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BackgroundTwo antifibrotic medications, pirfenidone and nintedanib, are approved for the treatment of idiopathic pulmonary fibrosis (IPF). Little is known about their real-world adoption.Research questionWhat are the real-world antifibrotic utilization rates and factors associated with uptake among a national cohort of veterans with IPF?Study design and methodsThis study identified veterans with IPF who received care either provided by the Veterans Affairs (VA) Healthcare System or non-VA care paid for by the VA. Patients who had filled at least one antifibrotic prescription through the VA pharmacy or Medicare Part D between October 15, 2014, and December 31, 2019, were identified. Hierarchical logistic regression models were used to examine factors associated with antifibrotic uptake, accounting for comorbidities, facility clustering, and follow-up time. Fine-Gray models were used to evaluate antifibrotic use by demographic factors, accounting for the competing risk of death.ResultsAmong 14,792 veterans with IPF, 17% received antifibrotics. There were significant disparities in adoption, with lower uptake associated with female sex (adjusted OR, 0.41; 95% CI, 0.27-0.63; P < .001), Black race (adjusted OR, 0.60; 95% CI, 0.49-0.73; P < .001), and rural residence (adjusted OR, 0.88; 95% CI, 0.80-0.97; P = .012). Veterans who received their index diagnosis of IPF outside the VA were less likely to receive antifibrotic therapy (adjusted OR, 0.15; 95% CI, 0.10-0.22; P < .001).InterpretationThis study is the first to evaluate the real-world adoption of antifibrotic medications among veterans with IPF. Overall uptake was low, and there were significant disparities in use. Interventions to address these issues deserve further investigation.

Rationale: There is limited literature exploring the relationship between military exposures and idiopathic pulmonary fibrosis (IPF). Objectives: To evaluate whether exposure to Agent Orange is associated with an increased risk of IPF among veterans. Methods: We used Veterans Health Administration data to identify patients diagnosed with IPF between 2010 and 2019. We restricted the cohort to male Vietnam veterans and performed multivariate logistic regression to examine the association between presumptive Agent Orange exposure and IPF. We conducted sensitivity analyses restricting the cohort to army veterans (highest theoretical burden of exposure, surrogate for dose response) and a more specific case definition of IPF. Fine-Gray competing risk models were used to evaluate age to IPF diagnosis. Measurements and Main Results: Among 3.6 million male Vietnam veterans, 948,103 (26%) had presumptive Agent Orange exposure. IPF occurred in 2.2% of veterans with Agent Orange exposure versus 1.9% without exposure (odds ratio, 1.14; 95% confidence interval [CI], 1.12-1.16; P

The Collaborative Cohort of Cohorts for COVID-19 Research (C4R) is a national prospective study of adults comprising 14 established US prospective cohort studies. Starting as early as 1971, investigators in the C4R cohort studies have collected data on clinical and subclinical diseases and their risk factors, including behavior, cognition, biomarkers, and social determinants of health. C4R links this pre-coronavirus disease 2019 (COVID-19) phenotyping to information on severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and acute and postacute COVID-related illness. C4R is largely population-based, has an age range of 18-108 years, and reflects the racial, ethnic, socioeconomic, and geographic diversity of the United States. C4R ascertains SARS-CoV-2 infection and COVID-19 illness using standardized questionnaires, ascertainment of COVID-related hospitalizations and deaths, and a SARS-CoV-2 serosurvey conducted via dried blood spots. Master protocols leverage existing robust retention rates for telephone and in-person examinations and high-quality event surveillance. Extensive prepandemic data minimize referral, survival, and recall bias. Data are harmonized with research-quality phenotyping unmatched by clinical and survey-based studies; these data will be pooled and shared widely to expedite collaboration and scientific findings. This resource will allow evaluation of risk and resilience factors for COVID-19 severity and outcomes, including postacute sequelae, and assessment of the social and behavioral impact of the pandemic on long-term health trajectories.

Rationale: The development of novel therapies for idiopathic pulmonary fibrosis (IPF) has brought increased attention to the population burden of disease. However, little is known about the epidemiology of IPF among U.S. Veterans. Objectives: This study examines temporal trends in incidence and prevalence, patient characteristics, and risk factors associated with IPF among a national cohort of U.S. Veterans. Methods: We used data from the Veterans Health Administration (VHA) electronic health record system to describe the incidence, prevalence, and geographic distribution of IPF between January 1, 2010, and December 31, 2019. We evaluated patient characteristics associated with IPF using multivariate logistic regression. Results: Among 10.7 million Veterans who received care from the VHA between 2010 and 2019, 139,116 (1.26%) were diagnosed with IPF. Using a narrow case definition of IPF, the prevalence increased from 276 cases per 100,000 in 2010 to 725 cases per 100,000 in 2019. The annual incidence increased from 73 cases per 100,000 person-years in 2010 to 210 cases per 100,000 person-years in 2019. Higher absolute incidence and prevalence rates were noted when a broader case definition of IPF was used. Risk factors associated with IPF among Veterans included older age, White race, tobacco use, and rural residence. After accounting for interactions, the average marginal difference in IPF prevalence between males and females was small. There was significant geographic heterogeneity of disease across the United States. Conclusions: This study is the first comprehensive epidemiologic analysis of IPF among the U.S. Veteran population. The incidence and prevalence of IPF among Veterans has increased over the past decade. The effect of sex on risk of IPF was attenuated once accounting for other risk factors. The geographic distribution of disease is heterogeneous across the United States with rural residence associated with higher odds of IPF. The reasons for these trends deserve further study.

