Genome-wide association study identifies multiple HLA loci for sarcoidosis susceptibility.

Sarcoidosis is a complex systemic disease. Our study aimed to (1) identify novel alleles associated with sarcoidosis susceptibility; (2) provide an in-depth evaluation of HLA alleles and sarcoidosis susceptibility and (3) integrate genetic and transcription data to identify risk loci that may more directly impact disease pathogenesis. We report a genome-wide association study of 1335 sarcoidosis cases and 1264 controls of European descent (EA) and investigate associated alleles in a study of African Americans (AA: 1487 cases and 1504 controls). The EA and AA cohort was recruited from multiple United States sites. HLA alleles were imputed and tested for association with sarcoidosis susceptibility. Expression quantitative locus and colocalization analysis were performed using a subset of subjects with transcriptome data. Forty-nine SNPs in the HLA region in HLA-DRA, -DRB9, -DRB5, -DQA1 and BRD2 genes were significantly associated with sarcoidosis susceptibility in EA, rs3129888 was also a risk variant for sarcoidosis in AA. Classical HLA alleles DRB1*0101, DQA1*0101 and DQB1*0501, which are highly correlated, were also associated with sarcoidosis. rs3135287 near HLA-DRA was associated with HLA-DRA expression in peripheral blood mononuclear cells and bronchoalveolar lavage from subjects and lung tissue and whole blood from GTEx. We identified six novel SNPs (out of the seven SNPs representing the 49 significant SNPs) and nine HLA alleles associated with sarcoidosis susceptibility in the largest EA population. We also replicated our findings in an AA population. Our study reiterates the potential role of antigen recognition and/or presentation HLA class II genes in sarcoidosis pathogenesis.

Multi-omic signatures of sarcoidosis and progression in bronchoalveolar lavage cells.

BACKGROUND: Sarcoidosis is a heterogeneous granulomatous disease with no accurate biomarkers of disease progression. Therefore, we profiled and integrated the DNA methylome, mRNAs, and microRNAs to identify molecular changes associated with sarcoidosis and disease progression that might illuminate underlying mechanisms of disease and potential biomarkers. METHODS: Bronchoalveolar lavage cells from 64 sarcoidosis subjects and 16 healthy controls were used. DNA methylation was profiled on Illumina HumanMethylationEPIC arrays, mRNA by RNA-sequencing, and miRNAs by small RNA-sequencing. Linear models were fit to test for effect of sarcoidosis diagnosis and progression phenotype, adjusting for age, sex, smoking, and principal components of the data. We built a supervised multi-omics model using a subset of features from each dataset. RESULTS: We identified 1,459 CpGs, 64 mRNAs, and five miRNAs associated with sarcoidosis versus controls and four mRNAs associated with disease progression. Our integrated model emphasized the prominence of the PI3K/AKT1 pathway, which is important in T cell and mTOR function. Novel immune related genes and miRNAs including LYST, RGS14, SLFN12L, and hsa-miR-199b-5p, distinguished sarcoidosis from controls. Our integrated model also demonstrated differential expression/methylation of IL20RB, ABCC11, SFSWAP, AGBL4, miR-146a-3p, and miR-378b between non-progressive and progressive sarcoidosis. CONCLUSIONS: Leveraging the DNA methylome, transcriptome, and miRNA-sequencing in sarcoidosis BAL cells, we detected widespread molecular changes associated with disease, many which are involved in immune response. These molecules may serve as diagnostic/prognostic biomarkers and/or drug targets, although future testing is required for confirmation.

Genetic predisposition to sarcoidosis.

Sarcoidosis is a complex systemic disease with clinical heterogeneity based on varying phenotypes and natural history. The detailed etiology of sarcoidosis remains unknown, but genetic predisposition as well as environmental exposures play a significant role in disease pathogenesis. We performed a comprehensive review of germline genetic (DNA) and transcriptomic (RNA) studies of sarcoidosis, including both previous studies and more recent findings. In this review, we provide an assessment of the following: genetic variants in sarcoidosis susceptibility and phenotypes, ancestry- and sex-specific genetic variants in sarcoidosis, shared genetic architecture between sarcoidosis and other diseases, and gene-environment interactions in sarcoidosis. We also highlight the unmet needs in sarcoidosis genetic studies, including the pressing requirement to include diverse populations and have consistent definitions of phenotypes in the sarcoidosis research community to help advance the application of genetic predisposition to sarcoidosis disease risk and manifestations.

