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Chronic inflammation is increasingly recognized as a risk factor for VTE, but unlike other inflammatory diseases including systemic lupus erythematosus and rheumatoid arthritis, data on the risk of VTE in patients with sarcoidosis are sparse. Do patients with sarcoidosis have a higher long-term risk of VTE (pulmonary embolism or DVT, and each of these individually) compared with the background population? Using Danish nationwide registries, patients aged ≥ 18 years with newly diagnosed sarcoidosis (two or more inpatient/outpatient visits, 1996-2020) without prior VTE were matched 1:4 by age, sex, and comorbidities with individuals from the background population. The primary outcome was VTE. We included 14,742 patients with sarcoidosis and 58,968 matched individuals (median age, 44.7 years; 57.2% male). The median follow-up was 8.8 years. Absolute 10-year risks of outcomes for patients with sarcoidosis vs the background population were the following: VTE, 2.9% vs 1.6% (P <.0001), pulmonary embolism, 1.5% vs 0.7% (P <.0001), and DVT, 1.6% vs 1.0% (P <.0001), respectively. In multivariable Cox regression, sarcoidosis was associated with an increased rate of all outcomes in the first year after diagnosis (VTE: hazard ratio [HR], 4.94; 95% CI, 3.61-6.75) and after the first year (VTE: HR, 1.65; 95% CI, 1.45-1.87) compared with the background population. These associations persisted when excluding patients with a history of cancer and censoring patients with incident cancer during follow-up. Three-month mortality was not significantly different between patients with VTE with and without sarcoidosis (adjusted HR, 0.84; 95% CI, 0.61-1.15). In this nationwide cohort study, sarcoidosis was associated with a higher long-term risk of VTE compared with a matched background population. [Display omitted] [ABSTRACT FROM AUTHOR]

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. [Display omitted] [ABSTRACT FROM AUTHOR]

Different patterns of fibrosis on high-resolution CT scans (HRCT) have been associated with reduced survival in some interstitial lung diseases. Nothing is known about HRCT scan patterns and survival in sarcoidosis. Will a detailed description of the extent and pattern of HRCT scan fibrosis in patients with stage IV pulmonary sarcoidosis impact pulmonary function and survival? Two hundred forty patients with stage IV sarcoidosis at two large tertiary institutions were studied. The earliest HRCT scan with fibrosis was reviewed for extent of fibrosis (< 10%, 10%-20%, and > 20%) and presence of bronchiectasis, upper lobe fibrocystic changes, basal subpleural honeycombing, ground-glass opacities (GGOs), large bullae, and mycetomas. Presence of sarcoidosis-associated pulmonary hypertension (SAPH) and pulmonary function testing performed within 1 year of HRCT were recorded. Patients were followed up until last clinic visit, death, or lung transplantation. The mean age was 58.4 years. Seventy-four percent were Black, 63% were female, and mean follow-up was 7.4 years. Death or LT occurred in 53 patients (22%). Thirty-one percent had > 20% fibrosis, 25% had 10%-20% fibrosis, and 44% had < 10% fibrosis. The most common HRCT abnormalities were bronchiectasis (76%), upper lobe fibrocystic changes (36%), and GGOs (28%). Twelve percent had basal subpleural honeycombing, and 32% had SAPH. Patients with > 20% fibrosis had more severe pulmonary impairment, were more likely to have SAPH (53%), and had worse survival (44% mortality; P <.001). Upper lobe fibrocystic changes, basal subpleural honeycombing, and large bullae were associated with worse pulmonary function and worse survival. Patients with basal subpleural honeycombing had the worst pulmonary function and survival (55% mortality; P <.001). GGOs were associated with worse pulmonary function but not worse survival, and mycetomas were associated with worse survival but not worse pulmonary function. A Cox proportional hazards model indicated that basal subpleural honeycombing (hazard ratio, 7.95), diffusion capacity for carbon monoxide < 40% (HR, 5.67) and White race (hazard ratio, 2.61) were independent predictors of reduced survival. HRCT scan features of fibrotic pulmonary sarcoidosis had an impact on pulmonary function and survival. Presence of >20% fibrosis and basal subpleural honeycombing are predictive of worse pulmonary function and worse survival in patients with stage IV pulmonary sarcoidosis. [ABSTRACT FROM AUTHOR]

