Idiopathic Usual Interstitial Pneumonia Research Articles

Canonical and noncanonical regulatory roles for JAK2 in the pathogenesis of rheumatoid arthritis‐associated interstitial lung disease and idiopathic pulmonary fibrosis

Idiopathic pulmonary fibrosis (IPF) and rheumatoid arthritis-associated interstitial lung disease (RA-ILD) are two fibrotic interstitial lung diseases that share the usual interstitial pneumonia (UIP) injury pattern. Here, we report that RNA sequencing of lung biopsies from patients with RA-ILD and IPF revealed shared and distinct disease-causing pathways. Analysis of transcriptomic data identified a JAK2 related JAK/STAT signaling pathway gene signature that distinguishes RA-UIP from idiopathic UIP. This was further confirmed by immunohistostaining, which identified JAK2 phosphorylation with two distinct forms of activation: a cytoplasmic form of JAK2 activation in most IPF cases (13/20) and a nuclear form of p-JAK2 in RA-UIP (5/5) and a minority of IPF (6/20) cases. Further immunohistostaining identified STAT5A&B as the downstream transcriptional activator for JAK2-mediated canonical signal transduction and phosphorylation of Tyr41 on histone H3 (H3Y41ph) as the downstream epigenetic regulation site for JAK2-mediated noncanonical signal transduction. Gene Set Enrichment Analysis (GSEA) of the RNA-Seq data further supported this shared pathogenic mechanism for the two diseases with the enrichment of STAT5A&B target gene sets as well as the JAK2 regulated H3Y41ph target gene set. This regulatory role of JAK2 in the pathogenesis of pulmonary fibrosis was further demonstrated by the attenuation of bleomycin-induced murine pulmonary fibrosis using a JAK2-selective pharmacological inhibitor CEP33779. In vitro studies with normal and IPF derived lung fibroblasts revealed a central role for JAK2 as an essential intermediary molecule in TGF-β-mediated myofibroblast trans-differentiation, proliferation, and extracellular matrix protein production. These observations support a crucial role for JAK2 as an intermediary molecule in fibrotic lung disease development.

Sex steroid receptor expression in idiopathic pulmonary fibrosis

Usual interstitial pneumonia (UIP) is characterized by progressive scarring of the lungs and is associated with high morbidity and mortality despite therapeutic interventions. Sex steroid receptors have been demonstrated to play an important role in chronic lung conditions; however, their significance is unknown in patients with UIP. We retrospectively reviewed 40 idiopathic UIP cases for the expression of hormonal receptors. Forty cases including 10 normal lung, 10 cryptogenic organizing pneumonia, 10 idiopathic organizing diffuse alveolar damage, 7 hypersensitivity pneumonitis, and 3 nonspecific interstitial pneumonitis served as controls. Immunohistochemistry for estrogen receptor α, progesterone receptor (PR), and androgen receptor was performed in all groups. Expression of these receptors was assessed in 4 anatomic/pathologic compartments: alveolar and bronchiolar epithelium, arteries/veins, fibroblastic foci/airspace organization, and old scar. All UIPs (100%) stained positive for PR in myofibroblasts in the scarred areas, whereas among the control cases, only 1 nonspecific interstitial pneumonitis case stained focally positive and the rest were negative. PR was positive in myocytes of the large-sized arteries within the fibrotic areas in 31 cases (77.5%). PR was negative within the alveolar and bronchial epithelium, airspace organization, and center of fibroblastic foci; however, weak PR positivity was noted in the peripheral fibroblasts of the fibroblastic foci where they merged with dense fibrous connective tissue scar. All UIP and control cases were negative for androgen receptor and estrogen receptor α. This is the first study to show the expression of PR within the established fibrotic areas of UIP, indicating that progesterone may have profibrotic effects in UIP patients. Hormonal therapy by targeting PR could be of potential benefit in patients with UIP/IPF.

