A prospective, single-center, randomized phase 2 trial of etoposide in severe COVID-19.

The systemic inflammatory response seen in patients with severe COVID-19 shares many similarities with the changes observed in hemophagocytic lymphohistiocytosis (HLH); a disease characterized by excessive immune activation. Many patients with severe COVID qualify for a diagnosis of HLH. Etoposide, an inhibitor of topoisomerase II is used to control inflammation in HLH. This randomized, open-label, single center phase II trial attempted to determine whether etoposide can be used to blunt the inflammatory response in severe COVID. This trial was closed early after eight patients were randomized. This underpowered trial did not meet its primary endpoint of improvement in pulmonary status by two categories on an 8 point ordinal scale of respiratory function. There were not significant differences in secondary outcomes including overall survival at 30 days, cumulative incidence of grade 2 through 4 adverse events during hospitalization, duration of hospitalization, duration of ventilation and improvement in oxygenation or paO2/FIO2 ratio or improvement in inflammatory markers associated with cytokine storm. A high rate of grade 3 myelosuppression was noted in this critically ill population despite dose reduction, a toxicity which will limit future attempts to explore the utility of etoposide for virally-driven cytokine storm or HLH.

Critical Care of Patients With Cardiopulmonary Complications of Sarcoidosis.

Sarcoidosis is a systemic inflammatory disease defined by the presence of aberrant granulomas affecting various organs. Due to its multisystem involvement, care of patients with established sarcoidosis becomes challenging, especially in the intensive care setting. While the lungs are typically involved, extrapulmonary manifestations also occur either concurrently or exclusively within a significant proportion of patients, complicating diagnostic and management decisions. The scope of this review is to focus on what considerations are necessary in the evaluation and management of patients with known sarcoidosis and their associated complications within a cardiopulmonary and critical care perspective.

Long-term outcomes of epoprostenol therapy in sarcoid associated pulmonary hypertension.

Sarcoidosis-Associated Pulmonary Hypertension (SAPH) is a common finding in patients with chronic sarcoidosis and is associated with increased mortality. The optimal treatment for SAPH is not known; however, therapies approved for Group 1 pulmonary hypertension have improved hemodynamics and functional status. Prostanoids, including epoprostenol, have been therapeutic in short-term studies of SAPH, but long-term efficacy is unknown. In this study, we evaluated the long-term effect of epoprostenol therapy in 12 patients with SAPH. Hemodynamic assessment after an average of 4.1 years of epoprostenol therapy demonstrated significant improvement in mean pulmonary arterial pressure, pulmonary vascular resistance, and cardiac output; furthermore, patients demonstrated improved NYHA functional class. To evaluate further the long-term effect of epoprostenol, we compared survival of SAPH patients to a cohort of hemodynamically matched patients from the same center treated with epoprostenol for Idiopathic Pulmonary Arterial Hypertension (IPAH). Interestingly, there was no difference in survival, despite the additional systemic disease burden of the SAPH subjects. Subgroup analysis by Scadding stage demonstrated that Scadding stages 1-3 had improved survival compared to Scadding stage 4. These observations suggest that epoprostenol is an effective long-term therapy for patients with SAPH; it improves hemodynamics, functional class, and provides survival similar to that seen in a hemodynamically-matched cohort of IPAH patients. Furthermore, we identify a subgroup of SAPH patients (nonfibrotic lung disease Scadding 1-3) who may derive significant benefit from prostanoid therapy. (Sarcoidosis Vasc Diffuse Lung Dis 2020; 37 (2): 184-191).

Treatment of newly diagnosed sarcoid-associated pulmonary hypertension with ambrisentan and tadalafil combination therapy.

