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Background: Sarcoidosis is a multi-system disease frequently affecting the lungs. It is thought to be mediated by gene-environment interaction; for example, epidemiological data show organic aerosol exposure increases risk of pulmonary sarcoidosis., Research Question: Does exposure to bioaerosol associate with worse lung disease in patients with pulmonary sarcoidosis?, Research Question: Using an observational, cohort study design, we measured residential exposure to fungal and bacterial cell wall material, β-(1,3)-D-glucan (BDG) and endotoxin, respectively, in healthy control subjects and those with pulmonary sarcoidosis. In the case cohort, we compared bioaerosol concentrations to pulmonary disease severity, assessed by pulmonary function testing, qualitative chest computed tomography (CT), and serum biomarkers. Log-transformed bioaerosol concentrations were compared to lung function and significance and correlation determined by Pearson correlation., Results: Homes of subjects with sarcoidosis had higher BDG and endotoxin concentrations than control subjects. Patients with significant pulmonary fibrosis had greater disease severity (Wasfi severity score, visual analogue scale) and reduced pulmonary function compared to those without fibrosis (all P <0.01). Residential fungal BDG correlated with declining FVC, only in patients with fibrosis on CT imaging ( P =0.02). Survey data revealed higher BDG concentrations were found in homes of cat-owners, and the number of houseplants owned correlated with declines in FVC and FEV 1 ( P =0.05 and 0.02, respectively). In patients without fibrosis, eight inflammatory markers correlated with BDG (6CKine/CCL21, IL-9, IL-17F, IL-21, IL-28A, I-309, MIP-1β, TARC), while in those with pulmonary fibrosis, BDG correlated with two inflammatory markers (Eotaxin-3, M-CSF), suggesting immune anergy to inhaled antigens in patients with fibrosis., Interpretation: In patients with pulmonary fibrosis, disease severity was correlated with residential exposure to fungal cell wall material, but not gram-negative bacterial cell wall material. These patients may experience immune anergy to inhaled antigens.

The management of pulmonary sarcoidosis is a complex interplay of disease characteristics, the impact of medications, and patient preferences. Foremost, it is important to weigh the risk of anti-granulomatous treatment with the benefits of lung preservation and improvement in quality of life. Because of its high spontaneous resolution rate, pulmonary sarcoidosis should only be treated in cases of significant symptoms due to granulomatous inflammation, lung function decline, or substantial inflammation on imaging that can lead to irreversible fibrosis. The longstanding basis of treatment has historically been corticosteroid therapy for the control of granulomatous inflammation. However, several corticosteroid-sparing options have increasing evidence for use in refractory disease, inability to taper steroids to an acceptable dose, or in those with toxicity to corticosteroids. Treatment of sarcoidosis should be individualized for each patient due to the heterogeneity of the clinical course, comorbid conditions, response to therapy, and tolerance of medication side effects.

Objective: While implicated in causing depression, no studies have examined the impact of montelukast on antidepressant effectiveness. We examined whether existing montelukast therapy was associated with acute antidepressant treatment failure (objective 1), and whether montelukast initiation was associated with depression relapse during maintenance antidepressant therapy (objective 2), relative to inhaled corticosteroid (ICS)., Methods: Patients with asthma and depression were identified using national Veterans Health Administration data from 2007 to 2019. Objective 1: 12,109 patients initiated an antidepressant after receiving montelukast or ICS for 6 months. The primary outcome was acute antidepressant treatment failure, defined as subsequent initiation of a new antidepressant or augmenting agent within 6 months. Objective 2: 14,673 patients initiated montelukast or ICS after receiving stable antidepressant monotherapy for 6 months. The primary outcome of depression relapse was defined by a subsequent change in the pre-existing maintenance antidepressant regimen within 6 months. Both objectives employed a retrospective cohort design with log-binomial regression., Results: Objective 1: Acute antidepressant failure was observed in 21.3% (628/2943) and 22.3% (2044/9166) of patients receiving montelukast versus ICS, respectively. Relative risk in adjusted analyses was 0.98 (95% CI: 0.90, 1.07). Objective 2: Depression relapse was observed in 24.4% (288/1182) and 22.4% (3027/13,491) of patients initiating montelukast versus ICS, respectively. Relative risk in adjusted analyses was 1.08 (95% CI: 0.96, 1.20) within 6 months and 1.50 (95% CI: 1.16, 1.93) within 45 days., Conclusion: Discontinuation of existing montelukast therapy is unnecessary when initiating antidepressants. However, potential evidence for depression relapse following montelukast initiation warrants additional investigation., Competing Interests: Declaration of Competing Interest The authors have no competing interests to report., (Published by Elsevier Inc.)

Objectives: Neuropsychiatric events (NEs) reported with montelukast during post-marketing surveillance by the US Food & Drug Administration resulted in a 2008 safety alert and a black box warning in 2020. Our objective was to evaluate montelukast exposure and NEs risk using sequence symmetry analysis., Methods: National Veterans Health Administration (VHA) administrative data were used to identify 11 840 patients prescribed incident montelukast during fiscal year 2014. Incident prescribing of neuropsychiatric medication was used as a proxy marker for incident NEs and included antidepressants, benzodiazepines, hypnotics, antipsychotics, mood stabilizers, and buspirone. Symmetry ratios were calculated as the ratio of patients with an incident neuropsychiatric event in the year following montelukast initiation to the year preceding initiation. Exposure counterfactual analyses were used to examine the relationship between potential therapeutic alternatives to montelukast and risk for NEs., Results: Incident NEs were observed in 2305 patients following montelukast initiation and 2734 patients preceding montelukast initiation (SR 0.84, 95% CI 0.80-0.89). Sensitivity analyses examining each of the 6 sub-types of psychiatric medications also failed to show increased risk of NEs following montelukast initiation. Therapeutic alternatives to montelukast, such as inhaled corticosteroids, were also not associated increased NE risk., Conclusions: Initiation of montelukast was not associated with increased risk of a variety of NEs in this sequence symmetry analysis involving adult patients in the VHA. Our findings do not support the hypothesis that NEs are associated with montelukast initiation.