The patient is a 49-year-old woman who had never used tobacco with a history of relapsing polychondritis and episcleritis. She sought treatment at our clinic for evaluation of multiple lung masses. She originally received a diagnosis by chest radiography performed to rule out sarcoidosis as the cause of episcleritis showing an abnormal findings. She had no contributory surgical, family, or social history. The autoimmune markers were notable for positive rheumatoid factor (153 IU/mL) and elevated erythrocyte sedimentation rate (97 mm/h) and C-reactive protein (65.5 mg/L). Pertinent studies with negative results included antineutrophilic cytoplasmic antibody, antinuclear antibody, cyclic citrullinated peptide antibody, Sjogren syndrome-related antigen A, and Sjogren syndrome-related antigen B tests. [ABSTRACT FROM AUTHOR]

The ability of high-definition (HD) videobronchoscopy to detect airway involvement in sarcoidosis has not been evaluated previously. What is the role of HD videobronchoscopy in the identification of sarcoidosis-associated airway abnormalities (AAs)? What are the patterns of AAs more commonly observed and more frequently associated with the detection of granulomas in endobronchial biopsy (EBB)? In this prospective international multicenter cohort study, consecutive patients with suspected sarcoidosis underwent airway inspection with an HD videobronchoscope and EBB using a standardized workflow. AAs were classified according to six patterns defined a priori: nodularity, cobblestoning, thickening, plaque, increased vascularity, and miscellaneous. We assessed diagnostic yield of EBB, prevalence of AAs, and interobserver agreement for different patterns of AAs. AAs were identified in 64 of 134 patients with sarcoidosis (47.8%), with nodularity (n = 23 [17.2%]), plaque (n = 19 [14.2%]), and increased vascularity (n = 19 [14.2%]) being the most prevalent. The diagnostic yield of EBB was 36.6%. AAs were significantly more prevalent in patients with than in those without nonnecrotizing granulomas on EBB (67.4% vs 36.5%; P =.001). Likewise, parenchymal disease on CT scan imaging was significantly more common in patients with than in those without nonnecrotizing granulomas on EBB (79.6% vs 54.1%; P =.003). On a per-lesion analysis, nonnecrotizing granulomas were seen especially in EBB samples obtained from areas of cobblestoning (9/10 [90%]) and nodularity (17/29 [58.6%]). The overall diagnostic yield of random EBB was low (31/134 [23.1%]). The interobserver agreement for the different patterns of AA was fair (Fleiss κ = 0.34). In a population with a large prevalence of White Europeans, HD videobronchoscopy detected AAs in approximately one-half of patients with sarcoidosis. The diagnostic yield of EBB was higher in patients with parenchymal involvement on CT scan imaging and in those with AAs, especially if manifesting as cobblestoning and nodularity. ClinicalTrials.gov ; No.: NCT4743596; URL: www.clinicaltrials.gov [ABSTRACT FROM AUTHOR]

Background: Pulmonary sarcoidosis is characterized by the accumulation of immune cells that form granulomas affecting the lungs. Efzofitimod (ATYR1923), a novel immunomodulator, selectively binds neuropilin-2, which is upregulated on immune cells in response to lung inflammation.Research Question: What is the tolerability, safety, and effect on outcomes from efzofitimod in pulmonary sarcoidosis?Study Design and Methods: A randomized, double-blind, placebo-controlled study evaluating multiple ascending doses of efzofitimod administered intravenously every four weeks for 24 weeks. Randomized patients (2:1) underwent a steroid taper to 5 mg/day by Week 8 or <5 mg/day after Week 16. The primary endpoint was the incidence of adverse events; secondary endpoints included steroid reduction, change in lung function, and patient-reported outcomes on health-related quality of life scales.Results: Thirty-seven patients received at least one dose of study medication. Efzofitimod was well tolerated at all doses, with no new or unexpected adverse events and no dose-dependent adverse event incidence. Average daily steroid doses through end of study were 6.8, 6.5 and 5.6 mg for the 1, 3 and 5 mg/kg groups compared to 7.2 mg for placebo, resulting in a baseline-adjusted relative steroid reduction of 5%, 9% and 22%, respectively. Clinically meaningful improvements were achieved across several patient reported outcomes, several of which reached statistical significance in the 5 mg/kg dose arm. A dose-dependent but non-significant trend toward improved lung function was also observed for 3 and 5 mg/kg.Interpretation: Efzofitimod was safe and well tolerated and associated with dose-dependent improvements of several clinically-relevant endpoints compared to placebo. The results of this study support further evaluation of efzofitimod in pulmonary sarcoidosis. [ABSTRACT FROM AUTHOR]