Sarcoid Associated Pulmonary Hypertension (SAPH) is a common complication of sarcoidosis and is associated with poor prognosis. SAPH can be due to multiple synergistic mechanisms and current therapeutic strategies treat systemic sarcoidosis and pulmonary hypertension separately. Several studies have been performed to develop an effective therapy for SAPH but have been met with mixed results. The AMBITION trial successfully treated incident patients with pulmonary arterial hypertension (PAH) with the upfront combination of ambrisentan and tadalafil; however combination therapy has not yet been studied in patients with SAPH. Here we report a cohort of patients with newly diagnosed SAPH who were treated with upfront combination therapy per the AMBITION study protocol. We report three subjects with newly diagnosed SAPH who were treated with combination ambrisentan and tadalafil. Baseline hemodynamics were compared with those from surveillance right heart catheterization while on therapy. Mean follow up period was 17 months. Each subject demonstrated clinical and hemodynamic improvement with combination therapy. This series is the first to evaluate upfront combination ambrisentan and tadalafil therapy for treatment of newly diagnosed SAPH. Despite the impressive clinical and hemodynamic improvement, the study is limited by its small size and retrospective nature. While these initial results are promising, further work is needed to fully evaluate this regimen for treatment of SAPH. (Sarcoidosis Vasc Diffuse Lung Dis 2020; 37 (2): 234-238).

Diagnosis and Detection of Sarcoidosis. An Official American Thoracic Society Clinical Practice Guideline.

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.

Diagnosis and detection of sarcoidosis: an official American Thoracic Society Clinical Practice Guideline

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. 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. 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 best practice statement. All evidence was very low quality.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.

Comparison of Ultrasound Features of Major Salivary Glands in Sarcoidosis, Amyloidosis, and Sjögren's Syndrome.

OBJECTIVE: While salivary gland ultrasound (SGU) has gained prominence for evaluating Sjögren's syndrome, little information exists on SGU appearance of sarcoidosis and amyloidosis, potential mimics of Sjögren's syndrome. Our goal in this study was to estimate the diagnostic accuracy of major SGU features in differentiating Sjögren's syndrome from sarcoidosis, amyloidosis, and controls. METHODS: We enrolled consecutive adult ambulatory patients with a clinical diagnosis of Sjögren's syndrome fulfilling the 2016 American College of Rheumatology (ACR) classification criteria; we also enrolled patients with a clinical diagnosis of sarcoidosis or systemic immunoglobulin light chain (AL) amyloidosis, with histologic confirmation from any tissue, and rheumatology outpatients without diagnoses affecting salivary glands. Subjects underwent major SGU using the Hocevar protocol, with resulting video clips reviewed blind to clinical diagnosis. RESULTS: Sjögren's syndrome SGU scores were greater than in patients from the other groups, but there were no distinguishing salivary gland features from AL amyloidosis or sarcoidosis. None of the patients in the control group scored higher than 17, a cutoff previously suggested for Sjögren's syndrome, but 27% of patients with AL amyloidosis and 19% with sarcoidosis scored higher than 17. Adding Hocevar SGU scores of ≥17 to the 2016 ACR/European League Against Rheumatism criteria in a parallel scheme increased the sensitivity for Sjögren's syndrome from 87% to 98%, while combining the 2 criteria in series increased specificity from 81% to 98%. CONCLUSION: Sjögren's syndrome, sarcoidosis, and AL amyloidosis share common SGU features that can help distinguish these conditions from patients without systemic rheumatologic disease. Clinicians should carefully consider these potential mimics when interpreting salivary gland US results.

Obesity and sarcoidosis: consequence or contributor?

PURPOSE OF REVIEW: Sarcoidosis is a multisystem disease of unknown cause. Obesity can affect many physiological factors. The relationship between obesity and sarcoidosis is unclear, and can been described as posing a 'chicken and egg' scenario for the patient as it is not always clear whether it is a consequence of, or a risk factor for any disease. The purpose of this review is to examine the dual roles of obesity on sarcoidosis morbidity and the incidence. RECENT FINDINGS: Obesity magnifies the symptoms of sarcoidosis and corticosteroid therapy increases BMI. Prospective epidemiologic studies started to explore the role of obesity as a potential risk factor for sarcoidosis. Three studies in the United States, and one study in Denmark, have demonstrated significantly increased risks of sarcoidosis among obese compared with nonobese patients; risk estimates ranged from 1.42 [95% confidence interval (CI), 1.07-1.89] to 3.59 (95% CI, 2.31-5.57). SUMMARY: Obesity can be both a consequence of sarcoidosis treatment, and a contributor to disease risk likely through the pro-inflammatory environment of obesity. Prospective epidemiologic cohort studies are needed to explore the cause of sarcoidosis and insight into possible avenues of treatment development and prevention.

Transbronchial biopsies safely diagnose amyloid lung disease.