Matrix metalloproteinase-7 level is associated with worse baseline pulmonary function and worse transplant-free survival in scleroderma interstitial lung disease https://bit.ly/3zZhja7

BackgroundThe major risk factor for idiopathic pulmonary fibrosis (IPF), MUC5B rs35705950, was found to be associated with rheumatoid arthritis-associated interstitial lung disease (RA-ILD). Whilst the MUC5B rs35705950 T risk allele has been associated with better survival in IPF, its impact on RA-ILD prognosis remains to be determined. Our objective was to explore the influence of MUC5B rs35705950 on survival and progression in RA-ILD.MethodsThrough an international retrospective observational study, patients with RA-ILD were genotyped for the MUC5B rs35705950 variant and consecutive pulmonary function tests (PFTs) findings were collected. Longitudinal data up to a 10-year follow-up were considered and analyzed using mixed regression models. Proportional hazards and joint proportional hazards models were used to analyze the association of baseline and longitudinal variables with lung transplant-free survival. Significant progression of RA-ILD was defined as at least an absolute or relative 10% decline of forced vital capacity at 2 years from baseline.ResultsOut of 321 registered patients, 261 were included in the study: 139 women (53.3%), median age at RA-ILD diagnosis 65 years (interquartile range [IQR] 57 to 71), 151 ever smokers (59.2%). Median follow-up was 3.5 years (IQR 1.3 to 6.6). Mortality rate was 32% (95%CI 19 to 42) at 10 years. The MUC5B rs35705950 variant did not impact lung transplant-free survival (HR for the T risk allele carriers=1.26; 95%CI 0.61 to 2.62; P=0.53). Decline in pulmonary function at 2 years was not influenced by MUC5B rs35705950 (OR=0.95; 95%CI 0.44 to 2.05; P=0.89), irrespective of the HRCT pattern.ConclusionIn this study, the MUC5B rs35705950 promoter variant did not influence transplant- free survival or decline in pulmonary function in patients with RA-ILD.

BackgroundThe major risk factor for idiopathic pulmonary fibrosis (IPF), MUC5B rs35705950, was found to be associated with rheumatoid arthritis-associated interstitial lung disease (RA-ILD). Whilst the MUC5B rs35705950 T risk allele has been associated with better survival in IPF, its impact on RA-ILD prognosis remains to be determined. Our objective was to explore the influence of MUC5B rs35705950 on survival and progression in RA-ILD.MethodsThrough an international retrospective observational study, patients with RA-ILD were genotyped for the MUC5B rs35705950 variant and consecutive pulmonary function tests (PFTs) findings were collected. Longitudinal data up to a 10-year follow-up were considered and analyzed using mixed regression models. Proportional hazards and joint proportional hazards models were used to analyze the association of baseline and longitudinal variables with lung transplant-free survival. Significant progression of RA-ILD was defined as at least an absolute or relative 10% decline of forced vital capacity at 2 years from baseline.ResultsOut of 321 registered patients, 261 were included in the study: 139 women (53.3%), median age at RA-ILD diagnosis 65 years (interquartile range [IQR] 57 to 71), 151 ever smokers (59.2%). Median follow-up was 3.5 years (IQR 1.3 to 6.6). Mortality rate was 32% (95%CI 19 to 42) at 10 years. The MUC5B rs35705950 variant did not impact lung transplant-free survival (HR for the T risk allele carriers=1.26; 95%CI 0.61 to 2.62; P=0.53). Decline in pulmonary function at 2 years was not influenced by MUC5B rs35705950 (OR=0.95; 95%CI 0.44 to 2.05; P=0.89), irrespective of the HRCT pattern.ConclusionIn this study, the MUC5B rs35705950 promoter variant did not influence transplant- free survival or decline in pulmonary function in patients with RA-ILD.

Rationale: There is an urgent need for simple, cost-effective prognostic biomarkers for idiopathic pulmonary fibrosis (IPF); biomarkers that show potential include monocyte count. Objectives: We used pooled data from pirfenidone and IFNγ-1b trials to explore the association between monocyte count and prognosis in patients with IPF. Methods: This retrospective pooled analysis included patients (active and placebo arms) from the following four phase III, randomized, placebo-controlled trials: ASCEND (NCT01366209), CAPACITY (NCT00287729 and NCT00287716), and INSPIRE (NCT00075998). Outcomes included IPF progression (≥10% absolute decline in FVC% predicted, ≥50 m decline in 6-minute-walk distance, or death), all-cause hospitalization, and all-cause mortality over 1 year. The relationship between monocyte count (defined as time-dependent) and outcomes was assessed using bivariate and multivariable models. Measurements and Main Results: This analysis included 2,067 patients stratified by monocyte count (at baseline:

AimsIdiopathic pulmonary fibrosis (IPF) is a genetically mediated, age-associated, progressive form of pulmonary fibrosis characterised pathologically by a usual interstitial pneumonia (UIP) pattern of fibrosis. The UIP pattern is also found in pulmonary fibrosis attributable to clinical diagnoses other than IPF (non-IPF UIP), whose clinical course is similarly poor, suggesting common molecular drivers. This study investigates whether IPF and non-IPF UIP lungs similarly express markers of telomere dysfunction and senescence.Methods and resultsTo test whether patients with IPF and non-IPF UIP share molecular drivers, lung tissues from 169 IPF patients and 57 non-IPF UIP patients were histopathologically and molecularly compared. Histopathological changes in both IPF and non-IPF UIP patients included temporal heterogeneity, microscopic honeycombing, fibroblast foci, and dense collagen fibrosis. Non-IPF UIP lungs were more likely to have lymphocytic infiltration, non-caseating granulomas, airway-centred inflammation, or small airways disease. Telomeres were shorter in alveolar type II (AECII) cells of both IPF and non-IPF UIP lungs than in those of age-similar, unused donor, controls. Levels of molecular markers of senescence (p16 and p21) were elevated in lysates of IPF and non-IPF UIP lungs. Immunostaining localised expression of these proteins to AECII cells. The mucin 5B (MUC5B) gene promoter variant minor allele frequency was similar between IPF and non-IPF UIP patients, and MUC5B expression was similar in IPF and non-IPF UIP lungs.ConclusionsMolecular markers of telomere dysfunction and senescence are pathologically expressed in both IPF and non-IPF UIP lungs. These findings suggest that common molecular drivers may contribute to the pathogenesis of UIP-associated pulmonary fibrosis, regardless of the clinical diagnosis.

