Serum levels of specialised pro-resolving molecule pathways are greatly increased in SARS-CoV-2 patients and correlate with markers of the adaptive immune response.

BackgroundSpecialised pro-resolution molecules (SPMs) halt the transition to chronic pathogenic inflammation. We aimed to quantify serum levels of pro- and anti-inflammatory bioactive lipids in SARS-CoV-2 patients, and to identify potential relationships with innate responses and clinical outcome. MethodsSerum from 50 hospital admitted inpatients (22 female, 28 male) with confirmed symptomatic SARS-CoV-2 infection and 94 age and sex matched cohort collected prior to the pandemic, were processed for quantification of bioactive lipids. Anti-nucleocapsid and anti-spike quantitative binding assays were performed. ResultsSARS-CoV-2 serum had significantly higher concentrations of omega-6 derived pro-inflammatory lipids and omega-6 and omega-3 derived SPMs, compared to age and sex matched controls. Levels of SPMs were not markedly altered by age. There were significant positive correlations between SPMs and other bioactive lipids and anti-spike antibody binding. Levels of some SPMs were significantly higher in patients with an anti-spike antibody value >0.5. Levels of linoleic acid (LA) and 5,6-dihydroxy-8Z,11Z,14Z-eicosatrienoic acid (5,6-DHET) were significantly lower in SARS-COV-2 patients who died. DiscussionSARS-COV-2 infection was associated with a robust activation of the pathways that generate the specialised pro-resolution molecules and other anti-inflammatory bioactive lipids, supporting the future investigation of these pathways which may inform the development of novel treatments.

Pre-existing polymerase-specific T cells expand in abortive seronegative SARS-CoV-2 infection

Individuals with likely exposure to the highly infectious SARS-CoV-2 do not necessarily develop PCR or antibody positivity, suggesting some may clear sub-clinical infection before seroconversion. T cells can contribute to the rapid clearance of SARS-CoV-2 and other coronavirus infections1-5. We hypothesised that pre-existing memory T cell responses, with cross-protective potential against SARS-CoV-26-12, would expand in vivo to mediate rapid viral control, potentially aborting infection. We studied T cells against the replication transcription complex (RTC) of SARS-CoV-2 since this is transcribed first in the viral life cycle13-15and should be highly conserved. We measured SARS-CoV-2-reactive T cells in a cohort of intensively monitored healthcare workers (HCW) who remained repeatedly negative by PCR, antibody binding, and neutralisation for SARS-CoV-2 (exposed seronegative, ES). 16-weeks post-recruitment, ES had memory T cells that were stronger and more multispecific than an unexposed pre-pandemic cohort, and more frequently directed against the RTC than the structural protein-dominated responses seen post-detectable infection (matched concurrent cohort). The postulate that HCW with the strongest RTC-specific T cells had an abortive infection was supported by a low-level increase in IFI27 transcript, a robust early innate signature of SARS-CoV-2 infection16. We showed that the RNA-polymerase within RTC was the largest region of high sequence conservation across human seasonal coronaviruses (HCoV) and was preferentially targeted by T cells from UK and Singapore pre-pandemic cohorts and from ES. RTC epitope-specific T cells capable of cross-recognising HCoV variants were identified in ES. Longitudinal samples from ES and an additional validation cohort, showed pre-existing RNA-polymerase-specific T cells expanded in vivo following SARS-CoV-2 exposure, becoming enriched in the memory response of those with abortive compared to overt infection. In summary, we provide evidence of abortive seronegative SARS-CoV-2 infection with expansion of cross-reactive RTC-specific T cells, highlighting these highly conserved proteins as targets for future vaccines against endemic and emerging Coronaviridae.

