future goal of study by the ATS project on iNSIP and was not addressed in the 2008 report.7

DIFFERENTIAL DIAGNOSIS To accurately diagnose NSIP, one must first exclude other types of ILD. One entity that often masquerades as NSIP clinically and radiographically is usual interstitial pneumonia (UIP), the classic histologic finding of IPF. UIP can also be the histologic finding in chronic hypersensitivity pneumonitis (cHP) and in CTD-ILD.9,10 It is especially important to separate NSIP and IPF given their disparate outcomes, with IPF having a much poorer prognosis.11,12 Furthermore, the treatment algorithms for these diseases are divergent. New anti-fibrotic drugs, pirfenidone and nintedanib, have been shown to slow disease progression in IPF, although immunosuppressive therapy appears to be harmful.13–15 On the other hand, treatment of NSIP has largely been immunosuppressive therapy, as discussed later in the Treatment section. Other diseases that should be excluded radiographically and/or histologically include cryptogenic-organizing pneumonia (COP) as well as the smoking-related IIPs, desquamative interstitial pneumonia and respiratory bronchiolitis-ILD.2 HP is another diagnosis that must be entertained when evaluating patients with NSIP and is typically differentiated on historical, radiologic or histologic grounds. HP is caused by inhalation of one of a large variety of organic antigens leading to an amplified Respirology (2016) 21, 259–268

EA Belloli et al. Table 1

Differential diagnosis of idiopathic NSIP

Other ILD (e.g. UIP, RB-ILD, COP) Toxins/drugs Rheumatologic diseases Human immunodeficiency virus Hypersensitivity pneumonitis Familial ILD Miscellaneous† † Includes IgG4-related disease, bone marrow transplant associated NSIP. COP, cryptogenic-organizing pneumonia; ILD, interstitial lung disease; NSIP, non-specific interstitial pneumonia; RB, respiratory bronchiolitis; UIP, usual interstitial pneumonia.

immune reaction; common antigens include bird proteins, fungi and atypical bacteria.9 A complete evaluation can be exhausting, and the clinician may find specialized questionnaires helpful. Of note, patients with HP can also have NSIP pattern on biopsy.7,16 At this time, a clarification of terms is needed to understand an accurate diagnosis of iNSIP. A surgical lung biopsy (SLB) with histology consistent with NSIP is termed NSIP pattern. NSIP pattern by biopsy can be seen in HP, UIP as well as idiopathic or secondary NSIP. After determining an NSIP biopsy pattern, if other ILD diagnoses are excluded based on clinical, radiologic and histologic findings, a diagnosis of NSIP is made. A multi-disciplinary discussion (MDD) with a pathologist, radiologist and pulmonologist is needed to address all available data and is the preferred means to arrive at a diagnosis of NSIP and other ILD.2,7 If secondary causes of NSIP are excluded (Tables 1,2), a diagnosis of iNSIP is made. Obtaining a thorough exposure history, including prior and current medications, is of tantamount importance. Chemotherapy and immunomodulatory agents such as tumour necrosis factor inhibitors should be given particularly close attention, as these agents have been more clearly associated with the development of secondary NSIP.17,18 Human immunodeficiency virus (HIV) has also been associated with secondary NSIP, although this was much more common in the era prior to anti-retroviral therapy.19 HIV should be excluded as a diagnosis based on clinical history and/or laboratory data.19,20 Acquisition of a complete family history is important, as up to 10% of familial interstitial pneumonia cases have been classified as NSIP.21,22 Finally, rarer clinical entities that have been associated with NSIP, although less well characterized, include IgG4-related disease and bone marrow transplant-associated NSIP.23,24 Diseases in the rheumatologic spectrum are the most common underlying aetiology in patients presenting with NSIP, and an autoimmune workup in most patients with apparent iNSIP is suggested.25 Fujita et al. performed a retrospective review of 46 patients in Japan who by clinical, radiographic, physiologic and pathologic grounds were diagnosed with NSIP. Out of 46 patients, 26 (62%) had an underlying CTD, which included polymyositis/dermatomyositis © 2015 Asian Pacific Society of Respirology

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NSIP Table 2 Suggested initial evaluation of a patient with possible NSIP History Environmental exposures Drugs (amiodarone, chemotherapy, TNF inhibitors, nitrofurantoin) Antigens (bird proteins, molds, thermophilic actinomyctes)

Physical Exam Clubbing Crackles Oral ulcers Gottron papules Mechanics hands Sclerodactyly

Laboratory† Family history of ILD Non-pulmonary symptoms Weight loss Morning stiffness Sicca symptoms Skin changes Photosensitivity Raynaud’s phenomenon Muscle weakness Arthralgias

Sedimentation rate or C-reactive protein Anti-nuclear antigen Rheumatoid factor HIV

† Consider further laboratory testing based on patient presentation, which may include anti-CCP, aldolase, anti-SSA, anti-SSB, ANCA, CK, anti-dsDNA, anti-Scl-70, anti-RNP, anti-Smith, anti-Jo-1.10 ANCA, anti-neutrophil cytoplasmic antibody; CCP, cyclic citrullinated peptide; CK, creatine kinase; HIV, human immunodeficiency virus; ILD, interstitial lung disease; NSIP, non-specific interstitial pneumonia; RNP, ribonucleoprotein; TNF, tumour necrosis factor.

(12), systemic sclerosis (5), rheumatoid arthritis (2), Sjogren’s syndrome (2), ulcerative colitis (1), and primary biliary cirrhosis (1). Of the 22 patients determined to have iNSIP, 6 had autoantibodies.26 Some investigators have suggested that perhaps all ‘idiopathic’ NSIP is an autoimmune phenomenon. Kinder et al. reviewed all cases of IIP at their institution and found that of 75 cases with an ‘idiopathic’ aetiology, 28 patients met the criteria for undifferentiated connective tissue disease (UCTD). The label UCTD denoted the presence of autoimmunity, but without all diagnostic features of a defined rheumatologic diagnosis. In the study, UCTD diagnostic criteria included (i) symptom(s) associated with a CTD (e.g. Raynaud’s phenomenon, arthralgias, unintentional weight loss, gastro-oesophageal reflux (GER)) and (ii) a positive autoantibody or elevated inflammatory marker. Of patients with IIP who were found to have an NSIP pattern on biopsy, 88% met criteria for UCTD. Kinder et al. also argued that all NSIP, idiopathic or secondary, is likely autoimmune in nature. The definition of UCTD has been criticized, as the criteria necessary to meet this classification are vague, often subjective and easily met. For example, UCTD could be diagnosed by simply having a positive anti-nuclear antibody and GER.27 Others argue that perhaps an entity termed ‘lungdominant CTD’ should exist, which would be charac© 2015 Asian Pacific Society of Respirology

