Scadding Stage Research Articles

Elevated serum angiotensin converting enzyme correlates with specific HLA-DRB1 alleles and extrapulmonary manifestations in sarcoidosis

BackgroundGenetics influence the clinical picture in sarcoidosis, a granulomatous heterogeneous disease often accompanied by elevated serum angiotensin converting enzyme (s-ACE). We aimed to investigate if certain HLA-DRB1 alleles correlate with the levels of s-ACE, known as a marker of the granuloma burden. MethodsMedical journals of patients with sarcoidosis from a Swedish clinical registry were retrospectively examined to extract the highest recorded s-ACE value and analysed in relation to patient characteristics including phenotype [Löfgren syndrome (LS)/ non-LS], chest X-ray staging according to Scadding, treatment with immunosuppressants, presence of extrapulmonary manifestations (EPM), HLA-DRB1 alleles and prognosis (resolving vs. non-resolving disease within 2 years). Data were analysed with Fisher's exact test and Bonferroni correction was applied for HLA analyses. ResultsOf 1204 patients included, 40% had s-ACE levels above reference value. In comparison with patients with normal s-ACE, those with elevated levels were more often classified into non-LS (78% vs 59%, p < 0.001), and Scadding stage II (50% vs 38%, p < 0.001) but less often Scadding stage I (33% vs 46%, p < 0.001) and had more often EPM (45% vs 23%, p < 0.001). The patients with HLA-DRB1×04 had more often elevated s-ACE (p < 0.01) while those with HLA-DRB1×03 commonly had normal levels (p < 0.001). ConclusionsIn this retrospective study, HLA alleles associated with s-ACE levels in sarcoidosis patients, which in turn correlated with occurrence of EPM. These findings shed some new light on possible mechanisms behind differences in s-ACE levels.

Plasma collagen neoepitopes are associated with multiorgan disease in the ACCESS and GRADS sarcoidosis cohorts

IntroductionThe pathogenesis of sarcoidosis involves tissue remodelling mediated by the accumulation of abnormal extracellular matrix, which is partly the result of an imbalance in collagen synthesis, cross-linking and degradation. During...

Understanding the Added Value of High-Resolution CT Beyond Chest X-Ray in Determining Extent of Physiologic Impairment

BackgroundSarcoidosis staging has primarily relied on the Scadding chest radiographic system, although chest CT is finding increased clinical use. Research QuestionWhether standardized CT assessment provides additional understanding of lung function beyond Scadding stage and demographics is unknown and the focus of this study. Study Design and MethodsWe used the NHLBI study Genomics Research in Alpha-1 Anti-Trypsin Deficiency and Sarcoidosis (GRADS) sarcoidosis cases(N=351) with Scadding stage and Chest CT scans obtained in a standardized manner. One chest radiologist scored all CT scans with a visual scoring system, with a subset read by another chest radiologist. We compared demographic features, Scadding stage and CT findings, and correlation between these measures. Associations between spirometry and DLCO and CT and Scadding stage were determined using regression analysis (N=318). Agreement between readers was evaluated using Cohen’s Kappa. ResultsCT features were inconsistent with Scadding stage in about ∼40% of cases. Most CT features assessed on visual scoring were negatively associated with lung function. Associations persisted for FEV1 and DLCO when adjusting for Scadding stage, although some CT feature associations with FVC became insignificant. Scadding stage was primarily associated with FEV1 and inclusion of CT features reduced significance in association between Scadding and lung function. Multivariable regression modeling to identify radiologic measures explaining lung function included Scadding stage for FEV1 and FEV1/FVC (P<0.05) and marginally for DLCO (P<0.15). Combinations of CT measures accounted for Scadding stage for FVC. Correlations among Scadding and CT features were noted. Agreement between readers was poor to moderate for presence/absence of CT features and poor for degree/location of abnormality. InterpretationCT features explained additional variability in lung function beyond Scadding stage, with some CT features obviating the associations between lung function and Scadding. Whether CT features/phenotypes/endotypes could be useful for managing patients with sarcoidosis needs more study.

Cardiopulmonary exercise testing complements both spirometry and nuclear imaging for assessing sarcoidosis stage and for monitoring disease activity.

