Interleukin-1 blockade in cardiac sarcoidosis: study design of the multimodality assessment of granulomas in cardiac sarcoidosis: Anakinra Randomized Trial (MAGiC-ART).

BACKGROUND: Sarcoidosis is an inflammatory disease characterized by the formation of granulomas, which involve the heart in up to 25% of patients. Cardiac sarcoidosis can lead to life threatening arrhythmias and heart failure. While corticosteroids have been used as a treatment for over 50 years, they are associated with hypertension, diabetes, and weight gain, further increasing cardiovascular risk. Interleukin-1 (IL-1) is the prototypical proinflammatory cytokine that works to activate the nuclear transcription factor NF-kB, one of the targets of glucocorticoids. IL-1 also plays an important role also in the pathophysiology of heart disease including atherosclerosis, myocardial infarction, and myocarditis. METHODS: Building on a network of research collaborators developed in the Cardiac Sarcoidosis Consortium, we will investigate the feasibility and tolerability of treatment of CS with anakinra at two National Institute of Health Clinical and Translational Science Award (CTSA) hubs with expertise in cardiac sarcoidosis. In this pilot study, up to 28 patients with cardiac sarcoidosis will be recruited to compare the administration of an IL-1 blocker, anakinra, 100 mg daily on top of standard of care versus standard of care only for 28 days and followed for 180 days. Utilizing surrogate endpoints of changes in systemic inflammatory biomarkers and cardiac imaging, we aim to determine whether IL-1 blockade with anakinra can combat systemic and cardiac inflammation in patients with cardiac sarcoidosis. DISCUSSION: The current trial demonstrates an innovative collaborative approach to clinical trial development in a rare, understudied disease that disproportionately affects females and minorities. Trial Registration The trial was registered prospectively with ClinicalTrials.gov on July 12, 2019, identifier NCT04017936.

Effect of Vitamin C Infusion on Organ Failure and Biomarkers of Inflammation and Vascular Injury in Patients With Sepsis and Severe Acute Respiratory Failure: The CITRIS-ALI Randomized Clinical Trial.

Importance: Experimental data suggest that intravenous vitamin C may attenuate inflammation and vascular injury associated with sepsis and acute respiratory distress syndrome (ARDS). Objective: To determine the effect of intravenous vitamin C infusion on organ failure scores and biological markers of inflammation and vascular injury in patients with sepsis and ARDS. Design, Setting, and Participants: The CITRIS-ALI trial was a randomized, double-blind, placebo-controlled, multicenter trial conducted in 7 medical intensive care units in the United States, enrolling patients (N = 167) with sepsis and ARDS present for less than 24 hours. The study was conducted from September 2014 to November 2017, and final follow-up was January 2018. Interventions: Patients were randomly assigned to receive intravenous infusion of vitamin C (50 mg/kg in dextrose 5% in water, n = 84) or placebo (dextrose 5% in water only, n = 83) every 6 hours for 96 hours. Main Outcomes and Measures: The primary outcomes were change in organ failure as assessed by a modified Sequential Organ Failure Assessment score (range, 0-20, with higher scores indicating more dysfunction) from baseline to 96 hours, and plasma biomarkers of inflammation (C-reactive protein levels) and vascular injury (thrombomodulin levels) measured at 0, 48, 96, and 168 hours. Results: Among 167 randomized patients (mean [SD] age, 54.8 years [16.7]; 90 men [54%]), 103 (62%) completed the study to day 60. There were no significant differences between the vitamin C and placebo groups in the primary end points of change in mean modified Sequential Organ Failure Assessment score from baseline to 96 hours (from 9.8 to 6.8 in the vitamin C group [3 points] and from 10.3 to 6.8 in the placebo group [3.5 points]; difference, -0.10; 95% CI, -1.23 to 1.03; P = .86) or in C-reactive protein levels (54.1 vs 46.1 µg/mL; difference, 7.94 µg/mL; 95% CI, -8.2 to 24.11; P = .33) and thrombomodulin levels (14.5 vs 13.8 ng/mL; difference, 0.69 ng/mL; 95% CI, -2.8 to 4.2; P = .70) at 168 hours. Conclusions and Relevance: In this preliminary study of patients with sepsis and ARDS, a 96-hour infusion of vitamin C compared with placebo did not significantly improve organ dysfunction scores or alter markers of inflammation and vascular injury. Further research is needed to evaluate the potential role of vitamin C for other outcomes in sepsis and ARDS. Trial Registration: ClinicalTrials.gov Identifier: NCT02106975.

Iloprost reverses established fibrosis in experimental right ventricular failure.