Multiomic Signatures of Chronic Beryllium Disease Bronchoalveolar Lavage Cells Relate to T-Cell Function and Innate Immunity.

Chronic beryllium disease (CBD) is a Th1 granulomatous lung disease preceded by sensitization to beryllium (BeS). We profiled the methylome, transcriptome, and selected proteins in the lung to identify molecular signatures and networks associated with BeS and CBD. BAL cell DNA and RNA were profiled using microarrays from CBD (n = 30), BeS (n = 30), and control subjects (n = 12). BAL fluid proteins were measured using Olink Immune Response Panel proteins from CBD (n = 22) and BeS (n = 22) subjects. Linear models identified features associated with CBD, adjusting for covariation and batch effects. Multiomic integration methods identified correlated features between datasets. We identified 1,546 differentially expressed genes in CBD versus control subjects and 204 in CBD versus BeS. Of the 101 shared transcripts, 24 have significant cis relationships between gene expression and DNA methylation, assessed using expression quantitative trait methylation analysis, including genes not previously identified in CBD. A multiomic model of top DNA methylation and gene expression features demonstrated that the first component separated CBD from other samples and the second component separated control subjects from remaining samples. The top features on component one were enriched for T-lymphocyte function, and the top features on component two were enriched for innate immune signaling. We identified six differentially abundant proteins in CBD versus BeS, with two (SIT1 and SH2D1A) selected as important RNA features in the multiomic model. Our integrated analysis of DNA methylation, gene expression, and proteins in the lung identified multiomic signatures of CBD that differentiated it from BeS and control subjects.

Clinical phenotyping in sarcoidosis using cluster analysis.

BACKGROUND: Most phenotyping paradigms in sarcoidosis are based on expert opinion; however, no paradigm has been widely adopted because of the subjectivity in classification. We hypothesized that cluster analysis could be performed on common clinical variables to define more objective sarcoidosis phenotypes. METHODS: We performed a retrospective cohort study of 554 sarcoidosis cases to identify distinct phenotypes of sarcoidosis based on 29 clinical features. Model-based clustering was performed using the VarSelLCM R package and the Integrated Completed Likelihood (ICL) criteria were used to estimate number of clusters. To identify features associated with cluster membership, features were ranked based on variable importance scores from the VarSelLCM model, and additional univariate tests (Fisher's exact test and one-way ANOVA) were performed using q-values correcting for multiple testing. The Wasfi severity score was also compared between clusters. RESULTS: Cluster analysis resulted in 6 sarcoidosis phenotypes. Salient characteristics for each cluster are as follows: Phenotype (1) supranormal lung function and majority Scadding stage 2/3; phenotype (2) supranormal lung function and majority Scadding stage 0/1; phenotype (3) normal lung function and split Scadding stages between 0/1 and 2/3; phenotype (4) obstructive lung function and majority Scadding stage 2/3; phenotype (5) restrictive lung function and majority Scadding stage 2/3; phenotype (6) mixed obstructive and restrictive lung function and mostly Scadding stage 4. Although there were differences in the percentages, all Scadding stages were encompassed by all of the phenotypes, except for phenotype 1, in which none were Scadding stage 4. Clusters 4, 5, 6 were significantly more likely to have ever been on immunosuppressive treatment and had higher Wasfi disease severity scores. CONCLUSIONS: Cluster analysis produced 6 sarcoidosis phenotypes that demonstrated less severe and severe phenotypes. Phenotypes 1, 2, 3 have less lung function abnormalities, a lower percentage on immunosuppressive treatment and lower Wasfi severity scores. Phenotypes 4, 5, 6 were characterized by lung function abnormalities, more parenchymal abnormalities, an increased percentage on immunosuppressive treatment and higher Wasfi severity scores. These data support using cluster analysis as an objective and clinically useful way to phenotype sarcoidosis subjects and to empower clinicians to identify those with more severe disease versus those who have less severe disease, independent of Scadding stage.