Pulmonary sarcoidosis is a systemic disease that can confound established follow-up tools. Pulmonary function tests (PFTs) are recommended in initial and follow-up patient evaluations yet are imperfect predictors of disease progression. The cardiopulmonary exercise test (CPET) is another potentially useful monitoring tool, although previous studies report conflicting findings regarding which variables are altered by the disease. Nuclear imaging tests are also employed to assess inflammatory activity and may be predictive of functional deterioration. We asked whether PFTs or CPET are more diagnostic of disease stage, which subsets of functional variables are impacted by the disease, and how these relate to nuclear imaging signs of active inflammation. We collected retrospective data (spirometry, CPET, Gallium-67 scintigraphy, 18F-FDG PET/CT) from 48 patients and 10 controls. Disease severity was assessed following Scadding classification. First, we correlated individual PFTs and CPET parameters to Scadding stage and nuclear imaging data. Next, we performed Principal Component Analysis (PCA) on PFTs and CPET parameters, separated into respiratory, cardiovascular and metabolic subsets. Finally, we constructed multiple regression models to determine which variable subsets were the best predictors of Scadding stage and disease activity. The majority of PFTs and CPET single parameters were significantly correlated with patient stage, while only few correlated with disease activity. Nevertheless, multiple regression models were able to significantly relate PFTs and CPET to both disease stage and activity. Additionally, these analyses highlighted CPET cardiovascular parameters as the best overall predictors of disease stage and activity. Our results display how CPET and spirometry data complement each other for sarcoidosis disease staging, and how these tests are able to detect disease activity. Our findings suggest that CPET, a repeatable and non-invasive functional test, should be more routinely performed and taken into account in sarcoidosis patient follow-up.

Circulating Mitochondrial DNA Is Associated With High Levels of Fatigue in Two Independent Sarcoidosis Cohorts

Patients with sarcoidosis who develop severe clinical phenotypes of pulmonary fibrosis or multiorgan disease experience debilitating symptoms, with fatigue being a common chief complaint. Studies that have investigated this patient-related outcome measure (PROM) have used the Fatigue Assessment Scale (FAS), a self-reported questionnaire that reflects mental and physical domains. Despite extensive work, its cause is unknown and treatment options remain limited. Previously, we showed that the plasma of patients with sarcoidosis with extrapulmonary disease endorsing fatigue was enriched for mitochondrial DNA (mtDNA), a ligand for the innate immune receptor toll-like receptor 9 (TLR9). Through our cross-disciplinary platform, we investigated a relationship between sarcoidosis-induced fatigue and circulating mtDNA. Is there a psychobiologic mechanism that connects sarcoidosis-induced fatigue and mtDNA-mediated TLR9 activation? Using a local cohort of patients at Yale (discovery cohort) and the National Institutes of Health-sponsored Genomic Research in Alpha-1 Antitrypsin Deficiency and Sarcoidosis study (validation cohort), we scored the FAS and quantified in the plasma, mtDNA concentrations, TLR9 activation, and cytokine levels. Although FAS scores were independent of corticosteroid use and Scadding stage, we observed a robust association between FAS scores, which included mental and physical domains, and multiorgan sarcoidosis. Subsequently, we identified a significant correlation between plasma mtDNA concentrations and all domains of fatigue. Additionally, we found that TLR9 activation is associated with all aspects of the FAS and partially mediates this PROM through mtDNA. Last, we found that TLR9-associated soluble mediators in the plasma are independent of all facets of fatigue. Through our cross-disciplinary translational platform, we identified a previously unrecognized psychobiologic connection between sarcoidosis-induced fatigue and circulating mtDNA concentrations. Mechanistic work that investigates the contribution of mtDNA-mediated innate immune activation in this PROM and clinical studies with prospective cohorts has the potential to catalyze novel therapeutic strategies for this patient population and those with similar conditions.

Elderly-onset pulmonary sarcoidosis: A radiological approach to diagnosis.

