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The hallmark of idiopathic pulmonary fibrosis (IPF) is the myofibroblast, the cellular origin of which in the lung is unknown. We hypothesized that alveolar epithelial cells (AECs) may serve as a source of myofibroblasts through epithelial-mesenchymal transition (EMT). Effects of chronic exposure to transforming growth factor (TGF)-β1 on the phenotype of isolated rat AECs in primary culture and a rat type II cell line (RLE-6TN) were evaluated. Additionally, tissue samples from patients with IPF were evaluated for cells co-expressing epithelial (thyroid transcription factor (TTF)-1 and pro-surfactant protein-B (pro-SP-B), and mesenchymal (α-smooth muscle actin (α-SMA)) markers. RLE-6TN cells exposed to TGF-β1 for 6 days demonstrated increased expression of mesenchymal cell markers and a fibroblast-like morphology, an effect augmented by tumor necrosis factor-α (TNF-α). Exposure of rat AECs to TGF-β1 (100 pmol/L) resulted in increased expression of α-SMA, type I collagen, vimentin, and desmin, with concurrent transition to a fibroblast-like morphology and decreased expression of TTF-1, aquaporin-5 (AQP5), zonula occludens-1 (ZO-1), and cytokeratins. Cells co-expressing epithelial markers and α-SMA were abundant in lung tissue from IPF patients. These results suggest that AECs undergo EMT when chronically exposed to TGF-β1, raising the possibility that epithelial cells may serve as a novel source of myofibroblasts in IPF.

Objective Scleroderma is characterized by the presence of 3 predominant, yet almost mutually exclusive, antibodies: anticentromere antibody (ACA), antitopoisomerase antibody, and anti–RNA polymerase antibody. The purpose of this study was to investigate tumor necrosis factor (TNF) polymorphisms in scleroderma, with the specific aim of determining whether TNF polymorphisms would prove to be stronger markers for ACA than class II major histocompatibility complex (MHC). Methods We studied 214 UK white scleroderma patients and 354 healthy controls. All subjects were investigated for 5 TNF promoter region polymorphisms by sequence-specific polymerase chain reaction. Results We showed that an NF-κB binding site polymorphism (known to be functionally relevant) in the TNF promoter region was present in 51.8% of patients with ACA and 16.3% of patients without ACA (χ2 = 25.1, P = 0.000004 [corrected P = 0.00002]). Using haplotype mapping, we showed that this was a primary TNF association that could explain the previous weak links between ACA production and class II MHC alleles. In marked contrast to our ACA results, HLA class II (especially DRB1*11) appeared to be primary in that it could explain the weaker TNF association with antitopoisomerase production. Further, we observed a separate TNF haplotype to be associated with scleroderma per se, although the level of significance was much lower (χ2 = 8.7, P = 0.003 [corrected P = 0.02]). Conclusion We believe these findings may have importance both for the directional pathogenesis of scleroderma progression and for the treatment of scleroderma with anti-TNF agents.

A glutamic acid at residue 69(Glu69) in the HLA-DPB1 gene (Glu69) is associated with chronic beryllium disease (CBD) and possibly beryllium sensitization (BeS). This study tested the hypothesis that MHC class II polymorphisms are important in susceptibility to BeS and CBD and that the Glu69 variant is related to markers of disease severity. Genomic DNA was obtained from BeS (n = 50), CBD (n = 104), and beryllium-exposed nondiseased (Be-nondiseased) (n = 125) subjects. HLA-DPB1, -DRB1, and -DQB1 genotypes were determined by (sequence-specific primers) PCR. Disease severity was assessed by pulmonary function and exercise testing. A higher frequency of the DPB1 Glu69 gene was found in CBD and BeS compared with the Be-nondiseased subjects, with odds ratios of 10.1 for CBD vs Be-nondiseased and 9.5 for BeS vs Be-nondiseased. The majority of BeS and CBD subjects displayed non-0201 Glu69 alleles. Glu69 homozygosity was higher in the CBD subjects, while BeS subjects were intermediate and Be-nondiseased lowest. DRB1*01 and DQB1*05 phenotypes were reduced in CBD vs Be-nondiseased subjects, while DRB1*13 and DQB1*06 were associated with CBD in the absence of Glu69. Markers of disease severity, including a lower forced vital capacity, diffusion capacity for carbon monoxide, PaO2 at rest, maximum workload on exercise testing, and a higher arterial-alveolar gradient at rest, were associated with Glu69 homozygosity. We conclude that DPB1 Glu69 is a marker of sensitization and not specific for disease. Glu69 homozygosity acts as a functional marker associated with markers of CBD severity.

To identify differences, if any, in thin-section computed tomographic (CT) features between asbestosis and idiopathic pulmonary fibrosis (IPF) and to test the findings in a subset of histopathologically proved cases of usual interstitial pneumonia (UIP) and nonspecific interstitial pneumonia (NSIP).Consecutive patients with a diagnosis of IPF (n = 212) or asbestosis (n = 74) were included. The relationships derived from the initial comparison were tested in a separate group of biopsy-proved UIP (n = 30) and NSIP (n = 23) cases. Two observers independently scored thin-section CT images for extent, distribution, and coarseness of fibrosis; proportion of ground-glass opacification; severity of traction bronchiectasis; and extent of emphysema.After controlling for extent of fibrosis, patients with asbestosis had coarser fibrosis than those with IPF (odds ratio, 1.52; 95% CI: 1.25, 1.84; P.001). Compared with the biopsy-proved cases, the asbestosis cases involved coarser fibrosis (after controlling for disease extent) than the NSIP cases (odds ratio, 2.48; 95% CI: 1.49, 4.11; P.001) but fibrosis similar to that in the UIP cases. A basal and subpleural distribution of disease was usual in all subgroups but significantly more prevalent (P,.01 to.001) with asbestosis than with UIP or NSIP.The thin-section CT pattern of asbestosis closely resembles that of biopsy-proved UIP and differs markedly from that of biopsy-proved NSIP.

