Background An important feature of severe acute respiratory syndrome coronavirus 2 pathogenesis is COVID-19associated coagulopathy, characterised by increased thrombotic and microvascular complications. Previous studies have suggested a role for endothelial cell injury in COVID-19-associated coagulopathy. To determine whether endotheliopathy is involved in COVID-19-associated coagulopathy pathogenesis, we assessed markers of endothelial cell and platelet activation in critically and non-critically ill patients admitted to the hospital with COVID-19. Methods In this single-centre cross-sectional study, hospitalised adult (≥18 years) patients with laboratory-confirmed COVID-19 were identified in the medical intensive care unit (ICU) or a specialised non-ICU COVID-19 floor in our hospital. Asymptomatic, non-hospitalised controls were recruited as a comparator group for biomarkers that did not have a reference range. We assessed markers of endothelial cell and platelet activation, including von Willebrand Factor (VWF) antigen, soluble thrombomodulin, soluble P-selectin, and soluble CD40 ligand, as well as coagulation factors, endogenous anticoagulants, and fibrinolytic enzymes. We compared the level of each marker in ICU patients, non-ICU patients, and controls, where applicable. We assessed correlations between these laboratory results with clinical outcomes, including hospital discharge and mortality. Kaplan-Meier analysis was used to further explore the association between biochemical markers and survival. Findings 68 patients with COVID-19 were included in the study from April 13 to April 24, 2020, including 48 ICU and 20 non-ICU patients, as well as 13 non-hospitalised, asymptomatic controls. Markers of endothelial cell and platelet activation were significantly elevated in ICU patients compared with non-ICU patients, including VWF antigen (mean 565% [SD 199] in ICU patients vs 278% [133] in non-ICU patients; p<0•0001) and soluble P-selectin (15•9 ng/mL [4•8] vs 11•2 ng/mL [3•1]; p=0•0014). VWF antigen concentrations were also elevated above the normal range in 16 (80%) of 20 non-ICU patients. We found mortality to be significantly correlated with VWF antigen (r=0•38; p=0•0022) and soluble thrombomodulin (r=0•38; p=0•0078) among all patients. In all patients, soluble thrombomodulin concentrations greater than 3•26 ng/mL were associated with lower rates of hospital discharge (22 [88%] of 25 patients with low concentrations vs 13 [52%] of 25 patients with high concentrations; p=0•0050) and lower likelihood of survival on Kaplan-Meier analysis (hazard ratio 5•9, 95% CI 1•9-18•4; p=0•0087).Interpretation Our findings show that endotheliopathy is present in COVID-19 and is likely to be associated with critical illness and death. Early identification of endotheliopathy and strategies to mitigate its progression might improve outcomes in COVID-19.
CD14 and the toll-like receptor 4 have been known to play an important role in lipopolysaccharide-induced cellular responses in bacterial infections. Although CD14 and toll-like receptor 4 expression has been demonstrated in a number of myeloid cells, much less is known about the expression and function of these lipopolysaccharide receptors on nonleukocytes. In this study, we demonstrate that human keratinocytes are capable of expressing functional CD14 and toll-like receptor 4. Keratinocytes were found to constitutively express CD14 and toll-like receptor 4 mRNA that was augmented by exposure to lipopolysaccharide. Cell surface expression of keratinocyte CD14 and toll-like receptor 4 was detected by flow cytometry. Lipopolysaccharide binding to keratinocyte CD14 and toll-like receptor 4 resulted in a rapid intracellular Ca2+ response, nuclear factor-kappaB nuclear translocation, and the secretion of proinflammatory cytokines and chemokines. These results have important implications for our understanding of cutaneous innate immunity to bacterial infections of the skin.