Introduction: Sarcoidosis is a rare inflammatory disease with unclear natural history. Using a large, retrospective, longitudinal, population-based cohort, we sought to define its natural history in order to guide future clinical studies., Methods: We identified 722 newly diagnosed cases of sarcoidosis within Kaiser Permanente Northwest health care records between 1995 and 2015. We investigated immunosuppressive medication use in the two years following diagnosis, analyzed demographic and clinical characteristics, and quantified chest imaging and pulmonary function testing (PFTs) across the clinical course., Results: Over two years of follow-up, 41% of patients were treated with prednisone. Of those, 75% tapered off their first course within 100 days, although half of those patients required recurrent therapy. Five percent of the entire cohort remained on prednisone for longer than one year, with an average daily dose of 10-20 mg. Chest imaging was associated with early prednisone use, and chest CT was associated with changes in prednisone dose. PFTs or demographics were not associated with prednisone use. Cumulative prednisone doses were significantly higher in African Americans (1,845 mg additional) and those who had a chest CT (2,015 mg additional). Overall, PFTs were less frequently obtained than chest imaging and had no significant change over disease course., Discussion: The natural history of sarcoidosis varies greatly. For those requiring therapy, corticosteroid burden is high. Chest imaging drives medication dose changes as compared to PFTs, but neither outcome fully captures the entire history of disease. Prospective cohorts are needed with purposefully collected, repeated measures that include objective clinical assessments and symptoms., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Objective: To study how demographic differences impact disease manifestation of sarcoidosis using the WASOG tool in a large multicentric study., Methods: Clinical data regarding 1445 patients with sarcoidosis from 14 clinical sites in 10 countries were prospectively reviewed from Feb 1, 2020 to Sep 30, 2020. Organ involvement was evaluated for the whole group and for subgroups differentiated by sex, race, and age., Results: The median age of the patients at diagnosis was 46 years old; 60.8% of the patients were female. The most commonly involved organ was lung (96%), followed by skin (24%) and eye (22%). Black patients had more multiple organ involvement than White patients (OR = 3.227, 95% CI: 2.243-4.643) and females had more multiple organ involvement than males (OR = 1.238, 95% CI: 1.083-1.415). Black patients had more frequent involvement of neurologic, skin, eye, extra thoracic lymph node, liver and spleen than White and Asian patients. Women were more likely to have eye (OR = 1.522, 95%CI: 1.259-1.838) or skin involvement (OR = 1.369, 95%CI: 1.152-1.628). Men were more likely to have cardiac involvement (OR = 1.326, 95%CI: 1.096-1.605). A total of 262 (18.1%) patients did not receive systemic treatment for sarcoidosis. Therapy was more common in Black patients than in other races., Conclusion: The initial presentation and treatment of sarcoidosis was related to sex, race, and age. Black and female individuals are found to have multiple organ involvement more frequently. Age at diagnosis<45, Black patients and multiple organ involvement were independent predictors of treatment., (Copyright © 2021. Published by Elsevier Ltd.)

Objectives: Missed opportunities to diagnose tuberculosis are costly to patients and society. In this study, we (1) estimate the frequency and duration of diagnostic delays among patients with active pulmonary tuberculosis and (2) determine the risk factors for experiencing a diagnostic delay., Design: A retrospective cohort study of patients with tuberculosis using longitudinal healthcare encounters prior to diagnosis., Setting: Commercially insured enrollees from the Commercial Claims and Encounters or Medicare Supplemental IBM Marketscan Research Databases, 2001-2017., Participants: All patients diagnosed with, and receiving treatment for, pulmonary tuberculosis, enrolled at least 365 days prior to diagnosis., Primary and Secondary Outcome Measures: We estimated the number of visits with tuberculosis-related symptoms prior to diagnosis that would be expected to occur in the absence of delays and compared this estimate to the observed pattern. We computed the number of visits representing a delay and used a simulation-based approach to estimate the number of patients experiencing a delay, number of missed opportunities per patient and duration of delays (ie, time between diagnosis and earliest missed opportunity). We also explored risk factors for missed opportunities., Results: We identified 3371 patients diagnosed and treated for active tuberculosis that could be followed up for 1 year prior to diagnosis. We estimated 77.2% (95% CI 75.6% to 78.7%) of patients experienced at least one missed opportunity; of these patients, an average of 3.89 (95% CI 3.65 to 4.14) visits represented a missed opportunity, and the mean duration of delay was 31.66 days (95% CI 28.51 to 35.11). Risk factors for delays included outpatient or emergency department settings, weekend visits, patient age, influenza season presentation, history of chronic respiratory symptoms and prior fluoroquinolone use., Conclusions: Many patients with tuberculosis experience multiple missed diagnostic opportunities prior to diagnosis. Missed opportunities occur most commonly in outpatient settings and numerous patient-specific, environment-specific and setting-specific factors increase risk for delays., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Sarcoidosis is a systemic disease of unknown etiology defined by the presence of noncaseating granulomatous inflammation that can cause organ damage and diminished quality of life. Treatment is indicated to protect organ function and decrease symptomatic burden. Current treatment options focus on interruption of granuloma formation and propagation. Clinical trials guiding evidence for treatment are lacking due to the rarity of disease, heterogeneous clinical course, and lack of prognostic biomarkers, all of which contribute to difficulty in clinical trial design and implementation. In this review, a multidisciplinary treatment approach is summarized, addressing immunuosuppressive drugs, managing complications of chronic granulomatous inflammation, and assessing treatment toxicity. Discovery of new therapies will depend on research into pathogenesis of antigen presentation and granulomatous inflammation. Future treatment approaches may also include personalized decisions based on pharmacogenomics and sarcoidosis phenotype, as well as patient-centered approaches to manage immunosuppression, symptom control, and treatment of comorbid conditions., Competing Interests: The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2020 Gerke.)

Background: It is widely unknown why respiratory infections follow a seasonal pattern. Variations in ultraviolet B (UVB) light during seasons affects cutaneous synthesis of vitamin D 3 . Serum vitamin D concentration influences the expression of airway surface liquid (ASL) antimicrobial peptides such as LL-37., Objective: We sought to determine the effect of seasons on serum vitamin D levels and ASL antimicrobial activity., Methods: Forty participants, 18-60 years old, were randomized 1:1 to receive 90 days of 1000 IU vitamin D 3 or placebo. We collected ASL via bronchoscopy and measured serum 25(OH) vitamin D from participants before and after intervention across seasons. We measured ASL antimicrobial activity by challenging samples with bioluminescent Staphylococcus aureus and measured relative light units (RLUs) after four minutes. We also investigated the role of LL-37 using a monoclonal neutralizing antibody., Results: We found that participants, prior to any intervention, during summer-fall ( n = 20) compared to winter-spring ( n = 20) had (1) decreased live bacteria after challenge (5542 ± 175.2 vs. 6585 ± 279 RLU, p = 0.003) and (2) higher serum vitamin D (88.25 ± 24.25 vs. 67.5 ± 45.25 nmol/L, p = 0.026). Supplementation with vitamin D 3 increased vitamin D levels and restored ASL antimicrobial activity only during the winter-spring. The increased ASL antimicrobial activity seen during the summer-fall was abrogated by adding the LL-37 neutralizing antibody., Conclusion: ASL kills bacteria more effectively during the summer-fall compared to the winter-spring. Supplementation of vitamin D during winter-spring restores ASL antimicrobial activity by increasing the expression of antimicrobial peptides including LL-37.