There is now ample evidence that differences in sex and gender contribute to the incidence, susceptibility, presentation, diagnosis, and clinical course of many lung diseases. Some conditions are more prevalent in women, such as pulmonary arterial hypertension and sarcoidosis. Some life stages-such as pregnancy-are unique to women and can affect the onset and course of lung disease. Clinical presentation may differ as well, such as the higher number of exacerbations experienced by women with cystic fibrosis (CF), more fatigue in women with sarcoidosis, and more difficulty in achieving smoking cessation. Outcomes such as mortality may be different as well, as indicated by the higher mortality in women with CF. In addition, response to therapy and medication safety may also differ by sex, and yet, pharmacogenomic factors are often not adequately addressed in clinical trials. Various aspects of lung/sleep biology and pathobiology are impacted by female sex and female reproductive transitions. Differential gene expression or organ development can be impacted by these biological differences. Understanding these differences is the first step in moving toward precision medicine for all patients. This article is the second part of a state-of-the-art review of specific effects of sex and gender focused on epidemiology, disease presentation, risk factors, and management of selected lung diseases. We review the more recent literature and focus on guidelines incorporating sex and gender differences in pulmonary hypertension, CF and non-CF bronchiectasis, sarcoidosis, restless legs syndrome and insomnia, and critical illness. We also provide a summary of the effects of pregnancy on lung diseases and discuss the impact of sex and gender on tobacco use and treatment of nicotine use disorder. [ABSTRACT FROM AUTHOR]

Although sarcoidosis is an established cause of multiorgan dysfunction, acute presentation with thrombotic microangiopathy resulting in severe renal and hematological sequelae has not been reported. We describe the case of a patient presenting with hypercalcemia, pancreatitis, and acute renal failure, followed by microangiopathic hemolytic anemia. Although there were no significant respiratory symptoms, thoracic radiology and mediastinal lymph node biopsy results were in keeping with sarcoidosis as the underlying cause of this multisystem presentation. Corticosteroids were commenced with clinical and biochemical improvement. This novel case highlights the need to consider sarcoidosis as part of the differential diagnosis for unusual multiorgan presentations and for early multidisciplinary involvement in such cases to permit optimal treatment. [ABSTRACT FROM AUTHOR]

Background: Previous studies have demonstrated an association between BMI and the development of sarcoidosis. We investigated this association and the association between OSA and the development of sarcoidosis in a US Veterans Health Administration database.Research Questions: Is the presence of OSA or the BMI associated with the development of sarcoidosis over the subsequent 12 months?Study Design and Methods: We identified patients with sarcoidosis and OSA through International Classification of Diseases, Ninth and Tenth Revision, codes. We selected a random sample of control participants with no record of sarcoidosis. All patients with sarcoidosis had at least one BMI value recorded in the 12 months before the sarcoidosis diagnosis was made. For the patients without sarcoidosis, the BMI values were obtained over intervals 12 months before a random date. We compared the BMI and the percentage of patients with OSA in the sarcoidosis group and in patients without sarcoidosis.Results: We analyzed 10,512 patients with sarcoidosis and 2,709,884 patients without sarcoidosis. We found no association between BMI and the rate of sarcoidosis developing. Post hoc statistical power calculations verified that these null results were meaningful and not the result of insufficient statistical power. We also found that a diagnosis of OSA was protective of sarcoidosis developing. Using a conditional logistic regression model with strata for age, sex, and BMI in the same 12-month period, a 49.0% lower odds of sarcoidosis was found in patients with OSA compared with patients without a diagnosis of OSA. Although the primary outcomes were assessed at 12 months before the diagnosis of sarcoidosis, these results basically held when examined at 3 and 6 months before the diagnosis was made.Interpretation: These findings suggest that increased BMI is not associated positively with a greater odds of sarcoidosis developing. Furthermore, these results suggest that the presence of OSA lowers the odds of sarcoidosis developing. [ABSTRACT FROM AUTHOR]