terized by a lack of extra-thoracic features suggestive of CTD, but the presence of key histologic findings (e.g. lymphoid follicles, organizing pneumonia (OP), pleuritis) and autoantibodies that would prompt this label.28,29 Thus, although it is key to rule out a clearly defined CTD in patients found to have NSIP, many experts propose that patients with iNSIP actually do have an underlying autoimmune process, defined or not. Disagreement exists between the pulmonary and rheumatology communities on this topic, as despite positive serologies, these cases currently remain classified as iNSIP as long as a formal rheumatologic diagnosis cannot be made according to national guidelines.2 These discrepancies highlight the need for MDD of patients with NSIP; some argue that this discussion should include rheumatology consultants to facilitate consistent evaluations and diagnoses.2,28 Regardless of the thoroughness of evaluation at initial presentation following the diagnosis of iNSIP, it is known that a subsequent diagnosis of UCTD or CTD may occur at a later date in 9–33% of patients.30–33 Features linked to a later diagnosis of UCTD or CTD include younger age and female sex, but these associations have not been confirmed in all studies.30,32,34 As such, performance of at least a brief rheumatologic review of systems at each clinical encounter is suggested (Table 2) to determine if an occult, undiagnosed rheumatologic condition has emerged as an explanation for a patient’s NSIP.

CLINICAL PRESENTATION The clinical presentation of patients with iNSIP is non-specific. Characterization of presenting symptoms for iNSIP is limited by literature that often combines patients with idiopathic and secondary NSIP. In general, patients with NSIP regardless of aetiology experience cough (33–91%) and dyspnoea (68–100%) as the most common presenting symptoms.1,7,26,32,35,36 Fever (8–36%) and constitutional symptoms including fatigue, anorexia and weight loss may occur.1,7,26,35–37 Physical exam features inspiratory crackles (79–100%)26,35–38 and digital clubbing in some patients (0–40%).7,26,36–38 Most authors report a slight female predominance1,7,26,32,37 with average age in the 50s.7,11,32,36 Approximately one half (42–69%) of patients have never smoked.7,32,35,39 Pulmonary function testing classically reveals a restrictive ventilatory defect with a decreased diffusing capacity of the lung for carbon monoxide (DLCO).7,11,26,32,35,37,38 Mild resting hypoxaemia may also be present.26,35,36 Non-specific inflammatory markers are elevated in some patients.26,37 Bronchoalveolar lavage fluid often shows a lymphocytic population (29–47% of white blood cells)26,37,40–42 with higher lymphocyte counts more likely in cellular NSIP; however, some studies have found no difference between bronchoalveolar lavage cell populations in IPF compared with NSIP.38,43 Clearly there is not a single clinical feature that distinguishes NSIP from other IIPs, but further evaluation of suspected ILD will include chest imaging, serologic studies and often the obtainment of either a Respirology (2016) 21, 259–268

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oedema. However, persistence of symptoms, physical exam changes, and chest X-ray findings often lead to suspicion of ILD, prompting the appropriate next diagnostic study, a high-resolution computed tomography (HRCT) scan. Appropriate protocols for HRCT to evaluate ILD have been published and can be seen in Table 3.45 An HRCT scan is instrumental for the evaluation of NSIP to confirm the presence of ILD as well as to assess for findings that would suggest or diagnose other types of ILD. Findings typical of iNSIP are best described in the 2008 ATS expert consensus evaluation of biopsy/MDD-confirmed iNSIP cases drawn from multiple institutions.7 Radiologic abnormalities were predominantly lower lung (92%) and were either diffuse (47%) or peripheral (46%) in the axial dimension. Commonest findings were reticular abnormalities (87%), traction bronchiectasis (82%) and lobar volume loss (77%), but ground-glass attenuation (44%), sub-pleural sparing (21%) and peribronchial thickening (6.6%) were also seen. Subpleural sparing, when present, suggests NSIP but is not pathognomonic.46 A single centre study in Korea found ground-glass (94%), reticular findings (95%) and honeycombing (11%) more frequently in iNSIP than the ATS working group.30 A sample image from a patient with iNSIP and corresponding histology can be seen in Figure 1. One of the chief competing diagnoses for NSIP, UIP, can reliably be diagnosed by radiologic findings without the need for SLB when certain features are present.45 Lower lobe, subpleural predominance of interstitial thickening with honeycombing and minimal ground-glass opacity all suggest UIP.45 Exclusion of atypical findings solidifies the radiologic diagnosis of UIP; a list of these can be found in Table 4.45 A confident diagnosis of UIP by HRCT often hinges on the presence of honeycombing; however, in the absence of radiologic honeycombing, UIP can still be the underlying diagnosis nearly one third of the

cryobiopsy or SLB. Further discussion of the workup of patients with possible NSIP continues below.

RADIOLOGICAL FINDINGS Chest radiography is typically the first study ordered for patients with symptoms of ILD. Usually, this is performed at initial presentation, as symptoms and physical findings may mimic more common conditions such as infection or pulmonary oedema. In patients with NSIP, chest X-ray usually shows increased interstitial markings or lower lobe infiltrates,1,35,44 which in the acute setting would not differentiate it from acute pneumonia or pulmonary

Table 3 Optimal HRCT technique for evaluation of interstitial lung disease† The scans should be non-contrast and include at a minimum: • Scans obtained on full inspiration without respiratory motion • Contiguous or non-contiguous axial scans with thin sections, reconstructed at ≤2 cm intervals • Reconstructed slice collimation ≤ 2 mm • High-resolution reconstruction algorithm • Field of view to include lungs only • Expiratory scans are helpful to exclude lobular air trapping suggestive of hypersensitivity pneumonitis • Prone scans if dependent density obscures detail on supine images • Optional coronal and sagittal reconstructions if volumetric images are obtained † These criteria represent the consensus opinion of the committee members. From Raghu et al. electronic supplement.45 Reprinted with permission of the American Thoracic Society. Copyright © 2015 American Thoracic Society.

a

b

Figure 1 A 47-year-old man with no past medical history presented with 4 months of cough, malaise and dyspnoea unresponsive to antibiotics. He had no history of tobacco abuse and no relevant exposure history. Physical exam was unremarkable and without rales. Spirometry demonstrated restriction with a total lung capacity of 70% predicted and diffusing capacity of the lung for carbon monoxide of 64% predicted. (a) A representative high-resolution computed tomography image demonstrates lower lobe predominant peripheral ground-glass opacities with areas of sub-pleural sparing. (b) A representative image of the patient’s surgical lung biopsy, which was characteristic of cellular non-specific interstitial pneumonia. The underlying alveolar architecture is preserved, and mononuclear cells have invaded the alveolar interstitium. The abnormalities demonstrate temporal uniformity. This sample also contains prominent fibromyxoid tissue. HE: 100×. Respirology (2016) 21, 259–268

© 2015 Asian Pacific Society of Respirology

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NSIP Table 4 Characteristic radiographic and pathologic findings in NSIP and UIP Radiologic findings† UIP§