Rationale: Socioeconomic factors are associated with worse disease severity at presentation in sarcoidosis, but the relative importance of socioeconomic variables on morbidity and disease burden has not been fully elucidated. Objectives: To determine the association between income and sarcoidosis outcomes after controlling for socioeconomic and disease-related factors. Methods: Using the Sarcoidosis Advanced Registry for Cures database, we analyzed data from 2,318 patients with sarcoidosis in the United States to determine the effect of income and other variables on outcomes. We divided comorbidities arising after diagnosis into those likely related to steroid use and those likely related to sarcoidosis. We assessed the development of health-related, functional, and socioeconomic outcomes following the diagnosis of sarcoidosis. Measurements and Main Results: In multivariate analysis, low-income patients had significantly higher rates of new sarcoidosis-related comorbidities (<$35,000, odds ratio [OR], 2.4 [1.7-3.3]; $35,000-84,999, OR, 1.4 [1.1-1.9]; and ≥$85,000 [reference (Ref)]) and new steroid-related comorbidities (<$35,000, OR, 1.3 [0.9-2.0]; $35,000-84,999, OR, 1.5 [1.1-2.1]; and ≥$85,000 [Ref]), had lower health-related quality of life as assessed by the Sarcoidosis Health Questionnaire ( P  < 0.001), and experienced more impact on family finances (<$35,000, OR, 7.9 [4.9-12.7]; $35,000-84,999, OR, 2.7 [1.9-3.9]; and ≥$85,000 [Ref]). The use of supplemental oxygen, need for assistive devices, and job loss were more common in lower income patients. Development of comorbidities after diagnosis of sarcoidosis occurred in 63% of patients and were strong independent predictors of poor outcomes. In random forest modeling, income was consistently a leading predictor of outcome. Conclusions: These results suggest the burden from sarcoidosis preferentially impacts the economically disadvantaged.

Background: The diagnosis of sarcoidosis is not standardized but is based on three major criteria: a compatible clinical presentation, finding nonnecrotizing granulomatous inflammation in one or more tissue samples, and the exclusion of alternative causes of granulomatous disease. There are no universally accepted measures to determine if each diagnostic criterion has been satisfied; therefore, the diagnosis of sarcoidosis is never fully secure. Methods: Systematic reviews and, when appropriate, meta-analyses were performed to summarize the best available evidence. The evidence was appraised using the Grading of Recommendations, Assessment, Development, and Evaluation approach and then discussed by a multidisciplinary panel. Recommendations for or against various diagnostic tests were formulated and graded after the expert panel weighed desirable and undesirable consequences, certainty of estimates, feasibility, and acceptability. Results: The clinical presentation, histopathology, and exclusion of alternative diagnoses were summarized. On the basis of the available evidence, the expert committee made 1 strong recommendation for baseline serum calcium testing, 13 conditional recommendations, and 1 best practice statement. All evidence was very low quality. Conclusions: The panel used systematic reviews of the evidence to inform clinical recommendations in favor of or against various diagnostic tests in patients with suspected or known sarcoidosis. The evidence and recommendations should be revisited as new evidence becomes available.

In patients treated with repository corticotrophin injection (RCI) for pulmonary sarcoidosis, effective management of adverse events may improve adherence. However, management of adverse events may be challenging due to limitations in real-world clinical experience with RCI and available published guidelines.We surveyed 12 physicians with a modified Delphi process using three questionnaires. Questionnaire 1 consisted of open-ended questions. Panellists' answers were developed into a series of statements for Questionnaires 2 and 3. In these, physicians rated their agreement with the statements using a Likert scale.Key consensus recommendations included a starting dose of 40 units twice a week for patients with less severe disease, continued at a maintenance dose for patients who responded, particularly those with chronic refractory sarcoidosis. Panellists reached consensus that concomitant steroids should be quickly tapered in patients receiving RCI, but that concomitant use of immunosuppressive medications should be continued. Panellists developed consensus recommendations for adverse event management, and reached consensus that RCI should be down-titrated or discontinued if other interventions for the adverse effects fail or if the adverse effect is severe.In the absence of clinical evidence, our Delphi consensus opinions may provide practical guidance to physicians on the management of RCI to treat pulmonary sarcoidosis., Competing Interests: Conflict of interest: F.F. Rahaghi reports grants and consulting fees from Mallinckrodt, during the conduct of the study. Conflict of interest: N.J. Sweiss has nothing to disclose. Conflict of interest: L.A. Saketkoo has nothing to declare. Conflict of interest: M.B. Scholand reports other from Boehringer Ingelheim, Genentech, Fibrogen and Global Blood Therapeutics, outside the submitted work. In addition, M.B. Scholand has a patent Apparatus, Compositions and Methods for Assessment of Chronic Obstructive Pulmonary Disease Progression among Rapid and Slow Decline Conditions issued. Conflict of interest: J.B. Barney has nothing to disclose. Conflict of interest: A.K. Gerke has nothing to disclose. Conflict of interest: E.E. Lower has nothing to disclose. Conflict of interest: M. Mirsaeidi reports grants and personal fees from Mallinckrodt, outside the submitted work. Conflict of interest: L. O'Hare has nothing to disclose. Conflict of interest: M.J. Rumbak has nothing to disclose. Conflict of interest: L. Samavati has participated in a Questcor Advisory Board Meeting in 2014 and received $6500 compensation. Conflict of interest: R.P. Baughman reports grants and personal fees from Malllinckrodt, Novartis and Celgene, grants from Gilead, Genentech and Bayer, personal fees from West Pharmaceutical, during the conduct of the study., (Copyright ©ERS 2020.)