Rationale: There is an urgent need for simple, cost-effective prognostic biomarkers for idiopathic pulmonary fibrosis (IPF); biomarkers that show potential include monocyte count. Objectives: We used pooled data from pirfenidone and IFNγ-1b trials to explore the association between monocyte count and prognosis in patients with IPF. Methods: This retrospective pooled analysis included patients (active and placebo arms) from the following four phase III, randomized, placebo-controlled trials: ASCEND (NCT01366209), CAPACITY (NCT00287729 and NCT00287716), and INSPIRE (NCT00075998). Outcomes included IPF progression (≥10% absolute decline in FVC% predicted, ≥50 m decline in 6-minute-walk distance, or death), all-cause hospitalization, and all-cause mortality over 1 year. The relationship between monocyte count (defined as time-dependent) and outcomes was assessed using bivariate and multivariable models. Measurements and Main Results: This analysis included 2,067 patients stratified by monocyte count (at baseline:

AimsIdiopathic pulmonary fibrosis (IPF) is a genetically mediated, age-associated, progressive form of pulmonary fibrosis characterised pathologically by a usual interstitial pneumonia (UIP) pattern of fibrosis. The UIP pattern is also found in pulmonary fibrosis attributable to clinical diagnoses other than IPF (non-IPF UIP), whose clinical course is similarly poor, suggesting common molecular drivers. This study investigates whether IPF and non-IPF UIP lungs similarly express markers of telomere dysfunction and senescence.Methods and resultsTo test whether patients with IPF and non-IPF UIP share molecular drivers, lung tissues from 169 IPF patients and 57 non-IPF UIP patients were histopathologically and molecularly compared. Histopathological changes in both IPF and non-IPF UIP patients included temporal heterogeneity, microscopic honeycombing, fibroblast foci, and dense collagen fibrosis. Non-IPF UIP lungs were more likely to have lymphocytic infiltration, non-caseating granulomas, airway-centred inflammation, or small airways disease. Telomeres were shorter in alveolar type II (AECII) cells of both IPF and non-IPF UIP lungs than in those of age-similar, unused donor, controls. Levels of molecular markers of senescence (p16 and p21) were elevated in lysates of IPF and non-IPF UIP lungs. Immunostaining localised expression of these proteins to AECII cells. The mucin 5B (MUC5B) gene promoter variant minor allele frequency was similar between IPF and non-IPF UIP patients, and MUC5B expression was similar in IPF and non-IPF UIP lungs.ConclusionsMolecular markers of telomere dysfunction and senescence are pathologically expressed in both IPF and non-IPF UIP lungs. These findings suggest that common molecular drivers may contribute to the pathogenesis of UIP-associated pulmonary fibrosis, regardless of the clinical diagnosis.

Chronic lung allograft dysfunction (CLAD) is the major barrier to long-term survival following lung transplantation, and new mechanistic biomarkers are needed. Lymphocytic bronchitis (LB) precedes CLAD and has a defined molecular signature. We hypothesized that this LB molecular signature would be associated with CLAD in small airway brushings independent of infection. We quantified RNA expression from small airway brushings and transbronchial biopsies, using RNAseq and digital RNA counting, respectively, for 22 CLAD cases and 27 matched controls. LB metagene scores were compared across CLAD strata by Wilcoxon rank sum test. We performed unbiased host transcriptome pathway and microbial metagenome analysis in airway brushes and compared machine-learning classifiers between the two tissue types. This LB metagene score was increased in CLAD airway brushes (p = .002) and improved prediction of graft failure (p = .02). Gene expression classifiers based on airway brushes outperformed those using transbronchial biopsies. While infection was associated with decreased microbial alpha-diversity (p ≤ .04), neither infection nor alpha-diversity was associated with LB gene expression. In summary, CLAD was associated with small airway gene expression changes not apparent in transbronchial biopsies in this cohort. Molecular analysis of airway brushings for diagnosing CLAD merits further examination in multicenter cohorts.

Chronic lung allograft dysfunction (CLAD) is the major barrier to long-term survival following lung transplantation, and new mechanistic biomarkers are needed. Lymphocytic bronchitis (LB) precedes CLAD and has a defined molecular signature. We hypothesized that this LB molecular signature would be associated with CLAD in small airway brushings independent of infection. We quantified RNA expression from small airway brushings and transbronchial biopsies, using RNAseq and digital RNA counting, respectively, for 22 CLAD cases and 27 matched controls. LB metagene scores were compared across CLAD strata by Wilcoxon rank sum test. We performed unbiased host transcriptome pathway and microbial metagenome analysis in airway brushes and compared machine-learning classifiers between the two tissue types. This LB metagene score was increased in CLAD airway brushes (p = .002) and improved prediction of graft failure (p = .02). Gene expression classifiers based on airway brushes outperformed those using transbronchial biopsies. While infection was associated with decreased microbial alpha-diversity (p ≤ .04), neither infection nor alpha-diversity was associated with LB gene expression. In summary, CLAD was associated with small airway gene expression changes not apparent in transbronchial biopsies in this cohort. Molecular analysis of airway brushings for diagnosing CLAD merits further examination in multicenter cohorts.

Rationale: Chronic hypersensitivity pneumonitis (CHP) is caused by an immune response to antigen inhalation and is characterized by variable histopathological and clinical features. A subset of subjects with CHP have usual interstitial pneumonia and appear to be clinically similar to subjects with idiopathic pulmonary fibrosis (IPF).Objectives: To determine the common and unique molecular features of CHP and IPF.Methods: Transcriptome analysis of lung samples from CHP (n = 82), IPF (n = 103), and unaffected controls (n = 103) was conducted. Differential gene expression was determined adjusting for sex, race, age, and smoking history and using false discovery rate to control for multiple comparisons.Measurements and Main Results: When compared with controls, we identified 413 upregulated and 317 downregulated genes in CHP and 861 upregulated and 322 downregulated genes in IPF. Concordantly upregulated or downregulated genes in CHP and IPF were related to collagen catabolic processes and epithelial development, whereas genes specific to CHP (differentially expressed in CHP when compared with control and not differentially expressed in IPF) were related to chemokine-mediated signaling and immune responsiveness. Using weighted gene coexpression network analysis, we found that among subjects with CHP, genes involved in adaptive immunity or epithelial cell development were associated with improved or reduced lung function, respectively, and that MUC5B expression was associated with epithelial cell development. MUC5B expression was also associated with lung fibrosis and honeycombing.Conclusions: Gene expression analysis of CHP and IPF identified signatures common to CHP and IPF, as well as genes uniquely expressed in CHP. Select modules of gene expression are characterized by distinct clinical and pathological features of CHP.