Management of patients with combined pulmonary fibrosis and emphysema

Combined pulmonary fibrosis and emphysema (CPFE) was first introduced as a distinct clinical entity to describe the coexistence of any type and grade of radiological pulmonary emphysema and the idiopathic usual interstitial pneumonia CT pattern as well as any pathologically confirmed case and has been extended to include patients with emphysema and other interstitial lung diseases (ILDs), such as nonspecific interstitial pneumonia, and connective tissue disease-ILD as well. Since no certain recommendation or guideline regarding treatment strategy for CPFE patients exists, the current therapeutic option is to follow both pulmonary fibrosis and emphysema current management approach. Smoking cessation, influenza and pneumococcal vaccination should be proposed to all patients. Bronchodilator therapy could be considered in symptomatic CPFE patients with a significant obstructive pattern component in their pulmonary function testing. Dyspneic patients with CPFE might benefit from rehabilitation programs while hypoxemic patients from supplemental oxygen. No exact data exist on treatment with specific drugs for pulmonary fibrosis or/and pulmonary hypertension. In case of acute deterioration best supportive care, extensive search for the etiologic factor and extended spectrum antimicrobials should be provided. Referral for lung transplantation should be encouraged in appropriate CPFE patients.

Differential diagnosis of usual interstitial pneumonia: when is it truly idiopathic?

Idiopathic pulmonary fibrosis (IPF), the most common and lethal of the idiopathic interstitial pneumonias, is defined by a radiological and/or pathological pattern of usual interstitial pneumonia (UIP). However, UIP is not synonymous with IPF as other clinical conditions may be associated with UIP, including chronic hypersensitivity pneumonitis, collagen vascular disease, drug toxicity, asbestosis, familial IPF and Hermansky-Pudlak syndrome. Differentiating IPF ("idiopathic UIP") from conditions that mimic IPF ("secondary UIP") has substantial therapeutic and prognostic implications. A number of radiological and histological clues may help distinguish IPF from other conditions with a UIP pattern of fibrosis, but their appreciation requires extensive expertise in interstitial lung disease as well as an integrated multidisciplinary approach involving pulmonologists, radiologists and pathologists. In addition, multidisciplinary discussions may decrease the time to initial IPF diagnosis and, thus, enable more timely management. This concept was strongly emphasised by the 2011 ATS/ERS/JRS/ALAT guidelines. This article highlights, with the aid of a clinical case, the difficulties in making a diagnosis of IPF in clinical practice. Yet, an accurate diagnosis is critical, particularly given the availability of drugs that may reduce the pace of functional decline and disease progression in IPF.

Combined pulmonary fibrosis and emphysema

The advent of computed tomography permitted recognition of the coexistence of pulmonary fibrosis and emphysema (CPFE). Emphysema is usually encountered in the upper lobes preceding fibrosis of the lower lobes, and patients are smokers, predominantly male, with distinct physiologic profile characterized by preserved lung volumes and markedly reduced diffusion capacity. Actually, the term CPFE is reserved for the coexistence of any type and grade of radiological pulmonary emphysema and the idiopathic usual interstitial pneumonia computed tomography pattern as well as any pathologically confirmed case. CPFE is complicated by pulmonary hypertension, lung cancer and acute lung injury and may present different outcome than that of its components.

Pathologic Quantification of Connective Tissue Disease–Associated Versus Idiopathic Usual Interstitial Pneumonia

Usual interstitial pneumonia (UIP) is a common chronic interstitial pneumonitis. It can occur idiopathically (I-UIP) or in the setting of systemic connective tissue disease (CTD-UIP). Some studies suggest that CTD-UIP has a better prognosis than I-UIP. The histologic differences between CTD-UIP and I-UIP are not clearly defined. The purpose of this study was to evaluate histologic criteria that may differentiate CTD-UIP from I-UIP, including fibroblastic foci (FFs), lymphoid aggregates (LAs), and the presence of nonspecific interstitial pneumonia pattern. Thirty-five patients with histologic diagnoses of UIP were identified (27 biopsies [77%]; 8 explants [23%]). Biopsy slides were scanned and analyzed quantitatively for FF size, FF area, LA size, and LA area. Biopsy and explant slides were examined qualitatively for the presence of a nonspecific interstitial pneumonia pattern in areas away from UIP fibrosis. Results.-Of 27 biopsies, the number and size of FFs in CTD-UIP were smaller than they were in I-UIP. The number and size of LAs were larger in patients with rheumatoid arthritis than they were in patients with I-UIP. There was no interobserver variability among 3 pathologists using this quantitative system. Of 35 biopsies and explants, there was a higher prevalence of the nonspecific interstitial pneumonia pattern among patients with CTD-UIP than there was among patients with I-UIP (P = .005). Patients with CTD-UIP had fewer, smaller FFs than did patients with I-UIP, and patients with rheumatoid arthritis-UIP had more, larger LAs than did patients with I-UIP. Of importance, the coexistence of UIP and the nonspecific interstitial pneumonia patterns was one of the most salient features in distinguishing CTD-UIP from I-UIP because CTD-UIP demonstrated an increased prevalence of multilobar, cellular, nonspecific interstitial pneumonia patterns in areas away from the UIP fibrosis.

