To investigate the immune response and mechanisms associated with severe coronavirus disease 2019 (COVID-19), we performed single-cell RNA sequencing on nasopharyngeal and bronchial samples from 19 clinically well-characterized patients with moderate or critical disease and from five healthy controls We identified airway epithelial cell types and states vulnerable to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection In patients with COVID-19, epithelial cells showed an average three-fold increase in expression of the SARS-CoV-2 entry receptor ACE2, which correlated with interferon signals by immune cells Compared to moderate cases, critical cases exhibited stronger interactions between epithelial and immune cells, as indicated by ligand-receptor expression profiles, and activated immune cells, including inflammatory macrophages expressing CCL2, CCL3, CCL20, CXCL1, CXCL3, CXCL10, IL8, IL1B and TNF The transcriptional differences in critical cases compared to moderate cases likely contribute to clinical observations of heightened inflammatory tissue damage, lung injury and respiratory failure Our data suggest that pharmacologic inhibition of the CCR1 and/or CCR5 pathways might suppress immune hyperactivation in critical COVID-19

/pdf/covid-19-severity-correlates-with-airway-epithelium-immune-2xzfsrwau8.pdf

COVID-19 severity correlates with airway epithelium-immune cell interactions identified by single-cell analysis.

Background Although the detection of SARS-CoV-2 viral load in respiratory specimens has been widely used to diagnose coronavirus disease-19 (COVID-19), it is undeniable that serum SARS-CoV-2 nucleic acid (RNAaemia) could be detected in a fraction of COVID-19 patients. However, it is not clear whether testing for RNAaemia is correlated with the occurrence of cytokine storms or with the specific class of patients. Methods This study enrolled 48 patients with COVID-19 admitted to the General Hospital of Central Theater Command, PLA, a designated hospital in Wuhan, China. The patients were divided into three groups according to the "Diagnosis and Treatment of New Coronavirus Pneumonia (6th edition)" issued by the National Health Commission of China. The clinical and laboratory data were collected. The serum viral load and IL-6 levels were determined. . Results Clinical characteristics analysis of 48 cases of COVID-19 showed that RNAaemia was diagnosed only in the critically ill group and seemed to reflect the severity of the disease. Furthermore, the level of inflammatory cytokine IL-6 in critically ill patients increased significantly, almost 10 times that in other patients. More importantly, the extremely high IL-6 level was closely correlated with the detection of RNAaemia (R = 0.902). Conclusions Detectable serum SARS-Cov-2 RNA(RNAaemia) in COVID-19 patients was associated with elevated IL-6 concentration and poor prognosis. Because the elevated IL-6 may be part of a larger cytokine storm which could worsen outcome, IL-6 could be a potential therapeutic target for critically ill patients with an excessive inflammatory response.

Detectable Serum Severe Acute Respiratory Syndrome Coronavirus 2 Viral Load (RNAemia) Is Closely Correlated With Drastically Elevated Interleukin 6 Level in Critically Ill Patients With Coronavirus Disease 2019.

The severity and outcome of coronavirus disease 2019 (COVID-19) largely depends on a patient's age. Adults over 65 years of age represent 80% of hospitalizations and have a 23-fold greater risk of death than those under 65. In the clinic, COVID-19 patients most commonly present with fever, cough and dyspnea, and from there the disease can progress to acute respiratory distress syndrome, lung consolidation, cytokine release syndrome, endotheliitis, coagulopathy, multiple organ failure and death. Comorbidities such as cardiovascular disease, diabetes and obesity increase the chances of fatal disease, but they alone do not explain why age is an independent risk factor. Here, we present the molecular differences between young, middle-aged and older people that may explain why COVID-19 is a mild illness in some but life-threatening in others. We also discuss several biological age clocks that could be used in conjunction with genetic tests to identify both the mechanisms of the disease and individuals most at risk. Finally, based on these mechanisms, we discuss treatments that could increase the survival of older people, not simply by inhibiting the virus, but by restoring patients' ability to clear the infection and effectively regulate immune responses.

Why does COVID-19 disproportionately affect older people?

Despite major advances in vaccination over the past century, resurgence of vaccine-preventable illnesses has led the World Health Organization to identify vaccine hesitancy as a major threat to global health. Vaccine hesitancy may be fueled by health information obtained from a variety of sources, including new media such as the Internet and social media platforms. As access to technology has improved, social media has attained global penetrance. In contrast to traditional media, social media allow individuals to rapidly create and share content globally without editorial oversight. Users may self-select content streams, contributing to ideological isolation. As such, there are considerable public health concerns raised by anti-vaccination messaging on such platforms and the consequent potential for downstream vaccine hesitancy, including the compromise of public confidence in future vaccine development for novel pathogens, such as SARS-CoV-2 for the prevention of COVID-19. In this review, we discuss the current position of social media platforms in propagating vaccine hesitancy and explore next steps in how social media may be used to improve health literacy and foster public trust in vaccination.

https://www.tandfonline.com/doi/pdf/10.1080/21645515.2020.1780846

Social media and vaccine hesitancy: new updates for the era of COVID-19 and globalized infectious diseases.