The aim was to compare the radiological and clinical characteristics of sarcoidosis between elderly and non-elderly patients. This retrospective observational study was carried out in patients with sarcoidosis. Elderly-onset sarcoidosis was defined as sarcoidosis diagnosed in patients ≥65 years-old. Patients were stratified by age (≥65 years versus <65 years) and radiological and clinical data were compared between age groups. Of the 163 patients, 38 (23.3%) were in the elderly group and 125 (76.7%) were in the non-elderly group. Elderly patients more frequently demonstrated arthralgia (50% vs. 12.8%, p<0.001), coronary artery disease (15.8% vs. 2.4%, p=0.005), congestive heart failure (13.2% vs. 0.8%, p=0.003), pneumonia (7.9% vs. 0.8%, p=0.04), and pleural fluid (18.4% vs. 0.0%, p<0.001). Clinical remission was significantly more likely in younger patients than in the elderly (76.8% vs. 55.3%, p=0.01). The clinical course to chronic-progressive disease was similar in both groups (p=0.635). Radiologically, lymph nodes measuring 10-25 mm in the short axis (89.5% vs. 72.6%, p=0.032), usual interstitial pneumonia pattern (10.5% vs. 0.8%, p=0.011), and main pulmonary artery diameter above 30 mm (34.2% vs. 16.0%, p=0.014) were significantly more frequent in the elderly group. Elderly patients tended to demonstrate Scadding stage I and II sarcoidosis (39.5% and 31.6%). Presentation of elderly-onset sarcoidosis appears to differ from young-onset sarcoidosis. Radiologically, lymph node enlargement and the pattern of fibrosis may be distinctive.

Correlation of the High-Resolution Computed Tomography Patterns of Intrathoracic Sarcoidosis with Serum Levels of SAA, CA 15.3, SP-D, and Other Biomarkers of Interstitial Lung Disease.

Studies on the serum biomarkers of granulomatous inflammation and pulmonary interstitial disease in intrathoracic sarcoidosis have shown conflicting results. We postulated that differences in the concentrations of serum biomarkers can be explained by the heterogenous patterns of sarcoidosis seen on thoracic HRCT. Serum biomarker levels in 79 consecutive patients, newly diagnosed with intrathoracic sarcoidosis, were compared to our control group of 56 healthy blood donors. An analysis was performed with respect to HRCT characteristics (the presence of lymph node enlargement, perilymphatic or peribronchovascular infiltrates, ground-glass lesions, or fibrosis), CXR, and disease extent. Serum levels of CXCL9, CXCL10, CTO, and CCL18 were statistically significantly increased in all patients compared to controls. Serum levels of CA15.3 were statistically significantly increased in all patients with parenchymal involvement. SAA was increased in patients with ground-glass lesions while SP-D levels were statistically significantly increased in patients with lung fibrosis. Only SP-D and CA15.3 showed a significant correlation to interstitial disease extent. In conclusion, we found that sarcoidosis patients with different HRCT patterns of intrathoracic sarcoidosis have underlying biochemical differences in their serum biomarkers transcending Scadding stages. The stratification of patients based on both radiologic and biochemical characteristics could enable more homogenous patient selection for further prognostic studies.

Fatigue in Patients with Sarcoidosis in Denmark.

Sarcoidosis is a systemic granulomatous disease of unknown etiology, primarily affecting the lungs and thoracic lymph nodes. Fatigue is a frequent and disabling symptom in sarcoidosis with a significant impact on quality of life. In Denmark, the incidence of sarcoidosis has increased; however, the extent and risk factors of fatigue have not been investigated and no recent reports of the characteristics of patients with sarcoidosis in Denmark exist. To assess the frequency of fatigue in patients with sarcoidosis in Denmark at diagnosis and to investigate if fatigue correlated with relevant disease parameters. Moreover, to characterize patients with sarcoidosis in Denmark at time of diagnosis. Data were collected in 150 patients with recently diagnosed sarcoidosis. Fatigue was measured using the Fatigue Assessment Scale (FAS). Patients with fatigue were compared to non-fatigue patients regarding clinical parameters. FAS was completed by 145 of 150 patients. Fifty-one percent reported significant fatigue. Mean FAS score was 23.6 and 51% had a FAS score ≥ 22. Fatigue in 89 incident patients did not correlate significantly with demographics, physiological, or clinical parameters. Fifty-nine percent were males. Mean age was 47years; mean values (% predicted) for pulmonary function tests were normal and 71% at Scadding stage 0-I. In Denmark, fatigue was frequent in patients with sarcoidosis. The majority of patients had mild disease at diagnosis and were older but lower at Scadding stage at diagnosis compared to previous cohorts.