BALF cell findings in patients with BOOP, particularly in comparison with UIP

It is possible to differentiate to some degree to bronchiolitis obliterans organizing pneumonia (BOOP) of unknown etiology from idiopathic usual interstitial pneumonia (UIP) on the basis of clinical symptoms, chest X-ray findings, pulmonary function test and blood gas findings, but in certain patients it can be difficult. Cell findings in bronchoalveolar lavage fluids (BALF) were compared between 8 patients with BOOP and 28 patients with UIP, both diagnosed histologically by open lung biopsy. Findings characteristic of BOOP included (1) an increase in the percentage of lymphocytes, (2) an increase in the percentage of eosinophils, and (3) a decrease in the OKT4+/OKT8+ ratio. These findings provide useful information in making a clinical diagnosis of BOOP and in evaluating proper steroid treatment in patients who unable to undergo open lung biopsy.

Pathologic Patterns and Survival in Chronic Hypersensitivity Pneumonitis

The objective of the study was to examine the relationship of pathologic pattern and prognosis in hypersensitivity pneumonitis (HP). We analyzed 24 cases of subacute (cellular, nonfibrotic) and 25 cases of chronic (fibrotic) HP. Nineteen (79%) of the subacute cases showed a pattern of bronchiolocentric interstitial pneumonia and 5 (21%) a pattern mimicking cellular nonspecific interstitial pneumonia (NSIP). Giant cells or granulomas or Schaumann bodies were present in 19 cases (79%). Eighteen (72%) chronic cases showed a pattern resembling usual interstitial pneumonia (UIP), but, in most cases, with more peribronchiolar fibrosis than one would expect in UIP. Three fibrotic cases (12%) had only peribronchiolar fibrosis, whereas 4 (16%) resembled fibrotic NSIP. Giant cells or granulomas or Schaumann bodies were present in 22 (88%) cases. Areas of subacute HP were present in 12 cases with a UIP-like pattern. Only 2 UIP-like cases could not be morphologically distinguished from idiopathic UIP. The median survival for patients who had no fibrosis was 22.4 years; for patients with a fibrotic NSIP pattern was 2.1 years; and for those with a UIP-like pattern 2.8 years (not statistically different). Patients with a pattern of only peribronchiolar fibrosis had a median survival of 11.3 years. These data confirm that the presence of fibrosis is associated with a generally poor prognosis in patients with HP, and suggest that pure peribronchiolar fibrosis may portend a longer survival than does a UIP-like or fibrotic NSIP-like pattern of fibrosis. Most cases of chronic HP have distinctive pathologic features, but a small percentage of cases cannot be pathologically distinguished from UIP.

Idiopathic Interstitial Pneumonias

The idiopathic interstitial pneumonias (IIPs) are a group of diffuse parenchymal lung diseases of unknown etiology characterized by the presence of various degrees of inflammation and fibrosis. Confident definitive diagnosis of the various IIPs requires dynamic interaction among clinicians, radiologists, and pathologists to arrive at a clinico-radiologic-pathologic diagnosis. The aims of this manuscript are to summarize the characteristic clinical and histologic manifestations, and to describe and illustrate the high-resolution computed tomography manifestations of the IIPs. The focus will be on idiopathic pulmonary fibrosis (idiopathic usual interstitial pneumonia), nonspecific interstitial pneumonia, cryptogenic organizing pneumonia, and acute interstitial pneumonia. High-resolution computed tomography plays an important role in the initial diagnosis, the assessment of disease extent, the likelihood of response to treatment and prognosis, and the assessment of complications.

