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Abstract Background In 2002 the American Thoracic Society/European Respiratory Society (ATS/ERS) classification of idiopathic interstitial pneumonias (IIPs) defined seven specific entities, and provided standardized terminology and diagnostic criteria. In addition, the historical “gold standard” of histologic diagnosis was replaced by a multidisciplinary approach. Since 2002 many publications have provided new information about IIPs. Purpose The objective of this statement is to update the 2002 ATS/ERS classification of IIPs. Methods An international multidisciplinary panel was formed and developed key questions that were addressed through a review of the literature published between 2000 and 2011. Results Substantial progress has been made in IIPs since the previous classification. Nonspecific interstitial pneumonia is now better defined. Respiratory bronchiolitis–interstitial lung disease is now commonly diagnosed without surgical biopsy. The clinical course of idiopathic pulmonary fibrosis and nonspecific interstitial pneumonia is recognized to be heterogeneous. Acute exacerbation of IIPs is now well defined. A substantial percentage of patients with IIP are difficult to classify, often due to mixed patterns of lung injury. A classification based on observed disease behavior is proposed for patients who are difficult to classify or for entities with heterogeneity in clinical course. A group of rare entities, including pleuroparenchymal fibroelastosis and rare histologic patterns, is introduced. The rapidly evolving field of molecular markers is reviewed with the intent of promoting additional investigations that may help in determining diagnosis, and potentially prognosis and treatment. Conclusions This update is a supplement to the previous 2002 IIP classification document. It outlines advances in the past decade and potential areas for future investigation.

BackgroundRelatives of patients with familial interstitial pneumonia (FIP) are at increased risk for pulmonary fibrosis. We assessed the prevalence and risk factors for preclinical pulmonary fibrosis (PrePF) in first-degree relatives of patients with FIP and determined the utility of deep learning in detecting PrePF on CT.MethodsFirst-degree relatives of patients with FIP over 40 years of age who believed themselves to be unaffected by pulmonary fibrosis underwent CT scans of the chest. Images were visually reviewed, and a deep learning algorithm was used to quantify lung fibrosis. Genotyping for common idiopathic pulmonary fibrosis risk variants in MUC5B and TERT was performed.FindingsIn 494 relatives of patients with FIP from 263 families of patients with FIP, the prevalence of PrePF on visual CT evaluation was 15.6% (95% CI 12.6 to 19.0). Compared with visual CT evaluation, deep learning quantitative CT analysis had 84% sensitivity (95% CI 0.72 to 0.89) and 86% sensitivity (95% CI 0.83 to 0.89) for discriminating subjects with visual PrePF diagnosis. Subjects with PrePF were older (65.9, SD 10.1 years) than subjects without fibrosis (55.8 SD 8.7 years), more likely to be male (49% vs 37%), more likely to have smoked (44% vs 27%) and more likely to have the MUC5B promoter variant rs35705950 (minor allele frequency 0.29 vs 0.21). MUC5B variant carriers had higher quantitative CT fibrosis scores (mean difference of 0.36%), a difference that remains significant when controlling for age and sex.InterpretationPrePF is common in relatives of patients with FIP. Its prevalence increases with age and the presence of a common MUC5B promoter variant. Quantitative CT analysis can detect these imaging abnormalities.

Autoantibodies to melanoma differentiation-associated gene 5 (MDA5) are specifically expressed in patients with dermatomyositis (DM) and are associated with a subset of DM patients with rapidly progressive interstitial lung disease (RP-ILD). Here, we examined the clinical utility of a newly developed enzyme-linked immunosorbent assay (ELISA) system for detecting these antibodies. Here we developed an improved ELISA for detecting anti-MDA5 antibodies. We then performed a multicenter clinical study involving 8 medical centers and enrolled 242 adult patients with polymyositis (PM)/DM, 190 with non-PM/DM connective tissue disease (CTD), 154 with idiopathic interstitial pneumonia (IIP), and 123 healthy controls. Anti-MDA5 antibodies in the patients' serum samples were quantified using our newly developed ELISA, and the results were compared to those obtained using the gold-standard immunoprecipitation (IP) assay. In addition, correlations between the ELISA-quantified anti-MDA5 antibodies and clinical characteristics were evaluated. In patients with PM/DM, the anti-MDA5 antibody measurements obtained from the ELISA and IP assay were highly concordant; the ELISA exhibited an analytical sensitivity of 98.2%, specificity of 100%, positive predictive value of 100%, and negative predictive value of 99.5% (compared to the IP assay). Anti-MDA5 antibodies were detected in 22.7% of the DM patients, but not in any of the patients with PM, non-PM/DM CTD, or IIP. Clinically amyopathic DM, RP-ILD, arthritis, and fever were more prevalent in DM patients who were anti-MDA5 antibody-positive than in those who were antibody-negative (P ≤ 0.0002 for all comparisons). In addition, anti-MDA5 antibody-positive patients with RP-ILD exhibited higher antibody levels than those without RP-ILD (P = 0.006). Our newly developed ELISA can detect anti-MDA5 antibodies as efficiently as the gold standard IP assay and has the potential to facilitate the routine clinical measurement of anti-MDA5 antibodies in patients who suspected to have DM.