Widespread acceptance of COVID-19 vaccines is crucial for achieving sufficient immunization coverage to end the global pandemic, yet few studies have investigated COVID-19 vaccination attitudes in lower-income countries, where large-scale vaccination is just beginning. We analyze COVID-19 vaccine acceptance across 15 survey samples covering 10 low- and middle-income countries (LMICs) in Asia, Africa and South America, Russia (an upper-middle-income country) and the United States, including a total of 44,260 individuals. We find considerably higher willingness to take a COVID-19 vaccine in our LMIC samples (mean 80.3%; median 78%; range 30.1 percentage points) compared with the United States (mean 64.6%) and Russia (mean 30.4%). Vaccine acceptance in LMICs is primarily explained by an interest in personal protection against COVID-19, while concern about side effects is the most common reason for hesitancy. Health workers are the most trusted sources of guidance about COVID-19 vaccines. Evidence from this sample of LMICs suggests that prioritizing vaccine distribution to the Global South should yield high returns in advancing global immunization coverage. Vaccination campaigns should focus on translating the high levels of stated acceptance into actual uptake. Messages highlighting vaccine efficacy and safety, delivered by healthcare workers, could be effective for addressing any remaining hesitancy in the analyzed LMICs.

https://www.econstor.eu/bitstream/10419/236517/1/Full-text-article-Solis-Arce-et-al-COVID-19-vaccine.pdf

COVID-19 vaccine acceptance and hesitancy in low- and middle-income countries.

Coronaviruses may activate dysregulated host immune responses. As exploratory studies have suggested that interleukin-6 (IL-6) levels are elevated in cases of complicated Covid-19, we undertook a systematic review and meta-analysis to assess the evidence in this field. We systematically searched MEDLINE and EMBASE for studies investigating the immunological response in Covid-19; additional grey literature searches were undertaken. Study selection and data abstraction was undertaken independently by two authors. Meta-analysis was undertaken using random effects models to compute ratios of means with 95% confidence intervals (95%CIs). Eight published studies and two preprints (n = 1798) were eligible for inclusion. Meta-analysis of mean IL-6 concentrations demonstrated 2.9-fold higher levels in patients with complicated Covid-19 compared with patients with noncomplicated disease (six studies; n = 1302; 95%CI, 1.17-7.19; I2 = 100%). Consistent results were found in sensitivity analyses exclusively restricted to studies comparing patients requiring ICU admission vs no ICU admission (two studies; n = 540; ratio of means = 3.24; 95%CI, 2.54-4.14; P < .001; I2 = 87%). Nine of ten studies were assessed to have at least moderate risk of bias. In patients with Covid-19, IL-6 levels are significantly elevated and associated with adverse clinical outcomes. Inhibition of IL-6 may be a novel target for therapeutics for the management of dysregulated host responses in patients with Covid-19 and high-quality studies of intervention in this field are urgently required.

https://onlinelibrary.wiley.com/doi/pdf/10.1002/rmv.2141

Interleukin-6 in Covid-19: A systematic review and meta-analysis.

Purpose Coronaviruses may activate dysregulated host immune responses. As exploratory studies have suggested that interleukin-6 (IL-6) levels are elevated in cases of complicated COVID-19 and that the anti-IL-6 biologic tocilizumab may be beneficial, we undertook a systematic review and meta-analysis to assess the evidence in this field. Methods We systematically searched MEDLINE and EMBASE for studies investigating the immunological response in COVID-19 or its treatment with tocilizumab; additional grey literature searches were undertaken. Meta-analysis was undertaken using random effects models. Results Eight published studies, three pre-prints, and five registered trials were eligible. Meta-analysis of mean IL-6 concentrations demonstrated 2.9-fold higher levels in patients with complicated COVID-19 compared with patients with non-complicated disease (six studies; n=1302; 95%CI, 1.17-7.19; I2=100%). A single non-randomized, single-arm study assessed tocilizumab in patients with severe COVID-19, demonstrating decreased oxygen requirements, resolution of radiographic abnormalities, and clinical improvement. No adverse events or deaths were observed. Conclusions In patients with COVID-19, IL-6 levels are significantly elevated and associated with adverse clinical outcomes. While inhibition of IL-6 with tocilizumab appears to be efficacious and safe in preliminary investigation, the results of several ongoing clinical trials should be awaited to better define the role of tocilizumab in COVID-19 prior to routine clinical application. PROSPERO Registration CRD42020175879