Survival is linked to the histopathologic distinction between usual interstitial pneumonia (UIP) and nonspecific interstitial pneumonia (NSIP), the most commonly encountered fibrotic idiopathic interstitial pneumonia. We retrospectively compared the prognostic significance of histopathologic diagnoses, baseline pulmonary function indices, and serial trends in pulmonary function indices (diffusing capacity, FVC, FEV1, the recently defined composite physiologic index) at 6 and 12 months in 104 patients (UIP, n = 63; fibrotic NSIP, n = 41). Survival was lower in UIP than in fibrotic NSIP (p = 0.001) but not in patients with severe functional impairment; mortality during the first 2 years was linked solely to the severity of functional impairment at presentation. The composite physiologic index was the strongest determinant of outcome (p0.001). At 6 months, serial diffusing capacity levels (p = 0.003) and histopathologic diagnosis (p = 0.002) were prognostically equivalent. At 12 months, serial pulmonary function trends were the only major prognostic determinant (p0.0005 for all variables), with no independent significance associated with the distinction between UIP and fibrotic NSIP. We conclude that at 12 months, serial pulmonary function trends have considerable prognostic value in UIP and NSIP. Their histologic distinction provides no additional prognostic information when pulmonary function trends are clear cut or when functional impairment is severe.

Purpose: To assess the visual acuity outcome after treatment, in patients with differing types of uveitis associated with sarcoidosis, and to determine the types of sight-threatening complications. Methods: This was an retrospective, non-comparative, interventional study of patients who had uveitis with a confirmed diagnosis of sarcoidosis and a minimum follow-up duration of 6 months from presentation. The worst affected eye at presentation was selected for the study. Complications causing impaired vision were documented, changes in visual acuity after completion of treatment were measured, and the risk of ‘poor outcome’ (visual acuity 6/12 and less) was compared in the various types of uveitis, using ‘exact’ multiple logistic regression to control confounding by other prognostic factors. Results: Seventy-five patients were studied. The spectrum of ocular inflammation in sarcoidosis is wide. Presentation may be acute and non-granulomatous or chronic and granulomatous with posterior segment involvement being varied. Poor visual outcome was significantly more frequent in multifocal choroiditis (5/7, 71.4%), and in panuveitis without multifocal choroiditis (13/28, 46.4%), compared to only 3/24 (12.5%) patients with anterior uveitis. The excess risks remained significant after adjustment for confounding effects of other prognostic factors including age, sex and manifest systemic sarcoidosis. Causes of visual loss were cataract, glaucoma, macular oedema, vitreous haemorrhage and retinal detachment. Conclusion: Multifocal choroiditis is a less common manifestation of uveitis associated with sarcoidosis but appears to be associated with a worse visual prognosis despite immunosuppressive therapy.

Acute exacerbations of idiopathic pulmonary fibrosis/cryptogenic fibrosing alveolitis (IPF/CFA) are rare and typically terminal events, but their relationship to underlying patterns of idiopathic interstitial pneumonias is unknown. We reviewed autopsy material from patients who died of diffuse alveolar damage in the clinical setting of pulmonary fibrosis, both idiopathic and with background fibrosing alveolitis with connective tissue disorders (FA-CTDs), and compared them with cases of acute interstitial pneumonia. Of 15 patients with acute exacerbations of IPF/CFA (n = 12) or FA-CTD (n = 3), 12 had a background pattern of usual interstitial pneumonia and 3 had fibrotic nonspecific interstitial pneumonia. All cases of fibrotic nonspecific interstitial pneumonia were seen in association with FA-CTD. The cause of acute exacerbations is unknown, but our data suggest that toxic effects of oxygen and triggering infection are unlikely causes. In patients with CTDs, it remains uncertain whether the acute exacerbation is related to the fibrosis, the associated CTD, or a combination of these factors. Acute exacerbations of IPF/CFA may be a more common terminal event than previously thought.

In idiopathic pulmonary fibrosis, the quantitation of disease severity using pulmonary function tests is often confounded by emphysema. We have identified the composite physiologic index (CPI) most closely reflecting the morphologic extent of pulmonary fibrosis. Consecutive patients with a clinical/computed tomography (CT) diagnosis of idiopathic pulmonary fibrosis (n = 212) were divided into group I (n = 106) and group II (n = 106). The CPI was derived in group I (by fitting pulmonary function tests against disease extent on CT) and was tested in Group II. The formula for the CPI was as follows: extent of disease on CT = 91.0 - (0.65 x percent predicted diffusing capacity for carbon monoxide [DLCO]) - (0.53 x percent predicted FVC) + (0.34 x percent predicted FEV1). In group II, the CPI correlated more strongly with disease extent on CT (r2 = 0.51) than the individual pulmonary function test (DLCO the highest value, r2 = 0.38). A subanalysis demonstrated that the better fit of the CPI was ascribable to a correction of the confounding effects of emphysema. Mortality was predicted more accurately by the CPI than by a pulmonary function test in all clinical subgroups, including a separate cohort of 36 patients with histologically proven usual interstitial pneumonia (CPI, p < 0.0005; FVC, p = 0.002; PO2, p = 0.002). In conclusion, a new CPI, derived against CT and validated using split sample testing, is a more accurate prognostic determinant in usual interstitial pneumonia than an individual pulmonary function test.

Background:CC chemokine ligand (CCL)5 and its receptor CCR5 contribute to leukocyte migration into lungs of patients with diffuse lung diseases (DLD). Pharmacological regulation of CCL5 and CCR5 expression was therefore explored in bronchoalveolar cells obtained from patients with DLD.Methods:Cells from 21 patients were co-cultivatedin vitrowith tumour necrosis factor-α and dexamethasone, cyclosporin A (CyA) or pentoxifylline. Chemokine mRNA expression and protein production was assessed by reverse transcription-polymerase chain reaction and enzyme-linked immunosorbent assay, respectively.Results:Dexamethasone altered CCL5 mRNA expression and suppressed its protein levels. CyA inhibited chemokine mRNA expression but not protein production. Pentoxifylline did not affected chemokine expression. Both dexamethasone and CyA suppressed CCR5 mRNA transcripts.Conclusion:In conclusion, while dexamethasone downregulates the CCL5 functional form, CyA and pentoxifylline have no effects on CCL5 protein. These data providein vitrocorrelation for clinical applications of immunomodulators in therapy of DLD.