Systemic sclerosis and idiopathic interstitial pneumonia: histomorphometric differences in lung biopsies

The aim of this study was to examine the parenchymal and extracellular matrix remodeling process in two histologic patterns-nonspecific interstitial pneumonia (NSIP) and usual interstitial pneumonia (UIP)-in cases of idiopathic and sclerosis/systemic sclerosis (SSc)-associated interstitial pneumonia. We examined 15 cases of idiopathic NSIP, 10 cases of idiopathic UIP, 5 cases of SSc-UIP and 9 cases of SSc-NSIP. In the lung parenchyma, epithelial cells, endothelial cells and myofibroblasts were evaluated by immunohistochemical staining, whereas histochemical staining was used in order to evaluate collagen/elastic fibers in the extracellular matrix. The percentage of surfactant protein A-positive epithelial cells was significantly greater in idiopathic NSIP than in SSc-NSIP, as well as being greater in idiopathic UIP than in SSc-UIP. Idiopathic NSIP and idiopathic UIP presented significantly higher immunoexpression of alpha smooth muscle actin in myofibroblasts than did SSc-NSIP and SSc-UIP. The percentage of CD34 endothelial cells in the pulmonary microvasculature was significant lower in idiopathic UIP than in SSc-UIP. The density of collagen fibers was significantly greater in idiopathic NSIP and idiopathic UIP than in SSc-NSIP and UIP. In contrast, the elastic fiber density was significantly lower in idiopathic UIP than in SSc-UIP. Increased collagen synthesis, destruction of elastic fibers, high myofibroblast proliferation and poor microvascularization might represent a remodeling process found in idiopathic interstitial pneumonia, whereas the reverse might represent a repair process in SSc-associated interstitial pneumonia.

Elucidating the causes and examining the latest clinical findings in pulmonary fibrosis: recent progress and future objectives

In the last decade, we have witnessed many important advances in the current understanding of the clinical disease process that is now defined as idiopathic pulmonary fibrosis (IPF) and how it differs from the other “members” of the idiopathic interstitial pneumonias (IIPs). We have gained insight into the genetic associations with IPF and new insights into pathogenesis. Importantly, we have begun to distinguish IPF from the other IIPs with much more precision and confidence. Recent investigations have been published that identify clues to potential future therapeutic strategies. Each of these developments has been reflected within the articles in the present issue of European Respiratory Review , providing a comprehensive update across the field of IPF but, most importantly, highlighting areas of more rapid evolution and future potential. The articles have summarised what are perceived to be the areas of growth in this group of fibrosing lung diseases, and, more specifically, in IPF. The histopathological patterns of fibrosis observed in each of the IIPs are different, and this is also reflected by the clinical behaviour of the individual diseases. Idiopathic usual interstitial pneumonia (UIP) generally progresses in a more aggressive fashion than the other IIPs and each has some distinctive clinical features that distinguish them. Despite these differences, obtaining a consistent and uniform diagnosis of each of the IIPs can be difficult, and further investigation is needed to reduce the inconsistencies in diagnosis between expert and community clinicians. Issues of overlapping patterns of disease and combinations of patterns will be challenges for the future, particularly with regard to concepts of pathogenesis, outcome and treatment. Despite these confounders, the imaging of patients using high-resolution computed tomography (HRCT) has, in general, enabled a growing number of physicians to make a confident clinical diagnosis without recourse to surgical lung biopsy (SLB). In this regard, …

Eosinophilic Globules in Bronchoalveolar Lavage Fluid of Patients With Systemic Sclerosis–Related Interstitial Lung Disease

Bronchoalveolar lavage (BAL) is a minimally invasive method possibly representing a diagnostic tool in the evaluation of interstitial lung diseases (ILDs) of different causes. We first describe herein the morphologic, histochemical, and immunohistochemical features of previously unreported eosinophilic globular deposits of acellular amorphous material of uncertain nature in a relatively large series of 227 BAL samples obtained from patients with various ILDs. Overall, eosinophilic globules were detected in 18 cases (7.9%), 16 of which were in patients with systemic sclerosis (SSc)-related ILD (16/50 [32%]) and in 2 cases of apparently idiopathic usual interstitial pneumonia. Apart from the possible diagnostic information of this finding, in patients with SSc, the globules were significantly related to BAL neutrophilia or eosinophilia and extensive ILD in high-resolution computed tomography (P < .0001). Differential diagnosis with other types of acellular globular materials observed in BAL samples is also discussed.