NSIP Subpleural, basal predominance Ground-glass possible Diffuse or peripheral Rare honeycombing (∼5%) Reticular abnormality Traction bronchiectasis

Subpleural, basal predominance Ground-glass minimal Should be less than reticulation Honeycombing‡ Reticular abnormality Traction bronchiectasis

Histologic findings NSIP Temporal uniformity with contiguous involvement Inflammation and fibrosis (cellular or fibrosing) No architectural distortion Rare honeycombing Bronchiolectasis Rare fibroblastic foci Organizing pneumonia (usually < 10%)

UIP Temporal heterogeneity with patchwork involvement Fibrosis Architectural distortion Prominent honeycombing Paraseptal, subpleural distribution Prominent fibroblastic foci No organizing pneumonia¶

† NSIP and UIP may be indistinguishable by HRCT. Additionally, atypical features may still be present in CT scans of patients with UIP. This underscores the need for biopsy and MDD. Listed are common characteristics. ‡ Honeycombing is needed to make a radiologic diagnosis of UIP, but on its own, it is not completely sensitive or specific for UIP. § Upper or mid-lung predominance, peribronchovascular predominance, extensive ground-glass, profuse micronodules, discrete cysts, mosaic attenuation, air trapping and consolidation of a segment or lobe must be absent for a radiologic diagnosis of UIP. ¶ Hyaline membranes and organizing pneumonia may be present in pathology seen during acute exacerbations of IPF. References:1,2,7,47,48 CT, computed tomography; HRCT, high-resolution computed tomography; ILD, interstitial lung disease; MDD, multidisciplinary discussion; NSIP, non-specific interstitial pneumonia; UIP, usual interstitial pneumonia. Adapted from Raghu et al.42 with permission of the American Thoracic Society. Copyright © 2015 American Thoracic Society. The American Journal of Respiratory and Critical Care Medicine is an official journal of the American Thoracic Society. This document was published in March 2011 and is currently in revision. Certain aspects of this document may be out of date and caution should be used when applying these in clinical practice or other usages.

time.12,49,50 Hence, the lack of honeycombing on HRCT does not rule out UIP and the diagnosis must be made by SLB. Honeycombing, the sine qua non of a radiologic diagnosis of UIP, is seen rarely (4.9%) in iNSIP.7 Obvi© 2015 Asian Pacific Society of Respirology

ously, honeycombing should raise questions regarding the underlying diagnosis of UIP. As discussed above, honeycombing as an isolated finding does not make a diagnosis of UIP. If the remainder of the HRCT scan suggests against this (such as with extensive ground-glass opacities), NSIP may be the final underlying diagnosis after biopsy and MDD. Honeycombing, when seen in NSIP, has been associated with worse prognosis.30 It is noted that in the absence of honeycombing, NSIP and UIP can be indistinguishable by HRCT (Table 4). In other words, UIP can be diagnosed in the correct setting by radiology alone, whereas NSIP requires a biopsy, either surgical or cryobiopsy, for diagnosis.6,7,45 Other findings atypical of NSIP should be essentially absent on HRCT, such as the upper lobe predominant centrilobular nodules and air trapping of HP46 and the consolidation of COP.7 Some degree of OP may be seen and may suggest NSIP secondary to CTD-ILD.2 Indeed, even in biopsy findings of definite or probable NSIP, atypical HRCT findings may overshadow the pathologic findings and lead to an alternative diagnosis based on HRCT alone in MDD.7 This underscores the need for a MDD of pathologists, pulmonologists and radiologists familiar with ILD to arrive at a definitive diagnosis of iNSIP, with no single clinical, radiologic or pathologic finding being outright diagnostic of iNSIP.2,6,7,51,52 HRCT of patients with NSIP, when followed over time, is variable. Some improve with treatment, whereas others develop findings consistent with progressive fibrosis.46,47,53,54 Interestingly, some develop CT scans consistent with UIP,46,53 which has been associated with worse prognosis.53

HISTOLOGY After the exclusion of radiologic UIP, medication toxicity, HP and CTD, if the suspicion of iNSIP remains, the most important step a clinician must take is to confirm the histologic diagnosis, which is needed to exclude alternative diagnoses. Often, tissue is obtained by SLB, but bronchoscopic cryobiopsy is emerging as a viable alternative and was recently reviewed.48 The establishment of the histologic category of NSIP was originally out of necessity. Following the initial formalized histologic classification of IIPs by Liebow et al.,55 it was recognized that some cases of interstitial pneumonia did not fit nicely into one of the proposed categories. In 1994, Katzenstein and Fiorelli published a landmark article characterizing 64 of such cases of interstitial pneumonia, and they labelled this pattern NSIP.1 These authors did exclude patients with underlying malignancy, chemotherapy treatment or acquired immune deficiency syndrome, but they included patients with a diagnosis of CTD. For years after the initial description, some experts regarded this as a ‘catch-all’ term, but NSIP is now recognized as an independent IIP.2 In general, key histologic characteristics of NSIP are (i) temporal uniformity and (ii) inflammation and/or fibrosis of the alveolar walls.1,7,56 Temporal uniformity Respirology (2016) 21, 259–268

264 contrasts sharply with the temporal heterogeneity seen in UIP, where histologic changes reflect prior injury with areas of honeycomb lung in concert with ongoing inflammation. In UIP, normal lung tissue may abut active fibrosis in the form of fibrobastic foci and/or microscopic honeycombing on the same microscopic slide. The pathologic infiltrate in NSIP is characterized by a mixture of lymphocytes and plasma cells.56 When fibrosis is present, collagen bundles with few fibroblasts will be noticeable, which distinguishes this entity from UIP in which active fibrosis is occurring, with pronounced fibroblastic foci.56 A comparison of NSIP and UIP histology can be found in Table 4. Katzenstein and Fiorelli proceeded to classify NSIP patterns into three groups according to the degree of inflammation and fibrosis present: Group I: cellular inflammation with little fibrosis; Group II: lymphoplasmacytic inflammation and fibrosis; and Group III: predominantly fibrosis.1 More recently, these categories have been simplified into cellular and fibrosing patterns.11,57 The majority of cases are typically classified as fibrosing, with less than 20% deemed to be cellular.7 Other histologic features may also occur in NSIP, but are much less prominent than in other interstitial pneumonias. These include fibroblastic foci (21%), foci of OP (52%), lymphoid follicles (57%) and spotty intra-alveolar macrophages.7,56 Marked architectural distortion is not present.56,57 A sample biopsy from a patient with cellular NSIP can be seen in Figure 1 along with a HRCT from the same patient. A number of important points exist when interpreting pathology from a patient with apparent NSIP. First, the categorization of an IIP can be far from straightforward for a pathologist. Inter-observer agreement between pulmonary pathologists in classifying diffuse parenchymal lung disease by SLB has been shown to be low, with kappa values between 0.26 and 0.49 reported, with agreement tending to be slightly higher if biopsies from multiple lobes were available.11,58 Second, the presence of NSIP on a biopsy specimen from one lobe does not exclude the presence of another IIP, particularly UIP. In their review of 109 patients with SLB from multiple lobes, Flaherty et al. demonstrated that 26% of patients had UIP in one lobe and NSIP in another. These authors concluded that if both patterns were present in the same patient, the patient should be categorized as having UIP given prognostic implications.59 Finally, Katzenstein et al. found that the majority of biopsy specimens and explanted lungs from patients with UIP had areas characteristic of NSIP, demonstrating that exclusion of UIP on a biopsy specimen with NSIP is essential.60 These points suggest that when pursuing a SLB in a patient with possible NSIP and all IIP, biopsies should be obtained from multiple lobes. Recently, Kambouchner et al. sought to determine if minor histologic features seen in some patients with a histologic diagnosis of NSIP could aid in determining the aetiology for the pattern. They described six histologic ‘overlap’ syndromes including NSIP/UIP, NSIP/cHP, and NSIP/OP overlap. According to their Respirology (2016) 21, 259–268