Prostacyclin and its analogues improve cardiac output and functional capacity in patients with pulmonary arterial hypertension (PAH); however, the underlying mechanism is not fully understood. We hypothesised that prostanoids have load-independent beneficial effects on the right ventricle (RV). Angio-obliterative PAH and RV failure were induced in rats with a single injection of SU5416 followed by 4 weeks of exposure to hypoxia. Upon confirmation of RV dysfunction and PAH, rats were randomised to 0.1 µg·kg(-1) nebulised iloprost or drug-free vehicle, three times daily for 2 weeks. RV function and treadmill running time were evaluated pre- and post-iloprost/vehicle treatment. Pulmonary artery banded rats were treated 8 weeks after surgery to allow for significant RV hypertrophy. Inhaled iloprost significantly improved tricuspid annulus plane systolic excursion and increased exercise capacity, while mean pulmonary artery pressure and the percentage of occluded pulmonary vessels remained unchanged. Rats treated with iloprost had a striking reduction in RV collagen deposition, procollagen mRNA levels and connective tissue growth factor expression in both SU5416/hypoxia and pulmonary artery banded rats. In vitro, cardiac fibroblasts treated with iloprost showed a reduction in transforming growth factor (TGF)-ß1-induced connective tissue growth factor expression, in a protein kinase A-dependent manner. Iloprost decreased TGF-ß1-induced procollagen mRNA expression as well as cardiac fibroblast activation and migration. Iloprost significantly induced metalloproteinase-9 gene expression and activity and increased the expression of autophagy genes associated with collagen degradation. Inhaled iloprost improves RV function and reverses established RV fibrosis partially by preventing collagen synthesis and by increasing collagen turnover.

Phase I safety trial of intravenous ascorbic acid in patients with severe sepsis.

BACKGROUND: Parenterally administered ascorbic acid modulates sepsis-induced inflammation and coagulation in experimental animal models. The objective of this randomized, double-blind, placebo-controlled, phase I trial was to determine the safety of intravenously infused ascorbic acid in patients with severe sepsis. METHODS: Twenty-four patients with severe sepsis in the medical intensive care unit were randomized 1:1:1 to receive intravenous infusions every six hours for four days of ascorbic acid: Lo-AscA (50 mg/kg/24 h, n = 8), or Hi-AscA (200 mg/kg/24 h, n = 8), or Placebo (5% dextrose/water, n = 8). The primary end points were ascorbic acid safety and tolerability, assessed as treatment-related adverse-event frequency and severity. Patients were monitored for worsened arterial hypotension, tachycardia, hypernatremia, and nausea or vomiting. In addition Sequential Organ Failure Assessment (SOFA) scores and plasma levels of ascorbic acid, C-reactive protein, procalcitonin, and thrombomodulin were monitored. RESULTS: Mean plasma ascorbic acid levels at entry for the entire cohort were 17.9 ± 2.4 µM (normal range 50-70 µM). Ascorbic acid infusion rapidly and significantly increased plasma ascorbic acid levels. No adverse safety events were observed in ascorbic acid-infused patients. Patients receiving ascorbic acid exhibited prompt reductions in SOFA scores while placebo patients exhibited no such reduction. Ascorbic acid significantly reduced the proinflammatory biomarkers C-reactive protein and procalcitonin. Unlike placebo patients, thrombomodulin in ascorbic acid infused patients exhibited no significant rise, suggesting attenuation of vascular endothelial injury. CONCLUSIONS: Intravenous ascorbic acid infusion was safe and well tolerated in this study and may positively impact the extent of multiple organ failure and biomarkers of inflammation and endothelial injury. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT01434121.

Neutrophil elastase activates the release of extracellular traps from COPD blood monocyte-derived macrophages.

Neutrophil elastase (NE), a major inflammatory mediator in chronic obstructive pulmonary disease (COPD) airways, impairs macrophage function, contributing to persistence of airway inflammation. We hypothesized that NE activates a novel mechanism of macrophage-induced inflammation: release of macrophage extracellular traps (METs). The METs are composed of extracellular DNA decorated with granule proteinases and oxidants and may trigger persistent airway inflammation in COPD. To test the hypothesis, human blood monocytes were isolated from whole blood of subjects with COPD recruited following informed written consent. Patient demographics and clinical data were collected. Cells were cultured in media with GM-CSF to differentiate into blood monocyte derived macrophages (BMDMs). The BMDMs were treated with FITC-NE and unlabeled NE to determine intracellular localization by confocal microscopy and intracellular proteinase activity by DQ-Elastin assay. After NE exposure, released extracellular traps were quantified by abundance of extracellular DNA in conditioned media using the Pico Green assay. BMDM cell lysates were analyzed by Western analysis for proteolytic degradation of histone H3 or H4 or upregulation of peptidyl arginine deiminase (PAD) 2 and 4, two potential mechanisms to mediate extracellular trap DNA release. We observed that NE was taken up by COPD BMDM, localized to the cytosol and nucleus, and retained proteinase activity in the cell. NE induced MET release at doses as low as 50 nM. NE treatment caused histone H3 clipping but no effect on histone H4 nor PAD 2 or 4 abundance or activity. In summary, NE activated COPD MET release by clipping histone H3, a prerequisite for chromatin decondensation.