BackgroundGiven the phenotypic similarities between rheumatoid arthritis (RA)-associated interstitial lung disease (ILD) (hereafter, RA-ILD) and idiopathic pulmonary fibrosis, we hypothesized that the strongest risk factor for the development of idiopathic pulmonary fibrosis, the gain-of-function MUC5B promoter variant rs35705950, would also contribute to the risk of ILD among patients with RA.MethodsUsing a discovery population and multiple validation populations, we tested the association of the MUC5B promoter variant rs35705950 in 620 patients with RA-ILD, 614 patients with RA without ILD, and 5448 unaffected controls.ResultsAnalysis of the discovery population revealed an association of the minor allele of the MUC5B promoter variant with RA-ILD when patients with RA-ILD were compared with unaffected controls (adjusted odds ratio, 3.8; 95% confidence interval [CI], 2.8 to 5.2; P=9.7×10-17). The MUC5B promoter variant was also significantly overrepresented among patients with RA-ILD, as compared with unaffected controls, in an analysis of the multiethnic case series (adjusted odds ratio, 5.5; 95% CI, 4.2 to 7.3; P=4.7×10-35) and in a combined analysis of the discovery population and the multiethnic case series (adjusted odds ratio, 4.7; 95% CI, 3.9 to 5.8; P=1.3×10-49). In addition, the MUC5B promoter variant was associated with an increased risk of ILD among patients with RA (adjusted odds ratio in combined analysis, 3.1; 95% CI, 1.8 to 5.4; P=7.4×10-5), particularly among those with evidence of usual interstitial pneumonia on high-resolution computed tomography (adjusted odds ratio in combined analysis, 6.1; 95% CI, 2.9 to 13.1; P=2.5×10-6). However, no significant association with the MUC5B promoter variant was observed for the diagnosis of RA alone.ConclusionsWe found that the MUC5B promoter variant was associated with RA-ILD and more specifically associated with evidence of usual interstitial pneumonia on imaging. (Funded by Société Française de Rhumatologie and others.).

Doxorubicin (DOX) is commonly used to treat human malignancies, and its efficacy can be maximized by limiting the cardiac toxicity when combined with nanoparticles. Here, we reported a unique type of reversibly disulfide cross-linked micellar formulation of DOX (DOX-DCMs) for the targeted therapy of B-cell lymphoma. DOX-DCMs exhibited high drug loading capacity, optimal particle sizes (15-20 nm), outstanding stability in human plasma, and stimuli-responsive drug release profile under reductive conditions. DOX-DCMs significantly improved the pharmacokinetics of DOX, and its elimination half-life (t1/2) and area under curve (AUC) were 5.5 and 12.4 times of that of free DOX, respectively. Biodistribution studies showed that DOX-DCMs were able to preferentially accumulate in the tumor site and significantly reduce the cardiac uptake of DOX. In a xenograft model of human B-cell lymphoma, compared with the equivalent dose of free DOX and non-crosslinked counterpart, DOX-DCMs not only significantly inhibited the tumor growth and prolonged the survival rate, but also remarkably reduced DOX-associated cardiotoxicity. Furthermore, the exogenous administration of N-acetylcysteine (NAC) at 24 h further improved the therapeutic efficacy of DOX-DCMs, which provides a "proof-of-concept" for precise drug delivery on-demand, and may have great translational potential as future cancer nano-therapeutics.

RationaleCurrent diagnosis of chronic hypersensitivity pneumonitis (cHP) involves considering a combination of clinical, radiological, and pathological information in multidisciplinary team discussions. However, this approach is highly variable with poor agreement between centers.ObjectivesWe aimed to identify diagnostic criteria for cHP that reach consensus among international experts.MethodsA 3-round modified Delphi survey was conducted between April and August 2017. Forty-five experts in interstitial lung disease from 14 countries participated in the online survey. Diagnostic items included in round 1 were generated using expert interviews and literature review. During rounds 1 and 2, experts rated the importance of each diagnostic item on a 5-point Likert scale. The a priori threshold of consensus was ≥ 75% of experts rating a diagnostic item as very important or important. In the third round, experts graded the items that met consensus as important and provided their level of diagnostic confidence for a series of clinical scenarios.Measurements and main resultsConsensus was achieved on 18 of the 40 diagnostic items. Among these, experts gave the highest level of importance to the identification of a causative antigen, time relation between exposure and disease, mosaic attenuation on chest imaging, and poorly formed non-necrotizing granulomas on pathology. In clinical scenarios, the diagnostic confidence of experts in cHP was heightened by the presence of these diagnostic items.ConclusionThis consensus-based approach for the diagnosis of cHP represents a first step towards the development of international guidelines for the diagnosis of cHP.

BackgroundInterstitial lung disease (ILD) is an important cause of morbidity and mortality in patients with scleroderma (Scl). Risk prediction and prognostication in patients with Scl-ILD are challenging because of heterogeneity in the disease course.MethodsWe aimed to develop a clinical mortality risk prediction model for Scl-ILD. Patients with Scl-ILD were identified from two ongoing longitudinal cohorts: 135 patients at the University of California, San Francisco (derivation cohort) and 90 patients at the Mayo Clinic (validation cohort). Using these two separate cohorts, a mortality risk prediction model was developed and validated by testing every potential candidate Cox model, each including three or four variables of a possible 19 clinical predictors, for time to death. Model discrimination was assessed using the C-index.ResultsThree variables were included in the final risk prediction model (SADL): ever smoking history, age, and diffusing capacity of the lung for carbon monoxide (% predicted). This continuous model had similar performance in the derivation (C-index, 0.88) and validation (C-index, 0.84) cohorts. We created a point scoring system using the combined cohort (C-index, 0.82) and used it to identify a classification with low, moderate, and high mortality risk at 3 years.ConclusionsThe SADL model uses simple, readily accessible clinical variables to predict all-cause mortality in Scl-ILD.

The objective of this study was to investigate the reliability, feasibility and analytical impact of home-based measurement of forced vital capacity (FVC) and dyspnoea as clinical endpoints in idiopathic pulmonary fibrosis (IPF).Patients with IPF performed weekly home-based assessment of FVC and dyspnoea using a mobile hand-held spirometer and self-administered dyspnoea questionnaires. Weekly variability in FVC and dyspnoea was estimated, and sample sizes were simulated for a hypothetical 24-week clinical trial using either traditional office-based interval measurement or mobile weekly assessment.In total, 25 patients were enrolled. Mean adherence to weekly assessments over 24 weeks was greater than 90%. Compared with change assessment using baseline and 24-week measurements only, weekly assessment of FVC resulted in enhanced precision and power. For example, a hypothetical 24-week clinical trial with FVC as the primary endpoint would require 951 patients using weekly home spirometry compared with 3840 patients using office spirometry measures at weeks 1 and 24 only. The ability of repeated measures to reduce clinical trial sample size was influenced by the correlation structure of the data.Home monitoring can improve the precision of endpoint assessments, allowing for greater efficiency in clinical trials of therapeutics for IPF.