Bronchoalveolar lavage (BAL) is crucial for the diagnosis of interstitial lung disease (ILD). Although BAL lymphocytosis is found in patients with connective tissue disease (CTD)-related ILD, the effects of CTD-associated features on BAL lymphocytosis have not been elucidated. To identify CTD-associated features that affect BAL lymphocyte fraction in patients with idiopathic interstitial pneumonia (IIP). This post hoc analysis of a prospective, multicentre cohort study was conducted between 2015 and 2020. Overall, 222 patients newly diagnosed with IIP were consecutively enrolled, and 74 autoimmune features were comprehensively analysed during IIP diagnosis. The median age was 71 years, and the median observation period was 36 months. The clinical characteristics related to a significant increase in BAL lymphocyte fraction were consolidation opacity on high-resolution computed tomography (HRCT), morphologic domain of interstitial pneumonia with autoimmune features (IPAF), serum CXCL10 concentration, and acute/subacute onset (all p < 0.05). In contrast, presence of joint lesion/mucocutaneous lesion/dry symptoms, autoantibodies, or other CTD-like features on HRCT and surgical lung biopsy did not affect the BAL lymphocyte fraction (all p ≥ 0.05). Furthermore, a high BAL lymphocyte fraction (≥ 8.5%) was related to a low proportion of progressive pulmonary fibrosis ( p < 0.001) and favourable survival (log-rank, p = 0.020) in patients with non-idiopathic pulmonary fibrosis (IPF). IPAF morphologic domain especially with consolidation opacity on HRCT and high CXCL10 concentration, but not CTD-like symptoms, autoantibodies, or CTD-like features on lung biopsy, were related to a high BAL lymphocyte fraction with favourable survival in patients with non-IPF.

Abstract Rationale Pulmonary hypertension (PH) associated with fibrotic idiopathic interstitial pneumonia (IIP; idiopathic pulmonary fibrosis and nonspecific interstitial pneumonia) confers important additional morbidity and mortality. Objectives To evaluate the safety and clinical efficacy of the dual endothelin-1 receptor antagonist bosentan in this patient group. Methods In a randomized, double-blind, placebo-controlled study, 60 patients with fibrotic IIP and right heart catheter confirmed PH were randomized 2:1 to bosentan (n = 40) or placebo (n = 20). The primary study endpoint was a fall from baseline pulmonary vascular resistance index (PVRi) of 20% or more over 16 weeks. Measurements and Main Results Sixty patients (42 men; mean age, 66.6 ± 9.2 yr), with a mean pulmonary artery pressure of 36.0 (± 8.9) mm Hg, PVRi 13.0 (± 6.7) Wood Units/m2 and reduced cardiac index of 2.21 (± 0.5) L/min/m2 were recruited to the study. Accounting for deaths and withdrawals, paired right heart catheter data were available for analysis in 39 patients (bosentan = 25, placebo = 14). No difference in the primary outcome was detected, with seven (28.0%) patients receiving bosentan, and four (28.6%) receiving placebo achieving a reduction in PVRi of greater than or equal to 20% (P = 0.97) at 16 weeks. There was no change in functional capacity or symptoms between the two groups at 16 weeks, nor any difference in rates of serious adverse events or deaths (three deaths in each group). Conclusions This study shows no difference in invasive pulmonary hemodynamics, functional capacity, or symptoms between the bosentan and placebo groups over 16 weeks. Our data do not support the use of the dual endothelin-1 receptor antagonist, bosentan, in patients with PH and fibrotic IIP. Clinical trial registered with www.clinicaltrials.gov (NCT 00637065).