Blood Transcriptomics Predicts Progression of Pulmonary Fibrosis and Associated Natural Killer Cells.

Rationale: Disease activity in idiopathic pulmonary fibrosis (IPF) remains highly variable, poorly understood, and difficult to predict. Objectives: To identify a predictor using short-term longitudinal changes in gene expression that forecasts future FVC decline and to characterize involved pathways and cell types. Methods: Seventy-four patients from COMET (Correlating Outcomes with Biochemical Markers to Estimate Time-Progression in IPF) cohort were dichotomized as progressors (≥10% FVC decline) or stable. Blood gene-expression changes within individuals were calculated between baseline and 4 months and regressed with future FVC status, allowing determination of expression variations, sample size, and statistical power. Pathway analyses were conducted to predict downstream effects and identify new targets. An FVC predictor for progression was constructed in COMET and validated using independent cohorts. Peripheral blood mononuclear single-cell RNA-sequencing data from healthy control subjects were used as references to characterize cell type compositions from bulk peripheral blood mononuclear RNA-sequencing data that were associated with FVC decline. Measurements and Main Results: The longitudinal model reduced gene-expression variations within stable and progressor groups, resulting in increased statistical power when compared with a cross-sectional model. The FVC predictor for progression anticipated patients with future FVC decline with 78% sensitivity and 86% specificity across independent IPF cohorts. Pattern recognition receptor pathways and mTOR pathways were downregulated and upregulated, respectively. Cellular deconvolution using single-cell RNA-sequencing data identified natural killer cells as significantly correlated with progression. Conclusions: Serial transcriptomic change predicts future FVC decline. An analysis of cell types involved in the progressor signature supports the novel involvement of natural killer cells in IPF progression.

The Club Cell Marker SCGB1A1 Downstream of FOXA2 is Reduced in Asthma.

Human SCGB1A1 protein has been shown to be significantly reduced in BAL, sputum, and serum from humans with asthma as compared with healthy individuals. However, the mechanism of this reduction and its functional impact have not been entirely elucidated. By mining online datasets, we found that the mRNA of SCGB1A1 was significantly repressed in brushed human airway epithelial cells from individuals with asthma, and this repression appeared to be associated with reduced expression of FOXA2. Consistently, both Scgb1A1 and FoxA2 were downregulated in an ovalbumin-induced mouse model of asthma. Furthermore, compared with wild-type mice, Scgb1a1 knockout mice had increased airway hyperreactivity and inflammation when they were exposed to ovalbumin, confirming the antiinflammatory role of Scgb1a1 in protection against asthma phenotypes. To search for potential asthma-related stimuli of SCGB1A1 repression, we tested T-helper cell type 2 cytokines. Both IL-4 and IL-13 repressed epithelial expression of SCGB1A1 and FOXA2. Importantly, infection of epithelial cells with human rhinovirus similarly reduced expression of these two genes, which suggests that FOXA2 may be the common regulator of SCGB1A1. To establish the causal role of reduced FOXA2 in SCGB1A1 repression, we demonstrated that FOXA2 was required for SCGB1A1 expression at baseline. FOXA2 overexpression was sufficient to drive promoter activity and expression of SCGB1A1 and was also able to restore the repressed SCGB1A1 expression in IL-13-treated or rhinovirus-infected cells. Taken together, these findings suggest that low levels of epithelial SCGB1A1 in asthma are caused by reduced FOXA2 expression.

Nonisolated Small Bowel Gastrointestinal Angiodysplasias are Associated With Higher Rebleeding Rates When Compared With Isolated Small Bowel Gastrointestinal Angiodysplasia on Video Capsule Endoscopy.