The objective of this study was to investigate the reliability, feasibility and analytical impact of home-based measurement of forced vital capacity (FVC) and dyspnoea as clinical endpoints in idiopathic pulmonary fibrosis (IPF).Patients with IPF performed weekly home-based assessment of FVC and dyspnoea using a mobile hand-held spirometer and self-administered dyspnoea questionnaires. Weekly variability in FVC and dyspnoea was estimated, and sample sizes were simulated for a hypothetical 24-week clinical trial using either traditional office-based interval measurement or mobile weekly assessment.In total, 25 patients were enrolled. Mean adherence to weekly assessments over 24 weeks was greater than 90%. Compared with change assessment using baseline and 24-week measurements only, weekly assessment of FVC resulted in enhanced precision and power. For example, a hypothetical 24-week clinical trial with FVC as the primary endpoint would require 951 patients using weekly home spirometry compared with 3840 patients using office spirometry measures at weeks 1 and 24 only. The ability of repeated measures to reduce clinical trial sample size was influenced by the correlation structure of the data.Home monitoring can improve the precision of endpoint assessments, allowing for greater efficiency in clinical trials of therapeutics for IPF.

RationaleHealth-related quality of life (HRQL) is impaired among patients with interstitial lung disease (ILD). Little is understood about HRQL in specific subtypes of ILD.ObjectivesThe aim of this study was to characterize and identify clinical determinants of HRQL among patients with rheumatoid arthritis-associated interstitial lung disease (RA-ILD) and compare them to patients with idiopathic pulmonary fibrosis (IPF).MethodsWe identified patients with a diagnosis of RA-ILD and IPF from an ongoing longitudinal cohort of ILD patients. HRQL was measured at their baseline visit using the Short Form Health Survey (SF-36), versions 1 and 2. Regression models were used to characterize and understand the relationship between selected baseline clinical covariates, the physical component score (PCS) and mental component score (MCS) of the SF-36.Measurements and main resultsRA-ILD patients (n = 50) were more likely to be younger and female compared to IPF patients (n = 50). After controlling for age and pulmonary function, RA-ILD patients had a lower HRQL compared to IPF patients, as measured by the PCS (P = 0.03), with significant differences in two of four PCS domains - bodily pain (P

BackgroundRheumatoid arthritis-associated interstitial lung disease (RA-ILD) is associated with significant morbidity and mortality. Similarities have been observed between patients with idiopathic pulmonary fibrosis (IPF) and the UIP (usual interstitial pneumonia) form of RA-ILD. The GAP (gender, age, physiology) model has been shown to predict mortality in patients with IPF, but its ability to predict mortality in RA-ILD is not known.MethodsWe identified 309 patients with RA-ILD at 4 academic centers with ongoing longitudinal cohorts of patients with ILD. The primary endpoint was mortality. To handle missing data (n = 219 subjects with complete dataset), multiple imputation by iterative chained equations was used. Using the GAP model as a baseline, we assessed improvements in mortality risk prediction achieved by incorporating additional variables. Model discrimination was assessed using the c-index, and calibration was checked by comparing observed and expected incidence of death.ResultsPatients had a mean age of 65 years and were predominantly female (54%). The mean forced vital capacity (FVC) % predicted was 73 and the mean diffusing capacity for carbon monoxide (DLCO) % predicted was 55. Twenty-four percent of the 236 patients with a high-resolution computed tomography scan available for review had a definite UIP pattern. The original GAP model, including gender, age, FVC%, and DLCO%, had a c-index of 0.746 in our cohort. Calibration of this model was satisfactory at 1, 2 and 3 years. Model discrimination was not meaningfully improved by adding other clinical variables.ConclusionThe GAP model that was derived for IPF performs similarly as a mortality risk prediction tool in RA-ILD.

BackgroundRheumatoid arthritis-associated interstitial lung disease (RA-ILD) is associated with significant morbidity and mortality. Similarities have been observed between patients with idiopathic pulmonary fibrosis (IPF) and the UIP (usual interstitial pneumonia) form of RA-ILD. The GAP (gender, age, physiology) model has been shown to predict mortality in patients with IPF, but its ability to predict mortality in RA-ILD is not known.MethodsWe identified 309 patients with RA-ILD at 4 academic centers with ongoing longitudinal cohorts of patients with ILD. The primary endpoint was mortality. To handle missing data (n = 219 subjects with complete dataset), multiple imputation by iterative chained equations was used. Using the GAP model as a baseline, we assessed improvements in mortality risk prediction achieved by incorporating additional variables. Model discrimination was assessed using the c-index, and calibration was checked by comparing observed and expected incidence of death.ResultsPatients had a mean age of 65 years and were predominantly female (54%). The mean forced vital capacity (FVC) % predicted was 73 and the mean diffusing capacity for carbon monoxide (DLCO) % predicted was 55. Twenty-four percent of the 236 patients with a high-resolution computed tomography scan available for review had a definite UIP pattern. The original GAP model, including gender, age, FVC%, and DLCO%, had a c-index of 0.746 in our cohort. Calibration of this model was satisfactory at 1, 2 and 3 years. Model discrimination was not meaningfully improved by adding other clinical variables.ConclusionThe GAP model that was derived for IPF performs similarly as a mortality risk prediction tool in RA-ILD.

Purpose of reviewA number of recent studies have explored the possibility to apply personalized medicine to interstitial lung diseases (ILDs), particularly idiopathic pulmonary fibrosis (IPF), the most common and deadly of the idiopathic interstitial pneumonias. In our review, we summarize and discuss the most recent literature on personalized medicine in IPF as well as hypersensitivity pneumonitis and sarcoidosis, with emphasis on patient subgroups for which a personalized approach to disease prognostication and management may become a reality in the near future.Recent findingsMost of the studies that have explored the applicability of personalized medicine to ILDs have been conducted in patients with IPF. Such studies have suggested the existence of several distinct disease subgroups defined by similar genetic profiles, molecular pathways, exposures and individual lifestyles. Personalized medicine in hypersensitivity pneumonitis is in its infancy. The development and applicability of personalized medicine to sarcoidosis, on the other hand, remains problematic for several reasons, including the lack of a diagnostic gold standard, the highly variable and unpredictable disease course, particularly across patients of different ethnicities, the poor correlation between disease activity and disease severity and the lack of a validated management algorithm.SummaryA number of distinct patient subgroups have been identified in ILDs. Although available data need to be validated longitudinally, the possibility to study homogeneous groups of patients may allow prediction of disease behavior and response to treatment with dramatic clinical implications.

