Clinical severity classes in COVID-19 pneumonia have distinct immunological profiles, facilitating risk stratification by machine learning

ObjectiveClinical triage in coronavirus disease 2019 (COVID-19) places a heavy burden on senior clinicians during a pandemic situation. However, risk stratification based on serum biomarker bioprofiling could be implemented by a larger, nonspecialist workforce.MethodMeasures of Complement Activation and inflammation in patientS with CoronAvirus DisEase 2019 (CASCADE) patients (n = 72), (clinicaltrials.gov: NCT04453527), classified as mild, moderate, or severe (by support needed to maintain SpO2 > 93%), and healthy controls (HC, n = 20), were bioprofiled using 76 immunological biomarkers and compared using ANOVA. Spearman correlation analysis on biomarker pairs was visualised via heatmaps. Linear Discriminant Analysis (LDA) models were generated to identify patients likely to deteriorate. An X-Gradient-boost (XGB) model trained on CASCADE data to triage patients as mild, moderate, and severe was retrospectively employed to classify COROnavirus Nomacopan Emergency Treatment for covid 19 infected patients with early signs of respiratory distress (CORONET) patients (n = 7) treated with nomacopan.ResultsThe LDA models distinctly discriminated between deteriorators, nondeteriorators, and HC, with IL-27, IP-10, MDC, ferritin, C5, and sC5b-9 among the key predictor variables during deterioration. C3a and C5 were elevated in all severity classes vs. HC (p < 0.05). sC5b-9 was elevated in the “moderate” and “severe” categories vs. HC (p < 0.001). Heatmap analysis shows a pairwise increase of negatively correlated pairs with IL-27. The XGB model indicated sC5b-9, IL-8, MCP1, and prothrombin F1 and F2 were key discriminators in nomacopan-treated patients (CORONET study).ConclusionDistinct immunological fingerprints from serum biomarkers exist within different severity classes of COVID-19, and harnessing them using machine learning enabled the development of clinically useful triage and prognostic tools. Complement-mediated lung injury plays a key role in COVID-19 pneumonia, and preliminary results hint at the usefulness of a C5 inhibitor in COVID-19 recovery

Multiple novel prostate cancer susceptibility signals identified by fine-mapping of known risk loci among Europeans

Genome-wide association studies (GWAS) have identified numerous common prostate cancer (PrCa) susceptibility loci. We have fine-mapped 64 GWAS regions known at the conclusion of the iCOGS study using large-scale genotyping and imputation in 25 723 PrCa cases and 26 274 controls of European ancestry. We detected evidence for multiple independent signals at 16 regions, 12 of which contained additional newly identified significant associations. A single signal comprising a spectrum of correlated variation was observed at 39 regions; 35 of which are now described by a novel more significantly associated lead SNP, while the originally reported variant remained as the lead SNP only in 4 regions. We also confirmed two association signals in Europeans that had been previously reported only in East-Asian GWAS. Based on statistical evidence and linkage disequilibrium (LD) structure, we have curated and narrowed down the list of the most likely candidate causal variants for each region. Functional annotation using data from ENCODE filtered for PrCa cell lines and eQTL analysis demonstrated significant enrichment for overlap with bio-features within this set. By incorporating the novel risk variants identified here alongside the refined data for existing association signals, we estimate that these loci now explain ∼38.9% of the familial relative risk of PrCa, an 8.9% improvement over the previously reported GWAS tag SNPs. This suggests that a significant fraction of the heritability of PrCa may have been hidden during the discovery phase of GWAS, in particular due to the presence of multiple independent signals within the same regio