Pulmonary sarcoidosis presents substantial management challenges, with limited evidence on effective therapies and phenotypes. In the absence of definitive evidence, expert consensus can supply clinically useful guidance in medicine. An international panel of 26 experts participated in a Delphi process to identify consensus on pharmacological management in sarcoidosis with the development of preliminary recommendations.The modified Delphi process used three rounds. The first round focused on qualitative data collection with open-ended questions to ensure comprehensive inclusion of expert concepts. Rounds 2 and 3 applied quantitative assessments using an 11-point Likert scale to identify consensus.Key consensus points included glucocorticoids as initial therapy for most patients, with non-biologics (immunomodulators), usually methotrexate, considered in severe or extrapulmonary disease requiring prolonged treatment, or as a steroid-sparing intervention in cases with high risk of steroid toxicity. Biologic therapies might be considered as additive therapy if non-biologics are insufficiently effective or are not tolerated with initial biologic therapy, usually with a tumour necrosis factor-α inhibitor, typically infliximab.The Delphi methodology provided a platform to gain potentially valuable insight and interim guidance while awaiting evidenced-based contributions., Competing Interests: Conflict of interest: F.F. Rahaghi reports grants and consulting fees from Mallinckrodt, during the conduct of the study. Conflict of interest: R.P. Baughman reports grants and personal fees from Malllinckrodt, Novartis and Celgene, grants from Gilead, Genentech, Bayer and West Pharmaceutical, during the conduct of the study. Conflict of interest: L.A. Saketkoo has nothing to disclose. Conflict of interest: N.J. Sweiss has nothing to disclose. Conflict of interest: J.B. Barney has nothing to disclose. Conflict of interest: S.S. Birring has nothing to disclose. Conflict of interest: U. Costabel has nothing to disclose. Conflict of interest: E.D. Crouser has no relevant conflicts of interest to disclose. Conflict of interest: M. Drent has nothing to disclose. Conflict of interest: A.K. Gerke has nothing to disclose. Conflict of interest: J.C. Grutters has nothing to disclose. Conflict of interest: N.Y. Hamzeh has a patent pending from Prothena Inc. Conflict of interest: I. Huizar has no relevant conflicts of interest to disclose. Conflict of interest: W.E. James has nothing to disclose. Conflict of interest: S. Kalra has nothing to disclose. Conflict of interest: S. Kullberg has nothing to disclose. Conflict of interest: H. Li has nothing to disclose. Conflict of interest: E.E. Lower has nothing to disclose. Conflict of interest: L.A. Maier reports grants from National Institutes of Health: 1R01 HL127461-01A, 1R01HL11487-01A1, R01HL136681-01A1, 1R21 128738A-02, R21 HL140012-1, outside the submitted work. Conflict of interest: M. Mirsaeidi reports grants and personal fees from Mallinckrodt, outside the submitted work. Conflict of interest: J. Müller-Quernheim has nothing to disclose. Conflict of interest: E.M. Carmona Porquera reports other from ReSaph (Gilead), personal fees from American College of Chest Physicians (CHEST), outside the submitted work. Conflict of interest: L. Samavati participated in the Questcor Advisory Board Meeting 2014 and received $6500 compensation. Conflict of interest: D. Valeyre reports personal fees from Roche, Boehringer Ingelheim, AstraZeneca and Boehringer Ingelheim, outside the submitted work. Conflict of interest: M.B. Scholand reports other from Boehringer Ingelheim, Fibrogen, Global Blood Therapeutics and Genetech, outside the submitted work. In addition, M.B. Scholand has a patent Apparatus, Compositions and Methods for Assessment of Chronic Obstructive Pulmonary Disease Progression among Rapid and Slow Decline Conditions issued., (Copyright ©ERS 2020.)

Autosomal recessive diseases, such as cystic fibrosis (CF), require inheritance of 2 mutated genes. However, some studies indicate that CF carriers are at increased risk for some conditions associated with CF. These investigations focused on single conditions and included small numbers of subjects. Our goal was to determine whether CF carriers are at increased risk for a range of CF-related conditions. Using the Truven Health MarketScan Commercial Claims database (2001-2017), we performed a population-based retrospective matched-cohort study. We identified 19,802 CF carriers and matched each carrier with 5 controls. The prevalence of 59 CF-related diagnostic conditions was evaluated in each cohort. Odds ratios for each condition were computed for CF carriers relative to controls. All 59 CF-related conditions were more prevalent among carriers compared with controls, with significantly increased risk ( P < 0.05) for 57 conditions. Risk was increased for some conditions previously linked to CF carriers (e.g., pancreatitis, male infertility, bronchiectasis), as well as some conditions not previously reported (e.g., diabetes, constipation, cholelithiasis, short stature, failure to thrive). We compared our results with 23,557 subjects with CF, who were also matched with controls; as the relative odds of a given condition increased among subjects with CF, so did the corresponding relative odds for carriers ( P < 0.001). Although individual-level risk remained low for most conditions, because there are more than 10 million carriers in the US, population-level morbidity attributable to the CF carrier state is likely substantial. Genetic testing may inform prevention, diagnosis, and treatment for a broad range of CF carrier-related conditions., Competing Interests: The authors declare no competing interest., (Copyright © 2020 the Author(s). Published by PNAS.)

Purpose of Review: Sarcoidosis is a multisystemic granulomatous disease, which commonly affects the lung. The natural course of the disease and prognosis are variable from asymptomatic, spontaneous remission to progressive disease, which requires treatment. Once treatment is initiated, tapering therapy can be problematic., Recent Findings: Corticosteroids are recommended as first-line therapy, but optimal regimen and duration of treatment is not well established. Treatment may differ based on severity of disease, extrapulmonary involvement, physician and patient preferences. We reviewed currently recommended regimens, particularly, in pulmonary sarcoidosis and the use of alternative treatments as corticosteroid-sparing agents., Summary: Corticosteroid use is quite effective as initial therapy but is associated with significant side effects. An approach to tapering sarcoidosis therapy is not standardized, given the lack of evidence-based data. This review provides guidance based on the current literature.

Background: Smoking is a leading cause of respiratory infections worldwide. Tobacco particulate matter disrupts iron homeostasis in the lungs and increases the iron content in the airways of smokers. The airway epithelia secrete lactoferrin to quench iron required for bacteria to proliferate and cause lung infections. We hypothesized that smokers would have increased bacterial growth and biofilm formation via iron lactoferrin imbalance., Methods: We collected bronchoalveolar lavage (BAL) samples from non-smokers and smokers. We challenged these samples using a standard inoculum of Staphylococcus aureus and Pseudomonas aeruginosa and quantified bacterial growth and biofilm formation. We measured both iron and lactoferrin in the samples. We investigated the effect of supplementing non-smoker BAL with cigarette smoke extract (CSE) or ferric chloride and the effect of supplementing smoker BAL with lactoferrin on bacterial growth and biofilm formation., Results: BAL from smokers had increased bacterial growth and biofilm formation compared to non-smokers after both S. aureus and P. aeruginosa challenge. In addition, we found that samples from smokers had a higher iron to lactoferrin ratio. Supplementing the BAL of non-smokers with cigarette smoke extract and ferric chloride increased bacterial growth. Conversely, supplementing the BAL of smokers with lactoferrin had a concentration-dependent decrease in bacterial growth and biofilm formation., Conclusion: Cigarette smoking produces factors which increase bacterial growth and biofilm formation in the BAL. We propose that smoking disrupts the iron-to-lactoferrin in the airways. This finding offers a new avenue for potential therapeutic interventions to prevent respiratory infections in smokers.