BACKGROUND: Gastrointestinal angiodysplasias (GIAD) are commonly diagnosed in the small bowel but can be located in other areas of the gastrointestinal tract. About half of patients diagnosed with GIAD have more than 1 lesion and 20% of patients have GIAD in both the small bowel and a source outside of the small bowel (nonisolated to small bowel GIAD or NISGIAD). The remaining patients with GIAD have lesions isolated to the small bowel (ISGIAD). Complications including rebleeding, hospitalization and mortality rates have not been previously analyzed between these 2 groups. AIM: To compare rebleeding, hospitalization and mortality rates between ISGIAD and NISGIAD. The secondary goals were to evaluate comorbidities that may be associated with ISGIAD and/or NISGIAD, and to determine if any of these comorbidities are associated with a higher risk of rebleeding from GIAD. MATERIALS AND METHODS: This was a retrospective study that included 425 patients who underwent video capsule endoscopy between 2006 and 2013. Patients underwent esophagogastroduodenoscopy and colonoscopy before video capsule endoscopy. The primary indications for workup included obscure gastrointestinal bleeding. After exclusion criteria, 87 patients diagnosed with GIAD remained, 57 patients with ISGIAD and 30 with NISGIAD. Categorical variables were compared by the Fisher exact test or χ test and continuous data were compared using the Student T test. RESULTS: Risk factors associated with rebleeding rates included coronary artery disease, chronic kidney disease, and congestive heart failure on multivariate analysis. Odds ratios for rebleeding was found in patients with NISGIAD (odds ratio, 4.222; P=0.036). There was no difference in hospitalization rates between patients with ISGIAD and NISGIAD. There was no statistically significant difference in mortality from any cause at 30, 60, and 90 days in patients with ISGIAD and NISGIAD. CONCLUSIONS: In this retrospective analysis of GIAD at a single institution, patients with NISGIAD compared with ISGIAD had a 4 times odds of rebleeding within 1 year after capsule endoscopy. This is a novel study, as the distribution of GIAD has not been previously described as being a risk factor for rebleeding.

Genome-wide association and network analysis of lung function in the Framingham Heart Study.

Single nucleotide polymorphisms have been found to be associated with pulmonary function using genome-wide association studies. However, lung function is a complex trait that is likely to be influenced by multiple gene-gene interactions besides individual genes. Our goal is to build a cellular network to explore the relationship between pulmonary function and genotypes by combining SNP level and network analyses using longitudinal lung function data from the Framingham Heart Study. We analyzed 2,698 genotyped participants from the Offspring cohort that had an average of 3.35 spirometry measurements per person for a mean length of 13 years. Repeated forced expiratory volume in one second (FEV1 ) and the ratio of FEV1 to forced vital capacity (FVC) were used as outcomes. Data were analyzed using linear-mixed models for the association between lung function and alleles by accounting for the correlation among repeated measures over time within the same subject and within-family correlation. Network analyses were performed using dmGWAS and validated with data from the Third Generation cohort. Analyses identified SMAD3, TGFBR2, CD44, CTGF, VCAN, CTNNB1, SCGB1A1, PDE4D, NRG1, EPHB1, and LYN as contributors to pulmonary function. Most of these genes were novel that were not found previously using solely SNP-level analysis. These novel genes are involving the transforming growth factor beta (TGFB)-SMAD pathway, Wnt/beta-catenin pathway, etc. Therefore, combining SNP-level and network analyses using longitudinal lung function data is a useful alternative strategy to identify risk genes.

Occupational exposures and longitudinal lung function decline.

BACKGROUND: Few longitudinal studies have been conducted on occupational exposure and lung function. This study investigated occupational dust exposure effects on lung function and whether genetic variants influence such effects. METHODS: The study population (1,332 participants) was from the Framingham Heart Study, in which participant lung function measures were available from up to five examinations over nearly 17 years. Occupational dust exposures were classified into "more" and "less" likely dust exposure. We used linear mixed effects models for the analysis. RESULTS: Participants with more likely dust exposure had a mean 4.5 mL/year excess loss rate of FEV1 over time. However, occupational dust exposures alone or interactions with age or time had no significant effect on FEV1 /FVC. No statistically significant effects of genetic modifications in the different subgroups were identified for FEV1 loss. CONCLUSIONS: Occupational dust exposures may accelerate the rate of FEV1 loss but not FEV1 /FVC loss.