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classification of 136 cases, 36% of patients had ‘essential’ NSIP and 60% fit into an overlap category, with the remainder being unclassifiable. Patients with NSIP/cHP overlap were more likely to have a clinical diagnosis of cHP, and NSIP/OP overlap patients more often had a clinical diagnosis of CTD.29 In contrast, others have described that distinguishing between iNSIP and NSIP secondary to a CTD is impossible.26 Survival also differed between groups, with NSIP/ organizing diffuse alveolar damage and NSIP/UIP overlap patterns having a poorer prognosis.29 The use of minor histologic criteria requires more study and validation. After histologic diagnosis of NSIP is established, it is necessary to re-evaluate and rule out other secondary causes of NSIP with renewed vigilance, such as occult CTD or previously overlooked inhalational exposure, ensuring the case is, in fact, idiopathic. This step is more difficult than one may realize and requires shrewd history taking, careful physical examination and the ability to synthesize all information before labelling the disease as idiopathic. Occupational and pharmacologic histories are of utmost importance but are often omitted if the physician is unfamiliar with the diagnosis and evaluation of ILD and NSIP. A brief, but useful, algorithm to assist the clinician in workup of a patient with a potential NSIP diagnosis is shown in Figure 2. A clinical suspicion following the history, physical exam and pulmonary function tests should prompt a HRCT scan. If the CT does not yield a diagnosis and the patient does not have a defined CTD diagnosis, then SLB or cryobiopsy is likely indicated if safe to perform. Importantly, biopsy in CTDILD is usually not indicated as it does not change clinical management given that immunosuppression is typically instituted regardless of underlying histology. However, a SLB in cases of CTD-ILD may offer prognostic information if UIP cannot be diagnosed radiologically, as multiple studies have shown improved survival in CTD-related NSIP compared with CTD-related UIP.61,62 In patients with suspected ILD who undergo a SLB, complication rates range from 8% to 16% and include most commonly prolonged air leak, pneumonia, need for mechanical ventilation and non-pulmonary complications (myocardial infarction, cerebrovascular event).63–65 Thirty-day mortality rates are cited at 3–6.3%,63–66 with risk factors for mortality including mechanical ventilation prior to biopsy, immunosuppression treatment, low DLCO and acute exacerbation at the time of biopsy.64,66 Despite these risks, histologic findings may result in management changes in >50% of cases.63

PROGNOSIS The prognosis for iNSIP is overall favourable in comparison with IPF,12,36,37,67–69 although there is an approximate 20% mortality rate in 5 years.7,30,68 In the 2008 ATS report of 67 cases of iNSIP, 5 and 10-year survival rates of 82% and 73%, respectively, were reported.7 The prognosis for iNSIP is similar to that of secondary NSIP from CTD.70 © 2015 Asian Pacific Society of Respirology

265

NSIP Clinical suspicion of ILD

HRCT scan

Not ILD a) Exclude rheumatologic disease (see Table 2) b) Complete thorough exposure/medication history

ILD

Undifferentiated ILD

NSIP pattern

Other ILD (e.g. UIP pattern, sarcoidosis, hypersensitivity pneumonitis)

Consider SLB or cryobiopsy Proceed with usual work-up

SLB or cryobiopsy

Indications for SLB: a) Uncertain diagnosis Avoid SLB if: a) Patient is at high risk of complications (see text) b) Patient preference

Not NSIP Pattern

Figure 2 Decision algorithm for patients suspected of having NSIP. DLCO, diffusing capacity of the lung for carbon monoxide; HRCT, high-resolution computed tomography; ILD, interstitial lung disease; MDD, multi-disciplinary discussion; NSIP, nonspecific interstitial pneumonia; SLB, surgical lung biopsy; UIP, usual interstitial pneumonia.

The GAP (Gender–Age–Physiology) and ILD-GAP scoring systems are simple, easily applicable tools that can aid practitioners in prognostic determination by utilizing readily accessible clinical information. The GAP score and ILD-GAP score, which are factors in the underlying ILD diagnosis, have been shown to accurately predict the risk of death in iNSIP among other fibrotic ILDs.71,72 Histopathologic features at initial presentation not only provide diagnostic confirmation of NSIP but are also valuable in assessing prognosis. Travis et al. examined histologic features from open lung biopsies performed on 101 patients with IIP. They compared survival rates and found that among patients characterized as having iNSIP (29/101), cellular histology patients (7/29), when compared with those with fibrosing disease (22/29), had better 5-year (100% vs 90%) and 10-year (100% vs 35%) survival, respectively.57 Although fibrosing NSIP patients have worse outcomes than those with cellular NSIP, they had better survival rates than an IPF cohort at 5 (90% vs 43%) and 10 years (35% vs 15%).57 Thus, in reports of NSIP outcomes, the relative frequency of cellular and fibrosing iNSIP subtypes must be taken into consideration. An effective tool for prognostic assessment over time lies in longitudinal monitoring of pulmonary function tests. Changes in spirometric values are useful markers of survival and have been studied in patients specifically with iNSIP. A 15% decline in DLCO over 12 months has been found to correlate with mor© 2015 Asian Pacific Society of Respirology

NSIP Pattern Continue to perform surveillance for secondary causes of NSIP (rheumatologic symptoms, newly reported exposures, etc.) MDD Not NSIP Idiopathic NSIP

tality.69 DLCO measurements are, however, variable. Forced vital capacity (FVC) is a more reliable and reproducible measurement. A fall in FVC of >10% within 6–12 months of follow-up has independently been associated with mortality.30,68,73 At the time of diagnosis, histology is the best indicator of prognosis; however, changes in spirometry overtime outweigh the prognostic value of histologic subtype.68,69 Patients who have declines in FVC > 10% or DLCO > 15% unexplained by other causes (e.g. infection, pulmonary hypertension) should be considered for escalation of treatment and/or lung transplantation.

