The devastating impact of the COVID19 pandemic caused by SARS coronavirus 2 (SARSCoV2) has raised important questions on the origins of this virus, the mechanisms of any zoonotic transfer from exotic animals to humans, whether companion animals or those used for commercial purposes can act as reservoirs for infection, and the reasons for the large variations in susceptibilities across animal species. Traditional lab-based methods will ultimately answer many of these questions but take considerable time. In silico modeling methods provide the opportunity to rapidly generate information on newly emerged pathogens to aid countermeasure development and also to predict potential future behaviors. We used a structural homology modeling approach to characterize the SARSCoV2 spike protein and predict its binding strength to the human ACE2 receptor. We then explored the possible transmission path by which SARSCoV2 might have crossed to humans by constructing models of ACE2 receptors of relevant species, and calculating the binding energy of SARSCoV2 spike protein to each. Notably, SARSCoV2 spike protein had the highest overall binding energy for human ACE2, greater than all the other tested species including bat, the postulated source of the virus. This indicates that SARSCoV2 is a highly adapted human pathogen. Of the species studied, the next highest binding affinity after human was pangolin, which is most likely explained by a process of convergent evolution. Binding of SARSCoV2 for dog and cat ACE2 was similar to affinity for bat ACE2, all being lower than for human ACE2, and is consistent with only occasional observations of infections of these domestic animals. Overall, the data indicates that SARSCoV2 is uniquely adapted to infect humans, raising questions as to whether it arose in nature by a rare chance event or whether its origins lie elsewhere.
The unprecedented pandemic of pneumonia caused by a novel coronavirus, SARS-CoV-2, in China and beyond has had major public health impacts on a global scale [1, 2]. Although bats are regarded as the most likely natural hosts for SARS-CoV-2 , the origins of the virus remain unclear. Here, we report a novel bat-derived coronavirus, denoted RmYN02, identified from a metagenomic analysis of samples from 227 bats collected from Yunnan Province in China between May and October 2019. Notably, RmYN02 shares 93.3% nucleotide identity with SARS-CoV-2 at the scale of the complete virus genome and 97.2% identity in the 1ab gene, in which it is the closest relative of SARS-CoV-2 reported to date. In contrast, RmYN02 showed low sequence identity (61.3%) to SARS-CoV-2 in the receptor-binding domain (RBD) and might not bind to angiotensin-converting enzyme 2 (ACE2). Critically, and in a similar manner to SARS-CoV-2, RmYN02 was characterized by the insertion of multiple amino acids at the junction site of the S1 and S2 sub- units of the spike (S) protein. This provides strong evidence that such insertion events can occur naturally in animal betacoronaviruses.
Objective To estimate the infection fatality rate of coronavirus disease 2019 (COVID-19) from data of seroprevalence studies. Methods Population studies with sample size of at least 500 and published as peer-reviewed papers or preprints as of May 12, 2020 were retrieved from PubMed, preprint servers, and communications with experts. Studies on blood donors were included, but studies on healthcare workers were excluded. The studies were assessed for design features and seroprevalence estimates. Infection fatality rate was estimated from each study dividing the number of COVID-19 deaths at a relevant time point by the number of estimated people infected in each relevant region. Correction was also attempted accounting for the types of antibodies assessed. Results Twelve studies were identified with usable data to enter into calculations. Seroprevalence estimates ranged from 0.113% to 25.9% and adjusted seroprevalence estimates ranged from 0.309% to 33%. Infection fatality rates ranged from 0.03% to 0.50% and corrected values ranged from 0.02% to 0.40%. Conclusions The infection fatality rate of COVID-19 can vary substantially across different locations and this may reflect differences in population age structure and case-mix of infected and deceased patients as well as multiple other factors. Estimates of infection fatality rates inferred from seroprevalence studies tend to be much lower than original speculations made in the early days of the pandemic.
Background: Over 40 000 patients with COVID-19 have been hospitalised in New York City (NY, USA) as of April 28, 2020. Data on the epidemiology, clinical course, and outcomes of critically ill patients with COVID-19 in this setting are needed.
Methods: This prospective observational cohort study took place at two NewYork-Presbyterian hospitals affiliated with Columbia University Irving Medical Center in northern Manhattan. We prospectively identified adult patients (aged ≥18 years) admitted to both hospitals from March 2 to April 1, 2020, who were diagnosed with laboratory-confirmed COVID-19 and were critically ill with acute hypoxaemic respiratory failure, and collected clinical, biomarker, and treatment data. The primary outcome was the rate of in-hospital death. Secondary outcomes included frequency and duration of invasive mechanical ventilation, frequency of vasopressor use and renal replacement therapy, and time to in-hospital clinical deterioration following admission. The relation between clinical risk factors, biomarkers, and in-hospital mortality was modelled using Cox proportional hazards regression. Follow-up time was right-censored on April 28, 2020 so that each patient had at least 28 days of observation.
Findings: Between March 2 and April 1, 2020, 1150 adults were admitted to both hospitals with laboratory-confirmed COVID-19, of which 257 (22%) were critically ill. The median age of patients was 62 years (IQR 51–72), 171 (67%) were men. 212 (82%) patients had at least one chronic illness, the most common of which were hypertension (162 [63%]) and diabetes (92 [36%]). 119 (46%) patients had obesity. As of April 28, 2020, 101 (39%) patients had died and 94 (37%) remained hospitalised. 203 (79%) patients received invasive mechanical ventilation for a median of 18 days (IQR 9–28), 170 (66%) of 257 patients received vasopressors and 79 (31%) received renal replacement therapy. The median time to in-hospital deterioration was 3 days (IQR 1–6). In the multivariable Cox model, older age (adjusted hazard ratio [aHR] 1·31 [1·09–1·57] per 10-year increase), chronic cardiac disease (aHR 1·76 [1·08–2·86]), chronic pulmonary disease (aHR 2·94 [1·48–5·84]), higher concentrations of interleukin-6 (aHR 1·11 [95%CI 1·02–1·20] per decile increase), and higher concentrations of D-dimer (aHR 1·10 [1·01–1·19] per decile increase) were independently associated with in-hospital mortality.