Occupational and environmental exposures in the Genomic Research in Alpha-1 Antitrypsin Deficiency and Sarcoidosis (GRADS) study

IntroductionSarcoidosis is a granulomatous disorder thought to be caused by exposures in genetically susceptible individuals. This study investigated whether specific exposures were associated with different sarcoidosis phenotypes. MethodsExtensive demographic, occupational and environmental exposure data was analyzed from subjects enrolled in the NHLBI Genomic Research in Alpha-1 Antitrypsin Deficiency and Sarcoidosis (GRADS) study. ResultsIn patients with sarcoidosis, radiation exposure was significantly associated with an increased risk of cardiac sarcoidosis versus non-cardiac sarcoidosis. No exposures were significantly associated with pulmonary only disease versus extrapulmonary disease with or without pulmonary involvement, Scadding Stage II/III/IV versus Scadding Stage 0/I, acute or remitting disease versus non-acute or non-remitting disease, nor chronic versus non-chronic disease. Although not reaching statistically significance after adjustment for multiple comparisons, there were a number of exposures associated with specific disease phenotypes, including exposures where relationships to sarcoidosis have previously been described such as rural exposures and pesticide exposures. ConclusionsRadiation exposure may be a risk factor for cardiac sarcoidosis. Other exposures may also be associated with specific phenotypes and should be further explored. The study was limited by small groups of exposed subjects for individual exposures and multiple comparisons. The development of novel and innovative exposure assessment tools is needed.

Clinical, imaging and functional determinants of sarcoidosis phenotypes in a Greek population.

BackgroundThe aim of the present study was the application of the latest phenotype recommendations in Greek patients, in order to identify specific clinical, imaging and spirometric characteristics, at initial diagnosis of sarcoidosis, related to disease phenotypes.MethodsOur cohort included 147 patients coming from Northern Greece, recruited from the Outpatient Sarcoidosis Clinic, of Aristotle University of Thessaloniki. The observation period was 5 years. The Scadding staging system and the World Association of Sarcoidosis and other Granulomatous Disorders (WASOG) Clinical Outcome Status instrument were used. Phenotypes were defined by the latest DELPHI consensus recommendations.ResultsThe following clinical phenotypes were identified: asymptomatic 59%, acute 14.3%, chronic 12.9% and advanced 33.3%. The observed phenotypes were not related to Scadding stages. Lung function decline was in line with phenotype severity. The presence of fibrosis to any extent upon diagnosis differed among phenotypes (asymptomatic 13.8%, acute 38.1%, chronic 57.9%, advanced 61.2%, P<0.001) and was common for relapsing patients (P<0.001). In spontaneously remitting patients, fibrosis upon diagnosis was found less often than in non-remitting patients (P<0.001). Renal involvement was more frequently found in the advanced phenotype (P=0.032). Skin involvement was more common for patients with acute onset (P<0.001) and spontaneous remission (P=0.012). Ocular involvement was mainly found in relapsing patients (P<0.001).ConclusionsIn our cohort, sarcoidosis clinical phenotypes have certain clinical, imaging and functional characteristics, at initial diagnosis of the disease, which could be assessed in everyday practice.

CD103 Expression on Regulatory and Follicular T Cells in Lymph Nodes, Bronchoalveolar Lavage Fluid and Peripheral Blood of Sarcoidosis Patients.

(1) Background: Sarcoidosis is a chronic multisystem disorder of unknown aetiology, driven by a T-cell mechanism allowing T-cell attachment and transmigration through the endothelium, and endorsed by the expression of an integrin alpha-E beta-7 (CD103). This study aimed to analyse the different distribution and compartmentalisation of CD103 expression on T cell subsets in BAL, peripheral blood mononuclear cells (PBMC) and lymph nodes (LLN) from sarcoidosis patients. (2) Patients: We consecutively and prospectively enrolled 14 sarcoidosis patients. We collected PBMC, LLN and BAL at the same time from all patients. Through flow cytometric analysis, we analysed the expression of CD103 on regulatory and follicular T cell subsets. (3) Results: All patients were in radiological Scadding stage II. The multivariate analysis found that the variables which most influenced the peripheral blood compartment were high CD8+ and low ThReg, CD8+CD103+ and Tfh cell percentages. A principal component analysis plot performed to distinguish LLN, BAL and PBMC showed that they separated on the basis of CD4+, CD4+CD103+, CD8+, CD8+CD103+, TcEffector, TcNaive, ThNaive, ThEffector, Threg, ThregCD103+, Tfh, TcfCXC5+ and CD4+CD103+/CD4+ with 65.96% of the total variance. (4) Conclusions: Our study is the first to report a link between the imbalance in circulating, alveolar and lymph node CD8+ and CD8+CD103+ T cells, ThReg, Tfh and ThNaive and the CD103+CD4+/CD4+ T cell ratio in the development of sarcoidosis. These findings shine a spotlight on the pathogenesis of sarcoidosis and may offer new predictors for diagnosis. Our study provides additional understanding for a personalised, and hopefully more effective treatment of sarcoidosis.