BACKGROUND: Autopsy identifies lung involvement in 58-92% of patients with the most prevalent forms of systemic amyloidoses. In the absence of lung biopsies, amyloid lung disease often goes unrecognized. Report of a death following transbronchial biopsies in a patient with systemic amyloidosis cautioned against the procedure in this patient cohort. We reviewed our experience with transbronchial biopsies in patients with amyloidosis to determine the safety and utility of bronchoscopic lung biopsies. METHODS: We identified patients referred to the Amyloidosis Center at Boston Medical Center with lung amyloidosis diagnosed by transbronchial lung biopsies (TBBX). Amyloid typing was determined by immunohistochemistry or mass spectrometry. Standard end organ assessments, including pulmonary function test (PFT) and chest tomography (CT) imaging, and extra-thoracic biopsies established the extent of disease. RESULTS: Twenty-five (21.7%) of 115 patients with lung amyloidosis were diagnosed by TBBX. PFT classified 33.3% with restrictive physiology, 28.6% with obstructive disease, and 9.5% mixed physiology; 9.5% exhibited isolated diffusion defects while 19% had normal pulmonary testing. Two view chest or CT imaging identified focal opacities in 52% of cases and diffuse interstitial disease in 48%. Amyloid type and disease extent included 68% systemic AL disease, 16% localized (lung limited) AL disease, 12% ATTR disease, and 4% AA amyloidosis. Fluoroscopy was not used during biopsy. No procedure complications were reported. CONCLUSIONS: Our case series of 25 patients supports the use of bronchoscopic transbronchial biopsies for diagnosis of parenchymal lung amyloidosis. Normal PFTs do not rule out the histologic presence of amyloid lung disease.

The response of FDG uptake to immunosuppressive treatment on FDG PET/CT imaging for cardiac sarcoidosis.

BACKGROUND: Immunosuppression is used to treat cardiac sarcoidosis, despite limited data. FDG PET/CT is used for detecting cardiac inflammation in patients with CS, yet there is variability in interpretation of FDG PET/CT. Our aim was to compare quantitative and qualitative interpretation of FDG PET/CT for CS in defining the FDG response to immunosuppression. METHODS AND RESULTS: Patients with CS (N = 43 total studies from 17 patients) had serial FDG PET/CT studies before/after immunosuppression. FDG uptake was analyzed qualitatively (visually; FDG-positive segments) and quantitatively (SUVmax; cardiac metabolic volume and activity (CMV, CMA); volume above SUV thresholds 2.7 and 4.1 g/mL). Complete resolution of FDG uptake was common using CMA (10/17), CMV (10/17), but a 2.7 g/mL SUV threshold (13/17) and SUVmax (14/17) were more likely to define partial responses. In six patients imaged after a reduction in immunosuppression, 4/6 had a rebound quantitative FDG uptake. CONCLUSIONS: Quantitative interpretation of FDG PET/CT in CS can detect changes in FDG uptake in response to immunosuppression. Further studies are needed to see if quantitative changes in FDG uptake are associated with improved outcomes.

The Diagnosis of Sarcoidosis.

Sarcoidosis is a diagnosis of exclusion; there exists neither a pathognomonic clinical feature nor a perfect diagnostic test. Missed diagnosis and overdiagnosis are common. A careful history and physical examination look for "footprints" of sarcoidosis or features suggesting alternative diagnoses. Some presentations are classic and do not require tissue confirmation. A tissue biopsy should be performed if doubt exists. Sampling intrathoracic disease by transbronchial or ultrasound-guided biopsy of mediastinal lymph nodes provide high diagnostic yield with low complication rates. Even with tissue confirmation, diagnosis is never secure and follow-up is required to be fully confident of the diagnosis.

Obesity and weight gain in relation to incidence of sarcoidosis in US black women: data from the Black Women's Health Study.