Interpretation: Critical illness among patients hospitalised with COVID-19 in New York City is common and associated with a high frequency of invasive mechanical ventilation, extrapulmonary organ dysfunction, and substantial in-hospital mortality.
Background: Coronavirus disease 2019 (COVID-19) pandemic caused by SARS-CoV-2 has been affecting many people on earth and our society. Japan is known to have relatively less number of infections as well as deaths among developed nations. However, accurate prevalence of COVID-19 in Japan remains unknown. Therefore, we conducted a cross-sectional study to estimate seroprevalence of SARS-CoV-2 infection.
Methods: We conducted a cross-sectional serologic testing for SARS-CoV-2 antibody using 1,000 samples from patients at outpatient settings who visited the clinic from March 31 to April 7, 2020, stratified by the decade of age and sex.
Results: There were 33 positive IgG among 1,000 serum samples (3.3%, 95%CI: 2.3-4.6%). By applying this figure to the census of Kobe City (population: 1,518,870), it is estimated that the number of people with positive IgG be 50,123 (95%CI: 34,934-69,868). Age and sex adjusted prevalence of positivity was calculated 2.7% (95%CI: 1.8-3.9%), and the estimated number of people with positive IgG was 40,999 (95%CI: 27,333-59,221). These numbers were 396 to 858 fold more than confirmed cases with PCR testing in Kobe City.
Conclusions: Our cross-sectional serological study suggests that the number of people with seropositive for SARS-CoV-2 infection in Kobe, Japan is far more than the confirmed cases by PCR testing.
The novel coronavirus disease 2019 (COVID-19) is an acute infectious disease caused by infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Currently, the World Health Organization has confirmed that COVID-19 is a global infectious disease pandemic. This is the third acute infectious disease caused by coronavirus infection in this century, after sudden acute respirator syndrome and Middle East respiratory syndrome. The damage mechanism of SARS-CoV-2 is still unclear. It is possible that protein S binds to angiotensin-converting enzyme 2 receptors and invades alveolar epithelial cells, causing direct toxic effects and an excessive immune response. This stimulates a systemic inflammatory response, thus forming a cytokine storm, which leads to lung tissue injury. In severe cases, the disease can lead to acute respiratory distress syndrome, septic shock, metabolic acidosis, coagulation dysfunction, and multiple organ dysfunction syndromes. Patients with severe COVID-19 have a relatively high mortality rate. Currently, there are no specific antiviral drugs for the treatment of COVID-19. Most patients need to be admitted to the intensive care unit for intensive monitoring and supportive organ function treatments. This article reviews the epidemiology, pathogenesis, clinical manifestations, diagnosis, and treatment methods of severe COVID-19 and puts forward some tentative ideas, aiming to provide some guidance for the diagnosis and treatment of severe COVID-19.
The coronavirus disease 2019 (COVID-19) pandemic, caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has affected millions of people worldwide, igniting an unprecedented effort from the scientific community to understand the biological underpinning of COVID19 pathophysiology. In this review, we summarize the current state of knowledge of innate and adaptive immune responses elicited by SARS-CoV-2 infection and the immunological pathways that likely contribute to disease severity and death. We also discuss the rationale and clinical outcome of current therapeutic strategies as well as prospective clinical trials to prevent or treat SARS- CoV-2 infection.
Understanding adaptive immunity to SARS-CoV-2 is important for vaccine development, interpreting coronavirus disease 2019 (COVID-19) pathogenesis, and calibration of pandemic control measures. Using HLA class I and II predicted peptide ‘megapools’, circulating SARS-CoV-2−specific CD8+ and CD4+ T cells were identified in ∼70% and 100% of COVID-19 convalescent patients, respectively. CD4+ T cell responses to spike, the main target of most vaccine efforts, were robust and correlated with the magnitude of the anti-SARS-CoV-2 IgG and IgA titers. The M, spike and N proteins each accounted for 11-27% of the total CD4+ response, with additional responses commonly targeting nsp3, nsp4, ORF3a and ORF8, among others. For CD8+ T cells, spike and M were recognized, with at least eight SARS-CoV-2 ORFs targeted. Importantly, we detected SARS-CoV-2−reactive CD4+ T cells in ∼40-60% of unexposed individuals, suggesting cross-reactive T cell recognition between circulating ‘common cold’ coronaviruses and SARS-CoV-2.
Covid-19 is a major pandemic facing the world today caused by SARS-CoV-2 which has implications on our understanding of infectious diseases. Although, SARS-Cov-2 primarily causes lung infection through binding of ACE2 receptors present on the alveolar epithelial cells, yet it was recently reported that SARS-CoV-2 RNA was found in the faeces of infected patients. Interestingly, the intestinal epithelial cells particularly the enterocytes of the small intestine also express ACE2 receptors. Role of the gut microbiota in influencing lung diseases has been well articulated. It is also known that respiratory virus infection causes perturbations in the gut microbiota. Diet, environmental factors and genetics play an important role in shaping gut microbiota which can influence immunity. Gut microbiota diversity is decreased in old age and Covid-19 has been mainly fatal in elderly patients which again points to the role the gut microbiota may play in this disease. Improving gut microbiota profile by personalized nutrition and supplementation known to improve immunity can be one of the prophylactic ways by which the impact of this disease can be minimized in old people and immune-compromised patients. More trials may be initiated to see the effect of co-supplementation of personalized functional food including prebiotics/probiotics along with current therapies.