COPD with elevated sputum group 2 innate lymphoid cells is characterized by severe disease.

Rationale: Pulmonary innate immune cells play a central role in the initiation and perpetuation of chronic obstructive pulmonary disease (COPD), however the precise mechanisms that orchestrate the development and severity of COPD are poorly understood. Objectives: We hypothesized that the recently described family of innate lymphoid cells (ILCs) play an important role in COPD. Methods: Subjects with COPD and healthy controls were clinically evaluated, and their sputum samples were assessed by flow cytometry. A mouse model of spontaneous COPD [genetically deficient in surfactant protein-D (SP-D -/- )] and ozone (O 3 ) exposure were used to examine the mechanism by which lack of functional SP-D may skew ILC2s to produce IL-17A in combination with IL-5 and IL-13, leading to a mixed inflammatory profile and more severe disease. Measurements and Main Results: COPD was characterized by poor spirometry, sputum inflammation, and the emergence of sputum GATA3 + ILCs (ILC2s), but not T-bet + ILCs (ILC1s) nor RORγt + ILCs (ILC3s). COPD subjects with elevated sputum ILC2s (the ILC2 high group) had worse spirometry and sputum neutrophilia and eosinophilia than healthy and ILC2 low subjects. This was associated with the presence of dual-positive IL-5 + IL-17A + and IL-13 + IL-17A + ILCs and nonfunctional SP-D in the sputum in ILC2 high subjects. SP-D -/- mice showed spontaneous airway neutrophilia. Lack of SP-D in the mouse lung licensed ILC2s to produce IL-17A, which was dose-dependently inhibited by recombinant SP-D. SP-D -/- mice showed enhanced susceptibility to O 3 -induced airway neutrophilia, which was associated with the emergence of inflammatory IL-13 + IL-17A + ILCs. Conclusions: We report that the presence of sputum ILC2s predicts the severity of COPD, and unravel a novel pathway of IL-17A plasticity in lung ILC2s, prevented by the immunomodulatory protein SP-D.

The textures of sarcoidosis: quantifying lung disease through variograms.

Objective: Sarcoidosis is a granulomatous disease affecting the lungs in over 90% of patients. Qualitative assessment of chest CT by radiologists is standard clinical practice and reliable quantification of disease from CT would support ongoing efforts to identify sarcoidosis phenotypes. Standard imaging feature engineering techniques such as radiomics suffer from extreme sensitivity to image acquisition and processing, potentially impeding generalizability of research to clinical populations. In this work, we instead investigate approaches to engineering variogram-based features with the intent to identify a robust, generalizable pipeline for image quantification in the study of sarcoidosis. Approach: For a cohort of more than 300 individuals with sarcoidosis, we investigated 24 feature engineering pipelines differing by decisions for image registration to a template lung, empirical and model variogram estimation methods, and feature harmonization for CT scanner model, and subsequently 48 sets of phenotypes produced through unsupervised clustering. We then assessed sensitivity of engineered features, phenotypes produced through unsupervised clustering, and sarcoidosis disease signal strength to pipeline. Main results: We found that variogram features had low to mild association with scanner model and associations were reduced by image registration. For each feature type, features were also typically robust to all pipeline decisions except image registration. Strength of disease signal as measured by association with pulmonary function testing and some radiologist visual assessments was strong (optimistic AUC ≈ 0.9, p ≪ 0.0001 in models for architectural distortion, conglomerate mass, fibrotic abnormality, and traction bronchiectasis) and fairly consistent across engineering approaches regardless of registration and harmonization for CT scanner. Significance: Variogram-based features appear to be a suitable approach to image quantification in support of generalizable research in pulmonary sarcoidosis.

Gene-environment interaction effects on lung function- a genome-wide association study within the Framingham heart study.