Respiratory bronchiolitis-associated interstitial lung disease (RBILD) can be viewed as an exaggerated respiratory bronchiolitic response to cigarette smoke. The histologic, high-resolution computed tomographic (HRCT) and bronchoalveolar lavage (BAL) features of RBILD overlap substantially with those of respiratory bronchiolitis, with the diagnosis of RBILD being based upon the severity of disease, as judged by symptoms, clinical signs, the severity of lung function impairment, and the extent of abnormalities on HRCT. Typical histologic appearances consist of an accumulation of pigmented macrophages within respiratory bronchioles, associated with peribronchial chronic inflammatory cell infiltration and, variably, peribronchial fibrotic alveolar septal thickening. Characteristic HRCT findings include poorly defined centrilobular micronodules, patchy limited ground-glass attenuation, bronchial wall thickening, and areas of regional hypoattenuation. The ventilatory defect is often mixed but is usually predominantly restrictive. The diagnosis of RBILD is often made on clinical and HRCT criteria, with BAL findings providing useful diagnostic support, but a thoracoscopic biopsy continues to be required when other features are atypical. RBILD may regress with discontinuation of smoking but often persists with no functional improvement despite smoking cessation and treatment. Nonetheless, the course tends to be benign, without inexorable deterioration. This article outlines the rationale for viewing RBILD and desquamative interstitial pneumonia as separate entities, rather than two ends of the same disease spectrum (based upon overlapping histologic and HRCT features).

Human leukocyte antigen (HLA)-DQB1 is one of the intriguing candidate genes in sarcoidosis. We performed high resolution molecular HLA-DQB1 typing on two groups of white patients (British [UK] and Dutch [NL]) in order to investigate the relationship between 19 DQB1 alleles and disease severity and progression. A total of 803 individuals were studied (133 UK and 102 NL patients, and 354 UK and 214 NL control subjects). Disease severity data included extrapulmonary disease, chest X-ray stage, lung diffusing capacity for carbon monoxide, and FVC. Progression was evaluated on follow-up chest radiographs (2 and 4 yr). The results showed DQB1*0201 to be strongly protective against severe sarcoidosis in both populations; in other words, it localized to Stage I at all time points (P < 0.0001, P(corrected) (P(c)) = 0.002), whereas another DQB1 allele, *0602, tended to have opposite effects. Further, a clear association was found between the *0201 allele and Lofgren's syndrome (P < 0.0001, P(c) = 0.001). More importantly, carriage of this allele reduced the risk of disease progression. In contrast, the other common split of DQB1*02, *0202, did not affect disease severity but was mildly protective against sarcoidosis in the UK population (P = 0.02, p(c) not significant). In conclusion, this study shows that DQB1*0201 is a strong marker for mild sarcoidosis. Additional mapping across the DQB1*0201-DRB1*0301 haplotype, including specific alleles at genes such as DRB3, tumor necrosis factor, lymphotoxin-alpha, I-kappa-B-like protein, and B-associated transcript 1, is necessary for a final localization of the protective effect on this haplotype.

We have retrospectively studied 53 patients with idiopathic pulmonary fibrosis and a histologic diagnosis of usual interstitial pneumonia and evaluated the prognostic significance of four individual histologic features (fibroblastic foci [FF], interstitial mononuclear cell infiltrate, established fibrosis, and intra-alveolar macrophages) using a semiquantitative scale of 0-6. An objective count of FF was also undertaken. Using weighted kappa coefficients, interobserver agreement between pathologists was moderate to good (0.56-0.76). Subjective and objective FF scores were strongly associated (R(S) = 0.88,0.00005). Mortality was independently linked to a high FF score, p = 0.006, and a low percent predicted carbon monoxide diffusing capacity (DL(CO)), p = 0.01. For pulmonary function, on univariate analysis, the strongest correlations were observed between increasing interstitial mononuclear cell infiltrate or FF scores and greater declines in forced vital capacity (FVC) or DL(CO) at 6 months. Multivariate models revealed that increasing FF scores were independently associated with greater declines in FVC and DL(CO) at both 6 and 12 months. Increasing interstitial mononuclear cell infiltrate scores were also independently linked to functional decline, but only at 6 months. These data suggest a reproducible method on biopsy for predicting rate of disease progression in patients with idiopathic pulmonary fibrosis.

Interindividual variation in the expression of tumor necrosis factor (TNF)-alpha suggests the existence of functionally distinct TNF alleles, which might play a role in sarcoidosis. We investigated five potentially functional biallelic TNF promoter polymorphisms at nucleotide positions -1,031(T/C), -863(C/A), -857(C/T), -307(G/A), and -237(G/A) in two clinically well-defined groups of white patients (British [UK] and Dutch [NL]) with sarcoidosis, each with their own control subjects. Polymorphisms were determined using SSP-PCR. A total of 772 individuals were studied (96 UK patients, 354 UK control subjects, 100 NL patients, 222 NL controls). A significant increase in the rarer TNF -857T allele was found in both sarcoidosis populations. In total 25.5% of the sarcoid patients carried the TNF -857T allele versus 14.1% of the control subjects (p = 0.003, p(c) = 0.02). In the sarcoidosis group the allele frequency of this polymorphism was 13.5% versus 7.3% in the control subjects (p = 0.0003, p(c) = 0.002). Subgroup analysis showed a significant increase in the rarer TNF -307A (TNF-2) allele in patients with Löfgren's syndrome (p = 0.006, p(c) = 0.03). Our finding does not necessarily imply that the two polymorphisms relate to different functions; it may be that one or both are in linkage disequilibrium with the causal site. This requires further studies of functionality and linkage disequilibrium.