The World health organization (WHO) declared Coronavirus disease 2019 (COVID-19) a global pandemic and a severe public health crisis. Drastic measures to combat COVID-19 are warranted due to its contagiousness and higher mortality rates, specifically in the aged patient population. At the current stage, due to the lack of effective treatment strategies for COVID-19 innovative approaches need to be considered. It is well known that host cellular miRNAs can directly target both viral 3'UTR and coding region of the viral genome to induce the antiviral effect. In this study, we did in silico analysis of human miRNAs targeting SARS (4 isolates) and COVID-19 (29 recent isolates from different regions) genome and correlated our findings with aging and underlying conditions. We found 848 common miRNAs targeting the SARS genome and 873 common microRNAs targeting the COVID-19 genome. Out of a total of 848 miRNAs from SARS, only 558 commonly present in all COVID-19 isolates. Interestingly, 315 miRNAs are unique for COVID-19 isolates and 290 miRNAs unique to SARS. We also noted that out of 29 COVID-19 isolates, 19 isolates have identical miRNA targets. The COVID-19 isolates, Netherland (EPI_ISL_422601), Australia (EPI_ISL_413214), and Wuhan (EPI_ISL_403931) showed six, four, and four unique miRNAs targets, respectively. Furthermore, GO, and KEGG pathway analysis showed that COVID-19 targeting human miRNAs involved in various age-related signaling and diseases. Recent studies also suggested that some of the human miRNAs targeting COVID-19 decreased with aging and underlying conditions. GO and KEGG identified impaired signaling pathway may be due to low abundance miRNA which might be one of the contributing factors for the increasing severity and mortality in aged individuals and with other underlying conditions. Further, in vitro and in vivo studies are needed to validate some of these targets and identify potential therapeutic targets.
As of 15 May 2020, more than 4 million confirmed cases of COVID-19, including more than 285,000 deaths have been reported to WHO. The risk of severe disease and death has been highest in older people and in persons with underlying noncommunicable diseases (NCDs), such as hypertension, cardiac disease, chronic lung disease and cancer.1-4 Limited data describe clinical manifestations of COVID-19 that are generally milder in children compared with adults,5-8 but also show that some children do require hospitalization and intensive care.9-11
Relatively few cases of infants confirmed to have COVID-19 have been reported; those who are infected have experienced mild illness.7 Robust evidence associating underlying conditions with severe illness in children is still lacking. Among 345 children with laboratory-confirmed COVID-19 and complete information about underlying conditions, 23% had an underlying condition, with chronic lung disease (including asthma), cardiovascular disease, and immunosuppression most commonly reported.12
Recently, however, reports from Europe and North America have described clusters of children and adolescents requiring admission to intensive care units with a multisystem inflammatory condition with some features similar to those of Kawasaki disease and toxic shock syndrome. Case reports and small series have described a presentation of acute illness accompanied by a hyperinflammatory syndrome, leading to multiorgan failure and shock.13-15 Initial hypotheses are that this syndrome may be related to COVID-19 based on initial laboratory testing. Children have been treated with anti-inflammatory treatment, including parenteral immunoglobulin and steroids.
It is essential to characterize this syndrome and its risk factors, to understand causality, and describe treatment interventions. It is not yet clear the full spectrum of disease, and whether the geographical distribution in Europe and North America reflects a true pattern, or if the condition has simply not been recognized elsewhere.
Background: The Bergamo province, which is extensively affected by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) epidemic, is a natural observatory of virus manifestations in the general population. In the past month we recorded an outbreak of Kawasaki disease; we aimed to evaluate incidence and features of patients with Kawasaki-like disease diagnosed during the SARS-CoV-2 epidemic.
Methods: All patients diagnosed with a Kawasaki-like disease at our centre in the past 5 years were divided according to symptomatic presentation before (group 1) or after (group 2) the beginning of the SARS-CoV-2 epidemic. Kawasaki- like presentations were managed as Kawasaki disease according to the American Heart Association indications. Kawasaki disease shock syndrome (KDSS) was defined by presence of circulatory dysfunction, and macrophage activation syndrome (MAS) by the Paediatric Rheumatology International Trials Organisation criteria. Current or previous infection was sought by reverse-transcriptase quantitative PCR in nasopharyngeal and oropharyngeal swabs, and by serological qualitative test detecting SARS-CoV-2 IgM and IgG, respectively.
Findings: Group 1 comprised 19 patients (seven boys, 12 girls; aged 3·0 years [SD 2·5]) diagnosed between Jan 1, 2015, and Feb 17, 2020. Group 2 included ten patients (seven boys, three girls; aged 7·5 years [SD 3·5]) diagnosed between Feb 18 and April 20, 2020; eight of ten were positive for IgG or IgM, or both. The two groups differed in disease incidence (group 1 vs group 2, 0·3 vs ten per month), mean age (3·0 vs 7·5 years), cardiac involvement (two of 19 vs six of ten), KDSS (zero of 19 vs five of ten), MAS (zero of 19 vs five of ten), and need for adjunctive steroid treatment (three of 19 vs eight of ten; all p<0·01).