https://medrxiv.org/content/10.1101/2020.03.30.20048058v1.full.pdf

Interleukin-6 in COVID-19: A Systematic Review and Meta-Analysis

Sir, A novel coronavirus, SARS-CoV-2, emerged in December 2019 in Wuhan, China, which is spreading far more rapidly than its predecessors, having already infected millions of patients worldwide as of 19 April 2020. As the scale of the ongoing COVID-19 outbreak has reached pandemic proportions, intensive worldwide public health efforts are underway to control the outbreak. However, as definitive therapies for established COVID-19 remain to be defined, significant interest exists in repurposing existing antiviral agents for use against COVID-19. Favipiravir triphosphate is a purine nucleoside analogue, which acts as a competitive inhibitor of RNA-dependent RNA polymerase. It has activity against influenza A and B, including activity against oseltamivirand zanamivir-resistant influenza viruses, several agents of viral haemorrhagic fever and SARS-CoV-2 in vitro. Favipiravir is approved for novel epidemic influenza strains that are unresponsive to standard antiviral therapies in Japan. Favipiravir was identified to have activity in vitro against SARS-CoV-2, albeit requiring a high concentration compared with chloroquine or remdesivir (EC50 = 61.88 lM). 3 Despite a similarly elevated EC50 identified for favipiravir and Ebola virus, it was identified in previous animal models to be highly effective as postexposure prophylaxis for mice exposed to Ebola virus challenges, with rapid virological response preventing mortality. Based on the dosing strategies and pharmacokinetic data from human influenza trials, an intensified dosing strategy of 6000 mg loading on day 1 followed by maintenance therapy of 1200 mg orally twice daily for 10 days was employed in a single-arm clinical trial for Ebola virus disease in Guinea. In a retrospective analysis of 124 patients with Ebola virus disease in Sierra Leone, those treated with favipiravir had a significantly higher survival rate compared with patients receiving supportive management (56.4% versus 35.3%; P = 0.027). Patients received favipiravir 800 mg orally twice daily on day 1 and 600 mg orally twice daily on days 3–11. Viral loads were quantified for 35 patients twice during their hospitalization and were significantly reduced amongst patients receiving favipiravir. Favipiravir has also been used as pharmacological postexposure prophylaxis for Ebola virus disease. In a case series of four healthcare workers with higher risk Ebola virus exposures, including two hollow-bore needlestick injuries, none of the patients who received 10 days of high-dose favipiravir developed Ebola virus disease. Early clinical experience with favipiravir for COVID-19 is promising. An open-label non-randomized trial of 80 patients with COVID-19 in China identified a significant reduction in the time to SARS-CoV-2 viral clearance in patients treated with favipiravir compared with historical controls treated with lopinavir/ritonavir. Patients with mild or moderate COVID-19 were enrolled within 7 days from disease onset; those 75 years old, with severe or critical disease, chronic liver disease or end-stage renal disease were excluded. Patients in the intervention arm received favipiravir 1600 mg orally twice daily on day 1 followed by 600 mg orally twice daily on days 2–14. Both arms were co-treated with inhaled IFN-a1b 60lg twice daily and therapy was continued until viral clearance, up to a maximum of 14 days. Thirty-five patients were assigned to favipiravir and 45 patients to lopinavir/ritonavir, with a median age of 47 years (IQR = 35.8–61); 13.7% were 65 years old. There was a significant reduction in the median time to viral clearance with favipiravir (4 days; IQR = 2.5–9) compared with lopinavir/ritonavir (11 days; IQR = 8–13; P < 0.001). Further, by day 14, 91.4% of patients in the favipiravir arm had radiographic improvement versus 62.2% in the lopinavir/ritonavir arm. There was a significantly lower rate of adverse events in patients receiving favipiravir (11.4% versus 55.6%; P < 0.01). Given the demonstrated in vitro of activity of favipiravir against SARS-CoV-2 and signals of benefit in early clinical experience for COVID-19, further studies are urgently needed. The results of several ongoing randomized controlled trials to assess the efficacy of favipiravir for COVID-19 will further elucidate the role of favipiravir in the management of the ongoing coronavirus pandemic.

/pdf/favipiravir-an-antiviral-for-covid-19-3gpf48rpty.pdf

Hourmazd Haghbayan

Papers

Social media and vaccine hesitancy: new updates for the era of COVID-19 and globalized infectious diseases.

Interleukin-6 in Covid-19: A systematic review and meta-analysis.

Interleukin-6 in COVID-19: A Systematic Review and Meta-Analysis

Favipiravir, an antiviral for COVID-19?

Temporal trends in anti-vaccine discourse on Twitter.