Members of the interleukin-1 (IL-1) family are implicated in the pathogenesis of sarcoidosis and idiopathic pulmonary fibrosis (IPF). We have, therefore, performed a case-control study to investigate a plausible association between sarcoidosis and the polymorphisms in the IL-1alpha, IL-1beta, and IL-1 receptor antagonist (IL-1Ra) genes. Further, as a separate question, we explored whether the aforementioned genes of the IL-1 cluster are associated with IPF. Using PCR with sequence-specific primers, IL-1alpha -889, IL-1beta -511, IL-1beta +3953, and IL-1Ra intron 2 VNTR polymorphisms were determined in 348 white subjects of West Slavonic ancestry (95 patients with sarcoidosis, 54 patients with IPF, and 199 healthy control subjects). The IL-1alpha -889 1.1 genotype was significantly overrepresented in patients with sarcoidosis in comparison with control subjects (60.0 versus 44.2%, p = 0.012, p(corr) = 0.047). The distribution of IL-1beta -511, IL-1beta +3953, and IL-1Ra VNTR genotypes and alleles did not significantly differ between the cases and controls. No association between IPF and the investigated polymorphisms was found. Strong linkage disequilibrium between pairs of polymorphic loci was observed. Further population studies are warranted to confirm the observed association between sarcoidosis and the IL-1alpha polymorphism and also to explore mechanisms of IL-1alpha -889 participation in aberrant immune response in sarcoidosis.

Rare diseases constitute a group of disorders linked by the common qualities of being infrequent and unusual. As a consequence, these conditions are generally poorly studied, frequently not well understood, and often have no effective therapy. Recognition of the importance of research into rare diseases has been growing. In fact, rare disease research findings not only benefit these patients directly, but may also elucidate mechanisms for common diseases. Major practical limitations include the small number of affected subjects and the scarcity of relevant knowledge and expertise. Thus, maximizing scarce resources, coordinating research efforts and worldwide sharing of information, data and samples are key elements for success in the rare diseases field.

Interstitial lung diseases encompass a wide range of diffuse lung disorders that are often complicated by the development of pulmonary fibrosis and that can occur in isolation or in systemic diseases. In the past decade, availability of high-throughput genotyping and large collaborative clinical networks has led to the identification of many genetic variants associated with sporadic and familial fibrotic interstitial pneumonias. Susceptibility to idiopathic pulmonary fibrosis seems to involve a combination of polymorphisms related to epithelial cell injury and dysfunction and abnormal wound healing, whereas chronic inflammation seems important in the development of pulmonary fibrosis in sarcoidosis or collagen vascular diseases such as systemic sclerosis or rheumatoid arthritis; however, each of the disease-associated variants typically has a small effect and they are therefore not helpful in prediction of risk. Genetic studies have substantially expanded understanding of the pathogenesis of pulmonary fibrosis. Future challenges will be to assess how multiple susceptibility alleles interact with each other and environmental factors to determine disease risk and several different phenotypes, to define the mechanism of action and cellular pathways involving susceptibility alleles, and to identify which of the gene products and molecular mechanisms implicated in disease pathobiology are good therapeutic targets.

Summary Rare diseases are a major health-care burden worldwide. Very little is known about the cause, behaviour, and treatment of these disorders, and thus non-specialist health-care providers and patients are left without sufficient knowledge to manage these diseases. Up to 3 million Europeans are estimated to have a rare lung disease. Several organisations—many of which are patient led—attempt to raise the profile of rare lung diseases to improve understanding and management of these disorders. Incentives have now been introduced in the USA and Europe that encourage the pharmaceutical industry to invest in targets that might otherwise not appeal because of small target populations. Despite many intrinsic challenges and obstacles, considerable progress is constantly being made in the research and development of drugs for rare disorders.

6-min walk distance (6MWD) has recently been shown to be associated with the risk of mortality in patients with idiopathic pulmonary fibrosis (IPF); however, the independent contribution of 6MWD to the prediction of mortality risk has not been evaluated in a large, well-defined population of patients with IPF. A Cox proportional hazards model was used to characterise the relationship between risk factors of interest and all-cause mortality in IPF patients who completed a week 24 study visit in a clinical trial evaluating interferon γ-1b (n=748). Risk factors of interest included the independent predictors of mortality in the previously published clinical prediction model together with 6MWD and 24-week change in 6MWD. Baseline 6MWD 50 m was associated with a nearly three-fold increase in mortality risk (hazard ratio 2.73; 95% CI 1.60-4.66). Inclusion of 6MWD data improved model discrimination compared with the original model (C-statistic 0.80 (95% CI 0.76-0.85) versus 0.75 (0.71-0.79)). Both 6MWD and change in 6MWD are independent predictors of mortality in patients with IPF. The addition of 6MWD to the clinical prediction model improves model discrimination compared with the original model.

Background and objective Pirfenidone is an oral antifibrotic agent that is approved in several countries for the treatment of idiopathic pulmonary fibrosis (IPF). We performed a comprehensive analysis of safety across four clinical trials evaluating pirfenidone in patients with IPF. Methods All patients receiving pirfenidone 2403 mg/day in the Phase 3 CAPACITY studies (Studies 004 and 006) and all patients receiving at least one dose of pirfenidone in one of two ongoing open-label studies in patients with IPF (Studies 002 and 012) were selected for inclusion. Safety outcomes were evaluated from baseline until 28 days after the last dose of study drug. Results A total of 789 patients were included in the analysis. The median duration of exposure to pirfenidone was 2.6 years (range, 1 week–7.7 years), and the cumulative total exposure was 2059 person exposure years (PEY). Gastrointestinal and skin-related events were the most commonly reported adverse events; these were almost always mild to moderate in severity, and rarely led to treatment discontinuation. Elevations (>3× upper limit of normal) in alanine aminotransferase (ALT) or aspartate aminotransferase (AST) occurred in 21/789 (2.7%) patients; the adjusted incidence of AST/ALT elevations was 1.7 per 100 PEY. Conclusions This comprehensive analysis of safety in a large cohort of IPF patients receiving pirfenidone for a total of 2059 PEY demonstrates that long-term treatment with pirfenidone is safe and generally well tolerated.