Interpretation: In the past month we found a 30-fold increased incidence of Kawasaki-like disease. Children diagnosed after the SARS-CoV-2 epidemic began showed evidence of immune response to the virus, were older, had a higher rate of cardiac involvement, and features of MAS. The SARS-CoV-2 epidemic was associated with high incidence of a severe form of Kawasaki disease. A similar outbreak of Kawasaki-like disease is expected in countries involved in the SARS-CoV-2 epidemic.
Source: Royal College of Paediatrics and Child Health
Here we provide a summary of key current evidence regarding COVID-19 in children and young people.
This summary is based on published and pre-print studies identified in our rapid review. As evidence is rapidly emerging the content of this page will be reviewed and updated regularly, the search strategy and inclusion criteria used to identify papers can be downloaded below.
Importance: The recent and ongoing coronavirus disease 2019 (COVID-19) pandemic has taken an unprecedented toll on adults critically ill with COVID-19 infection. While there is evidence that the burden of COVID-19 infection in hospitalized children is lesser than in their adult counterparts, to date, there are only limited reports describing COVID-19 in pediatric intensive care units (PICUs).
Results: Of the 48 children with COVID-19 admitted to participating PICUs, 25 (52%) were male, and the median (range) age was 13 (4.2-16.6) years. Forty patients (83%) had significant preexisting comorbidities; 35 (73%) presented with respiratory symptoms and 18 (38%) required invasive ventilation. Eleven patients (23%) had failure of 2 or more organ systems. Extracorporeal membrane oxygenation was required for 1 patient (2%). Targeted therapies were used in 28 patients (61%), with hydroxychloroquine being the most commonly used agent either alone (11 patients) or in combination (10 patients). At the completion of the follow-up period, 2 patients (4%) had died and 15 (31%) were still hospitalized, with 3 still requiring ventilatory support and 1 receiving extracorporeal membrane oxygenation. The median (range) PICU and hospital lengths of stay for those who had been discharged were 5 (3-9) days and 7 (4-13) days, respectively.
Conclusions and Relevance: This early report describes the burden of COVID-19 infection in North American PICUs and confirms that severe illness in children is significant but far less frequent than in adults. Prehospital comorbidities appear to be an important factor in children. These preliminary observations provide an important platform for larger and more extensive studies of children with COVID-19 infection.
South Thames Retrieval Service in London, UK, provides paediatric intensive care support and retrieval to 2 million children in South East England. During a period of 10 days in mid-April, 2020, we noted an unprecedented cluster of eight children with hyperinflammatory shock, showing features similar to atypical Kawasaki disease, Kawasaki disease shock syndrome,1 or toxic shock syndrome (typical number is one or two children per week). This case cluster formed the basis of a national alert.
All children were previously fit and well. Six of the children were of Afro-Caribbean descent, and five of the children were boys. All children except one were well above the 75th centile for weight. Four children had known family exposure to coronavirus disease 2019 (COVID-19). Demographics, clinical findings, imaging findings, treatment, and outcome for this cluster of eight children are shown in the table.
Animals produce antibodies much like those made by the human immune system. But some animals, such as llamas, also produce another type of antibody that’s only about a quarter of the size of a typical human antibody. Such “single-domain” antibodies, or nanobodies, have several features that make them of interest as potential therapeutics.
Nanobodies are very stable, so they could potentially be stored for a long time after production. They can also be delivered by an inhaler directly to the lungs, which makes them particularly promising for respiratory infections such as COVID-19.
The World Health Organization declared COVID-19 an international pandemic on March 11, 2020. To date, it has infected more than 4 million people worldwide and killed over a quarter million. Researchers are rushing to develop vaccines. In the meantime, effective treatments are urgently needed.
SARS-CoV-2 is a newly emerged coronavirus responsible for the current COVID-19 pandemic that has resulted in more than 3.7 million infections and 260,000 deaths as of 6 May 20201,2. Vaccine and therapeutic discovery efforts are paramount to curb the pandemic spread of this zoonotic virus. The SARS-CoV-2 spike (S) glycoprotein promotes entry into host cells and is the main target of neutralizing antibodies. Here we describe multiple monoclonal antibodies targeting SARS-CoV-2 S identified from memory B cells of an individual who was infected with SARS-CoV in 2003. One antibody, named S309, potently neutralizes SARS-CoV-2 and SARS-CoV pseudoviruses as well as authentic SARS-CoV-2 by engaging the S receptor-binding domain. Using cryo-electron microscopy and binding assays, we show that S309 recognizes a glycan-containing epitope that is conserved within the sarbecovirus subgenus, without competing with receptor attachment. Antibody cocktails including S309 along with other antibodies identified here further enhanced SARS-CoV-2 neutralization and may limit the emergence of neutralization-escape mutants. These results pave the way for using S309- and S309-containing antibody cocktails for prophylaxis in individuals at high risk of exposure or as a post-exposure therapy to limit or treat severe disease.
The global pandemic of COVID-19 cases caused by infection with SARS-CoV-2 is ongoing, with no approved antiviral intervention. We describe here the effects of treatment with interferon (IFN)-α2b in a cohort of confirmed COVID-19 cases in Wuhan, China. In this uncontrolled, exploratory study, 77 adults hospitalized with confirmed COVID-19 were treated with either nebulized IFN-α2b (5 mU b.i.d.), arbidol (200 mg t.i.d.) or a combination of IFN-α2b plus arbidol. Serial SARS-CoV-2 testing along with hematological measurements, including cell counts, blood biochemistry and serum cytokine levels, and temperature and blood oxygen saturation levels, were recorded for each patient during their hospital stay. Treatment with IFN-α2b with or without arbidol significantly reduced the duration of detectable virus in the upper respiratory tract and in parallel reduced duration of elevated blood levels for the inflammatory markers IL-6 and CRP. These findings suggest that IFN-α2b should be further investigated as a therapy in COVID-19 cases.