Sarcoidosis is a systemic inflammatory disease with substantial morbidity and increasing mortality. As part of the National Heart, Lung, and Blood Institute's workshop to better understand this disease and improve the outcomes of patients with sarcoidosis, we reviewed the available data on health care burden and outcomes of this disease in the United States. Disparities in outcomes exist by race, ethnicity, sex, and socioeconomic groups, with African Americans having disproportionately more severe disease. Mortality rates are highest in African Americans, but may be increasing in white individuals. The health care burden of sarcoidosis is defined not only by its somatic manifestations, but is also greatly impacted by psychosocial, economic, and comorbid conditions associated with this disease. Fatigue, depression, cognitive dysfunction, treatment side effects, and pain syndromes are highly prevalent in this population and contribute to poor outcomes. The direct and indirect economic costs to patients and society are likely also substantial, although not well defined. We recommend leveraging existing and future technology and infrastructure to more accurately define and monitor the overall total sarcoidosis-attributable health care burden and patient outcomes in the United States.

Background: Sustained exposure to ambient particulate matter (PM) is a global cause of mortality. Coal fly ash (CFA) is a byproduct of coal combustion and is a source of anthropogenic PM with worldwide health relevance. The airway epithelia are lined with fluid called airway surface liquid (ASL), which contains antimicrobial proteins and peptides (AMPs). Cationic AMPs bind negatively charged bacteria to exert their antimicrobial activity. PM arriving in the airways could potentially interact with AMPs in the ASL to affect their antimicrobial activity., Objectives: We hypothesized that PM can interact with ASL AMPs to impair their antimicrobial activity., Methods: We exposed pig and human airway explants, pig and human ASL, and the human cationic AMPs β-defensin-3, LL-37, and lysozyme to CFA or control. Thereafter, we assessed the antimicrobial activity of exposed airway samples using both bioluminescence and standard colony-forming unit assays. We investigated PM-AMP electrostatic interaction by attenuated total reflection Fourier-transform infrared spectroscopy and measuring the zeta potential. We also studied the adsorption of AMPs on PM., Results: We found increased bacterial survival in CFA-exposed airway explants, ASL, and AMPs. In addition, we report that PM with a negative surface charge can adsorb cationic AMPs and form negative particle-protein complexes., Conclusion: We propose that when CFA arrives at the airway, it rapidly adsorbs AMPs and creates negative complexes, thereby decreasing the functional amount of AMPs capable of killing pathogens. These results provide a novel translational insight into an early mechanism for how ambient PM increases the susceptibility of the airways to bacterial infection. https://doi.org/10.1289/EHP876.

Introduction: Vitamin D 3 supplementation has been reported to prevent lung infections and increase the gene expression of antimicrobial peptides such as cathelicidin. We investigated the effect of vitamin D 3 supplementation on the antimicrobial activity of airway surface liquid (ASL) in human subjects. Since smoking can increase the risk of respiratory infections, we also investigated the effect of smoking in the cathelicidin response to vitamin D 3 in human airway epithelia in vitro., Methods: This study is a subanalysis of single-centre community-based randomised placebo-controlled double-blind trial. Participants were randomised to receive 1000 international units per day of oral vitamin D 3 or identical placebo for 90 days. Blood and ASL samples were collected preintervention and postintervention. 105 participants were originally enrolled, 86 completed the trial, and due to low protein concentration in the samples, 40 participants were finally analysed. Our primary outcome was ASL antimicrobial activity. We also considered secondary outcomes including changes in serum concentration of 25-hydroxyvitamin D 3 (25(OH)D 3 ), 1,25-hydroxyvitamin D 3 , calcium and parathyroid hormone (PTH). In addition, we studied the effect of cigarette smoke extract (CSE) exposure to primary human airway epithelial cell cultures on the gene expression of cathelicidin in response to vitamin D 3 and expression of CYP27B1 (1-alpha hydroxylase), responsible for vitamin D 3 activation., Results: Vitamin D 3 supplementation significantly increased both ASL antimicrobial activity and serum concentration of 25(OH)D 3 . In a subgroup analysis, we found that smokers did not increase their baseline antimicrobial activity in response to vitamin D 3 . Exposure to CSE on human airway epithelia decreased baseline CYP27B1 gene expression and cathelicidin response to 25(OH)D 3 ., Conclusion: Vitamin D 3 supplementation for 90 days increases ASL antimicrobial activity. Data from this preliminary study suggest that smoking may alter the ability of airway epithelia to activate vitamin D 3 and increase the gene expression of cathelicidin antimicrobial peptide., Trial Registration Number: NCT01967628; Post-results., Competing Interests: Competing interests: None declared.

Background/objective: The objective is to present the development of a novel web-based patient registry for sarcoidosis. We describe recruitment efforts and assess efficacy of internet-based advertising on recruitment., Methods: "Worldwide Sarcoidosis Research Study (WISE)" started in 2011 under the domain www.sarcoidstudy.org. The registry includes thirteen patient-reported surveys about patient characteristics, diagnosis, and treatment. Effects of two internet-based advertising methods (geographically-broad versus geographically-targeted to high sarcoidosis search areas) on recruitment were analyzed with time series regression., Results: Since 2011, over 1500 participants have registered (82% whites, 9% African Americans, 5% mixed, 4% other), with 23% of participants providing saliva samples for DNA. Median age is 43 years (range 21-80). African Americans were more frequently recruited via support groups, while whites had a higher frequency of finding the registry via internet. Generalized internet-based advertising significantly improved recruitment in all demographic groups (p<0.001). However, a higher response rate to internet-based advertising was seen in whites compared to African Americans(p<0.001), females versus males(p=0.043), higher income categories(p=0.048), and increased education level(p<0.001). Targeting advertising campaigns to geographical areas with high internet-search patterns for sarcoidosis, with different demographics, was not effective in raising registry recruitment above baseline or increasing diversity., Conclusions: A web-based registry is an effective method for establishing a cohort of patients with sarcoidosis invested in clinical research with DNA specimens. Despite limitations, opportunities for research in patient-oriented outcomes and broad internet-based research methodology are possible. Our results demonstrate that web-based approaches to recruit study subjects need to be focused to match different target populations., Competing Interests: Conflicts of Interest: The authors have no conflicts of interest.