Background: Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) is commonly used to evaluate mediastinal lymphadenopathy. Studies focusing on malignant lymphadenopathy have compared 21- and 22-gauge (21G and 22G, respectively) needles and have not identified an advantage of one needle size over the other in terms of diagnostic yield.Research Question: Does the 19-gauge (19G) EBUS needle offer greater diagnostic yield and sensitivity vs the 21G and 22G EBUS needles for a diagnosis of sarcoidosis, lymphoma, or mediastinal lymphadenopathy not yet diagnosed?Study Design and Methods: This study retrospectively examined records of 730 patients from the Stather Canadian Outcomes Registry for Chest Procedures (SCOPE) database who underwent EBUS-TBNA for a diagnosis of suspected sarcoidosis, lymphoma, or mediastinal lymphadenopathy not yet diagnosed. A propensity score analysis of two groups was performed. One group comprised patients undergoing EBUS-TBNA with a 19G needle, the other with a 21G or 22G needle. Cases for analysis were selected with a 1:2 ratio of 19G vs 21/22G using logistic regression and random matching with all eligible 19G cases included.Results: There were 137 patients (312 targets) in the 19G group and 274 patients (631 targets) in the 21/22G group in the propensity score analysis. The diagnostic yield was 107 of 137 (78.1%) in the 19G group vs 194 of 274 (70.8%) in the 21/22G group (difference, 7.3%; 95% CI, -1.9 to 15.6; P = .116). The sensitivity of EBUS-TBNA for sarcoidosis was 80 of 83 (96.4%) in the 19G group vs 150 of 156 (96.2%) in the 21/22G group (difference, 0.24%; 95% CI, -6.6 to 85.1; P = .93). In patients with a final diagnosis of lymphoma, EBUS was diagnostic in 10 of 13 (76.9%) in the 19G group vs 12 of 12 (100%) in the 21/22G group (difference, 23.1%; 95% CI, -5.4 to 50.3; P = .08).Interpretation: The study did not identify an advantage of the 19G EBUS needle over the 21/22G EBUS needles for diagnostic yield nor sensitivity for sarcoidosis or lymphoma. [ABSTRACT FROM AUTHOR]

Background: Diagnosing sarcoidosis can be challenging, and a noninvasive diagnostic method is lacking. The electronic nose (eNose) technology profiles volatile organic compounds in exhaled breath and has potential as a point-of-care diagnostic tool.Research Question: Can eNose technology be used to distinguish accurately between sarcoidosis, interstitial lung disease (ILD), and healthy control subjects, and between sarcoidosis subgroups?Study Design and Methods: In this cross-sectional study, exhaled breath of patients with sarcoidosis and ILD and healthy control subjects was analyzed by using an eNose (SpiroNose). Clinical characteristics were collected from medical files. Partial least squares discriminant and receiver-operating characteristic analyses were applied to a training and independent validation cohort.Results: The study included 252 patients with sarcoidosis, 317 with ILD, and 48 healthy control subjects. In the validation cohorts, eNose distinguished sarcoidosis from control subjects with an area under the curve (AUC) of 1.00 and pulmonary sarcoidosis from other ILD (AUC, 0.87; 95% CI, 0.82-0.93) and hypersensitivity pneumonitis (AUC, 0.88; 95% CI, 0.75-1.00). Exhaled breath of sarcoidosis patients with and without pulmonary involvement, pulmonary fibrosis, multiple organ involvement, pathology-supported diagnosis, and immunosuppressive treatment revealed no distinctive differences. Breath profiles differed between patients with a slightly and highly elevated soluble IL-2 receptor level (median cutoff, 772.0 U/mL; AUC, 0.78; 95% CI, 0.64-0.92).Interpretation: Patients with sarcoidosis can be distinguished from ILD and healthy control subjects by using eNose technology, indicating that this method may facilitate accurate diagnosis in the future. Further research is warranted to understand the value of eNose in monitoring sarcoidosis activity. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background: Subglottic stenosis (SGS) and tracheal stenosis (TS) are characterized by a narrowing of the airways. The goal of this study was to describe the characteristics and prognosis of nontraumatic and nontumoral SGS or TS.Research Question: What are the inflammatory etiologies of SGS and TS, and what are their characteristics and prognosis?Study Design and Methods: This multicenter, observational retrospective study was performed in patients with SGS or TS that was neither traumatic nor tumoral.Results: Eighty-one patients were included, 33 (41%) with granulomatosis with polyangiitis (GPA) and 21 (26%) with relapsing polychondritis (RP). GPA-related stenoses exhibited circumferential subglottic narrowing in 85% of cases, without calcifications. In contrast, RP-related stenoses displayed anterior involvement in 76%, in a longer distance from vocal cords (4 cm), with calcifications in 62%, and extension to bronchi in 86%. Other diagnoses included bullous dermatoses (n = 3), amyloidosis (n = 3), sarcoidosis (n = 2), and Crohn's disease (n = 2); the remaining stenoses (n = 15) were idiopathic. SGS/TS was the initial manifestation of the disease in 66% of cases, with a median interval from stenosis to disease diagnosis of 12 months (interquartile range, 0-48 months). Despite the use of glucocorticoids in 80%, combined with methotrexate in 49%, endoscopic procedures were required in 68% of patients. Relapses of stenoses occurred in 76% without any difference between causes (82% in GPA, 67% in RP, and 75% in idiopathic SGS/TS). Three patients died due to the stenosis, two of RP and one of GPA.Interpretation: These data show that GPA and RP are the two main inflammatory diseases presenting with SGS/TS. GPA-related stenoses are mostly subglottic and circumferential, whereas RP-related stenoses are mostly tracheal, anterior, and calcified with a frequent extension to bronchi. Relapses of stenoses are common, and relapse rates do not differ between causes. Diagnosis and management of SGS/TS require a multidisciplinary approach. [ABSTRACT FROM AUTHOR]