Background: COVID-19 has rapidly emerged as a pandemic infection that has caused significant mortality and economic losses. Potential therapies and means of prophylaxis against COVID-19 are urgently needed to combat this novel infection. As a result of in vitro evidence suggesting zinc sulfate may be efficacious against COVID-19, our hospitals began using zinc sulfate as add-on therapy to hydroxychloroquine and azithromycin. We performed a retrospective observational study to compare hospital outcomes among patients who received hydroxychloroquine and azithromycin plus zinc versus hydroxychloroquine and azithromycin alone. Methods: Data was collected from electronic medical records for all patients being treated with admission dates ranging from March 2, 2020 through April 5, 2020. Initial clinical characteristics on presentation, medications given during the hospitalization, and hospital outcomes were recorded. Patients in the study were excluded if they were treated with other investigational medications. Results: The addition of zinc sulfate did not impact the length of hospitalization, duration of ventilation, or ICU duration. In univariate analyses, zinc sulfate increased the frequency of patients being discharged home, and decreased the need for ventilation, admission to the ICU, and mortality or transfer to hospice for patients who were never admitted to the ICU. After adjusting for the time at which zinc sulfate was added to our protocol, an increased frequency of being discharged home (OR 1.53, 95% CI 1.12-2.09) reduction in mortality or transfer to hospice remained significant (OR 0.449, 95% CI 0.271-0.744). Conclusion: This study provides the first in vivo evidence that zinc sulfate in combination with hydroxychloroquine may play a role in therapeutic management for COVID-19.
In Italy most positive and probable COVID-19 patients are at home if their clinical situation is mild. A group of homeopathic physicians treated 50 patients. The study describes their hospitalization rate, clinical evolution, homeopathic medicines used and gives an updated picture of use, limitations and perspectives of classical homeopathy in COVID-19 extra hospital patients.
The immune system protects the host from pathogenic organisms (bacteria, viruses, fungi, parasites). To deal with this array of threats, the immune system has evolved to include a myriad of specialised cell types, communicating molecules and functional responses. The immune system is always active, carrying out surveillance, but its activity is enhanced if an individual becomes infected. This heightened activity is accompanied by an increased rate of metabolism, requiring energy sources, substrates for biosynthesis and regulatory molecules, which are all ultimately derived from the diet. A number of vitamins (A, B6, B12, folate, C, D and E) and trace elements (zinc, copper, selenium, iron) have been demonstrated to have key roles in supporting the human immune system and reducing risk of infections. Other essential nutrients including other vitamins and trace elements, amino acids and fatty acids are also important. Each of the nutrients named above has roles in supporting antibacterial and antiviral defence, but zinc and selenium seem to be particularly important for the latter. It would seem prudent for individuals to consume sufficient amounts of essential nutrients to support their immune system to help them deal with pathogens should they become infected. The gut microbiota plays a role in educating and regulating the immune system. Gut dysbiosis is a feature of disease including many infectious diseases and has been described in COVID-19. Dietary approaches to achieve a healthy microbiota can also benefit the immune system. Severe infection of the respiratory epithelium can lead to acute respiratory distress syndrome (ARDS), characterised by excessive and damaging host inflammation, termed a cytokine storm. This is seen in cases of severe COVID-19. There is evidence from ARDS in other settings that the cytokine storm can be controlled by n-3 fatty acids, possibly through their metabolism to specialised pro-resolving mediators.
Authors: Gareth Davies, Attila R Garami and Joanna C Byers
Publication date: 06 May 2020
Journal: medRixv preprint
We analyse global data for COVID-19 deaths and recoveries and show that outbreak severity displays a striking latitude relationship with a northern hemisphere bias. Transmission rates can be explained by seasonal weather conditions, but this does not account for observed variations in fatality rates. Many factors point to Vitamin D as a candidate explanation but historical controversy surrounding Vitamin D studies and the lack of a coherent framework for causal inference has hampered acceptance of this explanation despite a wealth of evidence in its favour. We analyse global COVID-19 data using Causal Inference, constructing two contrasting directed acyclic graph (DAG) models, one causal and one acausal, and set out clearly multiple predictions made by each model. We show that observed data strongly match predictions made by the causal model but largely contradict those of the acausal model. We explore historic evidence further supporting the causal model. We review biochemical mechanisms that may explain the various ways in which vitamin D acts. We detail the mechanisms by which the SARS-Cov-2 virus causes the disease and known pathways that involve Vitamin D and show how these both protect against viral infection, as well as ameliorating disease symptoms in COVID-19 and other respiratory diseases. We examine the factors that govern confidence in causal inference models and conclude that a high level of confidence in a causal beneficial role for Vitamin D is justified.
This short original report aims to provide a balanced scientific view on vitamin D and SARS-CoV-2 virus/COVID-19 disease. It provides a succinct summary of the current scientific evidence of associations between vitamin D, influenza, upper respiratory tract infections (URTIs) and immune health. Importantly, the paper concludes with life- style strategies for avoiding vitamin D deficiency and ensuring a healthy balanced diet at any time, including during the current pandemic. The overarching messages are as follows: (1) Vitamin D is essential for good health. (2) Many people, particularly those living in northern latitudes (such as the UK, Ireland, Northern Europe, Canada and the northern parts of the USA, northern India and China), have poor vitamin D status, especially in winter or if confined indoors. (3) Low vitamin D status may be exacerbated during this COVID-19 crisis (eg, due to indoor living and hence reduced sun exposure), and anyone who is self-isolating with limited access to sunlight is advised to take a vitamin D supplement according to their government’s recommendations for the general population (ie, 400IU/day for the UK7 and 600IU/ day for the USA (800IU for >70 years))8 and the European Union (EU).9 (4) There is no strong scientific evidence to show that very high intakes (ie, mega supplements) of vitamin D will be beneficial in preventing or treating COVID-19. (5) There are evidenced health risks with excessive vitamin D intakes especially for those with other health issues such as a reduced kidney function.