Background: We conducted a systematic review and network meta-analysis to examine comparative efficacy and tolerability of pharmacologic interventions for pulmonary arterial hypertension (PAH)., Methods: MEDLINE, the Cochrane Register, EMBASE, CINAHL, and clinicaltrials.gov were searched (January 1, 1990 to March 3, 2016). Randomized controlled trials (RCTs) studying the approved pharmacologic agents endothelin receptor antagonists (ERA), phosphodiesterase inhibitors (PDE5i), the oral/inhaled (PO/INH) and IV/subcutaneous (SC) prostanoids, and riociguat and selexipag, alone or in combination, for pulmonary arterial hypertension (PAH) and reporting at least one efficacy outcome were selected., Results: Thirty-one RCTs with 6,565 patients were selected. In network meta-analysis, when compared with a median placebo rate of 14.5%, clinical worsening was estimated at 2.8% with riociguat (risk ratio [RR], 0.19; 95% CI, 0.05-0.76); at 3.9% with ERA + PDE5i (RR, 0.27; 95% CI, 0.14-0.52), and at 5.7% with PDE5i (RR, 0.39; 95% CI, 0.24-0.62). For improvement in functional status, when compared with 16.2% in the placebo group, improvement in at least one New York Heart Association/World Health Organization (NYHA/WHO) functional class was estimated at 81.8% with IV/SC prostanoids (RR, 5.06; 95% CI, 2.3211.04), at 28.3% with ERA + PDE5i (RR, 1.75; 95% CI, 1.05-2.92), and at 25.2% with ERA (RR, 1.56; 95% CI, 1.22-2.00). Differences in mortality were not significant. Adverse events leading to discontinuation of therapy were highest with the PO/INH prostanoids (RR, 2.92; 95% CI, 1.68-5.06) and selexipag (RR, 2.06; 95% CI, 1.04-3.88) compared with placebo., Conclusions: Currently approved pharmacologic agents have varying effects on morbidity and functional status in patients with PAH. Future comparative effectiveness trials are warranted with a focus on a patient-centered approach to therapy., Registration: PROSPERO CRD42016036803., (Copyright © 2016 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

Background: Although the relation between radiographic abnormalities and spirometric impairment in people with asbestosis has been studied extensively, the extent of spirometric impairment associated with milder radiographic abnormalities is not established., Objective: To test associations between mild radiographic abnormalities and Lower Limit of Normal (LLN)-based spirometry interpretation., Methods: Spirometry and CXRs were collected for 1,026 at low risk of exposure to pneumoconiotic agents participants in a medical screening program., Results: Individuals with each type of isolated or combined International Labour Organization (ILO) abnormalities had up to over sixfold statistically significant increase in odds of LLN-based restrictive pattern physiology (OR = 1.96, 95%CI 1.03-3.73 for parenchymal to OR = 6.09, 95%CI 1.94-19.10 for parenchymal and pleural) compared to those with normal films., Conclusions: The findings from this study confirm the association of mild profusion abnormalities with clinically relevant, LLN-based lung function abnormalities.

Background: Extracorporeal membrane oxygenation (ECMO) has been increasingly studied as a life support modality, but it is unclear if its use has changed over time. Recent publication shows no significant trend in use of ECMO over time; however, this report does not include more recent data. We performed trend analysis to determine if and when the use of ECMO changed in the past decade., Results: We identified hospitalizations (2000-2011) in the Nationwide Inpatient Sample during which ECMO was recorded. We used a segmented linear regression model to determine trend and to identify a temporal change point when rate of ECMO use increased. ECMO use gradually grew until 2007, at which time there was a dramatic increase in the rate (p = 0.0003). There was no difference in mortality after 2007 (p = 0.3374), but there was longer length of stay (p = 0.0001) and smaller percentage of women (p = 0.005)., Conclusions: There has been a marked increase in ECMO use since 2007. As ECMO use becomes more common, further study regarding indications, cost-effectiveness, and outcomes is warranted to guide optimal use.

Inclusion body myositis (IBM) is a slowly progressive inflammatory myopathy characterized by selective weakness of finger flexors and quadriceps muscles commonly refractory to treatment. Another chronic inflammatory disorder, sarcoidosis, commonly involves muscle. The comorbidity of inclusion body myositis and sarcoid myopathy is rare. We describe clinical and muscle biopsy findings of a patient with sarcoidosis and inclusion body myositis. A 66-year-old man presented with a 6-year history of progressive, asymmetrical and selective weakness of the quadriceps, biceps and finger flexor muscles; he had a remote history of pulmonary sarcoidosis. A quadriceps muscle biopsy revealed a chronic inflammatory myopathy with ubiquitinated inclusion bodies, rimmed vacuoles, expression of major histocompatibility complex class I, numerous COX-negative fibers and TDP-43 cytoplasmic aggregates (features of IBM) and multiple non-necrotizing granulomata (feature of sarcoidosis). Clinical and histopathologic features of the current illness suggested the patient had sarcoidosis with inclusion body myositis overlap. This patient may represent the coincidental occurrence of both idiopathic inflammatory disorders. Alternatively, sarcoidoisis may promote the development of inclusion body myositis by a similar immune-mediated pathophysiologic process., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Background: The clinical presentation of sarcoidosis can be varied. Prior investigations have shown that diagnosis is often delayed over six months, particularly in patients with pulmonary symptoms. Delays may lead to high healthcare use prior to diagnosis. , Objective: To investigate healthcare use prior to diagnosis of sarcoidosis for a cohort of insured patients., Methods: We conducted a case-control study using a de-identified limited dataset of private health insurance claims.  Cases were identified as persons with sarcoidosis from 2003-2009. Controls with other respiratory-related diagnoses (asthma, chronic obstructive pulmonary disease, pneumonia) were matched by age, gender, and diagnosis date. We compared frequencies of doctor visits, prescriptions, and imaging in the year prior to established diagnosis., Results: We identified 206 cases and 2060 controls and compared healthcare use patterns in the year prior to diagnosis. Among those receiving prescriptions, a larger proportion of cases received two or more antibiotic courses (69% vs. 55%, p=0.0020) or two or more corticosteroid prescriptions (63% vs. 50%, p=0.0137). On average, cases had more doctor visits (14.7 vs. 7.8, p&lt;0.0001), saw more specialties (3.9 vs. 2.1, p&lt;0.0001), and underwent more chest x-rays (2.0 vs. 1.5, p&lt;0.0001). A larger proportion of cases underwent two or more chest x-rays (54% vs. 24%, p&lt;0.0001)., Conclusions: Patients with sarcoidosis undergo a large amount of healthcare prior to diagnosis, some of which may not be necessary, compared to controls with respiratory-related disease. These results highlight the need for improved diagnostic algorithms to identify patients with sarcoidosis and avoid potentially excessive delays in diagnosis.

Purpose of Review: Chronic sarcoidosis is a complex disease with numerous comorbid conditions and can be fatal in some cases. Recognizing causes of morbidity and mortality is important to effectively select treatments, manage symptoms and improve outcomes. The purpose of this review is to examine emerging knowledge on morbidity and mortality in sarcoidosis., Recent Findings: Approximately 1-5% of patients with sarcoidosis die from complications of sarcoidosis. Recent population studies indicate that mortality may be increasing over the past decade. The reasons behind these trends are unclear, but could include increasing incidence, detection rates, severity of disease or age of the population. Morbidity of sarcoidosis is reflected by a trend of increased hospitalizations over recent years and increased use of healthcare resources. Morbidity can be caused by organ damage from granulomatous inflammation, treatment complications and psychosocial effects of the disease. Recent studies are focused on morbidity related to cardiopulmonary complications, bone health and ageing within the sarcoidosis population. Last, sarcoidosis is associated with autoimmune diseases, pulmonary embolism and malignancy; however, the underlying mechanisms linking diseases continue to be debated., Summary: Morbidity in sarcoidosis is significant and multifactorial. Mortality is infrequent, but may be increasing over the years.