Effects of Anacetrapib in Patients with Atherosclerotic Vascular Disease

BACKGROUND: Patients with atherosclerotic vascular disease remain at high risk for cardiovascular events despite effective statin-based treatment of low-density lipoprotein (LDL) cholesterol levels. The inhibition of cholesteryl ester transfer protein (CETP) by anacetrapib reduces LDL cholesterol levels and increases high-density lipoprotein (HDL) cholesterol levels. However, trials of other CETP inhibitors have shown neutral or adverse effects on cardiovascular outcomes. METHODS: We conducted a randomized, double-blind, placebo-controlled trial involving 30,449 adults with atherosclerotic vascular disease who were receiving intensive atorvastatin therapy and who had a mean LDL cholesterol level of 61 mg per deciliter (1.58 mmol per liter), a mean non-HDL cholesterol level of 92 mg per deciliter (2.38 mmol per liter), and a mean HDL cholesterol level of 40 mg per deciliter (1.03 mmol per liter). The patients were assigned to receive either 100 mg of anacetrapib once daily (15,225 patients) or matching placebo (15,224 patients). The primary outcome was the first major coronary event, a composite of coronary death, myocardial infarction, or coronary revascularization. RESULTS: During the median follow-up period of 4.1 years, the primary outcome occurred in significantly fewer patients in the anacetrapib group than in the placebo group (1640 of 15,225 patients [10.8%] vs. 1803 of 15,224 patients [11.8%]; rate ratio, 0.91; 95% confidence interval, 0.85 to 0.97; P=0.004). The relative difference in risk was similar across multiple prespecified subgroups. At the trial midpoint, the mean level of HDL cholesterol was higher by 43 mg per deciliter (1.12 mmol per liter) in the anacetrapib group than in the placebo group (a relative difference of 104%), and the mean level of non-HDL cholesterol was lower by 17 mg per deciliter (0.44 mmol per liter), a relative difference of -18%. There were no significant between-group differences in the risk of death, cancer, or other serious adverse events. CONCLUSIONS: Among patients with atherosclerotic vascular disease who were receiving intensive statin therapy, the use of anacetrapib resulted in a lower incidence of major coronary events than the use of placebo. (Funded by Merck and others; Current Controlled Trials number, ISRCTN48678192 ; ClinicalTrials.gov number, NCT01252953 ; and EudraCT number, 2010-023467-18 .)

Immune-Mediated Retinal Vasculitis in Posterior Uveitis and Experimental Models: The Leukotriene (LT)B4-VEGF Axis

Retinal vascular diseases have distinct, complex and multifactorial pathogeneses yet share several key pathophysiological aspects including inflammation, vascular permeability and neovascularisation. In non-infectious posterior uveitis (NIU), retinal vasculitis involves vessel leakage leading to retinal enlargement, exudation, and macular oedema. Neovascularisation is not a common feature in NIU, however, detection of the major angiogenic factor—vascular endothelial growth factor A (VEGF-A)—in intraocular fluids in animal models of uveitis may be an indication for a role for this cytokine in a highly inflammatory condition. Suppression of VEGF-A by directly targeting the leukotriene B4 (LTB4) receptor (BLT1) pathway indicates a connection between leukotrienes (LTs), which have prominent roles in initiating and propagating inflammatory responses, and VEGF-A in retinal inflammatory diseases. Further research is needed to understand how LTs interact with intraocular cytokines in retinal inflammatory diseases to guide the development of novel therapeutic approaches targeting both inflammatory mediator pathways

Dual inhibition of complement component 5 and leukotriene B4 by topical rVA576 in atopic keratoconjunctivis: TRACKER phase 1 clinical trial results

Abstract Purpose To evaluate the safety and preliminary efficacy of topical rVA576, a dual inhibitor of complement component 5 (C5) and leukotriene B4 (LTB4), in patients with recalcitrant atopic keratoconjunctivitis (AKC) in the open label phase 1 TRACKER clinical trial. Methods Three patients diagnosed with moderate or severe AKC who had been on maximal topical treatment (antihistamines and ciclosporin) for at least three months prior to entry, and showed persistent symptoms and signs of inflammation, were recruited into the trial. Patients received rVA576 eye drops twice a day for 8 weeks. Patients were seen at baseline and weeks 1, 2, 4, 6 and 8. Safety data was recorded and a composite sum score of symptoms and signs was obtained. This score comprised symptoms such as itching, mucous discharge and photophobia, and conjunctival and corneal signs such as hyperemia, tarsal papillae, punctate keratitis and corneal neovascularization, all rated individually from 0 to 3 for a maximum score of 33. Results Two of the three patients completed the initial open label phase of the trial. The third patient was unable to attend appointments and terminated the study early at day 14. Topical rVA576 was well tolerated with no serious adverse events reported. There was an average improvement in overall clinical score of 53%, composed of an improvement in symptoms of 65% [63.64–66.67%] and signs of 40% [40–40.12%] by day 56. Conclusions In this open label phase 1 TRACKER trial, rVA576 eye drops were well tolerated and showed a response across signs and symptoms of active inflammation. This study is exploratory but supports topical rVA576 safety and shows promising efficacy for recalcitrant AKC. A phase 2 randomised control trial is currently underway