Methods: In this population-based cohort study, we used linked primary and secondary care electronic health records from England (Health Data Research UK–CALIBER). We report prevalence of underlying conditions defined by Public Health England guidelines (from March 16, 2020) in individuals aged 30 years or older registered with a practice between 1997 and 2017, using validated, openly available phenotypes for each condition. We estimated 1-year mortality in each condition, developing simple models (and a tool for calculation) of excess COVID-19-related deaths, assuming relative impact (as relative risks [RRs]) of the COVID-19 pandemic (compared with background mortality) of 1·5, 2·0, and 3·0 at differing infection rate scenarios, including full suppression (0·001%), partial suppression (1%), mitigation (10%), and do nothing (80%). We also developed an online, public, prototype risk calculator for excess death estimation.
Findings: We included 3 862 012 individuals (1 957 935 [50·7%] women and 1 904 077 [49·3%] men). We estimated that more than 20% of the study population are in the high-risk category, of whom 13·7% were older than 70 years and 6·3% were aged 70 years or younger with at least one underlying condition. 1-year mortality in the high-risk population was estimated to be 4·46% (95% CI 4·41–4·51). Age and underlying conditions combined to influence background risk, varying markedly across conditions. In a full suppression scenario in the UK population, we estimated that there would be two excess deaths (vs baseline deaths) with an RR of 1·5, four with an RR of 2·0, and seven with an RR of 3·0. In a mitigation scenario, we estimated 18 374 excess deaths with an RR of 1·5, 36 749 with an RR of 2·0, and 73 498 with an RR of 3·0. In a do nothing scenario, we estimated 146 996 excess deaths with an RR of 1·5, 293 991 with an RR of 2·0, and 587 982 with an RR of 3·0.
Interpretation: We provide policy makers, researchers, and the public a simple model and an online tool for understanding excess mortality over 1 year from the COVID-19 pandemic, based on age, sex, and underlying condition-specific estimates. These results signal the need for sustained stringent suppression measures as well as sustained efforts to target those at highest risk because of underlying conditions with a range of preventive interventions. Countries should assess the overall (direct and indirect) effects of the pandemic on excess mortality.
Our understanding of the mechanisms of airborne transmission of viruses is incomplete. This paper employs computational multiphase fluid dynamics and heat transfer to investigate transport, dispersion, and evaporation of saliva particles arising from a human cough. An ejection process of saliva droplets in air was applied to mimic the real event of a human cough. We employ an advanced three-dimensional model based on fully coupled Eulerian–Lagrangian techniques that take into account the relative humidity, turbulent dispersion forces, droplet phase-change, evaporation, and breakup in addition to the droplet–droplet and droplet–air interactions. We computationally investigate the effect of wind speed on social distancing. For a mild human cough in air at 20 °C and 50% relative humidity, we found that human saliva-disease-carrier droplets may travel up to unexpected considerable distances depending on the wind speed. When the wind speed was approximately zero, the saliva droplets did not travel 2 m, which is within the social distancing recommendations. However, at wind speeds varying from 4 km/h to 15 km/h, we found that the saliva droplets can travel up to 6 m with a decrease in the concentration and liquid droplet size in the wind direction. Our findings imply that considering the environmental conditions, the 2 m social distance may not be sufficient. Further research is required to quantify the influence of parameters such as the environment’s relative humidity and temperature among others.
Reports of human-to-feline transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)1 and of limited airborne transmission among cats2 prompted us to evaluate nasal shedding of SARS-CoV-2 from inoculated cats and the subsequent transmission of the virus by direct contact between virus-inoculated cats and cats with no previous infection with the virus. Three domestic cats were inoculated with SARS-CoV-2 on day 0. One day after inoculation, a cat with no previous SARS-CoV-2 infection was cohoused with each of the inoculated cats to assess whether transmission of the virus by direct contact would occur between the cats in each of the three pairs (Table S1 in the Supplementary Appendix, available with the full text of this letter at NEJM.org). Nasal and rectal swab specimens were obtained daily and immediately assessed for infectious virus on VeroE6/TMPRSS2 cells.
Kate Bingham has today (16 May) been appointed chair of the UK’s Vaccine Taskforce – the group set up by the Government’s Chief Scientific Adviser, Deputy Chief Medical Officer, Business Secretary and Health Secretary to lead UK efforts to find and manufacture a COVID-19 vaccine.
This is a cross-government role and Kate Bingham will report directly to the Prime Minister.
Kate Bingham is a leading figure in the life sciences sector and her appointment will enable the Vaccine Taskforce to accelerate the development of a safe and effective vaccine, one of the long-term solutions to controlling the coronavirus pandemic and saving lives without social distancing or contact tracing in place.
As a growing number of countries push for an independent investigation into the origin of the COVID-19 pandemic, many scientists around the world are already trying to uncover when, where and how the new coronavirus got into people.
Finding the source is important for preventing further reinfection, but scientists’ investigations — which include modelling, cell studies and animal experiments — are revealing how tricky pinpointing the source might be.
“It is quite possible we won’t find it. In fact, it would be exceptionally lucky if we land on something,” says Lucy van Dorp, a geneticist from University College London (UCL).