TREATMENT The natural history of untreated iNSIP is unknown. No randomized trials exist, and due to this, the rate of spontaneous remission has not been reported. Due to symptomatic and physiologic improvement or stability achieved by immunosuppression, treatment is thought to be beneficial.30,74 In cases of mild or asymptomatic disease, serial monitoring of symptoms and pulmonary function may be employed. Treatment should be implemented if progression of disease is noted.25 This limits exposure to unnecessary therapy, thus abrogating risk of medication side effects in some patients. When therapy is warranted, immunosuppression remains the cornerstone of management. Corticosteroids are the predominant and often initial agent Respirology (2016) 21, 259–268

266 of choice. Cytotoxic agents such as azathioprine, cyclophosphamide, cyclosporine and mycophenolate mofetil are used to augment or, if possible, supplant corticosteroid treatment. Use of rituximab has been documented in case reports for NSIP patients with UCTD with good results.75 Growing literature on the use of cyclophosphamide for the management of NSIP shows favourable response, even in cases exemplifying disease progression despite prior alternative immunosuppressant therapy.76 When employed in the management of severe cases, cyclophosphamide is typically used in conjunction with steroids.76–78 More recent data in regard to the effect of treatment specifically in iNSIP are now available. In a single centre study specifically of iNSIP patients, Park et al. found an 81% response to initial treatment (as measured by stable or improved spirometry and DLCO) when treated with corticosteroids alone or corticosteroids plus a cytotoxic agent. Reinstitution of treatment was needed for recurrence in 36% of patients. A subset of patients (19%) deteriorated despite appropriate treatment over 5 years of follow-up.30 There are no clear guidelines regarding glucocorticoid dosage or duration of therapy. In a study of a mixed idiopathic/secondary NSIP cohort, Lee et al. reported that relapses were associated with low initial prednisolone therapy (0.5 mg/kg) as well as shorter duration of therapy (4.7 compared with 7.7 months) prior to steroid cessation.74 Initial daily doses ranging from 0.5 to 1 mg/kg of prednisone or 40–60 mg (in non-weight-based dosing) are most commonly reported.12,30,74,79 Typically, the initial dose is continued for 1 month prior to attempts at weaning.12,30 Average treatment length reported by Park et al. specifically for iNSIP was 17.4 ± 12.1 months.30 Optimal treatment length is not defined nor is known if indefinite treatment is beneficial. No consensus exists as to whether a cytotoxic agent should be started at diagnosis versus upon disease progression or corticosteroid dependence.80 As previously mentioned, cyclophosphamide may be considered in patients who fail other immunosuppressive regimens.76 Improvement or stability of spirometry, lung volumes, DLCO, radiographic findings as well as diminished symptoms of cough and dyspnoea herald a favourable treatment response.12,25,30,74 Despite initial response, relapse can occur with decrease or cessation of immunosuppression requiring reinitiation of treatment.30,35,74

CONCLUSION Idiopathic NSIP is an IIP with a relatively good prognosis but still with attributable mortality.7,30 Typical HRCT findings of NSIP have been reported, and findings of UIP, HP and COP should be conspicuously absent.7 Definitive diagnosis of NSIP can only be accomplished by histologic examination.6 After an NSIP pattern is established histologically, a comprehensive evaluation for secondary causes such as CTD, inhalational exposures and predisposing medications Respirology (2016) 21, 259–268

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should commence. NSIP pattern on biopsy, in itself, is not diagnostic of NSIP, and a MDD with a pathologist, radiologist and pulmonologist is requisite. Immunosuppression with corticosteroids ± cytotoxic agents are treatments of choice, although optimal regimen and duration are not defined. Spirometry and DLCO should be monitored to determine treatment response and disease progression. A certain percentage of iNSIP patients will progress despite treatment, and if an unexplained decrement of FVC by 10% or DLCO of 15% occur, escalation of therapy or lung transplant should be considered.

Acknowledgement The authors thank Kristine Konopka, MD, for her assistance with histologic slide photography and interpretation shown in Figure 1.

REFERENCES 1 Katzenstein AL, Fiorelli RF. Nonspecific interstitial pneumonia/ fibrosis. Histologic features and clinical significance. Am. J. Surg. Pathol. 1994; 18: 136–47. 2 Travis WD, Costabel U, Hansell DM, King TE Jr, Lynch DA, Nicholson AG, Ryerson CJ, Ryu JH, Selman M, Wells AU et al. 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. 2013; 188: 733–48. 3 Arakawa H, Yamada H, Kurihara Y, Nakajima Y, Takeda A, Fukushima Y, Fujioka M. Nonspecific interstitial pneumonia associated with polymyositis and dermatomyositis: serial highresolution CT findings and functional correlation. Chest 2003; 123: 1096–103. 4 Kim DS, Yoo B, Lee JS, Kim EK, Lim CM, Lee SD, Koh Y, Kim WS, Kim WD, Colby TV et al. The major histopathologic pattern of pulmonary fibrosis in scleroderma is nonspecific interstitial pneumonia. Sarcoidosis Vasc. Diffuse Lung Dis. 2002; 19: 121–7. 5 Yamadori I, Fujita J, Bandoh S, Tokuda M, Tanimoto Y, Kataoka M, Yamasaki Y, Yoshinouchi T, Ohtsuki Y, Ishida T. Nonspecific interstitial pneumonia as pulmonary involvement of primary Sjogren’s syndrome. Rheumatol. Int. 2002; 22: 89–92. 6 American Thoracic Society, European Respiratory Society. American Thoracic Society/European Respiratory Society International Multidisciplinary Consensus Classification of the Idiopathic Interstitial Pneumonias. This joint statement of the American Thoracic Society (ATS), and the European Respiratory Society (ERS) was adopted by the ATS board of directors, June 2001 and by the ERS Executive Committee, June 2001. Am. J. Respir. Crit. Care Med. 2002; 165: 277–304. 7 Travis WD, Hunninghake G, King TE Jr, Lynch DA, Colby TV, Galvin JR, Brown KK, Chung MP, Cordier JF, du Bois RM et al. Idiopathic nonspecific interstitial pneumonia: report of an American Thoracic Society project. Am. J. Respir. Crit. Care Med. 2008; 177: 1338–47. 8 Flaherty KR, Martinez FJ. Nonspecific interstitial pneumonia. Semin. Respir. Crit. Care Med. 2006; 27: 652–8. 9 Selman M, Pardo A, King TE Jr. Hypersensitivity pneumonitis: insights in diagnosis and pathobiology. Am. J. Respir. Crit. Care Med. 2012; 186: 314–24. 10 Vij R, Noth I, Strek ME. Autoimmune-featured interstitial lung disease: a distinct entity. Chest 2011; 140: 1292–9. 11 Nicholson AG, Colby TV, du Bois RM, Hansell DM, Wells AU. The prognostic significance of the histologic pattern of interstitial pneumonia in patients presenting with the clinical entity of cryptogenic fibrosing alveolitis. Am. J. Respir. Crit. Care Med. 2000; 162: 2213–17. © 2015 Asian Pacific Society of Respirology