A brief overview of mouse models of pulmonary arterial hypertension: problems and prospects.

Many chronic pulmonary diseases are associated with pulmonary hypertension (PH) and pulmonary vascular remodeling, which is a term that continues to be used to describe a wide spectrum of vascular abnormalities. Pulmonary vascular structural changes frequently increase pulmonary vascular resistance, causing PH and right heart failure. Although rat models had been standard models of PH research, in more recent years the availability of genetically engineered mice has made this species attractive for many investigators. Here we review a large amount of data derived from experimental PH reports published since 1996. These studies using wild-type and genetically designed mice illustrate the challenges and opportunities provided by these models. Hemodynamic measurements are difficult to obtain in mice, and right heart failure has not been investigated in mice. Anatomical, cellular, and genetic differences distinguish mice and rats, and pharmacogenomics may explain the degree of PH and the particular mode of pulmonary vascular adaptation and also the response of the right ventricle.

Tackling Health Care Disparities: How to Build a Sarcoidosis Center.

Sarcoidosis is a multi-organ system inflammatory disease of unknown etiology that disproportionately affects women and black patients in the United States. In addition, woman and minority patients have worse outcomes. In 2015, sarcoidosis physicians in cardiology, pulmonary medicine and rheumatology joined forces to create a multidisciplinary sarcoidosis at Virginia Commonwealth University. In 2019, the clinic was recognized as a World Association of Sarcoidosis and Other Granulomatous Disorders (WASOG) Center of Excellence. We identify four pillars of a patient-centered sarcoidosis clinic: clinical care, research, teaching, and community outreach. We detail how each of these facets plays a critical role in improving the health of individual patients, creating a strong infrastructure to improve the future of sarcoidosis treatment, and developing community-based resources that can empower patients. Most importantly, we highlight how a multidisciplinary clinic can help identify and combat healthcare disparities.

Sepsis in two hospitals in Rwanda: A retrospective cohort study of presentation, management, outcomes, and predictors of mortality.

PURPOSE: Few studies have assessed the presentation, management, and outcomes of sepsis in low-income countries (LICs). We sought to characterize these aspects of sepsis and to assess mortality predictors in sepsis in two referral hospitals in Rwanda. MATERIALS AND METHODS: This was a retrospective cohort study in two public academic referral hospitals in Rwanda. Data was abstracted from paper medical records of adult patients who met our criteria for sepsis. RESULTS: Of the 181 subjects who met eligibility criteria, 111 (61.3%) met our criteria for sepsis without shock and 70 (38.7%) met our criteria for septic shock. Thirty-five subjects (19.3%) were known to be HIV positive. The vast majority of septic patients (92.7%) received intravenous fluid therapy (median = 1.0 L within 8 hours), and 94.0% received antimicrobials. Vasopressors were administered to 32.0% of the cohort and 46.4% received mechanical ventilation. In-hospital mortality for all patients with sepsis was 51.4%, and it was 82.9% for those with septic shock. Baseline characteristic mortality predictors were respiratory rate, Glasgow Coma Scale score, and known HIV seropositivity. CONCLUSIONS: Septic patients in two public tertiary referral hospitals in Rwanda are young (median age = 40, IQR = 29, 59) and experience high rates of mortality. Predictors of mortality included baseline clinical characteristics and HIV seropositivity status. The majority of subjects were treated with intravenous fluids and antimicrobials. Further work is needed to understand clinical and management factors that may help improve mortality in septic patients in LICs.

Infection prevention in sarcoidosis: proposal for vaccination and prophylactic therapy.

Sarcoidosis is a systemic inflammatory disease characterized by granuloma formation in affected organs and caused by dysregulated immune response to an unknown antigen. Sarcoidosis patients receiving immunosuppressive medications are at increased risk of infection. Lymphopenia is also commonly seen among patient with sarcoidosis. In this review, risk of infections, including opportunistic infections, will be outlined. Recommendations for vaccinations and prophylactic therapy based on literature review will also be summarized. (Sarcoidosis Vasc Diffuse Lung Dis 2020; 37 (2): 87-98).