Sarcoidosis is an important member of the family of granulomatous lung diseases. Since its recognition in the late 19th century, sarcoidosis has been thought of as a disease of unknown cause. Over the past 20 years, this paradigm has been shifting, more rapidly in the past 10 years. Epidemiologic studies, bolstered by case reports, have provided evidence of causal associations between occupational exposure to specific agents and sarcoidosis. Pathogenesis has been more clearly defined, including the role of gene-exposure interactions. The use of in vitro lymphocyte proliferation testing to detect sensitization to inorganic antigens is being examined in patients with sarcoidosis. These antigens include silica and certain metals. Results of studies to date show differences in immunoreactivity of occupationally exposed sarcoidosis cases compared with control cases, suggesting that lymphocyte proliferation testing may prove useful in diagnosing work-related disease. This review discusses recently published findings regarding associations between occupational exposure to silica and silicates, World Trade Center dust, and metals and risk for sarcoidosis, as well as advances in the development of diagnostic tools. Not all cases of sarcoidosis have an identified cause, but some do. Where the cause is occupational, its recognition is critical to enable effective treatment through removal of the affected worker from exposure and to inform intervention aimed at primary prevention. [ABSTRACT FROM AUTHOR]

Background: Tobacco smoking is associated with a reduced risk of developing sarcoidosis, and we previously reported that nicotine normalizes immune responses to environmental antigens in patients with active pulmonary sarcoidosis. The effects of nicotine on the progression of pulmonary sarcoidosis are unknown.Research Question: Is nicotine treatment well tolerated, and will it improve lung function in patients with active pulmonary sarcoidosis?Study Design and Methods: With local institutional review board approval, a randomized, double-blind, controlled pilot trial was conducted of daily nicotine transdermal patch treatment (21 mg daily) or placebo patch use for 24 weeks. The Ohio State University Wexner Medical Center and Cleveland Clinic enrolled 50 consecutive subjects aged ≥ 18 years with active pulmonary sarcoidosis, based on symptoms (ie, dyspnea, cough) and objective radiographic evidence of infiltrates consistent with nonfibrotic lung disease. Each study group was compared at 26 weeks based on repeated measures of FVC, FEV1, quantitative lung texture score based on CT texture analysis, Fatigue Assessment Score (FAS), St. George's Respiratory Questionnaire (SGRQ), and the Sarcoidosis Assessment Tool.Results: Nicotine treatment was associated with a clinically significant, approximately 2.1% (70 mL) improvement in FVC from baseline to 26 weeks. FVC decreased by a similar amount (2.2%) in the placebo group, with a net increase of 140 mL (95% CI, 10-260) when comparing nicotine vs placebo groups at 26 weeks. FEV1 and FAS improved marginally in the nicotine-treated group, compared with those on placebo. No improvement was observed in lung texture score, FAS, St. George's Respiratory Questionnaire score, or the Sarcoidosis Assessment Tool. There were no reported serious adverse events or evidence of nicotine addiction.Interpretation: Nicotine treatment was well tolerated in patients with active pulmonary sarcoidosis, and the preliminary findings of this pilot study suggest that it may reduce disease progression, based on FVC.Clinical Trial Registration: ClinicalTrials.gov; No.: NCT02265874; URL: www.clinicaltrials.gov. [ABSTRACT FROM AUTHOR]