Idiopathic pulmonary fibrosis

Idiopathic pulmonary fibrosis (IPF; also known as cryptogenic fibrosing alveolitis) is a distinctive type of chronic fibrosing interstitial pneumonia of unknown cause associated with the histological pattern usual interstitial pneumonia (UIP). UIP is a distinct histological pattern observed in IPF but may also be found in other etiologies. The diagnosis of UIP can be established by surgical lung biopsy or by high-resolution thin-section CT scans (provided the radiographic features are classical). Historically, patients labeled as ‘IPF’ encompassed a group of disorders, including UIP, as well as other idiopathic interstitial pneumonias, which differ from UIP in prognosis and responsiveness to therapy. The term IPF should be restricted to patients with idiopathic UIP. The inciting cause(s) and pathogenesis of IPF have not been elucidated but alveolar epithelial cell injury and dysregulation or altered phenotypic expression of fibroblasts are key elements. Inflammatory cells may play minor roles in initiating or propagating the fibrotic process. The prognosis of idiopathic UIP is poor. Mean survival following diagnosis approximates at 3 years. Current medical therapies are of unproven value. Lung transplantation is a viable option for patients failing medical therapy.

La fibrose pulmonaire du syndrome de Hermansky Pudlak n’est pas totalement commune

A 55-year-old female patient with Hermansky-Pudlak syndrome (albinism, thrombopathia and ceroid accumulation) underwent a single lung transplantation for pulmonary fibrosis. Examination of explanted lung showed usual interstitial pneumonia pattern associated with two unusual lesions: presence of numerous macrophages containing ceroid pigments within fibrosis and characteristic foamy swelling of pneumocytes. This later lesion, which has only been recently described, seems related to the mechanism of the disease by defect of surfactant secretion. This lesion allows the histological individualization of pulmonary fibrosis associated with Hermansky-Pudlak syndrome from idiopathic usual interstitial pneumonia.

Usual Interstitial Pneumonia

Usual interstitial pneumonia (UIP) is a distinct histological lesion observed in idiopathic pulmonary fibrosis (IPF) but can be found in other etiologies. The diagnosis of UIP can be established by surgical lung biopsy or by high-resolution thin-section computed tomographic (CT) scans (provided the radiographic features are classical). Historically, patients labeled as "IPF" encompassed a group of disorders, including UIP as well as other idiopathic interstitial pneumonias that differ from UIP in prognosis and responsiveness to therapy. Current recommendations from international consensus statements restrict the term IPF to patients with idiopathic UIP. The inciting cause(s) and pathogenesis of UIP have not been elucidated, but alveolar epithelial cell injury and dysregulation or altered phenotypic expression of fibroblasts are key elements. Inflammatory cells may play minor roles in initiating or propagating the fibrotic process. The prognosis of UIP is poor. Mean survival following diagnosis approximates 3 years. Current therapies are of unproven value. Corticosteroids or immunosuppressive agents have been most often used, but data affirming benefit are lacking. Lung transplantation is a viable option for patients failing medical therapy. This review discusses diagnostic criteria for UIP (both histopathological and radiographic), natural history and clinical course, and therapeutic approaches (both current and future).