To compare the morphologic abnormalities on thin-section computed tomographic (CT) images in a group of patients with histopathologically confirmed nonspecific interstitial pneumonia (NSIP) or usual interstitial pneumonia (UIP) and a clinical presentation of idiopathic pulmonary fibrosis.Thin-section CT imaging patterns and distribution of disease in 53 patients with histologic diagnoses of NSIP (n = 21) or UIP (n = 32) were quantified retrospectively and independently by four observers. The appearances of NSIP and UIP at CT were compared with univariate and multivariate techniques.The use of thin-section CT proved to have moderate sensitivity (70%), specificity (63%), and accuracy (66%) in the diagnosis of NSIP. An increased proportion of ground-glass attenuation was the cardinal feature of NSIP at CT (odds ratio: 1.04 for each 1% increase in the proportion of ground-glass attenuation). A histologic diagnosis of NSIP was most frequent (in 24 of 35 observations [69%]) when ground-glass attenuation predominated, and was more frequent with mixed (35 of 79 observations [44%]) than with predominantly reticular disease (25 of 98 [26%] observations, P.005). Logistic regression analysis of the data indicated that misdiagnosis of UIP in patients with NSIP was associated with less ground-glass attenuation (P.005) at CT and a subpleural disease distribution (P = .02), with the converse being true for UIP cases misdiagnosed as NSIP.In patients with a clinical presentation of idiopathic pulmonary fibrosis, the accuracy of thin-section CT in identifying NSIP is considerably higher than previously reported. At CT, NSIP is characterized by more ground-glass attenuation and a finer reticular pattern than is UIP. Nevertheless, considerable overlap in thin-section CT patterns exists between NSIP and UIP.

PURPOSE: To describe the computed tomographic (CT) findings in patients with nonspecific interstitial pneumonia (NSIP) and to compare these with the CT findings of other chronic infiltrative lung diseases. MATERIALS AND METHODS: Findings in 50 patients with biopsy–proved NSIP and a CT scan were reviewed by two thoracic radiologists in consensus. After the findings were described, the observers judged whether the findings were compatible with previously published descriptions of NSIP or whether the findings would support the diagnosis of a different chronic infiltrative lung disease. RESULTS: Eleven (22%) of the 50 patients had CT findings that were compatible with previous descriptions of NSIP. Sixteen (32%) patients had CT findings that were more compatible with usual interstitial pneumonia. The other 23 (46%) patients had findings that were nondiagnostic or most compatible with the diagnosis of another chronic infiltrative lung disease. CONCLUSION: Contrary to previously published articles, there are a ...

Obliterative pulmonary vascular disease manifested clinically as pulmonary hypertension (PHT) may complicate systemic sclerosis (SSc). The aim of this study was to investigate possible endothelial dysfunction in patients with SSC complicated by PHT.Prospective, randomized trial.Postgraduate teaching hospital.Patients having SSc with PHT (SSc-PHT) and SSc without PHT (SSc), confirmed using Doppler echocardiography, and normal individuals (control subjects).I.v. infusion of the endothelially dependent vasodilator, substance P (maximum dose, 100 pmol/min), and the nonendothelially dependent vasodilator, adenosine (maximum dose, 0.05 mg/kg/min).Effective pulmonary capillary blood flow (cardiac output minus right-to-left shunt) was measured in inert gas rebreathing, and calculated stroke index (SI) was used to reflect changes in pulmonary vascular resistance. During adenosine infusion, patients with SSc-PHT (n=5; mean age, 53+/-18 years) displayed a 25+/-16% increase in SI (p0.05 compared with baseline), but no significant changes in SI were detected in the SSc (n=7; 54+/-6 years) or control (n=5; 35+/-5 years) groups. During infusion of substance P, SI rose by 32+/-18% in the control group at the maximum dose (p0.05), but no change was observed in the SSc group. However, a fall in SI of -6+/-7% was detected in patients with SSc-PHT (p0.05).Substance P-mediated pulmonary vasodilation is absent in patients with systemic sclerosis, suggesting that endothelial dysfunction occurs early in the course of the illness, but some responsiveness to adenosine remains.

OBJECTIVE To examine whether scleroderma lung fibroblasts show a pattern of aberrant type I collagen (CI) biosynthesis similar to that observed previously in studies of dermal fibroblasts in this disease. METHODS CI secretion and steady-state pro alpha1(I) collagen messenger RNA (mRNA) levels and COL1A2 gene activation were examined in fibroblasts grown from lung biopsy specimens obtained from 16 scleroderma patients with lung fibrosis and from 10 histologically normal lung specimens (controls). The effect of culture in a 3-dimensional (3-D) CI gel matrix culture on CI mRNA levels was also examined. RESULTS The mean (+/- SEM) collagen secretion in monolayer culture for scleroderma lung fibroblasts was 90.9 +/- 56 ng/ml/10(6) cells, significantly greater (P < 0.05) than controls (40.2 +/- 17.5). Pro alpha1(I) collagen mRNA levels in monolayer cultures were higher in scleroderma (mean +/- SEM collagen:GAPDH ratio 3.7 +/- 0.9) compared with control (1.9 +/- 0.8) lung fibroblasts. Transient expression assays confirmed that genes coding for CI are transcriptionally activated in scleroderma lung fibroblasts compared with control strains. Although all lung fibroblasts induced equivalent contraction of 3-D CI gel matrices, scleroderma strains failed to show a reduction in steady-state pro alpha1(I) collagen mRNA levels in gel culture. CONCLUSION We have demonstrated elevated CI biosynthesis and impaired mRNA down-regulation for CI by scleroderma lung fibroblasts. These properties are likely to be highly relevant to the pathogenesis of scleroderma-associated lung fibrosis.