Clinical phenotyping in sarcoidosis using cluster analysis

BackgroundMost 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.MethodsWe 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.ResultsCluster 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.ConclusionsCluster 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.

SARS-COV-2 PNEUMONIA LEADING TO PROGRESSION OF PULMONARY SARCOIDOSIS

TOPIC: Pulmonary Manifestations of Systemic Disease TYPE: Medical Student/Resident Case Reports INTRODUCTION: The implication of COVID 19 pneumonia on chronic inflammatory disorders is not clearly known. Due to a lack of data, it is difficult to predict the disease course post-COVID 19 pneumonia. Here, we present a case of stable sarcoidosis that progressed rapidly after COVID 19 pneumonia. CASE PRESENTATION: A 43-year-old male, with a history of sarcoidosis, briefly treated with steroids at initial diagnosis and in remission for the last six years, was admitted for dyspnea and hypoxia (room air oxygen saturation 83%) secondary to COVID 19 pneumonia diagnosed a week prior to admission. Chest X-ray on admission showed diffuse bilateral interstitial and airspace opacities. He was treated with dexamethasone and remdesevir. The clinical status of the patient improved after a week, and he was discharged on prednisone taper (10 mg for 5 days). Four weeks later, the patient had a recurrence of dyspnea on exertion with occasional hemoptysis. Computed Tomography (CT) scan of the chest showed honeycombing and reticulations in bilateral upper lobes, interstitial thickening, and worsening hilar and mediastinal lymphadenopathy (sarcoidosis Scadding stage IV). Labs were significant for elevated serum soluble interleukin-2 (IL-2) receptor and calcitriol levels. Pulmonary function test showed a restrictive defect with reduced diffusion capacity. The patient was started on prednisone. Repeat CT scan after three months showed improvement in ground-glass opacities and stable scarring. Fine needle aspiration biopsy of subcarinal lymph node confirmed non-caseating granulomatous inflammation. The patient was started on mycophenolate mofetil, tapered off prednisone, and is being evaluated for a lung transplant. DISCUSSION: The main pathogenesis related to sarcoidosis is the formation of granulomas due to sustained host immune system stimulation from various known and unknown antigens. Activation of the immune system as evidenced by elevated inflammatory makers in viral infections may in turn precipitate the relapse and progression of inflammatory disorders such as sarcoidosis. It is difficult to distinguish between the sequela of COVID 19 pneumonia and sarcoidosis progression. CT scan findings in fibrotic sarcoidosis have upper lobe predilection. However, the distribution of ground-glass opacities and fibrosis in COVID 19 pneumonia is usually peripheral and may have lower lobe predilection. Close monitoring is important to look for activation of sarcoidosis post COVID 19 pneumonia. CONCLUSIONS: Implications of COVID 19 infection on pathogenesis and progression of sarcoid are important to understand, and more research is required so that clinicians can be vigilant about worsening pulmonary function and intervene in a timely manner. REFERENCE #1: Ramdani H, Benelhosni K, Moatassim Billah N, Nassar I. COVID-19 pneumonia in a patient with sarcoidosis: A case report. Clin Case Rep. 2020 Dec 23;9(2):910-913. REFERENCE #2: Tana C, Mantini C, Cipollone F, Giamberardino MA. Chest Imaging of Patients with Sarcoidosis and SARS-CoV-2 Infection. Current Evidence and Clinical Perspectives. Diagnostics (Basel). 2021 Jan 27;11(2):183. DISCLOSURES: No relevant relationships by Salim Daouk, source=Web Response No relevant relationships by Samiksha Gupta, source=Web Response No relevant relationships by Ahmad Hassan, source=Web Response No relevant relationships by SYED HUSSAIN, source=Web Response No relevant relationships by Miloni Parmar, source=Web Response