There is strong evidence that the virus originated in bats. The biggest mystery remains how it got from bats to people. Researchers overwhelmingly think that it’s a wild virus, which probably passed to people through an intermediate species. But no one has found the virus in the wild yet, so other explanations cannot be ruled out entirely.
One in four people who have died in hospital with Covid-19 also had diabetes, the NHS’s first breakdown of underlying health conditions among the fatalities shows.
Of the 22,332 people who died in hospital in England between 31 March and 12 May, 5,873 (26%) suffered from either type 1 or type 2 diabetes, NHS England figures reveal.
That was the most common illness found in an analysis of what existing conditions patients had. The other commonest comorbidities were dementia (18%), serious breathing problems (15%) and chronic kidney disease (14%). One in ten (10%) suffered from ischaemic heart disease.
The finding about diabetes confirms anecdotal reports from intensive care doctors that many of the coronavirus patients they have been treating during the pandemic had underlying diabetes, as well as research by the UK’s Intensive Care National Audit and Research Centre.
NHS England said the one in four figure confirmed that diabetes – which 4.8 million Britons are estimated to have – increases the risk of death from Covid-19.
Moderna, Inc., (Nasdaq: MRNA) a clinical stage biotechnology company pioneering messenger RNA (mRNA) therapeutics and vaccines to create a new generation of transformative medicines for patients, today announced positive interim clinical data of mRNA-1273, its vaccine candidate against novel coronavirus (SARS-CoV-2), from the Phase 1 study led by the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health (NIH).
Immunogenicity data are currently available for the 25 µg and 100 µg dose level (ages 18-55) after two doses (day 43) and at the 250 µg level (ages 18-55) after one dose (day 29). Dose dependent increases in immunogenicity were seen across the three dose levels, and between prime and boost within the 25 µg and 100 µg dose levels. All participants ages 18-55 (n=15 per cohort) across all three dose levels seroconverted by day 15 after a single dose. At day 43, two weeks following the second dose, at the 25 µg dose level (n=15), levels of binding antibodies were at the levels seen in convalescent sera (blood samples from people who have recovered from COVID-19) tested in the same assay. At day 43, at the 100 µg dose level (n=10), levels of binding antibodies significantly exceeded the levels seen in convalescent sera. Samples are not yet available for remaining participants.
La Universitat de València ha registrat una sol·licitud de patent d’una candidata a vacuna contra la COVID-19, desenvolupada per un equip d’investigació del Departament de Microbiologia. Es tracta d’una vacuna del tipus de subunitat (aquelles dissenyades a partir de components de virus o bacteris) i està basada en la proteïna S del SARS-CoV-2.
The University of Valencia has registered a patent application for a vaccine candidate against COVID-19, developed by a research team from the Department of Microbiology. It is a subunit type vaccine (those designed from virus or bacterial components) and is based on the SARS-CoV-2 S protein.
Author: Gabriel Scully, Bobbie Jackson and Kamran Abbasi
Publication date: 15 May 2020
Journal: The BMJ
Too little, too late, too flawed
The UK government and its advisers were confident that they were “well prepared” when covid-19 swept East Asia. The four-pronged plan of 3 March to contain, delay, research, and mitigate was supported by all UK countries and backed, they claimed, by science.1 With over 30 000 hospital and community deaths by 12 May, where did the plan go wrong?2 What was the role of public health in the biggest public health crisis since the Spanish flu of 1918? And what now needs to be done?
What is clear is that the UK’s response so far has neither been well prepared nor remotely adequate (see infographic). The weakness of the preparations was exposed in 2016 by Exercise Cygnus, a pandemic simulation, and the necessary remedial steps were not taken.3 On 30 January, the World Health Organization declared a public health emergency of international concern and governments were urged to prepare for global spread of covid-19 from East Asia.4 Detailed case studies followed showing the need for high levels of mechanical ventilation and high death rates.56 But the UK ignored these warnings.
Loss of smell or taste have been added to the UK's list of coronavirus symptoms that people should look out for and self-isolate with.
Until now, only a fever and cough were triggers for people to shut themselves away in self-isolation in case they had and could spread the infection.
Ear, nose and throat doctors had been warning for weeks that more symptoms should be included.
Scientific advisers told the government to update the advice.
If you or someone you live with has any of these symptoms - a new, continuous cough, fever or loss of smell or taste (also called anosmia) - the advice is stay at home for seven days to stop the risk of giving coronavirus to others.
Staying indoors for much of lockdown means some people have been deprived of vitamin D.
Normally, many of us get it by spending time outside. Our skin makes it when exposed to the sun.
But what can we do about it, and why do we need vitamin D?
What is the advice?
People in the UK are already advised to consider taking a supplement of 10 micrograms a day during the winter months (from October to March), and all year round if we aren't spending much time outdoors.
Public Health England recommends vitamin D throughout the year if:
you are not often outdoors
you live in a care home
you usually wear clothes that cover up most of your skin when outside
People with dark skin may also not be getting enough, even if they spend time outdoors.
Ethnic minorities and the obese may be more at risk from Covid-19 due to a lack of vitamin D, research suggests.
Ministers are troubled by trends showing that the disease is far more deadly for some sections of society.
Now data from the outbreak in England shows that a deficiency of the vital hormone — which the body produces when sun hits the skin — may explain the patterns that have so far baffled government scientists.
The study by Surrey and Southampton universities, which has not been peer-reviewed, compared the blood samples of 1,300 adults on the UK Biobank health-monitoring programme, of which 580 had tested positive for the coronavirus.