We performed a genome-wide association study in non-Hispanic white subjects with fibrotic idiopathic interstitial pneumonias (N=1616) and controls (N=4683); replication was assessed in 876 cases and 1890 controls. We confirmed association with TERT and MUC5B on chromosomes 5p15 and 11p15, respectively, the chromosome 3q26 region near TERC, and identified 7 novel loci (PMeta = 2.4×10−8 to PMeta = 1.1×10−19). The novel loci include FAM13A (4q22), DSP (6p24), OBFC1 (10q24), ATP11A (13q34), DPP9 (19p13), and chromosomal regions 7q22 and 15q14-15. Our results demonstrate that genes involved in host defense, cell-cell adhesion, and DNA repair contribute to the risk of fibrotic IIP.

Objective.Small series suggest mycophenolate mofetil (MMF) is well tolerated and may be an effective therapy for connective tissue disease-associated interstitial lung disease (CTD-ILD). We examined the tolerability and longitudinal changes in pulmonary physiology in a large and diverse cohort of patients with CTD-ILD treated with MMF.Methods.We identified consecutive patients evaluated at our center between January 2008 and January 2011 and prescribed MMF for CTD-ILD. We assessed safety and tolerability of MMF and used longitudinal data analyses to examine changes in pulmonary physiology over time, before and after initiation of MMF.Results.We identified 125 subjects treated with MMF for a median 897 days. MMF was discontinued in 13 subjects. MMF was associated with significant improvements in estimated percentage of predicted forced vital capacity (FVC%) from MMF initiation to 52, 104, and 156 weeks (4.9% ± 1.9%, p = 0.01; 6.1% ± 1.8%, p = 0.0008; and 7.3% ± 2.6%, p = 0.004, respectively); and in estimated percentage predicted diffusing capacity (DLCO%) from MMF initiation to 52 and 104 weeks (6.3% ± 2.8%, p = 0.02; 7.1% ± 2.8%, p = 0.01). In the subgroup without usual interstitial pneumonia (UIP)-pattern injury, MMF significantly improved FVC% and DLCO%, and in the subgroup with UIP-pattern injury, MMF was associated with stability in FVC% and DLCO%.Conclusion.In a large diverse cohort of CTD-ILD, MMF was well tolerated and had a low rate of discontinuation. Treatment with MMF was associated with either stable or improved pulmonary physiology over a median 2.5 years of followup. MMF appears to be a promising therapy for the spectrum of CTD-ILD.

Idiopathic pulmonary fibrosis (IPF) is a progressive fibroproliferative disease that results in increasing morbidity. To date there is only one licensed therapy for this condition and other agents are needed for this attritional disease. Efforts to study other agents have been obstructed by an increasing division of opinion about the most clinically meaningful end-point of phase III clinical trials to demonstrate efficacy. Many clinicians believe that an agent that impedes progression of the disease is more than acceptable and will encourage the pharmaceutical industry to further develop their IPF programmes. We have been impressed by the behavioural and biological similarities of cancer and IPF, and wondered if lessons could be learned about clinical trial design from lung cancer studies. Here, we set out our arguments that the similarities with cancer justify comparing the magnitude of therapeutic effects in clinical trials in nonsmall cell lung cancer with those in successful trials in IPF. We demonstrate that efficacy is of a similar magnitude in the two chronic lung diseases. We recommend that the demonstration of similar magnitudes of progression-free disease effect in IPF, using appropriate indices, should be considered as clinically meaningful benefit in future phase III clinical trials of novel therapies.

Pulmonary fibrosis is the ultimate outcome of various interstitial lung diseases, many of which have a dismal prognosis. Pulmonary fibrosis, therefore, represents a critical unmet medical need. Progress in research over the past 30 years has been encouraging. This work, which has been funded by governments, charitable trusts, industries and patient groups, has resulted in clinical trials testing novel drugs, giving hope to patients. In late September 2012, representatives from academia, industry and funding agencies met at the 17th International Colloquium on Airway and Lung Fibrosis to discuss state-of-the-art knowledge of pulmonary fibrosis. This manuscript summarises the outcomes of the meeting, highlighting the most relevant results and discoveries. It also attempts to provide a roadmap for future studies. It is hoped that such a roadmap may help interested parties to generate new research, which will be vital to continued progress. We are encouraged by the commitment expressed by all participants at this meeting and the shared vision of promoting future progress through international collaboration, the pooling of valuable resources, and the involvement of a new generation of physicians and scientists.

Rationale and Objectives. Pulmonary hypertension may complicate systemic sclerosis in the absence of fibrosing alveolitis. Abnormal pulmonary perfusion is known to result in regional differences in lung density at computed tomographic (CT) scanning. We assessed possible disturbances in the normal CT density gradient in patients with systemic sclerosis and reduced gas transfer but no clinical or radiologic evidence of fibrosing alveolitis. Methods. We analyzed the CT scans of 15 patients with systemic sclerosis. Regions of interest were drawn in the most dependent and nondependent zones in the upper and lower lobes of each lung. Average densities for the most dependent and nondependent zones were calculated for the upper and lower lobes, and a global lung density measurement was derived. Zonal and global density gradients were derived from mean density measures (mean density of dependent areas minus mean densities of nondependent areas). Results. Five of the 15 patients had pulmonary hypertension, defined as an estimated systolic pressure in the pulmonary artery of greater than 30 mm Hg shown by Doppler echocardiography. Patients with pulmonary hypertension were characterized by higher global lung density for nondependent zones (median, −821 H versus −853 H; p = .07) but not for dependent zones (−800 H versus −815 H, p = .71). The lung density gradient was reduced globally and in the lower zones in patients with pulmonary hypertension ( p = .05). Conclusion. In cases of systemic sclerosis without fibrosing alveolitis, we found a significantly smaller density gradient between dependent and nondependent lung regions in patients with pulmonary hypertension compared with patients without pulmonary hypertension. This finding suggests that the normal CT density gradient depends in part on normal compliance of the pulmonary vasculature.

