The effect of TRV027 on coagulation in COVID-19: A pilot randomized, placebo-controlled trial.

COVID-19 causes significant thrombosis and coagulopathy, with elevated D-dimer a predictor of adverse outcome. The precise mechanism of this coagulopathy remains unclear; one hypothesis is that loss of angiotensin-converting enzyme 2 activity during viral endocytosis leads to pro-inflammatory angiotensin-II accumulation, loss of angiotensin-1-7 and subsequent vascular endothelial activation. We undertook a double-blind randomized, placebo-controlled experimental medicine study to assess the effect of TRV027, a synthetic angiotensin-1-7 analogue on D-dimer in 30 patients admitted to hospital with COVID-19. The study showed a similar rate of adverse events in TRV027 and control groups. There was a numerical decrease in D-dimer in the TRV027 group and increase in D-dimer in the placebo group; however, this did not reach statistical significance (P = .15). A Bayesian analysis demonstrated that there was a 92% probability that this change represented a true drug effect.

Adverse outcomes in COVID-19 and diabetes: a retrospective cohort study from three London teaching hospitals.

INTRODUCTION: Patients with diabetes mellitus admitted to hospital with COVID-19 have poorer outcomes. However, the drivers of poorer outcomes are not fully elucidated. We performed detailed characterization of patients with COVID-19 to determine the clinical and biochemical factors that may be drivers of poorer outcomes. RESEARCH DESIGN AND METHODS: This is a retrospective cohort study of 889 consecutive inpatients diagnosed with COVID-19 between March 9 and April 22, 2020 in a large London National Health Service Trust. Unbiased multivariate logistic regression analysis was performed to determine variables that were independently and significantly associated with increased risk of death and/or intensive care unit (ICU) admission within 30 days of COVID-19 diagnosis. RESULTS: 62% of patients in our cohort were of non-white ethnic background and the prevalence of diabetes was 38%. 323 (36%) patients met the primary outcome of death/admission to the ICU within 30 days of COVID-19 diagnosis. Male gender, lower platelet count, advancing age and higher Clinical Frailty Scale (CFS) score (but not diabetes) independently predicted poor outcomes on multivariate analysis. Antiplatelet medication was associated with a lower risk of death/ICU admission. Factors that were significantly and independently associated with poorer outcomes in patients with diabetes were coexisting ischemic heart disease, increasing age and lower platelet count. CONCLUSIONS: In this large study of a diverse patient population, comorbidity (ie, diabetes with ischemic heart disease; increasing CFS score in older patients) was a major determinant of poor outcomes with COVID-19. Antiplatelet medication should be evaluated in randomized clinical trials among high-risk patient groups.

TGF-ß mimic proteins form an extended gene family in the murine parasite Heligmosomoides polygyrus.

We recently reported the discovery of a new parasite-derived protein that functionally mimics the immunosuppressive cytokine transforming growth factor (TGF)-ß. The Heligmosomoides polygyrus TGF-ß Mimic (Hp-TGM) shares no homology to any TGF-ß family member, however it binds the mammalian TGF-ß receptor and induces expression of Foxp3, the canonical transcription factor of both mouse and human regulatory T cells. Hp-TGM consists of five atypical Complement Control Protein (CCP, Pfam 00084) domains, each lacking certain conserved residues and 12-15 amino acids longer than the 60-70 amino acids consensus domain, but with a recognizable 3-cysteine, tryptophan, cysteine motif. We now report on the identification of a family of nine related Hp-TGM homologues represented in the secreted proteome and transcriptome of H. polygyrus. Recombinant proteins from five of the nine new TGM members were tested for TGF-ß activity, but only two were functionally active in an MFB-F11 reporter assay, and by the induction of T cell Foxp3 expression. Sequence comparisons reveal that proteins with functional activity are similar or identical to Hp-TGM across the first three CCP domains, but more variable in domains 4 and 5. Inactive proteins diverged in all domains, or lacked some domains entirely. Testing truncated versions of Hp-TGM confirmed that domains 1-3 are essential for full activity in vitro, while domains 4 and 5 are not required. Further studies will elucidate whether these latter domains fulfill other functions in promoting host immune regulation during infection and if the more divergent family members play other roles in immunomodulation.