Key Points• Broad immune activation after a combination of lenalidomide and a-GalCer-loaded dendritic cells.• Proof of principle for harnessing NK T cells to prevent cancer in humans. Natural killer T (iNKT) cells can help IntroductionNatural killer T (NKT) cells are distinct innate CD1d-restricted T cells that recognize lipid antigens. 1 The best-studied subset of NKT cells in both mice and humans are type I NKT cells that express an invariant T-cell receptor. Several studies have described potent antitumor properties of iNKT cells in preclinical models and iNKT cells have also been implicated in immune surveillance against both spontaneous as well as carcinogeninduced murine tumors. 2,3 While iNKT cells can mediate lysis of tumor cells, their antitumor effects likely depend in large part on their ability to activate other immune cells such as NK and dendritic cells (DCs) and recruit adaptive immunity as well as mediate antiangiogenesis. 4-6 ␣-galactosylceramide (␣-GalCer) is a potent prototypic ligand for both human and murine iNKT cells. 7 The availability of clinical-grade ␣-GalCer (KRN7000; KHK) allowed testing of iNKT-targeted approaches in humans. 8 Initial studies with injection of soluble KRN7000 led to only modest effects in humans. [9][10][11] Preclinical studies suggested that targeting ␣-GalCer to DCs led to superior activation of NKT cells in vivo. 12 In a prior study, we have shown that the injection of ␣-GalCer-loaded human DCs led to a clear increase in circulating iNKT cells in vivo. 13 However, these cells were still functionally deficient and, importantly, little activation of downstream innate immune function (including NK cells) was observed.It is now clear that nearly all cases of clinical myeloma (MM) are preceded by an asymptomatic precursor state, including a phase termed as asymptomatic multiple myeloma (AMM). 14 Patients with AMM are currently observed but carry high risk for progression to clinical MM requiring therapy. Strategies to prevent clinical MM may therefore have a major impact on disease-related morbidity and mortality. 14 In prior studies, we have shown that progression from precursor to clinical MM is associated with progressive dysfunction of iNKT cells in vivo. 15 Myeloma is an attractive tumor for NKT-targeted approaches because tumor cells commonly express CD1d and are sensitive to lysis by both NKT as well as NK cells. 15,16 In the past decade, incorporation of immunomodulatory drugs such as lenalidomide (LEN) into clinical care has improved outcome in human MM. 17 An important property of these drugs is providing costimulation of both human T cells as well as NKT cells in culture in an antigen-dependent manner. 18-20 Therefore, we hypothesized that the combination of LEN with ␣-GalCer-loaded DCs will lead to synergistic activation of innate lymphocytes in vivo and mediate antitumor effects in the preventive setting. As LEN alone has some single-agent activity in MM, 21 we chose to test a LEN dose of 10 mg/d, which is lower than the usual starting dose (25 mg/d) in ...
The hypomethylating agents (HMAs) azacitidine and decitabine have been the de facto standard of care for patients with acute myeloid leukemia (AML) who are unfit for intensive therapy. Using the Surveillance, Epidemiology, and End Results-Medicare linked database, we identified 2263 older adults (age ≥66 years) diagnosed with AML during 2005-2015 who received a first-line HMA; 1154 (51%) received azacitidine, and 1109 (49%) received decitabine. Median survival from diagnosis was 7.1 and 8.2 months (P < .01) for azacitidine- and decitabine-treated patients, respectively. Mortality risk was higher with azacitidine vs decitabine (hazard ratio [HR], 1.11; 95% confidence interval [CI], 1.01-1.21; P = .02). The findings were similar when evaluating only patients completing ≥4 cycles (42% of patients treated with either azacitidine or decitabine). These findings lost significance when evaluating those completing a standard 7-day schedule of azacitidine (34%) vs 5-day schedule for decitabine (66%) (HR, 0.95; 95% CI, 0.83-1.08; P = .43). Red blood cell (RBC) transfusion independence (TI) was achieved in one-third of patients with no difference between the 2 HMAs. In conclusion, the majority of older AML patients did not receive the minimum of 4 cycles of HMA often needed to elicit clinical benefit. We observed no clinically meaningful differences between azacitidine- and decitabine-treated patients in their achievement of RBC TI or survival.
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