Idiopathic pulmonary fibrosis causes progressive morbidity and has a worldwide incidence that is increasing. There are a number of promising therapies, one of which has been approved in Europe, parts of Asia, and India, and others that are at various stages of development. Despite this, there continues to be debate about the most appropriate clinical endpoint that should be used in future randomized controlled clinical trials of novel therapies in idiopathic pulmonary fibrosis. In a recent Pulmonary Perspective in this journal, the case for the use of a variety of clinical endpoints was analyzed, and the article concluded that FVC, the endpoint most commonly used recently and in ongoing studies, was not an appropriate option. In this Pulmonary Perspective we present a counterpoint in which we explore the basis on which this conclusion is drawn and present data that strongly and logically support the use of FVC as a valid and robust measure that fulfils the criteria for an ideal clinical endpoint and that is meaningful to patient and clinician alike.

A combined pulmonary fibrosis/emphysema syndrome has been proposed, but the basis for this syndrome is currently uncertain. The aim was to evaluate the prevalence of emphysema in idiopathic pulmonary fibrosis (IPF) and rheumatoid lung (rheumatoid arthritis-interstitial lung disease (RA-ILD)), and to compare the morphological features of lung fibrosis between smokers and non-smokers.Using high-resolution computed tomography, the prevalence of emphysema and the pack-year smoking histories associated with emphysema were compared between current/ex-smokers with IPF (n = 186) or RA-ILD (n = 46), and non-chronic obstructive pulmonary disease (COPD) controls (n = 103) and COPD controls (n = 34). The coarseness of fibrosis was compared between smokers and non-smokers.Emphysema, present in 66/186 (35%) patients with IPF and 22/46 (48%) smokers with RA-ILD, was associated with lower pack-year smoking histories than in control groups (P0.05 for all comparisons). The presence of emphysema in IPF was positively linked to the pack-year smoking history (odds ratio 1.04, 95% confidence interval (CI) 1.02-1.06, P0.0005). In IPF, fibrosis was coarser in smokers than in non-smokers on univariate and multivariate analysis (P0.01 for all comparisons). In RA-ILD, fibrosis was coarser in patients with emphysema but did not differ significantly between smokers and non-smokers.In IPF and RA-ILD, a high prevalence of concurrent emphysema, in association with low pack-year smoking histories, and an association between coarser pulmonary fibrosis and a history of smoking in IPF together provide support for possible pathogenetic linkage to smoking in both diseases.

The goal of this chapter is to provide a practical approach to connective tissue disease (CTD)-associated lung disease by focusing on commonly encountered problems in the management of this complex and heterogeneous patient population. Several illustrative cases are incorporated into the text and interstitial lung disease is a major focus because it occurs across the spectrum of the CTDs, is potentially the most devastating of pulmonary manifestations, and often poses the most significant challenges to the practicing clinician.

RATIONALE: A previous trial of bosentan in idiopathic pulmonary fibrosis (IPF) showed a trend to delayed IPF worsening or death. Also, improvements in some measures of dyspnea and health-related quality of life were observed. OBJECTIVES: To demonstrate that bosentan delays IPF worsening or death. METHODS: Prospective, randomized (2:1), double-blind, placebo-controlled, event-driven, parallel-group, morbidity-mortality trial of bosentan in adults with IPF of less than 3 years' duration, confirmed by surgical lung biopsy, and without extensive honeycombing on high-resolution computed tomography. The primary endpoint was time to IPF worsening (a confirmed decrease from baseline in FVC ≥ 10% and diffusing capacity of the lung for carbon monoxide ≥ 15%, or acute exacerbation of IPF) or death up to End of Study. Effects of bosentan on health-related quality of life, dyspnea, and the safety and tolerability of bosentan were investigated. MEASUREMENTS AND MAIN RESULTS: Six hundred sixteen patients were randomized to bosentan (n=407) or placebo (=209). No significant difference between treatment groups was observed in the primary endpoint analysis (hazard ratio, 0.85; 95% confidence interval, 0.66-1.10; P=0.2110). No treatment effects were observed on health-related quality of life or dyspnea. Some effects of bosentan treatment were observed in changes from baseline to 1 year in FVC and diffusing capacity of the lung for carbon monoxide. The safety profile for bosentan was similar to that observed in other trials. CONCLUSIONS: The primary objective in the Bosentan Use in Interstitial Lung Disease-3 trial was not met. Bosentan was well tolerated. Clinical trial registered with www.clinicaltrials.gov (NCT 00391443).

Idiopathic pulmonary fibrosis is the most lethal form of diffuse lung fibrosis, killing approximately half of those affected within 2-3 years of diagnosis. Until recently, no therapies had been shown to have an impact on disease progression. The Clinical Studies Assessing Pirfenidone (Esbriet(®)) in IPF: Research of Efficacy and Safety Outcomes (CAPACITY) program comprised two almost identical double-blind placebo-controlled studies assessing the effects of pirfenidone on change in forced vital capacity, the primary end point, over a 72-week period. One of these studies was positive, matching in magnitude the benefit seen in two previous positive Japanese studies. The other study did not meet its primary end point but positive trends were consistent in this and a number of secondary end point indices. Safety was acceptable, comprising mainly problems of tolerability rather than toxicity. It is likely that pirfenidone will be utilised in many countries as first-line therapy and will also be included in studies of combination therapy for this attritional disease.