Outcomes of patients with cancer and sarcoid-like granulomatosis associated with immune checkpoint inhibitors: A case–control study

PurposeSarcoid-like granulomatosis (SLG) reaction caused by immunotherapy remains poorly understood. This study aims to investigate the outcome of patients with cancer and SLG associated with immunotherapy. Patients and methodsBetween April 2016 and June 2020, 434 patients with immunological adverse events were screened from the ImmunoTOX assessment board of Gustave Roussy, an academic cancer centre in France. Among them, 28 patients had SLG associated with immunotherapy (SLG cohort) and 406 patients had other immunological adverse events (control cohort). Clinical characteristics and outcome of patients were compared from SLG and control cohort. ResultsThe SLG cohort consisted of 28 patients, 14 women and 14 men, with the median (range) age of 56.5 (28.7–75.3) years. Patients in the SLG cohort with sarcoidosis were asymptomatic (only radiographical finding) in 13 (46.4%) cases; otherwise, the most frequent symptoms were dyspnoea in 8 (28.6%) patients and cough in 5 (17.8%) patients. The computerised tomography scan found sarcoidosis localisations in mediastinal or peri-hilar thoracic lymph nodes in 26 (92.9%) patients, and lung parenchymal involvement was found in 14 (50.0%) patients. The radiographic Scadding stages for sarcoidosis classification were distributed in stages 0, I, II, III and IV in 2 patients (7.1%), 13 patients (46.4%), 11 patients (39.3%), 1 patient (3.6%) and 1 patient (3.6%), respectively. Compared with patients with other immunological toxicities (cohort control), patients with sarcoidosis presented most frequently with melanoma (75.0% versus 21.9% of patients; p < 0.001) and more often received combined therapies of anti–programmed cell death 1 plus anti–cytotoxic T-lymphocyte antigen 4 protein (46.4% versus 12.6% of patients; p = 0.002). Patients with sarcoidosis had an improved overall survival (OS); the median OS was not reached in the SLG cohort and 40.4 months in the control cohort, hazard ratio = 0.232 (95% confidence interval: 0.086–0.630) (p = 0.002). ConclusionSarcoidosis-like reactions in patients receiving immunotherapy were reported as non-severe immunological reactions in most cases and were correlated with improved OS. SLG should not be misdiagnosed as tumour progression in patients receiving immunotherapy treatment for cancer.

Clinical characteristics and organ system involvement in sarcoidosis: comparison of the University of Minnesota Cohort with other cohorts

BackgroundSarcoidosis is a systemic granulomatous disease of unknown etiology. Clinical cohort studies of different populations are important to understand the high variability in clinical presentation and disease course of sarcoidosis. The aim of the study is to evaluate clinical characteristics, including organ involvement, pulmonary function tests, and laboratory parameters, in a sarcoidosis cohort at the University of Minnesota. We compare the organ system involvement of this cohort with other available cohorts.MethodsWe conducted a retrospective data collection and analysis of 187 subjects with biopsy-proven sarcoidosis seen at a tertiary center. Organ system involvement was determined using the WASOG sarcoidosis organ assessment instrument. Clinical phenotype groups were classified using the Genomic Research in Alpha-1 Antitrypsin Deficiency and Sarcoidosis criteria.ResultsMean subject age at diagnosis was 45.8 ± 12.4, with a higher proportion of males (55.1%), and a higher proportion of blacks (17.1%) compared to the racial distribution of Minnesota residents (5.95%). The majority (71.1%) of subjects required anti-inflammatory therapy for at least 1 month. Compared to the A Case Control Etiologic Study of Sarcoidosis cohort, there was a higher frequency of extra-thoracic lymph node (34.2% vs. 15.2%), eye (20.9% vs. 11.8%), liver (17.6% vs. 11.5%), spleen (20.9% vs. 6.7%), musculoskeletal (9.6% vs. 0.5%), and cardiac (10.7% vs. 2.3%) involvement in our cohort. A multisystem disease with at least five different organs involved was identified in 13.4% of subjects. A restrictive physiological pattern was observed in 21.6% of subjects, followed by an obstructive pattern in 17.3% and mixed obstructive and restrictive pattern in 2.2%. Almost half (49.2%) were Scadding stages II/III. Commonly employed disease activity markers, including soluble interleukin-2 receptor and angiotensin-converting enzyme, did not differ between treated and untreated groups.ConclusionsThis cohort features a relatively high frequency of high-risk sarcoidosis phenotypes including cardiac and multiorgan disease. Commonly-utilized serum biomarkers do not identify subpopulations that require or do better with treatment. Findings from this study further highlight the high-variability nature of sarcoidosis and the need for a more reliable biomarker to predict and measure disease severity and outcomes for better clinical management of sarcoidosis patients.