Despite the fact that alveolar macrophages play an important role in smoking-related disease, little is known about what regulates their pathophysiologic phenotype. Evaluating smoker macrophages, we found significant down-regulation of multiple microRNAs (miRNAs). This work investigates the hypothesis that cigarette smoke alters mature miRNA expression in lung macrophages by inhibiting processing of primary miRNA transcripts. Studies on smoker alveolar macrophages showed a defect in miRNA maturation. Studies on the miRNA biogenesis machinery led us to focus on the cytosolic RNA endonuclease, DICER. DICER cleaves the stem-loop structure from pre-miRNAs, allowing them to dissociate into their mature 20-22-nucleotide single-stranded form. DICER activity assays confirmed impaired DICER activity following cigarette smoke exposure. Further protein studies demonstrated a decreased expression of the native 217-kDa form of DICER and an accumulation of high molecular weight forms with cigarette smoke exposure. This molecular mass shift was shown to contain SUMO moieties and could be blocked by silencing RNA directed at the primary SUMOylating ligase, Ubc9. In determining the cigarette smoke components responsible for changes in DICER, we found that N-acetylcysteine, an antioxidant and anti-aldehyde, protected DICER protein and activity from cigarette smoke extract. This massive down-regulation of miRNAs (driven in part by alterations in DICER) may be an important regulator of the disease-promoting macrophage phenotype found in the lungs of smokers.

Background: Vitamin D deficiency has been implicated as a factor in a number of infectious and inflammatory lung diseases. In the lung, alveolar macrophages play a key role in inflammation and defense of infection, but there are little data exploring the immunomodulatory effects of vitamin D on innate lung immunity in humans. The objective of this study was to determine the effects of vitamin D supplementation on gene expression of alveolar macrophages., Methods: We performed a parallel, double-blind, placebo-controlled, randomized trial to determine the effects of vitamin D on alveolar macrophage gene expression. Vitamin D3 (1000 international units/day) or placebo was administered to adults for three months. Bronchoscopy was performed pre- and post-intervention to obtain alveolar macrophages. Messenger RNA was isolated from the macrophages and subjected to whole genome exon array analysis. The primary outcome was differential gene expression of the alveolar macrophage in response to vitamin D supplementation. Specific genes underwent validation by polymerase chain reaction methods., Results: Fifty-eight subjects were randomized to vitamin D (n = 28) or placebo (n = 30). There was a marginal overall difference between treatment group and placebo group in the change of 25-hydroxyvitaminD levels (4.43 ng/ml vs. 0.2 ng/ml, p = 0.10). Whole genome exon array analysis revealed differential gene expression associated with change in serum vitamin D levels in the treated group. CCL8/MCP-2 was the top-regulated cytokine gene and was further validated., Conclusions: Although only a non-significant increased trend was seen in serum vitamin D levels, subjects treated with vitamin D supplementation had immune-related differential gene expression in alveolar macrophages., Trial Registration: ClinicalTrials.org: NCT01967628.

Background and Objective: Although influenza has been associated with asthma exacerbations, it is not clear the extent to which this association affects health care use in the United States. The first goal of this project was to determine whether, and to what extent, the incidence of asthma hospitalizations is associated with seasonal variation in influenza. Second, we used influenza trends (2000-2008) to help predict asthma admissions during the 2009 H1N1 influenza pandemic., Methods: We identified all hospitalizations between 1998 and 2008 in the Nationwide Inpatient Sample from the Healthcare Cost and Utilization Project during which a primary diagnosis of asthma was recorded. Separately, we identified all hospitalizations during which a diagnosis of influenza was recorded. We performed time series regression analyses to investigate the association of monthly asthma admissions with influenza incidence. Finally, we applied these time series regression models using 1998-2008 data, to forecast monthly asthma admissions during the 2009 influenza pandemic., Results: Based on time series regression models, a strong, significant association exists between concurrent influenza activity and incidence of asthma hospitalizations (P-value < 0.0001). Use of influenza data to predict asthma admissions during the 2009 H1N1 pandemic improved the mean squared prediction error by 60.2%., Conclusions: Influenza activity in the population is significantly associated with asthma hospitalizations in the United States, and this association can be exploited to more accurately forecast asthma admissions. Our results suggest that improvements in influenza surveillance, prevention and treatment may decrease hospitalizations of asthma patients., (© 2013 The Authors. Respirology © 2013 Asian Pacific Society of Respirology.)

Although influenza has been associated with chronic obstructive pulmonary disease (COPD) exacerbations, it is not clear the extent to which this association affects healthcare use in the United States. The first goal of this project was to determine to what extent the incidence of COPD hospitalizations is associated with seasonal influenza. Second, as a natural experiment, we used influenza activity to help predict COPD admissions during the 2009 H1N1 influenza pandemic. To do this, we identified all hospitalizations between 1998 and 2010 in the Nationwide Inpatient Sample from the Healthcare Cost and Utilization Project (HCUP) during which a primary diagnosis of COPD was recorded. Separately, we identified all hospitalizations during which a diagnosis of influenza was recorded. We formulated time series regression models to investigate the association of monthly COPD admissions with influenza incidence. Finally, we applied these models, fit using 1998-2008 data, to forecast monthly COPD admissions during the 2009 pandemic. Based on time series regression models, a strong, significant association exists between concurrent influenza activity and incidence of COPD hospitalizations (p-value < 0.0001). The association is especially strong among older patients requiring mechanical ventilation. Use of influenza data to predict COPD admissions during the 2009 H1N1 pandemic reduced the mean-squared prediction error by 29.9%. We conclude that influenza activity is significantly associated with COPD hospitalizations in the United States and influenza activity can be exploited to more accurately forecast COPD admissions. Our results suggest that improvements in influenza surveillance, prevention, and treatment may decrease hospitalizations of patients diagnosed with COPD.

Objectives: To assess concordance between the fixed 70% ratio cutoff point with the fixed percent predicted values (Fixed-ratio) and the lower limit of normal (LLN) algorithms in interpreting spirometry results in an older population., Methods: Spirometries were interpreted using Third National Health and Nutrition Examination Survey reference equations for 2319 workers., Results: The Fixed-ratio algorithm characterized 34.5% (n = 801) results as abnormal, compared with 29.7% (n = 689) by the LLN. There were almost twice as many obstructive and mixed airways spirometries identified under the Fixed-ratio compared to LLN. Rates of restrictive pattern physiology were virtually the same under each algorithm. Overall agreement between the algorithms decreased with age from "almost perfect" for those younger than 60 years to "substantial" for those older than 80 years., Conclusions: This study found age-related discordance between two algorithms possibly related to the lack of reference equations and standards for individuals older than 80 years.