Background: Pulmonary sarcoidosis (PS) is a noncaseating granulomatous disease of unknown origin. Despite conflicting reports, it is considered that the regulatory T (Treg) cells are functionally impaired in PS, but the underlying mechanisms remain unclear. OX40, a pivotal costimulatory molecule, is essential for T-cell functions and memory development, but its impact on Treg cells is ambiguous.Research Question: Does the OX40 pathway influence the suppressive functions of Treg cells in PS?Study Design and Methods: Fifty treatment-naïve patients with PS and 30 healthy control participants were recruited for this study. Polychromatic flow cytometry-based immunologic assays were performed to enumerate effector T helper (Th) cells and Treg cells along with their functions. Using real-time polymerase chain reaction analysis, small interfering RNA, and pharmacologic inhibitors, the impact of OX40 on Treg cell function was investigated.Results: We observed enrichment of Th-9 cells perhaps for the first time along with Th-1, Th-17, and Treg cells in patients' BAL fluid (BALF) compared with peripheral blood. However, Treg cells were observed to be functionally defective at the pathological site. We observed higher expression of OX40 on both T effector (CD4+Foxp3-) and Treg (CD4+Foxp3+) cells obtained from the BALF of patients with PS. However, OX40 exerted contrasting impact on these T-cell subsets, enhancing effector T-cell functions (interferon γ, tumor necrosis factor α) while inhibiting Treg cell function (IL-10, transforming growth factor β). OX40 silencing or blocking on Treg cells resulted in restoration of their impaired functions.Interpretation: We propose that inhibiting the OX40 pathway may constitute a therapeutic strategy for controlling inflammatory T cells by restoring Treg cell functions in patients with PS. [ABSTRACT FROM AUTHOR]

Background: Sarcoidosis is a systemic granulomatous disease that in most patients affects the lung. Pulmonary fibrotic sarcoidosis is clinically, radiologically, and pathologically a heterogeneous condition. Although substantial indirect evidence suggests small airways involvement, direct evidence currently is lacking.Research Question: What is the role of the (small) airways in fibrotic sarcoidosis?Study Design and Methods: Airway morphologic features were investigated in seven explant lungs with end-stage fibrotic sarcoidosis using a combination of CT scanning (large airways), micro-CT scanning (small airways), and histologic examination and compared with seven unused donor lungs as controls with specific attention focused on different radiologically defined sarcoidosis subtypes.Results: Patients with central bronchial distortion (n = 3), diffuse bronchiectasis (n = 3), and usual interstitial pneumonia pattern (n = 1) were identified based on CT scan, showing a decrease and narrowing of large airways, a similar airway number and increased airway diameter of more distal airways, or an increase in airway number and airway diameter, respectively, compared with control participants. The number of terminal bronchioles per milliliter and the total number of terminal bronchioles were decreased in all forms of fibrotic sarcoidosis. Interestingly, the number of terminal bronchioles was inversely correlated with the degree of fibrosis. Furthermore, we identified granulomatous remodeling as a cause of small airways loss using serial micro-CT scanning and histologic examination.Interpretation: The large airways are involved differentially in subtypes of sarcoidosis, but the terminal bronchioles universally are lost. This suggests that small airways loss forms an important aspect in the pathophysiologic features of fibrotic pulmonary sarcoidosis. [ABSTRACT FROM AUTHOR]