Effects of environmental factors on severity and mortality of COVID-19

BackgroundMost respiratory viruses show pronounced seasonality, but for SARS-CoV-2 this still needs to be documented. MethodsWe examined the disease progression of COVID-19 in 6,914 patients admitted to hospitals in Europe and China. In addition, we evaluated progress of disease symptoms in 37,187 individuals reporting symptoms into the COVID Symptom Study application. FindingsMeta-analysis of the mortality risk in eight European hospitals estimated odds ratios per one day increase in the admission date to be 0.981 (0.973-0.988, p<0.001) and per increase in ambient temperature of one degree Celsius to be 0.854 (0.773-0.944, p=0.007). Statistically significant decreases of comparable magnitude in median hospital stay, probability of transfer to Intensive Care Unit and need for mechanical ventilation were also observed in most, but not all hospitals. The analysis of individually reported symptoms of 37,187 individuals in the UK also showed the decrease in symptom duration and disease severity with time. InterpretationSeverity of COVID-19 in Europe decreased significantly between March and May and the seasonality of COVID-19 is the most likely explanation. Mucosal barrier and mucociliary clearance can significantly decrease viral load and disease progression, and their inactivation by low relative humidity of indoor air might significantly contribute to severity of the disease.

Role of Drugs Affecting the Renin-Angiotensin-Aldosterone System on Susceptibility and Severity of COVID-19: A Large Case-Control Study from Zheijang Province, China.

The study aimed to investigate whether specific medications used in the treatment chronic diseases affected either the development and/ or severity of COVID-19 in a cohort of 610 COVID-19 cases and 48,667 population-based controls from Zheijang, China. Using a cohort of 578 COVID-19 cases and 48,667 population-based controls from Zheijang, China we tested the role of usage of cardiovascular, antidiabetic and other medications on risk and severity of COVID 19. Analyses were adjusted for age, sex and BMI and for presence of relevant comorbidities. Individuals with hypertension taking calcium channel blockers had significantly increased risk [odds ratio (OR)= 1.73 (95% CI 1.2-2.3)] of manifesting symptoms of COVID-19 whereas those taking angiotensin receptor blockers and diuretics had significantly lower disease risk (OR=0.22; 95%CI 0.15-0.30 and OR=0.30; 95%CI 0.19-0.58 respectively). Among those with type 2 diabetes, dipeptidyl peptidase-4 inhibitors (OR= 6.02; 95% CI 2.3-15.5) and insulin (OR= 2.71; 95% CI 1.6-5.5) were more and glucosidase inhibitors were less prevalent (OR= 0.11; 95% CI 0.1-0.3) among with COVID-19 patients. Drugs used in the treatment of hypertension and diabetes influence the risk of development of COVID-19, but, not its severity. Study highlightsO_ST_ABSWhat is the current knowledge on the topic?C_ST_ABSCardiovascular disease and Diabetes have been highlighted as comorbidities contributing to a more severe form of COVID-19 and medication to treat them may also influence the risk of COVID-19 and its clinical outcomes. What question did this study address?Does specific medications used in the treatment of chronic diseases influence the risk for the susceptibility to SARS CoV-2 infection of severity of COVID-19? What does this study add to our knowledge?The study confirms that higher BMI, diabetes and cardio/ cerebrovascular disease as independent risk factors for the development of COVID-19. Angtiotensin Receptor Blockers (ARBs) and diuretics were associated with reduced risk and Calcium Channel Blockers (CCBs) with increased risk of developing COVID-19. Among those with type 2 diabetes, dipeptidyl peptidase-4 and were associated with increased and glucosidase inhibitors with reduced risk development of COVID-19. None of the antihypertensive or anti-diabetic drugs were associated with increased risk of severe or critical form of the infection. Drugs used in the treatment of hypertension and diabetes influence the risk of development of COVID-19, but are not associated with severity of the disease. How might this change clinical pharmacology or translational science?Findings from the current large case-control study confirmed no evidence to alter ARBs or ACEIs therapy in the context of COVID-19 severity in clinical practice. Hypertension significantly increases the risk of severe or critical SARS-CoV-2 infection indicating that carefully controlled blood pressure should be a priority to reduce the healthcare burden of COVID-19.