The incidence of myocardial infarctions and influenza follow similar seasonal patterns. To determine if acute myocardial infarctions (AMIs) and ischaemic strokes are associated with influenza activity, we built time-series models using data from the Nationwide Inpatient Sample. In these models, we used influenza activity to predict the incidence of AMI and ischaemic stroke. We fitted national models as well as models based on four geographical regions and five age groups. Across all models, we found consistent significant associations between AMIs and influenza activity, but not between ischaemic strokes and influenza. Associations between influenza and AMI increased with age, were greatest in those aged >80 years, and were present in all geographical regions. In addition, the natural experiment provided by the second wave of the influenza pandemic in 2009 provided further evidence of the relationship between influenza and AMI, because both series peaked in the same non-winter month.

Background: The onset of sarcoidosis is thought to be seasonal, particularly Lofgren's syndrome. However, there are conflicting data on seasonality by country and by radiographic stage., Objective: The objective of this study was to determine if there is seasonality of the diagnosis of sarcoidosis in outpatients in the United States., Methods and Results: Using time series methods, we performed a retrospective analysis of 3791 incident cases of sarcoidosis in the Veteran's Health Administration national outpatient claims database (2000-2007). We did not find overall seasonality in the occurrence of new sarcoidosis in United States Veterans (p = 0.9860), even after we subdivided the United States by northern (p = 0.6824) and southern regions (p = 0.4588)., Conclusion: The lack of seasonality in this study indicates that season is not a dominant factor in complex gene-environment-host interaction that precedes presentation of new sarcoidosis cases in the United States Veteran population.

Cigarette smoking is implicated in numerous diseases, including emphysema and lung cancer. The clinical expression of lung disease in smokers is not well explained by currently defined variations in gene expression or simple differences in smoking exposure. Alveolar macrophages play a critical role in the inflammation and remodeling of the lung parenchyma in smoking-related lung disease. Significant gene expression changes in alveolar macrophages from smokers have been identified. However, the mechanism for these changes remains unknown. One potential mechanism for smoking-altered gene expression is via changes in cytosine methylation in DNA regions proximal to gene-coding sequences. In this study, alveolar macrophage DNA from heavy smokers and never smokers was isolated and methylation status at 25,000 loci determined. We found differential methylation in genes from immune-system and inflammatory pathways. Analysis of matching gene expression data demonstrated a parallel enrichment for changes in immune-system and inflammatory pathways. A significant number of genes with smoking-altered mRNA expression had inverse changes in methylation status. One gene highlighted by this data was the FLT1, and further studies found particular up-regulation of a splice variant encoding a soluble inhibitory form of the receptor. In conclusion, chronic cigarette smoke exposure altered DNA methylation in specific gene promoter regions in human alveolar macrophages.

Background: Diagnostic and treatment approaches for sarcoidosis have changed dramatically over the past decade. Yet, the most recent reports of trends in hospitalizations of sarcoidosis patients are over ten years old. The objectives of this study were to determine the incidence of sarcoidosis among hospitalized patients and to analyze recent trends and seasonality of hospitalizations in sarcoidosis patients., Methods: We performed a retrospective cohort study of the Nationwide Inpatient Sample from 1998 through 2008. We identified all hospitalizations with a primary or secondary diagnosis of sarcoidosis (ICD-9-CM code 135). Incidence was modeled as a seasonal time series about a linear trend., Results: Time series analysis of the monthly number of hospitalizations revealed a distinct positive linear trend. Over the study period, the number of hospitalized patients with sarcoidosis increased from 37,516 to 70,947 cases. Trends were most pronounced in patients older than 55 years (p < 0.0001), African Americans (p < 0.0001), females (p = 0.0289), and non-Medicaid populations (p < 0.0001). Hospitalizations are seasonal with highest incidence in January through March., Conclusions: Hospitalizations among sarcoidosis patients have almost doubled during the past decade, with disproportionate rate increases in African Americans, women, and older patients. The rate also increases among patients with insurance other than Medicaid. This study indicates the need for heightened surveillance of sarcoidosis patients given the unknown consequences of evolving treatment approaches. Our results point to a need for research investigating risk factors for hospitalization, including medications, co-morbidities, demographics, and socioeconomic status.

Rationale/objectives: Smoking has been associated with decreased incidence and prevalence of sarcoidosis, but few studies have evaluated effects of smoking on clinical parameters of the disease. The objectives were to determine the association of smoking with radiographic patterns and to evaluate the associations of these smoking-related radiographic patterns on airflow obstruction in sarcoidosis., Materials and Methods: Clinical data and computed tomography (CT) scans of 124 patients with sarcoidosis were reviewed. CT scans were assessed for lymph nodes, nodules, bronchiectasis, bronchovascular bundle thickening, displaced hilum, fibrosis, ground glass, emphysema, pleural changes, and alveolar opacities. CT patterns were compared between patients with and without a history of smoking. The effect of smoking on the associations between radiographic patterns and airflow obstruction was assessed with multivariable analysis., Results: Smokers had less frequency of bronchovascular bundle thickening than nonsmokers (11/38 subjects [29%] vs 50/86 subjects [58%], P = .003) and more emphysema (7/38 subjects [18%] vs 1/86 subjects [1%], P = .001). Patients who had bronchovascular bundle thickening were less likely to have ever smoked (11/61 subjects [18%] vs 27/63 subjects [43%], P = .003) or be current smokers (4/61 subjects [7%] vs 15/63 subjects [24%], P = .008). Age (P = .003) and bronchovascular bundle thickening (P = .02) were independent predictors of airflow obstruction. There were no differences in smoking history between patients with airflow obstruction versus those without (10/37 subjects [27%] vs 28/87 subjects [32%], P = .63)., Conclusions: In patients with sarcoidosis, smoking is associated with decreased frequency of bronchovascular bundle thickening, an important clinical manifestation of the lung disease. Further, bronchovascular bundle thickening and age are the only independent predictors of airflow obstruction, and smoking does not confound these associations., (Copyright © 2011 AUR. Published by Elsevier Inc. All rights reserved.)

Sarcoidosis continues to be a disease of research interest because of its complicated immune mechanisms and elusive etiology. So far, it has been established that granulomatous inflammation in sarcoidosis is predominantly a T-helper 1 immune response mediated by a complex network of lymphocytes, macrophages, and cytokines. The cause of progression to a chronic and potentially fibrotic form is unclear but may involve loss of apoptotic mechanisms, loss of regulatory response, or a persistent antigen that cannot be cleared. Recent genomic and proteomic technology has emphasized the importance of host susceptibility and gene-environment interaction in the expression of the disease.