Update in Diffuse Parenchymal Lung Diseases 2005

CLINICAL ADVANCES A number of publications have shed light on important clinical concepts surrounding the clinical evaluation and management of diffuse parenchymal lung diseases (DPLDs). These include approaches to idiopathic interstitial pneumonias (IIPs), including nonspecific interstitial pneumonia (NSIP) and idiopathic pulmonary fibrosis (IPF; idiopathic usual interstitial pneumonia [UIP]), connective tissue–associated DPLD, hypersensitivity pneumonitis (HP), and lymphangioleiomyomatosis (LAM). IIPs A series of sentinel observations have addressed diagnostic issues, staging approaches, unique phenotypes, and management strategies for IIPs. Diagnostic approach. The approach to diagnosis in patients with DPLDs has continued to evolve over the past decade. A recent centennial review described the major impact of highresolution computed tomography (HRCT) in guiding the diagnostic approach to patients with suspected IIP (1). It is evident that stereotypical imaging features have been described for many DPLDs, including some of the IIPs (2). The diagnostic accuracy of the radiological features of UIP has been demonstrated in well-designed clinical studies (3–5). Despite these data, there remains diagnostic confusion regarding the separation of UIP from other IIPs, particularly NSIP (6). On the other hand, increasing data have suggested that predominance of ground-glass opacity with no honeycombing is more common in NSIP. In a recent series, such a pattern was seen in 96% of patients with NSIP and 59% of patients with UIP (7). Unfortunately, the overall diagnostic accuracy of HRCT for separating these two disorders was 70% in this series. The contrast between expert and less experienced radiologists in applying HRCT criteria to the diagnosis of IPF has recently been reported in data from a landmark clinical therapeutic trial (8). As part of this trial, HRCT scans were interpreted by clinical site radiologists and an expert radiology core using predefined criteria. The core radiologists agreed with a diagnosis of IPF in 99% of those diagnosed by site radiologists; little difference was found if the clinical site was an “academic” center or a community-based practice. A survey of American College of Chest Physician members (52.6% responses to the survey) suggested that 67% of respondents accepted HRCT diagnosis for IPF (9). Interestingly, one investigative group has demonstrated that interaction between expert clinicians and radiologists improves the interobserver agreement of the former in evaluating patients with IIPs (10). It is evident that a consensus is developing that typical features of UIP in the appropriate clinical setting can be used to accurately diagnose IPF. In other IIPs, particularly

Expression of HSP47 in Usual Interstitial Pneumonia and Nonspecific Interstitial Pneumonia

BackgroundHeat shock protein (HSP) 47, a collagen-specific molecular chaperone, is involved in the processing and/or secretion of procollagens, and its expression is increased in various fibrotic diseases. The aim of this study was to determine whether quantitative immunohistochemical evaluation of the expression levels of HSP47, type I procollagen and α-smooth muscle actin (SMA) allows the differentiation of idiopathic usual interstitial pneumonia (UIP) from UIP associated with collagen vascular disease (CVD) and idiopathic nonspecific interstitial pneumonia (NSIP).MethodsWe reviewed surgical lung biopsy specimens of 19 patients with idiopathic UIP, 7 with CVD-associated UIP and 16 with idiopathic NSIP and assigned a score for the expression of HSP47, type I procollagen and α-SMA in type II pneumocytes and/or lung fibroblasts (score 0 = no; 1 = weak; 2 = moderate; 3 = strong staining).ResultsThe expression level of HSP47 in type II pneumocytes of idiopathic UIP was significantly higher than in CVD-associated UIP and idiopathic NSIP. The expression of HSP47 in fibroblasts was significantly higher in idiopathic UIP and idiopathic NSIP than in CVD-associated UIP. The expression of type I procollagen in type II pneumocytes was significantly higher in idiopathic UIP than in idiopathic NSIP. The expression of type I procollagen in fibroblasts was not different in the three groups, while the expression of α-SMA in fibroblasts was significantly higher in idiopathic UIP than in idiopathic NSIP.ConclusionOur results suggest the existence of different fibrotic pathways among these groups involved in the expression of HSP47 and type I procollagen.