BACKGROUND: Previous studies in occupational exposure and lung function have focused only on the main effect of occupational exposure or genetics on lung function. Some disease-susceptible genes may be missed due to their low marginal effects, despite potential involvement in the disease process through interactions with the environment. Through comprehensive genome-wide gene-environment interaction studies, we can uncover these susceptibility genes. Our objective in this study was to explore gene by occupational exposure interaction effects on lung function using both the individual SNPs approach and the genetic network approach. METHODS: The study population comprised the Offspring Cohort and the Third Generation from the Framingham Heart Study. We used forced expiratory volume in one second (FEV1) and ratio of FEV1 to forced vital capacity (FVC) as outcomes. Occupational exposures were classified using a population-specific job exposure matrix. We performed genome-wide gene-environment interaction analysis, using the Affymetrix 550 K mapping array for genotyping. A linear regression-based generalized estimating equation was applied to account for within-family relatedness. Network analysis was conducted using results from single-nucleotide polymorphism (SNP)-level analyses and from gene expression study results. RESULTS: There were 4,785 participants in total. SNP-level analysis and network analysis identified SNP rs9931086 (P(interaction) =1.16 × 10(-7)) in gene SLC38A8, which may significantly modify the effects of occupational exposure on FEV1. Genes identified from the network analysis included CTLA-4, HDAC, and PPAR-alpha. CONCLUSIONS: Our study implies that SNP rs9931086 in SLC38A8 and genes CTLA-4, HDAC, and PPAR-alpha, which are related to inflammatory processes, may modify the effect of occupational exposure on lung function.

Vaccine-elicited B- and T-cell immunity to SARS-CoV-2 is impaired in chronic lung disease patients.

Background: While vaccination against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) provides significant protection from coronavirus disease 2019, the protection afforded to individuals with chronic lung disease is less well established. This study seeks to understand how chronic lung disease impacts SARS-CoV-2 vaccine-elicited immunity. Methods: Deep immune phenotyping of humoral and cell-mediated responses to the SARS-CoV-2 vaccine was performed in patients with asthma, COPD and interstitial lung disease (ILD) compared to healthy controls. Results: 48% of vaccinated patients with chronic lung diseases had reduced antibody titres to the SARS-CoV-2 vaccine antigen relative to healthy controls. Vaccine antibody titres were significantly reduced among asthma (p<0.035), COPD (p<0.022) and a subset of ILD patients as early as 3-4 months after vaccination, correlating with decreased vaccine-specific memory B-cells in circulation. Vaccine-specific memory T-cells were significantly reduced in patients with asthma (CD8+ p<0.004; CD4+ p<0.023) and COPD (CD8+ p<0.008) compared to healthy controls. Impaired T-cell responsiveness was also observed in a subset of ILD patients (CD8+ 21.4%; CD4+ 42.9%). Additional heterogeneity between healthy and disease cohorts was observed among bulk and vaccine-specific follicular T-helper cells. Conclusions: Deep immune phenotyping of the SARS-CoV-2 vaccine response revealed the complex nature of vaccine-elicited immunity and highlights the need for more personalised vaccination schemes in patients with underlying lung conditions.

Vaccine-elicited B and T cell immunity to SARS-CoV-2 is impaired in chronic lung disease patients.

The protection afforded by vaccination against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) to individuals with chronic lung disease is not well established. To understand how chronic lung disease impacts SARS-CoV-2 vaccine-elicited immunity we performed deep immunophenotyping of the humoral and cell mediated SARS-CoV-2 vaccine response in an investigative cohort of vaccinated patients with diverse pulmonary conditions including asthma, chronic obstructive pulmonary disease (COPD), and interstitial lung disease (ILD). Compared to healthy controls, 48% of vaccinated patients with chronic lung diseases had reduced antibody titers to the SARS-CoV-2 vaccine antigen as early as 3-4 months after vaccination, correlating with decreased vaccine-specific memory B cells. Vaccine-specific CD4 and CD8 T cells were also significantly reduced in patients with asthma, COPD, and a subset of ILD patients compared to healthy controls. These findings reveal the complex nature of vaccine-elicited immunity in high-risk patients with chronic lung disease.

Multi-Omic Signatures of Sarcoidosis and Progression in Bronchoalveolar Lavage Cells.