Purpose of reviewA number of recent studies have explored the possibility to apply personalized medicine to interstitial lung diseases (ILDs), particularly idiopathic pulmonary fibrosis (IPF), the most common and deadly of the idiopathic interstitial pneumonias. In our review, we summarize and discuss the most recent literature on personalized medicine in IPF as well as hypersensitivity pneumonitis and sarcoidosis, with emphasis on patient subgroups for which a personalized approach to disease prognostication and management may become a reality in the near future.Recent findingsMost of the studies that have explored the applicability of personalized medicine to ILDs have been conducted in patients with IPF. Such studies have suggested the existence of several distinct disease subgroups defined by similar genetic profiles, molecular pathways, exposures and individual lifestyles. Personalized medicine in hypersensitivity pneumonitis is in its infancy. The development and applicability of personalized medicine to sarcoidosis, on the other hand, remains problematic for several reasons, including the lack of a diagnostic gold standard, the highly variable and unpredictable disease course, particularly across patients of different ethnicities, the poor correlation between disease activity and disease severity and the lack of a validated management algorithm.SummaryA number of distinct patient subgroups have been identified in ILDs. Although available data need to be validated longitudinally, the possibility to study homogeneous groups of patients may allow prediction of disease behavior and response to treatment with dramatic clinical implications.

The objective of this study was to develop a diagnostic model that allows for a highly specific diagnosis of chronic hypersensitivity pneumonitis using clinical and radiological variables alone. Chronic hypersensitivity pneumonitis and other interstitial lung disease cases were retrospectively identified from a longitudinal database. High-resolution CT scans were blindly scored for radiographic features (eg, ground-glass opacity, mosaic perfusion) as well as the radiologist's diagnostic impression. Candidate models were developed then evaluated using clinical and radiographic variables and assessed by the cross-validated C-statistic. Forty-four chronic hypersensitivity pneumonitis and eighty other interstitial lung disease cases were identified. Two models were selected based on their statistical performance, clinical applicability and face validity. Key model variables included age, down feather and/or bird exposure, radiographic presence of ground-glass opacity and mosaic perfusion and moderate or high confidence in the radiographic impression of chronic hypersensitivity pneumonitis. Models were internally validated with good performance, and cut-off values were established that resulted in high specificity for a diagnosis of chronic hypersensitivity pneumonitis.

RationaleThere is no standardized education program for patients with interstitial lung disease (ILD). Pulmonary rehabilitation is a resource for structured disease education that is still geared primarily toward patients with chronic obstructive pulmonary disease.ObjectivesThe goals of this qualitative study were to identify the educational needs of patients with ILD and explore how pulmonary rehabilitation can become an appropriate setting for ILD education.MethodsFour focus groups including 24 patients with ILD and 10 semistructured interviews with healthcare professionals with expertise in ILD and/or pulmonary rehabilitation were conducted in two academic centers (University of California San Francisco and Centre Hospitalier de l'Université de Montréal). We conducted a qualitative thematic analysis of the transcripts using an iteratively developed codebook.Measurements and main resultsThe transcript analysis highlighted four major themes: patient dissatisfaction with the current educational model, lack of attention to emotional well-being, specific recommendations for educational content, and operationalizing education in the context of pulmonary rehabilitation. Seven key topics to be included an ILD-specific, pulmonary rehabilitation-based education program were identified: disease education, symptom management, clinical tests, autonomy, oxygen use, medications, and end-of-life counseling.ConclusionsThis study provides a better understanding of the needs of patients and healthcare providers regarding education of patients with ILD. It lays the foundation for the development of a structured education intervention that could be delivered in the context of pulmonary rehabilitation.

Nanomedicine is an emerging form of therapy that harnesses the unique properties of particles that are nanometers in scale for biomedical application. Improving drug delivery to maximize therapeutic outcomes and to reduce drug-associated side effects are some of the cornerstones of present-day nanomedicine. Nanoparticles in particular have found a wide application in cancer treatment. Nanoparticles that offer a high degree of flexibility in design, application, and production based on the tumor microenvironment are projected to be more effective with rapid translation into clinical practice. The polymeric micellar nano-carrier is a popular choice for drug delivery applications. In this article, we describe a simple and effective protocol for synthesizing drug-loaded, disulfide cross-linked micelles based on the self-assembly of a well-defined amphiphilic linear-dendritic copolymer (telodendrimer, TD). TD is composed of polyethylene glycol (PEG) as the hydrophilic segment and a thiolated cholic acid cluster as the core-forming hydrophobic moiety attached stepwise to an amine-terminated PEG using solution-based peptide chemistry. Chemotherapy drugs, such as paclitaxel (PTX), can be loaded using a standard solvent evaporation method. The O2-mediated oxidation was previously utilized to form intra-micellar disulfide cross-links from free thiol groups on the TDs. However, the reaction was slow and not feasible for large-scale production. Recently, an H2O2-mediated oxidation method was explored as a more feasible and efficient approach, and it was 96 times faster than the previously reported method. Using this approach, 50 g of PTX-loaded, disulfide cross-linked nanoparticles have been successfully produced with narrow particle size distribution and high drug loading efficiency. The stability of the resulting micelle solution is analyzed using disrupting conditions such as co-incubation with a detergent, sodium dodecyl sulfate, with or without a reducing agent. The drug-loaded, disulfide cross-linked micelles demonstrated less hemolytic activity when compared to their non-cross-linked counterparts.

BackgroundSuccessful lung transplantation for patients with pulmonary fibrosis from telomerase mutations may be limited by systemic complications of telomerase dysfunction, including myelosuppression, cirrhosis, and malignancy. We describe clinical outcomes in 14 lung transplant recipients with telomerase mutations.MethodsSubjects underwent lung transplantation between February 2005 and April 2014 at 5 transplant centers. Data were abstracted from medical records, focusing on outcomes reflecting post-transplant treatment effects likely to be complicated by telomerase mutations.ResultsThe median age of subjects was 60.5 years (interquartile range = 52.0-62.0), 64.3% were male, and the mean post-transplant observation time was 3.2 years (SD ± 2.9). A mutation in telomerase reverse transcriptase was present in 11 subjects, a telomerase RNA component mutation was present in 2 subjects, and an uncharacterized mutation was present in 1 subject. After lung transplantation, 10 subjects were leukopenic and 5 did not tolerate lymphocyte anti-proliferative agents. Six subjects developed recurrent lower respiratory tract infections, 7 developed acute cellular rejection (A1), and 4 developed chronic lung allograft dysfunction. Eight subjects developed at least 1 episode of acute renal failure and 10 developed chronic renal insufficiency. In addition, 3 subjects developed cancer. No subjects had cirrhosis. At data censorship, 13 subjects were alive.ConclusionsThe clinical course for lung transplant recipients with telomerase mutations is complicated by renal disease, leukopenia with intolerance of lymphocyte anti-proliferative agents, and recurrent lower respiratory tract infections. In contrast, cirrhosis was absent, acute cellular rejection was mild, and development of chronic lung allograft dysfunction was comparable to other lung transplant recipients. Although it poses challenges, lung transplantation may be feasible for patients with pulmonary fibrosis from telomerase mutations.