Physiological predictors of survival in patients with sarcoidosis-associated pulmonary hypertension: results from an international registry.

Sarcoidosis-associated pulmonary hypertension (SAPH) is associated with reduced survival in single-centre studies. The international Registry for SAPH (ReSAPH) with long-term follow-up was established to enrich our knowledge of this complication of sarcoidosis. This analysis aims to elucidate factors associated with reduced transplant-free survival in SAPH patients. ReSAPH contains prospectively collected outcomes of SAPH patients since the time of registry enrolment. Information analysed includes right heart catheterisation data, pulmonary function testing, chest radiography, Scadding stage and 6-min walk distance (6MWD), among others. Cox regression models were used to identify independent predictors of transplant-free survival. Data from 215 patients followed for a mean±sd 2.5±1.9 years were available for analysis. In the 159 precapillary patients, the Kaplan-Meier-adjusted 1-, 3- and 5-year transplant-free survival was 89.2%, 71.7% and 62.0%, respectively. Kaplan-Meier-adjusted 1-, 3- and 5-year transplant-free survival in the incident group was 83.5%, 70.3% and 58.3%, respectively, and in the prevalent group was 94.7%, 72.2% and 66.3%, respectively. Patients with reduced diffusing capacity of the lung for carbon monoxide (D LCO) (<35% predicted) and 6MWD <300 m in the precapillary cohort had significantly worse transplant-free survival. Reduced 6MWD and preserved forced expiratory volume (FEV1)/forced vital capacity (FVC) ratio were identified as independent risk factors for reduced transplant-free survival in the precapillary cohort. Reduced D LCO (<35% pred) and 6MWD (<300 m) at the time of registry enrolment were associated with reduced transplant-free survival in the overall precapillary cohort. Preserved FEV1/FVC ratio was identified as an independent risk factor for worsened outcomes.

Obstructive sleep apnea in sarcoidosis and impact of cpap treatment on fatigue.

Rationale:An increased incidence of Obstructive Sleep Apnea (OSA) in sarcoidosis has been described in small sample size studies. Fatigue is common in sarcoidosis and OSA could be a relevant, treatable comorbidity. To date, the effect of Continuous Positive Airway Pressure (CPAP) on fatigue has never been assessed.Objectives:To investigate the prevalence of OSA in sarcoidosis, fatigue status and daytime sleepiness in patients of our center. To explore the effect of CPAP in fatigue and daytime sleepiness after 3 months using validated questionnaires.Method:Single group, one center, open-label prospective cohort study.Measurements and main result:We enrolled 68 patients and OSA was diagnosed in 60 (88.2%): 25 (36.8%) were mild while 35 (51.5%) were moderate-to-severe. 38 (55.9%) patients received CPAP but only 20 (30.9%) were compliant at 3-month evaluation. Questionnaires demonstrated fatigue in 34 (50%) and daytime sleepiness in 21 (30.9%). In multivariate regression analysis, Scadding stage and FAS behave as predictors of Apnea-Hypopnea Index (AHI) severity while sleepiness and steroids weren’t associated. FAS score (ΔFAS = 6.3; p = 0.001) and ESS score (ΔESS = 2.8; p = 0.005) improved after three months of CPAP.Conclusions:OSA is highly prevalent in patients affected by sarcoidosis. ESS questionnaire is not reliable for OSA screening and other pre-test probability tool should be evaluated in further studies. CPAP leads to a significative reduction of fatigue and daytime sleepiness at three-month. Further studies are needed to confirm the high prevalence of OSA in sarcoidosis and the positive role of CPAP in fatigue. (Sarcoidosis Vasc Diffuse Lung Dis 2020; 37 (2): 169-178)