267

NSIP 12 Flaherty KR, Toews GB, Travis WD, Colby TV, Kazerooni EA, Gross BH, Jain A, Strawderman RL 3rd, Paine R, Flint A et al. Clinical significance of histological classification of idiopathic interstitial pneumonia. Eur. Respir. J. 2002; 19: 275–83. 13 Richeldi L, du Bois RM, Raghu G, Azuma A, Brown KK, Costabel U, Cottin V, Flaherty KR, Hansell DM, Inoue Y et al. Efficacy and safety of nintedanib in idiopathic pulmonary fibrosis. N. Engl. J. Med. 2014; 370: 2071–82. 14 The Idiopathic Pulmonary Fibrosis Clinical Research Network, Ganesh R, Anstrom KJ, King TE Jr, Lasky JA, Martinez FJ. Prednisone, azathioprine, and N-acetylcysteine for pulmonary fibrosis. N. Engl. J. Med. 2012; 366: 1968–77. 15 King TE Jr, Bradford WZ, Castro-Bernardini S, Fagan EA, Glaspole I, Glassberg MK, Gorina E, Hopkins PM, Kardatzke D, Lancaster L et al. A phase 3 trial of pirfenidone in patients with idiopathic pulmonary fibrosis. N. Engl. J. Med. 2014; 370: 2083–92. 16 Churg A, Sin DD, Everett D, Brown K, Cool C. Pathologic patterns and survival in chronic hypersensitivity pneumonitis. Am. J. Surg. Pathol. 2009; 33: 1765–70. 17 Kim S, Tannock I, Sridhar S, Seki J, Bordeleau L. Chemotherapyinduced infiltrative pneumonitis cases in breast cancer patients. J. Oncol. Pharm. Pract. 2012; 18: 311–15. 18 Perez-Alvarez R, Perez-de-Lis M, Diaz-Lagares C, Pego-Reigosa JM, Retamozo S, Bove A, Brito-Zeron P, Bosch X, Ramos-Casals M. Interstitial lung disease induced or exacerbated by TNFtargeted therapies: analysis of 122 cases. Semin. Arthritis Rheum. 2011; 41: 256–64. 19 Doffman SR, Miller RF. Interstitial lung disease in HIV. Clin. Chest Med. 2013; 34: 293–306. 20 Suffredini AF, Ognibene FP, Lack EE, Simmons JT, Brenner M, Gill VJ, Lane HC, Fauci AS, Parrillo JE, Masur H et al. Nonspecific interstitial pneumonitis—a common cause of pulmonarydisease in the acquired-immunodeficiency-syndrome. Ann. Intern. Med. 1987; 107: 7–13. 21 Steele MP, Speer MC, Loyd JE, Brown KK, Herron A, Slifer SH, Burch LH, Wahidi MM, Phillips JA 3rd, Sporn TA et al. Clinical and pathologic features of familial interstitial pneumonia. Am. J. Respir. Crit. Care Med. 2005; 172: 1146–52. 22 Borie R, Kannengiesser C, Crestani B. Familial forms of nonspecific interstitial pneumonia/idiopathic pulmonary fibrosis: clinical course and genetic background. Curr. Opin. Pulm. Med. 2012; 18: 455–61. 23 Tanaka K, Nagata K, Tomii K, Imai Y. A case of isolated IgG4related interstitial pneumonia: a new consideration for the cause of idiopathic nonspecific interstitial pneumonia. Chest 2012; 142: 228–30. 24 Schlemmer F, Chevret S, Lorillon G, De Bazelaire C, Peffault de Latour R, Meignin V, Michallet M, Hermet E, Wyplosz B, Houdouin V et al. Late-onset noninfectious interstitial lung disease after allogeneic hematopoietic stem cell transplantation. Respir. Med. 2014; 108: 1525–33. 25 Bradley B, Branley HM, Egan JJ, Greaves MS, Hansell DM, Harrison NK, Hirani N, Hubbard R, Lake F, Millar AB et al. 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 2008; 63(Suppl. 5): v1–58. 26 Fujita J, Ohtsuki Y, Yoshinouchi T, Yamadori I, Bandoh S, Tokuda M, Miyawaki H, Kishimoto N, Ishida T. Idiopathic non-specific interstitial pneumonia: as an ‘autoimmune interstitial pneumonia. Respir. Med. 2005; 99: 234–40. 27 Kinder BW, Collard HR, Koth L, Daikh DI, Wolters PJ, Elicker B, Jones KD, King TE Jr. Idiopathic nonspecific interstitial pneumonia: lung manifestation of undifferentiated connective tissue disease? Am. J. Respir. Crit. Care Med. 2007; 176: 691–7. 28 Fischer A, West SG, Swigris JJ, Brown KK, du Bois RM. Connective tissue disease-associated interstitial lung disease: a call for clarification. Chest 2010; 138: 251–6. 29 Kambouchner M, Levy P, Nicholson AG, Schubel K, Magois E, Feuillet S, Valeyre D, Bernaudin JF, Nunes H. Prognostic rel© 2015 Asian Pacific Society of Respirology