Background: A Phase I, single-center investigation found that 8 weeks of antimycobacterial therapy improved sarcoidosis FVC. Safety and efficacy assessments have not been performed in a multicenter cohort.Research Question: The objective of this study was to determine the safety and efficacy of antimycobacterial therapy on the physiological and immunologic end points of sarcoidosis.Study Design and Methods: In a double-blind, placebo-controlled, multicenter investigation, patients with pulmonary sarcoidosis were randomly assigned to receive 16 weeks of concomitant levofloxacin, ethambutol, azithromycin, and rifabutin (CLEAR) or matching placebo to investigate the effect on FVC. The primary outcome was a comparison of change in percentage of predicted FVC among patients randomized to receive CLEAR or placebo in addition to their baseline immunosuppressive regimen. Secondary outcomes included 6-min walk distance (6MWD), St. George's Respiratory Questionnaire (SGRQ) score, adverse events, and decrease in mycobacterial early secreted antigenic target of 6 kDa (ESAT-6) immune responses.Results: The intention-to-treat analysis revealed no significant differences in change in FVC among the 49 patients randomized to receive CLEAR (1.1% decrease) compared with the 48 randomized to receive placebo (0.02% increase) (P = .64). Physiological parameters such as the change in 6MWD were likewise similar (P = .91); change in SGRQ favored placebo (-8.0 for placebo vs -1.5 for CLEAR; P = .028). The per-protocol analysis revealed no significant change in FVC at 16 weeks between CLEAR and placebo. There was no significant change in 6MWD (36.4 m vs 6.3 m; P = .24) or SGRQ (-2.3 vs -7.0; P = .14). A decline in ESAT-6 immune responses at 16 weeks was noted among CLEAR-treated patients (P = .0003) but not patients receiving placebo (P = .24).Interpretation: Despite a significant decline in ESAT-6 immune responses, a 16-week CLEAR regimen provided no physiological benefit in FVC or 6MWD among patients with sarcoidosis. [ABSTRACT FROM AUTHOR]

Case Presentation: A 44-year-old woman was referred for evaluation of dyspnea on exertion and multiple nodular opacities on a chest CT scan. She had a medical history of autoimmune encephalitis, diabetes mellitus, hypertension, migraines, and allergic rhinitis. Ten years earlier, the patient was admitted to an outside institution with symptoms of shortness of breath. She was found to have multiple pulmonary nodules and was diagnosed empirically with and treated for sarcoidosis. She was told that her pulmonary nodules had improved on follow up. However, she continued to have symptoms of dyspnea. Due to progressive symptoms of shortness of breath, she was referred to pulmonology. She reported a weight gain of 80 pounds over the last year. She denied fever, chills, hemoptysis, night sweats, joint swelling, or skin rash. She is a former cigarette smoker with a 15 pack-year smoking history, quit smoking in 2005. She denied alcohol or drug use. She resided in Arkansas and Texas over the past decade. She previously worked as a teacher and is currently unemployed. She had no other relevant exposures. She denied a family history of autoimmune diseases or malignancies. [ABSTRACT FROM AUTHOR]

Background: Chronic beryllium disease (CBD), a granulomatous disease with similarities to sarcoidosis, arises only in individuals exposed to beryllium. Inhaled beryllium can elicit a T-cell-dominated alveolitis leading nonnecrotizing granulomata. CBD can be distinguished from sarcoidosis by demonstrating beryllium sensitization in a lymphocyte proliferation test.Research Question: Beryllium exposure usually occurs in an occupational setting. Because of the diagnosis of CBD in a patient without evident beryllium exposure, we performed a beryllium-lymphocyte proliferation test (BeLPT) among his work colleagues.Study Design and Methods: This field study investigated a cohort of work colleagues without obvious beryllium exposure. Twenty-one of 30 individuals were assessed in our outpatient clinic for beryllium sensitization. Therefore, BeLPT was performed with freshly collected peripheral blood mononuclear cells. Data were extracted from clinical charts, including geographical data. Beryllium content in dust samples collected at the workplace was measured by graphite-furnace atomic absorption spectroscopy and was compared with samples from different areas of Germany.Results: For the initial patient, the diagnosis of sarcoidosis was reclassified as CBD based on two positive BeLPT results. Assessment of his workplace did not identify a source of beryllium. However, BeLPTs performed on his workmates demonstrated beryllium sensitization in 5 of 21 individuals, suggesting a local beryllium source. Concrete dust obtained from the building yard, the workplace of the index patient, contained high amounts of beryllium (1138 ± 162 μg/kg), whereas dust from other localities (control samples) showed much lower beryllium content (range, 147 ± 18-452 ± 206 μg/kg). Notably, the control dust collected from different places all over Germany exhibit different beryllium concentrations.Interpretation: We describe a cluster of beryllium-sensitized workers from an industry not related to beryllium caused by environmental exposure to beryllium-containing concrete dust, which exhibited markedly elevated beryllium content. Importantly, analyses of dust samples collected from different localities showed that they contain markedly different amounts of beryllium. Thus, besides workplace-related exposure, environmental factors also are capable of eliciting a beryllium sensitization. [ABSTRACT FROM AUTHOR]