Increased Levels of Interleukin-18 in Bronchoalveolar Lavage Fluid of Patients with Idiopathic Nonspecific Interstitial Pneumonia

Background: Interleukin-18 (IL-18) is a proinflammatory cytokine that can induce interferon-γ (IFN-γ), and it plays an important role in T-helper 1 responses. Among idiopathic interstitial pneumonia (IIP), nonspecific interstitial pneumonia (NSIP) has an increased number of lymphocytes in bronchoalveolar lavage (BAL) fluid compared with usual interstitial pneumonia (UIP). However, the difference in their pathogenesis is unclear. Objective: The present study aims to investigate the roles of IL-18 in patients with idiopathic UIP and idiopathic NSIP. Methods: We measured the serum and BAL fluid (BALF) levels of IL-18 and IFN-γ in 22 patients with IIP (12 with UIP, 10 with NSIP) and 9 healthy volunteers. Results: Lymphocyte proportions in BALF were significantly higher in NSIP than in UIP and healthy subjects. No significant differences were observed in the serum IL-18 levels of all subjects, while the BALF levels of IL-18 in patients with NSIP were significantly higher than in patients with UIP (p < 0.005) and in healthy subjects (p < 0.005). Among all subjects, the levels of IL-18 in BALF correlated significantly with those in serum and the lymphocyte proportions in BALF. The serum IFN-γ levels of all subjects were below sensitivity, but there was significant reverse correlation between the levels of IFN-γ and the lymphocyte proportions in BALF. Conclusion: The lymphocytosis in BALF of patients with idiopathic NSIP and a part of idiopathic UIP might be associated with the high levels of IL-18.

High-BAL fluid concentrations of RANTES in nonspecific interstitial pneumonia compared with usual interstitial pneumonia

Chemokines such as regulated on activation, normal T-cell expressed and secreted (RANTES), monocyte chemoattractant protein (MCP)-1, monocyte inflammatory protein (MIP)-1α have been reported to play an important role in the pathogenesis of interstitial lung diseases. Among idiopathic interstitial pneumonia (IIP), nonspecific interstitial pneumonia (NSIP) has elevated percentages of lymphocytes in bronchoalveolar lavage (BAL) fluid compared with usual interstitial pneumonia (UIP). These chemokines are candidate mediators for lymphocyte attraction to the lung in NSIP. Therefore, we measured the BAL fluid levels of RANTES, MCP-1 and MIP1-α in 15 patients with idiopathic NSIP, 20 with idiopathic UIP, 22 with sarcoidosis and 12 healthy volunteers to evaluate the contribution of these chemokines using enzyme-linked immunosorbent assays. The levels of RANTES in BAL fluid were significantly higher in patients with NSIP compared with healthy volunteers (P<0.01), UIP and sarcoidosis (P<0.05). In MCP-1, the levels in BAL fluid of NSIP and UIP patients were significantly elevated compared with healthy volunteers and sarcoidosis patients (P<0.01). These results suggest that RANTES and MCP-1 in BAL fluid may play an important role in inflammatory cell recruitment to the lung in idiopathic NSIP as well as other interstitial lung diseases.

Polymyositis-dermatomyositis-associated interstitial lung disease.

We report findings in 70 patients with both diffuse interstitial lung disease and either polymyositis (PM) or dermatomyositis (DM). Initial presentations were most commonly either musculoskeletal (arthralgias, myalgias, and weakness) or pulmonary (cough, dyspnea, and fever) symptoms alone; in only 15 patients (21.4%) did both occur simultaneously. Pulmonary disease usually took the form of acute to subacute antibiotic-resistant community-acquired pneumonia. Chest radiographs and computed tomography most commonly demonstrated bilateral irregular linear opacities involving the lung bases; occasionally consolidation was present. Jo-1 antibody was present in 19 (38%) of 50 patients tested. Synchronous associated malignancy was present in 4 of 70 patients (5.7%). Surgical lung biopsies disclosed nonspecific interstitial pneumonia (NSIP) in 18 of 22 patients (81.8%), organizing diffuse alveolar damage (DAD) in 2, bronchiolitis obliterans organizing pneumonia (BOOP) in 1, and usual interstitial pneumonia (UIP) in 1. Treatment usually included prednisone in 40-60 mg/d dosages for initial control, followed by lower dose prednisone plus an immunosuppressive agent such as azathioprine or methotrexate for disease suppression. Survival was significantly better than that observed for historical control subjects with idiopathic UIP, and was more consistent with survival previously reported in idiopathic NSIP. There was no difference in survival between Jo-1 positive and Jo-1 negative groups.