Introduction: Sarcoidosis is a heterogeneous, granulomatous disease that can prove difficult to diagnose, with no accurate biomarkers of disease progression. Therefore, we profiled and integrated the DNA methylome, mRNAs, and microRNAs to identify molecular changes associated with sarcoidosis and disease progression that might illuminate underlying mechanisms of disease and potential genomic biomarkers. Methods: Bronchoalveolar lavage cells from 64 sarcoidosis subjects and 16 healthy controls were used. DNA methylation was profiled on Illumina HumanMethylationEPIC arrays, mRNA by RNA-sequencing, and miRNAs by small RNA-sequencing. Linear models were fit to test for effect of diagnosis and phenotype, adjusting for age, sex, and smoking. We built a supervised multi-omics model using a subset of features from each dataset. Results: We identified 46,812 CpGs, 1,842 mRNAs, and 5 miRNAs associated with sarcoidosis versus controls and 1 mRNA, SEPP1 - a protein that supplies selenium to cells, associated with disease progression. Our integrated model emphasized the prominence of the PI3K/AKT1 pathway in sarcoidosis, which is important in T cell and mTOR function. Novel immune related genes and miRNAs including LYST, RGS14, SLFN12L, and hsa-miR-199b-5p, distinguished sarcoidosis from controls. Our integrated model also demonstrated differential expression/methylation of IL20RB, ABCC11, SFSWAP, AGBL4, miR-146a-3p, and miR-378b between non-progressive and progressive sarcoidosis. Conclusions: Leveraging the DNA methylome, transcriptome, and miRNA-sequencing in sarcoidosis BAL cells, we detected widespread molecular changes associated with disease, many which are involved in immune response. These molecules may serve as diagnostic/prognostic biomarkers and/or drug targets, although future testing will be required for confirmation.

National Temporal Trends in Hospitalization and Inpatient Mortality in Patients With Pulmonary Sarcoidosis in the United States Between 2007 and 2018.

BACKGROUND: Sarcoidosis-related hospitalizations have been increasing in the past decade. There is a paucity of data on mortality trends over time in patients with pulmonary sarcoidosis and respiratory failure who are hospitalized. RESEARCH QUESTION: What are the national temporal trends over time in hospitalization and inpatient mortality rates in patients with pulmonary sarcoidosis and respiratory failure hospitalized in the United States between 2007 and 2018? STUDY DESIGN AND METHODS: Hospitalization data between 2007 and 2018 were extracted from the National Inpatient Sample for subjects with pulmonary sarcoidosis. Inpatient mortality was stratified by age, respiratory failure, mechanical ventilation (MV), hospital location, and setting (rural vs urban, academic vs nonacademic). A Cochran-Armitage test for trend was used to assess the linear trend in mortality, respiratory failure, and need for MV. RESULTS: Hospitalizations in patients with pulmonary sarcoidosis increased from 258.5 per 1,000,000 hospitalizations in 2007 to 705.7 per 1,000,000 in 2018. Hospitalizations for respiratory failure increased ninefold from 25.9 to 239.4 per 1,000,000 hospitalizations, and the need for MV increased threefold from 9.4 per 1,000,000 in 2007 to 29.4 per 1,000,000 in 2018. All-cause inpatient mortality was 2.6%; however, mortality was 13 times higher in patients with respiratory failure (10.6% vs 0.8%) and 26 times higher in patients who required MV (31.2% vs 1.2%). Inpatient mortality associated with respiratory failure declined 50% from 17.2% in 2007 to 6.6% in 2018. Independent inpatient mortality predictors were older age (adjusted hazard ratio [aHR], 1.025), respiratory failure (aHR, 3.12), need for MV (aHR, 6.01), pulmonary hypertension (pHTN; aHR, 1.44), pulmonary embolism (aHR, 1.61), and frailty (aHR, 3.10). INTERPRETATION: Hospitalizations for respiratory failure in patients with pulmonary sarcoidosis are increasing; however, inpatient mortality from respiratory failure has declined. Older age, respiratory failure, pHTN, and frailty are important predictors of inpatient mortality in patients with pulmonary sarcoidosis who are hospitalized.