Background: In cohort studies of pulmonary sarcoidosis, abnormal ventilatory patterns have generally been subdivided into restrictive and obstructive defects. Mixed ventilatory defects have largely been overlooked in pulmonary sarcoidosis, as total lung capacity has seldom been taken into account in historical series.Research Question: This study evaluated the prevalence of mixed disease in pulmonary sarcoidosis and its clinical associations.Study Design and Methods: In patients with pulmonary sarcoidosis (N = 1,110), mixed defects were defined according to American Thoracic Society/European Respiratory Society criteria. Clinical data, pulmonary function variables, and vital status were abstracted from clinical records. Chest radiographs were evaluated independently by two experienced radiologists.Results: The prevalence of a mixed ventilatory defect was 10.4% in the whole cohort, rising to 25.9% in patients with airflow obstruction. Compared with isolated airflow obstruction, mixed defects were associated with lower diffusing lung capacity for carbon monoxide levels (50.7 ± 16.3 vs 70.8 ± 18.1; P < .0001), a higher prevalence of chest radiographic stage IV disease (63.5% vs 38.3%; P < .0001), and higher mortality (hazard ratio, 2.36; 95% CI, 1.34-4.15; P = .003). These findings were reproduced in all patient subgroup analyses, including patients with a histologic diagnosis, a clinical diagnosis, incident disease, and prevalent disease.Interpretation: Mixed disease is present in approximately 25% of patients with pulmonary sarcoidosis and airflow obstruction and is associated with lower diffusing lung capacity for carbon monoxide levels, a higher prevalence of stage IV disease, and higher mortality than seen in a pure obstructive defect. These observations identify a distinct phenotype associated with a mixed ventilatory defect, justifying future studies of its clinical and pathogenetic significance. [ABSTRACT FROM AUTHOR]

Background: Sarcoidosis, one of the most common interstitial lung diseases, has significant health disparities. Approximately 50% of individuals affected with sarcoidosis will undergo spontaneous remission, but those who do not undergo remission often require long-term or lifelong treatment to prevent disease progression. We sought to assess the association between medication adherence and clinical outcomes in sarcoidosis.Methods: Adult patients in the Johns Hopkins Sarcoidosis Clinic diagnosed with pulmonary sarcoidosis on treatment were eligible for enrollment. Questionnaires were administered to assess medication adherence, health-related quality of life (HRQoL), health-care utilization, and sociodemographic information. Clinical information was abstracted from medical charts including lung function, disease duration, comorbidities, and sarcoidosis organ involvement.Results: A total of 117 participants were enrolled (57% women; 55% black; median age, 57 years). Within the cohort, 66% of individuals reported at least one nonadherent behavior. Higher medication adherence was associated with better HRQoL (P < .05). There was no association between medication adherence and the odds of health-care utilization, FVC % predicted, FEV1 % predicted, or diffusion capacity of the lungs for carbon monoxide % predicted. Black participants reported lower medication adherence than white participants (P < .05).Conclusions: This is the first observational study of medication adherence in sarcoidosis. We found that higher medication adherence was associated with better HRQoL, with blacks more likely to report nonadherence. Medication adherence may be an important target to improve patient-reported outcomes and health disparities in sarcoidosis. [ABSTRACT FROM AUTHOR]

Common variable immunodeficiency disorders refer to a relatively common primary immune deficiency group of diseases that present with infectious and inflammatory complications secondary to defects in antibody production and sometimes in cellular immunity. The disorder often presents in middle age or later with recurrent sinopulmonary infections, bronchiectasis, or a plethora of noninfectious complications such as autoimmune disorders, granulomatous interstitial lung disease, GI diseases, malignancies (including lymphoma), and multisystem granulomatous disease resembling sarcoidosis. Infusion of immunoglobulin by IV or subcutaneous is the mainstay of therapy. Management of complications is often difficult as immune suppression may be necessary in these conditions and entails the use of medications and biologicals which may further increase the risk for infections. Specifically, bronchiectasis, granulomatous lymphocytic interstitial lung disease, repeated sinopulmonary infections, and malignancies are sequelae of antibody deficiency that may present to the pulmonologist. This review will provide an updated understanding of the molecular aspects, differential diagnosis, presentations, and the management of common variable immunodeficiency disorders. [ABSTRACT FROM AUTHOR]