Several predictors of mortality in patients with idiopathic pulmonary fibrosis have been described; however, there is a need for a practical and accurate method of quantifying the prognosis of individual patients.Develop a practical mortality risk scoring system for patients with idiopathic pulmonary fibrosis.We used a Cox proportional hazards model and data from two clinical trials (n = 1,099) to identify independent predictors of 1-year mortality among patients with idiopathic pulmonary fibrosis. From the comprehensive model, an abbreviated clinical model comprised of only those predictors that are readily and reliably ascertained by clinicians was derived. Beta coefficients for each predictor were then used to develop a practical mortality risk scoring system.Independent predictors of mortality included age, respiratory hospitalization, percent predicted FVC, 24-week change in FVC, percent predicted carbon monoxide diffusing capacity, 24-week change in percent predicted carbon monoxide diffusing capacity, and 24-week change in health-related quality of life. An abbreviated clinical model comprising only four predictors (age, respiratory hospitalization, percent predicted FVC, and 24-wk change in FVC), and the corresponding risk scoring system produced estimates of 1-year mortality risk consistent with observed data (9.9% vs. 9.7%; C statistic = 0.75; 95% confidence interval, 0.71–0.79).The prognosis for patients with idiopathic pulmonary fibrosis may be accurately determined using four readily ascertainable predictors. Our simplified scoring system may be a valuable tool for determining prognosis and guiding clinical management. Additional research is needed to validate the applicability and accuracy of the scoring system.

Sarcoidosis is an inflammatory, granulomatous disease of unknown etiology that most commonly afflicts the lungs. Despite aggressive immunosuppressive therapies, many sarcoidosis patients still chronically present significant symptoms. Infliximab, a therapeutic tumor necrosis factor alpha (TNF-α) monoclonal antibody (MAb), produced a small but significant improvement in forced vital capacity (FVC) in sarcoidosis patients in a double-blind, placebo-controlled, phase II clinical trial. In the current study, serum samples from this clinical trial were assessed to evaluate the underlying hypothesis that treatment with infliximab would reduce systemic inflammation associated with sarcoidosis, correlating with the extent of clinical response. A 92-analyte multiplex panel was used to assess the expression of serum proteins in 134 sarcoidosis patients compared with sera from 50 healthy controls. A strong systemic inflammatory profile was associated with sarcoidosis, with 29 analytes significantly elevated in sarcoidosis (false-discovery rate, 50% higher than controls). The associated analytes included chemokines, neutrophil-associated proteins, acute-phase proteins, and metabolism-associated proteins. This profile was evident despite patients receiving corticosteroids and immunosuppressive therapies. Following infliximab treatment, sarcoidosis patients expressing the highest levels of TNF-α, who had more severe disease, had the greatest improvement in FVC and reduction in serum levels of the inflammatory proteins MIP-1β and TNF-RII. This study supports the need for further exploration of anti-TNF therapy for chronic sarcoidosis patients, particularly for those expressing the highest serum levels of TNF-α.

Publisher Summary Systemic lupus erythematosus (SLE) is a multisystem autoimmune disease characterized by the presence of autoantibodies and tissue damage that may involve a myriad of organ systems. The respiratory system is commonly affected in patients with SLE, and any of its components can be impacted by the disease. This chapter provides an overview of the clinical assessment of SLE-associated lung disease and discusses the pulmonary manifestations associated with SLE. The detection of SLE-associated lung involvement is usually by the presentation of respiratory symptoms. Less commonly, respiratory involvement is detected by an abnormal physical examination finding or by coincidental identification via testing for other medical conditions. Clinical assessment of SLE-associated lung disease can be achieved by clinical assessment (physical examination), laboratory assessment (pulmonary function assessment, ambulatory oximetry, and pulmonary function testing), and thoracic imaging modalities (chest radiograph, thoracic high-resolution computed tomography, CT angiography and ventilation/perfusion scan, transthoracic echocardiography, bronchoscopy, and surgical lung biopsy). Infection is the most common form of pulmonary involvement in patients with SLE because these patients are at increased risk for infection in part due to intrinsic immune dysregulation but also as a result of the immunosuppressing medications required to manage the disease. Other SLE-associated lung manifestations include pleural disease, parenchymal disease, shrinking lung syndrome, and pulmonary vascular disease. Finally, this chapter presents some thoughts on several topics of debate within the arena of SLE-associated lung disease.

From the authors: We thank M. Mura for reminding us of the study published in the European Respiratory Journal ( ERJ ) in 2012 that confirmed the increasing importance of the 6-min walk test (6MWT) in the evaluation and prediction of outcome in patients suffering from idiopathic pulmonary fibrosis (IPF) [1]. In this prospective study by Mura et al. [1], of factors that predicted survival in 70 patients with newly diagnosed IPF, the major 6MWT findings were that the 6-min walk distance (6MWD) % predicted, but not 6MWD defined as metres walked, was independently associated with 3-year survival, and …

We performed 24-hr monitoring of pulse oximetric saturation (SpO(2)) with ECG and six-minute walk test (6MWT) in 19 patients with fibrotic interstitial lung diseases (ILD) to investigate; 1) The frequency and severity of hypoxemia and dysrhythmia during daily activities and 6MWT, 2) safety of 6MWT, and 3) the parameters of 6MWT which can replace 24-hr continuous monitoring of SpO(2) to predict hypoxemia during daily activities. All patients experienced waking hour hypoxemia, and eight of nineteen patients spent > 10% of waking hours in hypoxemic state. Most patients experienced frequent arrhythmia, mostly atrial premature contractions (APCs) and ventricular premature contractions (VPCs). There were significant correlation between the variables of 6MWT and hypoxemia during daily activities. All of the patients who desaturated below 80% before 300 meters spent more than 10% of waking hour in hypoxemia (P = 0.018). In contrast to waking hour hypoxemia, SpO(2) did not drop significantly during sleep except in the patients whose daytime resting SpO(2) was already low. In conclusion, patients with fibrotic ILD showed significant period of hypoxemia during daily activities and frequent VPCs and APCs. Six-minute walk test is a useful surrogate marker of waking hour hypoxemia and seems to be safe without continuous monitoring of SpO(2).