To investigate the clinical features, risk factors and outcomes of patients with interstitial pneumonia with autoimmune features (IPAF). A total of 1429 patients with idiopathic interstitial pneumonia (IIP) and undifferentiated connective tissue disease-associated interstitial lung disease (UCTD-ILD) were screened to identify patients who met IPAF criteria. Clinical, serological, and morphological features of patients with IPAF were characterized. Outcomes between patients with IPAF, UCTD-ILD, and IIP who were divided into idiopathic pulmonary fibrosis (IPF) and non-IPF groups were compared using survival as an endpoint. Patients with IPAF were much common in young female and had lower percentage of ever smoking and a significantly shorter survival than those with non-IPAF (P < 0.001). Subgroup analysis revealed that IPAF cohort survival was worse than that in non-IPF (P < 0.001), but better than that in IPF (P < 0.001). In IPAF cohort, the most common systemic symptom and serological abnormality were Raynaud’s phenomenon (12.9%) and ANA ≥ 1:320 (49.2%); the most frequent high-resolution computed tomography (HRCT) pattern was nonspecific interstitial pneumonia (NSIP) (61.6%). Multivariate analysis indicated that several factors including age, smoking history, organizing pneumonia (OP) pattern in HRCT, and anti-RNP positivity were independently associated with significantly worse survival. IPAF had the distinct clinical features and outcomes compared with other groups of ILD. Additional studies should be needed to explore the underlying autoimmune mechanism and to determine risk stratification in future clinical research.

High-mobility group box 1 (HMGB1) protein is important in acute lung injury. However, the role of HMGB-1 in acute exacerbation of fibrosing interstitial pneumonia (AE-FIP) has not been adequately studied. We prospectively measured serum HMGB1 level from disease onset to day 7 in 36 patients with AE-FIP6 patients had missing data because of early death (within 7 days). We then examined the association of HMGB1 level and outcome, and the associations of rhTM with HMGB1 level and outcome in 19 patients who were treated with rhTM (rhTM group) and 11 patients who were not (control group). Data from 36 AE-FIP patients (mean age, 73.5±6.7years) were analyzed. Serum HMGB1 level was significantly higher in patients with AE-FIP than in those with stable idiopathic pulmonary fibrosis (16.4±13.5 vs 5.7±2.6 ng/ml, respectively; p = 0.003). HMGB1 was significantly lower on day 7 than at AE-FIP onset in survivors (6.5±4.8 vs 14.7±12.9 ng/ml, respectively; p = 0.02) but not in nonsurvivors (14.6±10.5 vs 9.2±4.8 ng/ml, respectively; p = 0.08). Although HMGB1 level at day 7 was significantly lower after rhTM treatment than at AE-FIP onset (8.4±6.1 vs 15.2±12.5 ng/ml, respectively; p = 0.02), it did not significantly decrease in patients receiving treatments other than rhTM (11.3±11.3 vs 8.3±5.3 ng/ml, respectively; p = 0.37). Three-month survival was 60.0% in the rhTM group and 36.4% in the control group (p = 0.449). In multivariate analysis, a decrease in HMGB1 was a significant independent predictor of 3-month survival (Odds ratio, 12.4; p = 0.007). rhTM lowers serum HMGB1 level and may improve survival after AE-FIP. HMGB1 may be a promising therapeutic target for AE-FIP.