Complement C5 inhibition attenuates lung inflammation in H1N1 influenza

Background: Viral infection including pandemic influenza may be associated with severe acute respiratory distress syndrome (ARDS) characterised by rapidly developing alveolitis with dense neutrophil infiltration. Complement activation has been suggested as a trigger but until now evidence has been lacking. Here we show that blockade of the complement system at the C5 level substantially reduces the severe respiratory effects of H1N1 infection in a mouse model and that this inhibition is independent of the severity of the viral infection. Methods: BalbC mice were infected with a sub-lethal (104 PFU) or a lethal dose (106 PFU) of human H1N1 virus or sham infected. Severe respiratory infection developed within 4 days in low inoculum animals and more rapidly in the high inoculum group. Mice were injected intraperitoneally with coversin, a C5 antagonist, at the time of infection and daily thereafter. At Day 6 (low inoculum group) and Day 3 (high inoculum group) animals underwent broncholaveolar lavage (BAL) pre-sacrifice. BAL fluid was inspected for total cells, neutrophils, protein and cytokines. Results: Vehicle treated mice in both high and low inocula groups had significantly elevated total cells, protein, neutrophils and cytokines (IL-1b, IL-6 and CXCL2) compared to sham treated. Mice treated with coversin had significantly lower elevation of all inflammatory parameters. In particular there was 69% inhibition of the neutrophil response in the low inoculum group and 71% in the high inoculum group compared to vehicle. These differences were significant at 104 PFU (p < 0.01) and at 106 PFU (p < 0.001). Conclusions: Treatment of mice infected with H1N1 virus with a complement C5 inhibitor significantly attenuated respiratory inflammation. The alveolar inflammatory response and the inhibition appeared to be independent of the viral load. This suggests that the response is an all-or-none phenomenon which further supports the possibility that complement activation is involved

Arthropod-derived protein EV131 inhibits histamine action and allergic asthma

Histamine is an important mediator of allergic responses. Arthropods express several biologically active proteins in their saliva, which may allow a prolonged blood meal on the host. Proteins identified and expressed include histamine, serotonin, tryptase, and complement binding proteins. We review here data that scavenging of endogenous histamine by the histamine-binding protein EV131 has a profound inhibitory effect on allergic asthma. Aerosol administration of EV131 prevented airway hyperreactivity and abrogated peribronchial inflammation, eosinophil recruitment, mucus hypersecretion, and IL-4 and IL-5 secretion. Saturation with histamine abrogated the inhibitory effect of EV131 on bronchial hyperreactivity. The data suggest that histamine plays a role in allergies and that scavenging of histamine by EV131 may represent a novel therapeutic strategy in the treatment of allergic diseases

Arthropod-derived histamine-binding protein prevents murine allergic asthma

Because histamine receptor type I blockade attenuates allergic asthma, we asked whether complete neutralization of histamine by an arthropod-derived, high affinity histamine-binding protein (EV131) would prevent allergic asthma. Intranasal administration of EV131 given before Ag challenge in immunized mice prevented airway hyperreactivity by 70%, and abrogated peribronchial inflammation, pulmonary eosinophilia, mucus hypersecretion, and IL-4 and IL-5 secretion. Saturation with histamine abrogated the inhibitory effect of EV131 on bronchial hyperreactivity. The inhibitory effect of EV131 on bronchial hyperreactivity was comparable to that of glucocorticosteroids. These results demonstrate that histamine is a critical mediator of allergic asthma. Therefore, complete neutralization of histamine, rather than specific histamine receptor blockade, may have a profound effect on allergic asthma