18F-FDG PET/CT in Pulmonary Sarcoidosis:Quantifying Inflammation by the TLG index

ABSTRACTObjectives: In sarcoidosis progressive pulmonary disease affects prognosis. Pulmonary disease activity estimated by classic means poorly predicts severity and progressiveness. 18F-fluoro-2-deoxyglucose-positron-emission-tomography computed-tomography (18F-FDG-PET/CT) estimates pulmonary activity by inflammatory-cells metabolism. We aimed to investigate pulmonary sarcoidosis by 18F-FDG-PET/CT and evaluate the role of total-lesion-glycolysis (TLG) value, as an index quantifying the whole burden of lung inflammation.Methods: This is a retrospective study of sequentially gathered data. From a Greek cohort of 195 sarcoidosis-patients, 87 were identified with lung increased 18F-FDG uptake and further studied.Results: Visualizing lung by 18F-FDG-PET/CT identified new imaging patterns and revealed activity in all Scadding stages. Ever-smokers presented significantly higher TLG and lower DLCO compared to never-smokers. However, TLG value did not correlate with functional indices and did not differ between symptomatic and non-symptomatic patients. Among treatment-naïve patients, TLG did not differ significantly in those requiring therapy compared to those remained off.Conclusion: 18F-FDG PET/CT improved imaging and detection of pulmonary involvement and through TLG value revealed the deleterious smoking effect. The fact that TLG neither detected patients with clinical symptoms and functional impairment nor identified those requiring treatment once again confirms that in pulmonary sarcoidosis the link between activity, severity and decision to treat still eludes us.

Role of Bronchoscopic Techniques in the Diagnosis of Thoracic Sarcoidosis.

The diagnosis of sarcoidosis relies on clinical and radiological presentation, evidence of non-caseating granulomas in histopathology and exclusion of alternative causes of granulomatous inflammation. Currently, a proper diagnosis, with a high level of confidence, is considered as key to the appropriate diagnosis and management of the disease. In this sense, this review aims to provide a brief overview on the role of bronchoscopy in the diagnosis of thoracic sarcoidosis, incorporating newer techniques to establish, including endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA), endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA), transesophageal ultrasound-guided needle aspiration with the use of an echo bronchoscope (EUS-B-FNA) and transbronchial lung cryobiopsy (TBLC). Most of the literature reports the diagnostic superiority of endosonographic techniques, such as EBUS-TBNA alone or in combination with EUS-FNA, over conventional bronchoscopic modalities in diagnosing Scadding stages I and II of the disease. Moreover, TBLC may be considered a useful and safe diagnostic tool for thoracic sarcoidosis, overcoming some limitations of transbronchial lung biopsy (TBLB), avoiding more invasive modalities and being complementary to endosonographic procedures such as EBUS-TBNA.

Plasma mitochondrial DNA is associated with extrapulmonary sarcoidosis.

Sarcoidosis is an unpredictable granulomatous disease in which African Americans disproportionately experience aggressive phenotypes. Mitochondrial DNA (mtDNA) released by cells in response to various stressors contributes to tissue remodelling and inflammation. While extracellular mtDNA has emerged as a biomarker in multiple diseases, its relevance to sarcoidosis remains unknown. We aimed to define an association between extracellular mtDNA and clinical features of sarcoidosis.Extracellular mtDNA concentrations were measured using quantitative PCR for the human MT-ATP6 gene in bronchoalveolar (BAL) and plasma samples from healthy controls and patients with sarcoidosis from The Yale Lung Repository; associations between MT-ATP6 concentrations and Scadding stage, extrapulmonary disease and demographics were sought. Results were validated in the Genomic Research in Alpha-1 Antitrypsin Deficiency and Sarcoidosis cohort.Relative to controls, MT-ATP6 concentrations in sarcoidosis subjects were robustly elevated in the BAL fluid and plasma, particularly in the plasma of patients with extrapulmonary disease. Relative to Caucasians, African Americans displayed excessive MT-ATP6 concentrations in the BAL fluid and plasma, for which the latter compartment correlated with significantly higher odds of extrapulmonary disease.Enrichments in extracellular mtDNA in sarcoidosis are associated with extrapulmonary disease and African American descent. Further study into the mechanistic basis of these clinical findings may lead to novel pathophysiologic and therapeutic insights.