30

31

32

33

34

35

36

37

38

39

40

41

42

43

44

45

evance of histological variants in nonspecific interstitial pneumonia. Histopathology 2014; 65: 549–60. Park IN, Jegal Y, Kim DS, Do KH, Yoo B, Shim TS, Lim CM, Lee SD, Koh Y, Kim WS et al. Clinical course and lung function change of idiopathic nonspecific interstitial pneumonia. Eur. Respir. J. 2009; 33: 68–76. Homma Y, Ohtsuka Y, Tanimura K, Kusaka H, Munakata M, Kawakami Y, Ogasawara H. Can interstitial pneumonia as the sole presentation of collagen vascular diseases be differentiated from idiopathic interstitial pneumonia? Respiration 1995; 62: 248–51. Romagnoli M, Nannini C, Piciucchi S, Girelli F, Gurioli C, Casoni G, Ravaglia C, Tomassetti S, Gurioli C, Gavelli G et al. Idiopathic nonspecific interstitial pneumonia: an interstitial lung disease associated with autoimmune disorders? Eur. Respir. J. 2011; 38: 384–91. Sato T, Fujita J, Yamadori I, Ohtsuki Y, Yoshinouchi T, Bandoh S, Tokuda M, Ishida T. Non-specific interstitial pneumonia; as the first clinical presentation of various collagen vascular disorders. Rheumatol. Int. 2006; 26: 551–5. Corte TJ, Copley SJ, Desai SR, Zappala CJ, Hansell DM, Nicholson AG, Colby TV, Renzoni E, Maher TM, Wells AU. Significance of connective tissue disease features in idiopathic interstitial pneumonia. Eur. Respir. J. 2012; 39: 661–8. Cottin V, Donsbeck AV, Revel D, Loire R, Cordier JF. Nonspecific interstitial pneumonia. Individualization of a clinicopathologic entity in a series of 12 patients. Am. J. Respir. Crit. Care Med. 1998; 158: 1286–93. Bjoraker JA, Ryu JH, Edwin MK, Myers JL, Tazelaar HD, Schroeder DR, Offord KP. Prognostic significance of histopathologic subsets in idiopathic pulmonary fibrosis. Am. J. Respir. Crit. Care Med. 1998; 157: 199–203. Nagai S, Kitaichi M, Itoh H, Nishimura K, Izumi T, Colby TV. Idiopathic nonspecific interstitial pneumonia/fibrosis: comparison with idiopathic pulmonary fibrosis and BOOP. Eur. Respir. J. 1998; 12: 1010–19. Daniil ZD, Gilchrist FC, Nicholson AG, Hansell DM, Harris J, Colby TV, du Bois RM. A histologic pattern of nonspecific interstitial pneumonia is associated with a better prognosis than usual interstitial pneumonia in patients with cryptogenic fibrosing alveolitis. Am. J. Respir. Crit. Care Med. 1999; 160: 899– 905. Hamada K, Nagai S, Tanaka S, Handa T, Shigematsu M, Nagao T, Mishima M, Kitaichi M, Izumi T. Significance of pulmonary arterial pressure and diffusion capacity of the lung as prognosticator in patients with idiopathic pulmonary fibrosis. Chest 2007; 131: 650–6. Park CS, Chung SW, Ki SY, Lim GI, Uh ST, Kim YH, Choi DI, Park JS, Lee DW, Kitaichi M. Increased levels of interleukin-6 are associated with lymphocytosis in bronchoalveolar lavage fluids of idiopathic nonspecific interstitial pneumonia. Am. J. Respir. Crit. Care Med. 2000; 162: 1162–8. Ryu YJ, Chung MP, Han J, Kim TS, Lee KS, Chun EM, Kyung SY, Jeong SH, Colby TV, Kim H et al. Bronchoalveolar lavage in fibrotic idiopathic interstitial pneumonias. Respir. Med. 2007; 101: 655–60. Ishii H, Mukae H, Kadota J, Fujii T, Abe K, Ashitani J, Kohno S. Increased levels of interleukin-18 in bronchoalveolar lavage fluid of patients with idiopathic nonspecific interstitial pneumonia. Respiration 2005; 72: 39–45. Veeraraghavan S, Latsi PI, Wells AU, Pantelidis P, Nicholson AG, Colby TV, Haslam PL, Renzoni EA, du Bois RM. BAL findings in idiopathic nonspecific interstitial pneumonia and usual interstitial pneumonia. Eur. Respir. J. 2003; 22: 239–44. Park JS, Lee KS, Kim JS, Park CS, Suh YL, Choi DL, Kim KJ. Nonspecific interstitial pneumonia with fibrosis: radiographic and CT findings in seven patients. Radiology 1995; 195: 645–8. Raghu G, Collard HR, Egan JJ, Martinez FJ, Behr J, Brown KK, Colby TV, Cordier JF, Flaherty KR, Lasky JA et al. An official ATS/ ERS/JRS/ALAT statement: idiopathic pulmonary fibrosis: Respirology (2016) 21, 259–268

268

46

47

48

49

50

51

52

53

54

55 56

57

58

59

60

61

62

63

evidence-based guidelines for diagnosis and management. Am. J. Respir. Crit. Care Med. 2011; 183: 788–824. Silva CI, Muller NL, Lynch DA, Curran-Everett D, Brown KK, Lee KS, Chung MP, Churg A. Chronic hypersensitivity pneumonitis: differentiation from idiopathic pulmonary fibrosis and nonspecific interstitial pneumonia by using thin-section CT. Radiology 2008; 246: 288–97. Akira M, Inoue G, Yamamoto S, Sakatani M. Non-specific interstitial pneumonia: findings on sequential CT scans of nine patients. Thorax 2000; 55: 854–9. Poletti V, Casoni GL, Gurioli C, Ryu JH, Tomassetti S. Lung cryobiopsies: a paradigm shift in diagnostic bronchoscopy? Respirology 2014; 19: 645–54. Raghu G, Mageto YN, Lockhart D, Schmidt RA, Wood DE, Godwin JD. The accuracy of the clinical diagnosis of new-onset idiopathic pulmonary fibrosis and other interstitial lung disease: a prospective study. Chest 1999; 116: 1168–74. Hunninghake GW, Lynch DA, Galvin JR, Gross BH, Muller N, Schwartz DA, King TE Jr, Lynch JP 3rd, Hegele R, Waldron J et al. Radiologic findings are strongly associated with a pathologic diagnosis of usual interstitial pneumonia. Chest 2003; 124: 1215– 23. Flaherty KR, Andrei AC, King TE Jr, Raghu G, Colby TV, Wells A, Bassily N, Brown K, du Bois R, Flint A et al. Idiopathic interstitial pneumonia: do community and academic physicians agree on diagnosis? Am. J. Respir. Crit. Care Med. 2007; 175: 1054–60. Flaherty KR, King TE Jr, Raghu G, Lynch JP 3rd, Colby TV, Travis WD, Gross BH, Kazerooni EA, Toews GB, Long Q et al. Idiopathic interstitial pneumonia: what is the effect of a multidisciplinary approach to diagnosis? Am. J. Respir. Crit. Care Med. 2004; 170: 904–10. Akira M, Inoue Y, Arai T, Okuma T, Kawata Y. Long-term follow-up high-resolution CT findings in non-specific interstitial pneumonia. Thorax 2011; 66: 61–5. Nishiyama O, Kondoh Y, Taniguchi H, Yamaki K, Suzuki R, Yokoi T, Takagi K. Serial high resolution CT findings in nonspecific interstitial pneumonia/fibrosis. J. Comput. Assist. Tomogr. 2000; 24: 41–6. Liebow AA. Definition and classification of interstitial pneumonias in human pathology. Prog. Resp. Res. 1974; 8: 1–33. Katzenstein AL, Myers JL. Idiopathic pulmonary fibrosis: clinical relevance of pathologic classification. Am. J. Respir. Crit. Care Med. 1998; 157: 1301–15. Travis WD, Matsui K, Moss J, Ferrans VJ. Idiopathic nonspecific interstitial pneumonia: prognostic significance of cellular and fibrosing patterns: survival comparison with usual interstitial pneumonia and desquamative interstitial pneumonia. Am. J. Surg. Pathol. 2000; 24: 19–33. Nicholson AG, Addis BJ, Bharucha H, Clelland CA, Corrin B, Gibbs AR, Hasleton PS, Kerr KM, Ibrahim NBN, Stewart S et al. Inter-observer variation between pathologists in diffuse parenchymal lung disease. Thorax 2004; 59: 500–5. Flaherty KR, Travis WD, Colby TV, Toews GB, Kazerooni EA, Gross BH, Jain A, Strawderman RL, Flint A, Lynch JP et al. Histopathologic variability in usual and nonspecific interstitial pneumonias. Am. J. Respir. Crit. Care Med. 2001; 164: 1722–7. Katzenstein AL, Zisman DA, Litzky LA, Nguyen BT, Kotloff RM. Usual interstitial pneumonia: histologic study of biopsy and explant specimens. Am. J. Surg. Pathol. 2002; 26: 1567–77. Tsuchiya Y, Takayanagi N, Sugiura H, Miyahara Y, Tokunaga D, Kawabata Y, Sugita Y. Lung diseases directly associated with rheumatoid arthritis and their relationship to outcome. Eur. Respir. J. 2011; 37: 1411–17. Fischer A, Swigris JJ, Groshong SD, Cool CD, Sahin H, Lynch DA, Curran-Everett D, Gillis JZ, Meehan RT, Brown KK. Clinically significant interstitial lung disease in limited scleroderma: histopathology, clinical features, and survival. Chest 2008; 134: 601–5. Sigurdsson MI, Isaksson HJ, Gudmundsson G, Gudbjartsson T. Diagnostic surgical lung biopsies for suspected interstitial lung