BackgroundForced vital capacity (FVC) is a key measure of disease severity in patients with idiopathic pulmonary fibrosis (IPF) and is an important clinical trial endpoint. We hypothesize that reversible airflow limitation co-exists in a subgroup of patients with IPF, and that bronchodilator use will improve the performance characteristics of FVC.MethodsIPF patients with pre and post-bronchodilator spirometry testing performed were identified from two tertiary referral cohorts. The difference between pre and post-bronchodilator FVC (intra-test difference) was calculated. The test characteristics of pre and post-bronchodilator FVC change over time (inter-test difference) were assessed in patients with sequential spirometry, and were used to generate sample size estimates for hypothetical clinical trials using change in FVC as the primary endpoint.ResultsThere were 551 patients, contributing 967 unique spirometry tests. The mean intra-test increase in FVC with bronchodilator use was 0.04 L (2.71 vs. 2.75 L, p

BackgroundShort telomere lengths are found in a subset of patients with idiopathic pulmonary fibrosis, but their clinical significance is unknown. Our aim was to investigate whether patients with various blood leucocyte telomere lengths had different overall survival.MethodsIn this observational cohort study, we enrolled patients with interstitial lung disease from Dallas, TX (primary cohort), and from Chicago, IL, and San Francisco, CA (replication cohorts). We obtained genomic DNA samples from unrelated healthy controls in Dallas, TX, and spouses of patients were also enrolled as an independent control group. Telomere lengths were measured in genomic DNA samples isolated from peripheral blood obtained at the time of the initial enrolment assessment. The primary endpoint was transplant-free survival (ie, time to death or lung transplantation) in the Dallas cohort. Findings were validated in the two independent idiopathic pulmonary fibrosis cohorts (Chicago and San Francisco).Findings370 patients were enrolled into the Dallas cohort between June 17, 2003, and Aug 25, 2011. The 149 patients with idiopathic pulmonary fibrosis had shorter telomere lengths than did the 195 healthy controls (mean age-adjusted log-transformed ratio of telomere to single copy gene was -0.16 [SD 0.23] vs 0.00 [0.18]; p

BackgroundShort telomere lengths are found in a subset of patients with idiopathic pulmonary fibrosis, but their clinical significance is unknown. Our aim was to investigate whether patients with various blood leucocyte telomere lengths had different overall survival.MethodsIn this observational cohort study, we enrolled patients with interstitial lung disease from Dallas, TX (primary cohort), and from Chicago, IL, and San Francisco, CA (replication cohorts). We obtained genomic DNA samples from unrelated healthy controls in Dallas, TX, and spouses of patients were also enrolled as an independent control group. Telomere lengths were measured in genomic DNA samples isolated from peripheral blood obtained at the time of the initial enrolment assessment. The primary endpoint was transplant-free survival (ie, time to death or lung transplantation) in the Dallas cohort. Findings were validated in the two independent idiopathic pulmonary fibrosis cohorts (Chicago and San Francisco).Findings370 patients were enrolled into the Dallas cohort between June 17, 2003, and Aug 25, 2011. The 149 patients with idiopathic pulmonary fibrosis had shorter telomere lengths than did the 195 healthy controls (mean age-adjusted log-transformed ratio of telomere to single copy gene was -0.16 [SD 0.23] vs 0.00 [0.18]; p

BackgroundAbnormal acid gastro-oesophageal reflux is common in patients with idiopathic pulmonary fibrosis (IPF) and is considered a risk factor for development of IPF. Retrospective studies have shown improved outcomes in patients given anti-acid treatment. The aim of this study was to investigate the association between anti-acid treatment and disease progression in IPF.MethodsIn an analysis of data from three randomised controlled trials, we identified patients with IPF assigned to receive placebo. Case report forms had been designed to prospectively obtain data about diagnosis and treatment of abnormal acid gastro-oesophageal reflux in each trial. The primary outcome was estimated change in forced vital capacity (FVC) at 30 weeks (mean follow-up) in patients who were and were not using a proton-pump inhibitor or histamine-receptor-2 (H2) blocker.FindingsOf the 242 patients randomly assigned to the placebo groups of the three trials, 124 (51%) were taking a proton-pump inhibitor or H2 blocker at enrolment. After adjustment for sex, baseline FVC as a percentage of predicted, and baseline diffusing capacity of the lung for carbon monoxide as a percentage of predicted, patients taking anti-acid treatment at baseline had a smaller decrease in FVC at 30 weeks (-0·06 L, 95% CI -0·11 to -0·01) than did those not taking anti-acid treatment (-0·12 L, -0·17 to -0·08; difference 0·07 L, 95% CI 0-0·14; p=0·05).InterpretationAnti-acid treatment could be beneficial in patients with IPF, and abnormal acid gastro-oesophageal reflux seems to contribute to disease progression. Controlled clinical trials of anti-acid treatments are now needed.FundingNational Institutes of Health.

BackgroundAbnormal acid gastro-oesophageal reflux is common in patients with idiopathic pulmonary fibrosis (IPF) and is considered a risk factor for development of IPF. Retrospective studies have shown improved outcomes in patients given anti-acid treatment. The aim of this study was to investigate the association between anti-acid treatment and disease progression in IPF.MethodsIn an analysis of data from three randomised controlled trials, we identified patients with IPF assigned to receive placebo. Case report forms had been designed to prospectively obtain data about diagnosis and treatment of abnormal acid gastro-oesophageal reflux in each trial. The primary outcome was estimated change in forced vital capacity (FVC) at 30 weeks (mean follow-up) in patients who were and were not using a proton-pump inhibitor or histamine-receptor-2 (H2) blocker.FindingsOf the 242 patients randomly assigned to the placebo groups of the three trials, 124 (51%) were taking a proton-pump inhibitor or H2 blocker at enrolment. After adjustment for sex, baseline FVC as a percentage of predicted, and baseline diffusing capacity of the lung for carbon monoxide as a percentage of predicted, patients taking anti-acid treatment at baseline had a smaller decrease in FVC at 30 weeks (-0·06 L, 95% CI -0·11 to -0·01) than did those not taking anti-acid treatment (-0·12 L, -0·17 to -0·08; difference 0·07 L, 95% CI 0-0·14; p=0·05).InterpretationAnti-acid treatment could be beneficial in patients with IPF, and abnormal acid gastro-oesophageal reflux seems to contribute to disease progression. Controlled clinical trials of anti-acid treatments are now needed.FundingNational Institutes of Health.