There has been speculation that vitamin D may help to protect against coronavirus, and because our bodies make vitamin D from direct sunlight on exposed skin, it is especially important now to get outdoors in the sun when possible.
Vitamin D keeps bones healthy, and also plays a role in promoting our immune system, such as protecting against respiratory infections. A review of 21 clinical trials involving 11,000 participants taking vitamin D supplements found a reduced the risk of severe respiratory tract infection, especially in those people who had had low levels of the vitamin.
Covid-19 is also a respiratory disease, and some researchers have suggested that vitamin D deficiency might be involved in severe cases, although other underlying risk factors, such as heart disease,
Health Secretary Matt Hancock needs to launch a "public health revolution" to combat metabolic syndrome - a root cause of so many people in the UK dying from Covid-19, according to a leading anti-obesity expert.
Dr Aseem Malhotra, a London-based cardiologist who the Health Secretary asked to advise him on the links between ill health, obesity and the coronavirus, has written to Mr Hancock saying there is a "huge lack of awareness" among the public and scientific community about the role poor metabolic health is playing in the pandemic. It is also "likely" to be the most significant factor as to why those from Black, Asian and Minority Ethnic (BAME) backgrounds are disproportionately affected by Covid-19, he said.
Around half of the UK population could have access to a vaccine against coronavirus by September, the Government has claimed.
The Business Secretary Alok Sharma announced the target after a deal was struck between Oxford University and Astrazeneca.
It means if the vaccine candidate, known as Chaddox 1, works after trial then the pharmaceutical giant will pay for its commercialisation and manufacturing, before selling it at cost during the pandemic.
Mr Sharma said this agreement could lead to the delivery of 100 million doses in total, with 30 million of those available to Brits in as little as four months, well ahead of the predicted timeframe for developing a vaccine against Covid-19.
During a remote online testimony before the U.S. Senate’s Health, Education, Labor and Pensions Committee on May 12, 2020, Anthony Fauci, MD warned that moving forward too quickly with the development of a vaccine for COVID-19 may produce a vaccine that could make the disease worse.1 2 Dr. Fauci, who is the director of the National Institute of Allergy and Infectious Diseases (NIAID) and a leading member of the White House Coronavirus Task Force, said:
I must warn that there’s also the possibility of negative consequences where certain vaccines can actually enhance the negative effect of the infection. The big unknown is efficacy. Will it be present or absent, and how durable will it be.1 2
In the past two months, several pharmaceutical companies and at least one university have begun human clinical trials to test experimental vaccine candidates to prevent COVID-19 infections. Some of the manufacturers of these experimental vaccines claim they will them ready by the before the end of this year.3 4 5 6 7 Two of those companies, CureVac AG of Germany and Pfizer, Inc. of the United States (in partnership with BioNTech SE of Germany), and Oxford University of the United Kingdom have said that they expect to have COVID-19 vaccines ready by this fall.
Pubs and restaurants could reopen tomorrow without posing the threat of a second wave of coronavirus, a leading Oxford scientist has suggested.
Sunetra Gupta, a professor of Theoretical Epidemiology, said there was a "strong possibility" that the hospitality industry could get back to work without posing a danger to the public.
In an interview, Prof Gupta called for a "rapid exit" from lockdown and said the coronavirus epidemic was already "on the way out". Much of the UK population may already have been exposed to the virus before the Government ordered people to stay at home, she added.
In March, Prof Gupta and her team published a controversial study claiming coronavirus had been spreading for months, with up to half the UK population already exposed.
It may be a painful fact to contemplate during these locked-down days, but last year the world was more mobile than ever, with people taking 4.6bn flights. In April this year, though, planes carried just 47m passengers; that level of mobility, annualised, would set the clocks back to 1978. The virtual halt to travel has exacerbated the global economy’s woes, complicating trade ties, upending business and devastating the tourism industry. Little wonder that governments want to restore links. An idea gaining favour is the creation of travel “bubbles”, binding together countries that have fared well against the coronavirus.
The coronavirus crisis is expected to hit workers hard, with evidence from previous crises indicating that the young are likely to be affected to a greater degree than most. In this spotlight we move from speculation to evidence, presenting new findings on how different age groups – and in particular the young – have been affected.
Younger and older workers have experienced the brunt of the hit to jobs and pay, with the very youngest in the most challenging position. One-third of 18-24-year-old employees (excluding students) have lost jobs or been furloughed, compared to one-in-six prime-age adults, with these experiences also more common among employees in atypical jobs. Similarly, 35 per cent of non-full-time student 18-24-year-old employees are earning less than they did prior to the outbreak, and 30 per cent of those in their early 60s, compared to 23 per cent of 25-49-year-olds.
The Coronavirus Job Retention Scheme has been well-received, especially by the youngest workers: around two-thirds of 18-24-year-olds who have been furloughed are happy about that outcome. And around seven-in-ten 25-39-year-olds in work are currently working from home at least some of the time. This is also the age at which workers are most likely to expect to work from home more in the future than they did before the coronavirus outbreak.
Spain is to roll out a universal basic income (UBI) “as soon as possible” to mitigate the impact of coronavirus.
Minister for economic affairs Nadia Calvino told Spanish broadcaster La Sexta on Sunday night that the move was intended to help families during the pandemic.
But Ms Calvino, who is also deputy prime minister, said the government’s ambition was that UBI could become something that “stays forever, that becomes a structural instrument, a permanent instrument”.
If the payments are successfully implemented, Spain would become the first country in Europe to introduce them nationwide on a long-term basis.
Teacher, health practitioner and founder of The New School, Lucy Stephens, shares her concerns about the impact the new proposals for schools could have on child development, emotional health and wellbeing