Respirology (2016) 21, 259–268

EA Belloli et al.

64

65

66

67

68

69

70

71

72

73

74

75

76

77

78

79

80

diseases: a retrospective study. Ann. Thorac. Surg. 2009; 88: 227–32. Lettieri CJ, Veerappan GR, Helman DL, Mulligan CR, Shorr AF. Outcomes and safety of surgical lung biopsy for interstitial lung disease. Chest 2005; 127: 1600–5. Mouroux J, Clary-Meinesz C, Padovani B, Perrin C, Rotomondo C, Chavaillon JM, Blaive B, Richelme H. Efficacy and safety of videothoracoscopic lung biopsy in the diagnosis of interstitial lung disease. Eur. J. Cardiothorac. Surg. 1997; 11: 22–4, 5–6. Park JH, Kim DK, Kim DS, Koh Y, Lee SD, Kim WS, Kim WD, Park SI. Mortality and risk factors for surgical lung biopsy in patients with idiopathic interstitial pneumonia. Eur. J. Cardiothorac. Surg. 2007; 31: 1115–19. Riha RL, Duhig EE, Clarke BE, Steele RH, Slaughter RE, Zimmerman PV. Survival of patients with biopsy-proven usual interstitial pneumonia and nonspecific interstitial pneumonia. Eur. Respir. J. 2002; 19: 1114–18. Jegal Y, Kim DS, Shim TS, Lim CM, Do Lee S, Koh Y, Kim WS, Kim WD, Lee JS, Travis WD et al. Physiology is a stronger predictor of survival than pathology in fibrotic interstitial pneumonia. Am. J. Respir. Crit. Care Med. 2005; 171: 639–44. Latsi PI, du Bois RM, Nicholson AG, Colby TV, Bisirtzoglou D, Nikolakopoulou A, Veeraraghavan S, Hansell DM, Wells AU. Fibrotic idiopathic interstitial pneumonia: the prognostic value of longitudinal functional trends. Am. J. Respir. Crit. Care Med. 2003; 168: 531–7. Park JH, Kim DS, Park IN, Jang SJ, Kitaichi M, Nicholson AG, Colby TV. Prognosis of fibrotic interstitial pneumonia: idiopathic versus collagen vascular disease-related subtypes. Am. J. Respir. Crit. Care Med. 2007; 175: 705–11. Ryerson CJ, Vittinghoff E, Ley B, Lee JS, Mooney JJ, Jones KD, Elicker BM, Wolters PJ, Koth LL, King TE Jr et al. Predicting survival across chronic interstitial lung disease: the ILD-GAP model. Chest 2014; 145: 723–8. Flaherty KR, Mumford JA, Murray S, Kazerooni EA, Gross BH, Colby TV, Travis WD, Flint A, Toews GB, Lynch JP 3rd et al. Prognostic implications of physiologic and radiographic changes in idiopathic interstitial pneumonia. Am. J. Respir. Crit. Care Med. 2003; 168: 543–8. Ley B, Ryerson CJ, Vittinghoff E, Ryu JH, Tomassetti S, Lee JS, Poletti V, Buccioli M, Elicker BM, Jones KD et al. A multidimensional index and staging system for idiopathic pulmonary fibrosis. Ann. Intern. Med. 2012; 156: 684–91. Lee JY, Jin SM, Lee BJ, Chung DH, Jang BG, Park HS, Lee SM, Yim JJ, Yang SC, Yoo CG et al. Treatment response and long term follow-up results of nonspecific interstitial pneumonia. J. Korean Med. Sci. 2012; 27: 661–7. Suda T, Kono M, Nakamura Y, Enomoto N, Kaida Y, Fujisawa T, Imokawa S, Yasuda K, Hashizume H, Yokomura K et al. Distinct prognosis of idiopathic nonspecific interstitial pneumonia (NSIP) fulfilling criteria for undifferentiated connective tissue disease (UCTD). Respir. Med. 2010; 104: 1527–34. Corte TJ, Ellis R, Renzoni EA, Hansell DM, Nicholson AG, du Bois RM, Wells AU. Use of intravenous cyclophosphamide in known or suspected, advanced non-specific interstitial pneumonia. Sarcoidosis Vasc. Diffuse Lung Dis. 2009; 26: 132–8. Kondoh Y, Taniguchi H, Yokoi T, Nishiyama O, Ohishi T, Kato T, Suzuki K, Suzuki R. Cyclophosphamide and low-dose prednisolone in idiopathic pulmonary fibrosis and fibrosing nonspecific interstitial pneumonia. Eur. Respir. J. 2005; 25: 528–33. Nanki N, Fujita J, Yamaji Y, Maeda H, Kurose T, Kaji M, Satoh K, Miyatani K, Yamadori I, Ohtsuki Y et al. Nonspecific interstitial pneumonia/fibrosis completely recovered by adding cyclophosphamide to corticosteroids. Intern. Med. 2002; 41: 867–70. Xu W, Xiao Y, Liu H, Qin M, Zheng W, Shi J. Nonspecific interstitial pneumonia: clinical associations and outcomes. BMC Pulm. Med. 2014; 14: 175. Kinder BW. Nonspecific interstitial pneumonia. Clin. Chest Med. 2012; 33: 111–21.

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