BACKGROUND: Sarcoidosis, a systemic disorder characterized by chronic granulomatous inflammation, occurs more frequently among US black women, as do overweight and obesity. Little is known about the relation of overweight and obesity, which induce chronic inflammation, to incidence of sarcoidosis. METHODS: We assessed the relation of obesity and weight gain to the incidence of sarcoidosis in the Black Women's Health Study, a follow-up study of 59,000 US black women aged 21 to 69 years at baseline in 1995. Information on weight at age 18 years, height, current weight, incident sarcoidosis, and covariates was collected at baseline and on biennial follow-up questionnaires. Cox regression models adjusted for age, education, geographic region, smoking, alcohol consumption, and physical activity were used to estimate incidence rate ratios (IRRs) and 95% CIs. RESULTS: From 1995 through 2011, 454 incident cases of sarcoidosis occurred during 707,557 person-years of follow-up. The incidence of sarcoidosis increased with increasing BMI and weight gain. The IRR was 1.40 (95% CI, 0.88-2.25) for BMI ≥ 30 kg/m2 at age 18 years relative to 20 to 24 kg/m2 (P trend = .18), 1.42 (95% CI, 1.07-1.89) for BMI ≥ 35 kg/m2 at baseline relative to 20 to 24 kg/m2 (P trend = .01), and 1.47 (95% CI, 1.10-1.97) for a weight gain between age 18 years and baseline of ≥ 30 kg relative to 0 to 9 kg (P trend = .16). In stratified analyses, there were significant trends of sarcoidosis incidence with increasing BMI and weight gain in women aged ≥ 45 years and ever smokers. CONCLUSIONS: The present study provides evidence that weight gain and obesity during adulthood are associated with increased sarcoidosis incidence.

Quantitative interpretation of FDG PET/CT with myocardial perfusion imaging increases diagnostic information in the evaluation of cardiac sarcoidosis.

BACKGROUND: FDG PET/CT with myocardial perfusion imaging is a useful method for evaluating cardiac sarcoidosis (CS), but interpretation is not standardized. We developed a method for quantification of cardiac FDG PET/CT and evaluated its relationship to conventional interpretation, perfusion defects, clinical events, and immunosuppressive treatment. METHODS AND RESULTS: FDG PET/CT with MPI studies performed for CS (n = 38) were retrospectively compared to negative control studies acquired for oncologic indications (n = 10). Quantitative measures of FDG volume-intensity (Cardiac Metabolic Activity, CMA) was performed using standardized uptake values (SUVs). CMA (477.7 ± 909 vs 0.55 ± 2.1 vs 0.3 ± 0.3 g glucose, P = .02) was significantly greater in visually FDG-positive studies compared to visually negative and oncologic negative studies. Among patients with CS, CMA was greater in studies with an EF < 50% (760.3 ± 1,148 vs 87.4 ± 161 g glucose, P = .03) and preceding an adverse clinical event (1,095 ± 1,253 vs 73 ± 144 g glucose, P = .006). CMA was the only independent predictor of events by multivariate analysis. In patients with repeat examinations (n = 7), CMA decreased with prednisone treatment in 5 of 6 patients. CONCLUSIONS: Quantification of FDG uptake in CS correlates with lower EFs, clinical events, and immunosuppression treatment.

Cavin1; a regulator of lung function and macrophage phenotype.

Caveolae are cell membrane invaginations that are highly abundant in adipose tissue, endothelial cells and the lung. The formation of caveolae is dependent on the expression of various structural proteins that serve as scaffolding for these membrane invaginations. Cavin1 is a newly identified structural protein whose deficiency in mice leads to loss of caveolae formation and to development of a lipodystrophic phenotype. In this study, we sought to investigate the functional role of Cavin1 in the lung. Cavin1 deficient mice possessed dramatically altered distal lung morphology and exhibited significant physiological alterations, notably, increased lung elastance. The changes in distal lung architecture were associated with hypercellularity and the accumulation of lung macrophages. The increases in lung macrophages occurred without changes to circulating numbers of mononuclear cells and without evidence for increased proliferation. However, the increases in lung macrophages were associated with higher levels of macrophage chemotactic factors CXCL2 and CCL2 in BAL fluid from Cavin1-/- mice suggesting a possible mechanism by which these cells accumulate. In addition, lung macrophages from Cavin1-/- mice were larger and displayed measurable differences in gene expression when compared to macrophages from wild-type mice. Interestingly, macrophages were also increased in adipose tissue but not in liver, kidney or skeletal muscle from Cavin1-/- mice, and similar tissue specificity for macrophage accumulation was observed in lungs and adipose tissue from Caveolin1-/- mice. In conclusion, this study demonstrates an important role for Cavin1 in lung homeostasis and suggests that caveolae structural proteins are necessary for regulating macrophage number and phenotype in the lung.