Pulmonary hypertension (PH) is a common finding in patients with chronic fibrosing idiopathic interstitial pneumonias (IIP). Little is known about the response to pulmonary vasodilator therapy in this patient population. COMPERA is an international registry that prospectively captures data from patients with various forms of PH receiving pulmonary vasodilator therapies. We retrieved data from COMPERA to compare patient characteristics, treatment patterns, response to therapy and survival in newly diagnosed patients with idiopathic pulmonary arterial hypertension (IPAH) and PH associated with IIP (PH-IIP). Compared to patients with IPAH (n = 798), patients with PH-IIP (n = 151) were older and predominantly males. Patients with PH-IIP were treated predominantly with phosphodiesterase-5 inhibitors (88% at entry, 87% after 1 year). From baseline to the first follow-up visit, the median improvement in 6MWD was 30 m in patients with IPAH and 24.5 m in patients with PH-IIP (p = 0.457 for the difference between both groups). Improvements in NYHA functional class were observed in 22.4% and 29.5% of these patients, respectively (p = 0.179 for the difference between both groups). Survival rates were significantly worse in PH-IIP than in IPAH (3-year survival 34.0 versus 68.6%; p<0.001). Total lung capacity, NYHA class IV, and mixed-venous oxygen saturation were independent predictors of survival in patients with PH-IIP. Patients with PH-IIP have a dismal prognosis. Our results suggest that pulmonary vasodilator therapy may be associated with short-term functional improvement in some of these patients but it is unclear whether this treatment affects survival. clinicaltrials.gov NCT01347216.

Although acute exacerbation of idiopathic interstitial pneumonia (AE-IIP) is a critical event, the detailed features of connective tissue diseases (CTD) that affect the incidence of AE-IIP have not been fully elucidated. This study aimed to clarify the CTD-related features that affect the incidence of AE-IIP. This was a post hoc analysis of a prospective and multicenter cohort study conducted between 2015 and 2020. Newly diagnosed patients with IIP were consecutively enrolled, and 74 autoimmune features and autoantibodies were comprehensively checked during IIP diagnosis. In total, 222 patients with IIP were enrolled. The median observation period was 36 months, during which 34 patients developed AE-IIP. In multivariate models adjusted for age, gender, and %predicted FVC, AE-IIP frequently occurred in patients positive for anti-cyclic citrullinated peptide (CCP) antibody (hazard ratio [HR]: 4.407, p  = 0.004, q = 0.027), while it was less common in patients positive for antinuclear antibodies (ANA) ≥ 320 or polymyositis/dermatomyositis (PM/DM)- or systemic sclerosis (SSc)-related antibodies (HR < 0.001, p  < 0.001, q < 0.001). A composite model consisting of these items stratified the incidence of AE-IIP ( p  < 0.001), which was closely related to the mortality. These results indicate that the presence of anti-CCP antibodies, ANA, or PM/DM/SSc-related antibodies, in addition to decreased lung function, could help determine the risk of AE-IIP in patients with IIP.

Background Organizing pneumonia (OP) can be diagnosed pathologically, and cryptogenic OP (COP) and secondary OP (SOP) have been classified by cause and particular underlying context. Because it is clinically difficult to differentiate between COP and SOP, this study investigated characteristics that could distinguish between COP and SOP. Methods The medical records of patients who underwent lung biopsy for a diagnosis of OP at a single tertiary hospital from January 2016 to December 2018 were retrospectively reviewed. Results Eighty-five patients had pathologically proven OP, including 16 diagnosed with COP and 69 diagnosed with SOP. The most common cause of SOP was infectious pneumonia, observed in 57 (82.6%) of the 69 patients, followed by cancer and radiation pneumonitis. The pathogens causing infectious pneumonia were identified in 45 (65.2%) patients. There were no differences in age, sex, and lung function between the COP and SOP groups. Median body mass index was significantly lower ( P  = 0.030), and median time from symptom onset to hospital admission significantly shorter ( P  = 0.006), in the SOP than in the COP group. Fever was more common in the SOP group ( P  = 0.024), and CURB 65, an index of pneumonia severity, tended to be higher in the SOP group ( P  = 0.017). Some laboratory results differed significantly between the two groups. Lymphocyte counts in bronchoalveolar lavage (BAL) fluid were significantly higher in the COP than in the SOP group ( P  = 0.012). Radiologic findings showed that effusion was more common in the SOP group ( P  = 0.036). There were no between-group differences in steroid use, 30 day and in-hospital mortality rates, and rates of OP outcomes and recurrences. Pneumonia recurrence rate was significantly higher in SOP patients who were than were not treated with steroids ( P  = 0.035). Conclusions Infection is the main cause of SOP. Symptom onset is more rapid in patients with SOP than with COP. Some blood and BAL fluid test results differed significantly in the COP and SOP groups. Pleural effusion was more common in the SOP group but there were no differences in clinical course. Recurrence in patients with SOP was more common in those who were than were not treated with steroids.