The Renin-Angiotensin-Aldosterone System Regulates Sarcoidosis Granulomatous Inflammation.

Rationale: Sarcoidosis is a granulomatous disorder of unclear cause notable for abnormal elevation of blood and tissue angiotensin converting enzyme 1 (ACE1) levels and activity. ACE1 regulates the renin-angiotensin-aldosterone system (RAAS), the terminal product of which is aldosterone, which selectively engages mineralocorticoid receptors (MR) to promote inflammation. Objectives: We sought to determine whether the RAAS promotes sarcoidosis granuloma formation and related inflammatory responses. Methods: Using an established ex vivo model, we first determined whether aldosterone was produced by sarcoidosis granulomas and verified the presence of CYP11B2, the enzyme required for its production. We then evaluated the effects of selective inhibitors of ACE1 (captopril), angiotensin type 1 receptor (losartan) and MR (spironolactone, eplerenone) on granuloma formation, reflected by computer image analysis-generated granuloma area, and selected cytokines incriminated in sarcoidosis pathogenesis. Measurements and Main Results: Aldosterone was spontaneously produced by sarcoidosis PBMCs, and both intra- and extracellular levels steadily increased during granuloma formation. In parallel, PBMCs were shown to express more CYP11B2 during granuloma formation. Significant inhibition of sarcoidosis granulomas and related cytokines (TNFα, IL-1ß, IFNγ, IL-10) was observed in response to pretreatments with captopril, losartan, spironolactone or eplerenone, comparable to that of prednisone. Conclusions: The RAAS is intact in sarcoidosis granulomas and contributes significantly to early granuloma formation and to related inflammatory mediator responses with important implications for clinical management.

Sarcoid-like reactions to immune checkpoint inhibitors: Incidence, treatment course, and impact on cancer progression and survival.

INTRODUCTION: Sarcoid-like reactions (SLRs) to immune checkpoint inhibitors (ICIs) are a rare but increasingly recognized immune-related adverse event of which the clinical significance is unclear. METHODS: We conducted a retrospective cohort study at a tertiary academic center of consecutive patients who received at least one dose of ICI from 2013 to 2020. Patient characteristics, risk factors, and outcomes were compared between patients with and without SLR following ICI treatment. RESULTS: A total of 2963 cancer patients received at least 1 dose of ICI between 2013 and 2020, and 7 patients (0.24 %) developed SLR. There were no significant demographic differences between patients with and without SLR following ICI. SLRs occurred in 5 of 451 (1.07 %) melanoma patients and 2 of 840 (0.24 %) non-small cell lung cancer patients. Two of the 7 patients had multi-organ SLR, and both were symptomatic requiring systemic corticosteroids and permanent ICI discontinuation, while single organ SLR patients did not require immune suppression. Development of SLR did not appear to have negative impact on cancer progression or overall survival; in fact, a trend towards improved progression-free and overall survival was observed (median time: 1363 days vs 127 days, p = 0.091; 1387 days vs 428.5 days, p = 0.19, respectively). CONCLUSIONS: SLRs are a known but understudied complication associated with ICI therapy. Multisystem SLR patients were more symptomatic and required ICI discontinuation and immune suppression. Larger studies are needed to fully evaluate the impact of SLR on cancer outcomes.

Case report: Disseminated herpes simplex virus 1 infection and hemophagocytic lymphohistiocytosis after immunomodulatory therapy in a patient with coronavirus disease 2019.

Corticosteroids and immunomodulatory therapies are widely used to treat patients with severe coronavirus disease 2019 (COVID-19). Janus kinase (JAK) inhibitors such as tofacitinib have been recently studied as adjuvants in the treatment of COVID-19. Although immunomodulatory therapies may be linked to decreased mortality rates in the acute phase, subsequent severe infectious complications may result from them. We describe a case of a multiorgan system failure secondary to disseminated primary herpes simplex virus 1 (HSV-1) infection and hemophagocytic lymphohistiocytosis (HLH) following treatment with tofacitinib and high-dose dexamethasone therapy for severe COVID-19. Early diagnosis and treatment of these life-threatening conditions may have a significant impact on COVID-19 patients' outcomes.

The influence of age and sex in sarcoidosis.

PURPOSE OF REVIEW: This review aims to describe how the clinical manifestations of sarcoidosis may be shaped by the effects of sex hormones and by age dependent changes in immune functions and physiology This review is intended to highlight the need to consider the effects of sex and sex in future studies of sarcoidosis. RECENT FINDINGS: The clinical manifestations of sarcoidosis differ based on sex and gender There is emerging evidence that female and male hormones and X-linked genes are important determinants of immune responses to environmental antigens, which has important implications for granuloma formation in the context of sarcoidosis Furthermore, sex hormone levels predictably change throughout adolescence and adulthood, and this occurs in parallel with the onset immune senescence and changes in physiology with advanced age. SUMMARY: Recent studies indicate that sex and age are important variables shaping the immune response of humans to environmental antigens We posit herein that sex and age are important determinants of sarcoidosis clinical phenotypes Many gaps in our understanding of the roles played by sex and gender in sarcoidosis, and these need to be considered in future studies.

Reducing Unnecessary Laboratory Utilization in the Medical ICU: A Fellow-Driven Quality Improvement Initiative.

OBJECTIVES: Overutilization of laboratory services is now recognized as harmful to patients and wasteful. In fact, the American Board of Internal Medicine's Choosing Wisely campaign recommends against ordering routine testing that does not answer a clinical question. Per peer benchmarking, our institution as a whole occupied an extreme outlier position at the 100th percentile for laboratory utilization. We sought to address this problem starting in our medical ICUs with a quality improvement project. DESIGN: Quality improvement project using the design, measure, analyze, improve, and control process. The primary endpoint was a sustained reduction in laboratory utilization. Counterbalance metrics were also followed, and these included mortality, renal replacement therapy initiation rates, stat laboratory orders, and central catheter-associated blood stream infections. SETTING: The medical ICU at the Ohio State University Medical Center. PATIENTS: All patients admitted to the medical ICU from March 2019 to March 2020. INTERVENTIONS: Root causes were identified and addressed with the implementation of a wide range of interventions involving a multidisciplinary team led by trainee physicians. MEASUREMENTS AND MAIN RESULTS: There was a sustained 20% reduction in the number of tests performed per patient day, with no change in the counterbalance metrics. CONCLUSIONS: Trainees can affect positive change in the culture and processes at their institutions to safely reduce laboratory utilization.