BackgroundThe clinical significance of circulating autoantibodies in idiopathic pulmonary fibrosis is unclear. The objective of this study was to determine the frequency and clinical significance of circulating autoantibodies in idiopathic pulmonary fibrosis.MethodsWe measured an extensive panel of autoantibodies (including rheumatoid factor, anti-cyclic citrullinated peptide, and anti-nuclear antibodies by immunofluorescence) associated with connective tissue disease or vasculitis in a cohort of well-characterized patients with idiopathic pulmonary fibrosis (n = 67). The prevalence of circulating autoantibodies was compared between idiopathic pulmonary fibrosis patients and healthy controls (n = 52). We compared the clinical characteristics of patients with and without circulating autoantibodies, and analyzed the relationship between autoantibody positivity and transplant-free survival time.ResultsPositive autoantibodies were found in 22% of patients with IPF and 21% of healthy controls. There were no differences in the types of autoantibodies found between patients with idiopathic pulmonary fibrosis and healthy controls. Among patients with idiopathic pulmonary fibrosis, there were no significant differences in clinical characteristics between those with and without circulating autoantibodies. The presence of circulating autoantibodies was associated with longer transplant-free survival time on adjusted analysis, however the significance varied depending on which statistical model was used (HR 0.22-0.47, p value 0.02-0.17).ConclusionsThe frequency of circulating autoantibodies in patients with idiopathic pulmonary fibrosis is no different compared to healthy controls, but may be associated with longer survival.

BackgroundThe clinical significance of circulating autoantibodies in idiopathic pulmonary fibrosis is unclear. The objective of this study was to determine the frequency and clinical significance of circulating autoantibodies in idiopathic pulmonary fibrosis.MethodsWe measured an extensive panel of autoantibodies (including rheumatoid factor, anti-cyclic citrullinated peptide, and anti-nuclear antibodies by immunofluorescence) associated with connective tissue disease or vasculitis in a cohort of well-characterized patients with idiopathic pulmonary fibrosis (n = 67). The prevalence of circulating autoantibodies was compared between idiopathic pulmonary fibrosis patients and healthy controls (n = 52). We compared the clinical characteristics of patients with and without circulating autoantibodies, and analyzed the relationship between autoantibody positivity and transplant-free survival time.ResultsPositive autoantibodies were found in 22% of patients with IPF and 21% of healthy controls. There were no differences in the types of autoantibodies found between patients with idiopathic pulmonary fibrosis and healthy controls. Among patients with idiopathic pulmonary fibrosis, there were no significant differences in clinical characteristics between those with and without circulating autoantibodies. The presence of circulating autoantibodies was associated with longer transplant-free survival time on adjusted analysis, however the significance varied depending on which statistical model was used (HR 0.22-0.47, p value 0.02-0.17).ConclusionsThe frequency of circulating autoantibodies in patients with idiopathic pulmonary fibrosis is no different compared to healthy controls, but may be associated with longer survival.

BackgroundStress of the endoplasmic reticulum (ER) leading to activation of the unfolded protein response (UPR) and alveolar epithelial cell (AEC) apoptosis may play a role in the pathogenesis of idiopathic pulmonary fibrosis (IPF). Our objectives were to determine whether circulating caspase-cleaved cytokeratin-18 (cCK-18) is a marker of AEC apoptosis in IPF, define the relationship of cCK-18 with activation of the UPR, and assess its utility as a diagnostic biomarker.MethodsIPF and normal lung tissues were stained with the antibody (M30) that specifically binds cCK-18. The relationship between markers of the UPR and cCK-18 was determined in AECs exposed in vitro to thapsigargin to induce ER stress. cCK-18 was measured in serum from subjects with IPF, hypersensitivity pneumonitis (HP), nonspecific interstitial pneumonia (NSIP), and control subjects.ResultscCK-18 immunoreactivity was present in AECs of IPF lung, but not in control subjects. Markers of the UPR (phosphorylated IRE-1α and spliced XBP-1) were more highly expressed in IPF type II AECs than in normal type II AECs. Phosphorylated IRE-1α and cCK-18 increased following thapsigargin-induced ER stress. Serum cCK-18 level distinguished IPF from diseased and control subjects. Serum cCK-18 was not associated with disease severity or outcome.ConclusionscCK-18 may be a marker of AEC apoptosis and UPR activation in patients with IPF. Circulating levels of cCK-18 are increased in patients with IPF and cCK-18 may be a useful diagnostic biomarker.

Abstract Background Stress of the endoplasmic reticulum (ER) leading to activation of the unfolded protein response (UPR) and alveolar epithelial cell (AEC) apoptosis may play a role in the pathogenesis of idiopathic pulmonary fibrosis (IPF). Our objectives were to determine whether circulating caspase-cleaved cytokeratin-18 (cCK-18) is a marker of AEC apoptosis in IPF, define the relationship of cCK-18 with activation of the UPR, and assess its utility as a diagnostic biomarker. Methods IPF and normal lung tissues were stained with the antibody (M30) that specifically binds cCK-18. The relationship between markers of the UPR and cCK-18 was determined in AECs exposed in vitro to thapsigargin to induce ER stress. cCK-18 was measured in serum from subjects with IPF, hypersensitivity pneumonitis (HP), nonspecific interstitial pneumonia (NSIP), and control subjects. Results cCK-18 immunoreactivity was present in AECs of IPF lung, but not in control subjects. Markers of the UPR (phosphorylated IRE-1α and spliced XBP-1) were more highly expressed in IPF type II AECs than in normal type II AECs. Phosphorylated IRE-1α and cCK-18 increased following thapsigargin-induced ER stress. Serum cCK-18 level distinguished IPF from diseased and control subjects. Serum cCK-18 was not associated with disease severity or outcome. Conclusions cCK-18 may be a marker of AEC apoptosis and UPR activation in patients with IPF. Circulating levels of cCK-18 are increased in patients with IPF and cCK-18 may be a useful diagnostic biomarker.