Intravenous vitamin C as adjunctive therapy for enterovirus/rhinovirus induced acute respiratory distress syndrome.

We report a case of virus-induced acute respiratory distress syndrome (ARDS) treated with parenteral vitamin C in a patient testing positive for enterovirus/rhinovirus on viral screening. This report outlines the first use of high dose intravenous vitamin C as an interventional therapy for ARDS, resulting from enterovirus/rhinovirus respiratory infection. From very significant preclinical research performed at Virginia Commonwealth University with vitamin C and with the very positive results of a previously performed phase I safety trial infusing high dose vitamin C intravenously into patients with severe sepsis, we reasoned that infusing identical dosing to a patient with ARDS from viral infection would be therapeutic. We report here the case of a 20-year-old, previously healthy, female who contracted respiratory enterovirus/rhinovirus infection that led to acute lung injury and rapidly to ARDS. She contracted the infection in central Italy while on an 8-d spring break from college. During a return flight to the United States, she developed increasing dyspnea and hypoxemia that rapidly developed into acute lung injury that led to ARDS. When support with mechanical ventilation failed, extracorporeal membrane oxygenation (ECMO) was initiated. Twelve hours following ECMO initiation, high dose intravenous vitamin C was begun. The patient's recovery was rapid. ECMO and mechanical ventilation were discontinued by day-7 and the patient recovered with no long-term ARDS sequelae. Infusing high dose intravenous vitamin C into this patient with virus-induced ARDS was associated with rapid resolution of lung injury with no evidence of post-ARDS fibroproliferative sequelae. Intravenous vitamin C as a treatment for ARDS may open a new era of therapy for ARDS from many causes.

Intravenous Vitamin C Administered as Adjunctive Therapy for Recurrent Acute Respiratory Distress Syndrome.

This case report summarizes the first use of intravenous vitamin C employed as an adjunctive interventional agent in the therapy of recurrent acute respiratory distress syndrome (ARDS). The two episodes of ARDS occurred in a young female patient with Cronkhite-Canada syndrome, a rare, sporadically occurring, noninherited disorder that is characterized by extensive gastrointestinal polyposis and malabsorption. Prior to the episodes of sepsis, the patient was receiving nutrition via chronic hyperalimentation administered through a long-standing central venous catheter. The patient became recurrently septic with Gram positive cocci which led to two instances of ARDS. This report describes the broad-based general critical care of a septic patient with acute respiratory failure that includes fluid resuscitation, broad-spectrum antibiotics, and vasopressor support. Intravenous vitamin C infused at 50 mg per kilogram body weight every 6 hours for 96 hours was incorporated as an adjunctive agent in the care of this patient. Vitamin C when used as a parenteral agent in high doses acts "pleiotropically" to attenuate proinflammatory mediator expression, to improve alveolar fluid clearance, and to act as an antioxidant.

Intermittent aerosol delivery to the lungs during high-flow nasal cannula therapy.

INTRODUCTION: Use of submicrometer particles combined with condensational growth techniques has been proposed to reduce drug losses within components of high-flow nasal cannula therapy systems and to enhance the dose reaching the lower respiratory tract. These methods have been evaluated using continuous inhalation flow rather than realistic inhalation/exhalation breathing cycles. The goal of this study was to evaluate in vitro aerosol drug delivery using condensational growth techniques during high-flow nasal cannula therapy using realistic breathing profiles and incorporating intermittent aerosol delivery techniques. METHODS: A mixer-heater combined with a vibrating mesh nebulizer was used to generate a submicrometer aerosol using a formulation of 0.2% albuterol sulfate and 0.2% sodium chloride in water. Delivery efficiency of the aerosol for 1 min through a nasal cannula was considered using an intermittent delivery regime with aerosol being emitted for either the entire inhalation time (2 s) or half of the inhalation period (1 s) and compared with continuous delivery. The deposition of the aerosol was evaluated in the nasal delivery components (ventilator tubing and cannula) and an in vitro adult nose-mouth-throat (NMT) model using 3 realistic breathing profiles. RESULTS: Significant improvements in dose delivered to the exit of the NMT model (ex-NMT) were observed for both condensational growth methods using intermittent aerosol delivery compared with continuous delivery, and increasing the tidal volume was found useful. The combination of the largest tidal volume with the shortest intermittent delivery time resulted in the lowest respiration losses and the highest ex-NMT delivered dose. CONCLUSIONS: Intermittent aerosol delivery using realistic breathing profiles of submicrometer condensational growth aerosols was found to be efficient in delivering nasally administered drugs in an in vitro airway model.