COVID-19 pandemic – emerging information from experts

4 major respiratory emergence events in the 21st century, 3 of them caused by coronaviruses:

SARS-CoV 2003

H1N1 2009

MERS-CoV 2012

SARS-CoV 2 2019

Drivers of the evolution of the Coronavirus: Fidelity efficiency of replication machine can change due to environmental changes; high rates of RNA recombination allow high mutation rate and rapid evolution of coronaviruses. Plasticity of surface glycoproteins tolerates high rates of mutation that affect host range and virus transmissibility. Two possible transmission pathways for the emergence of SARS CoV (2003): bats to humans to civets bats to civets to humans Bat species host a huge reservoir of high-risk strains of coronaviruses capable of using human receptors for docking and entry, with a capacity to replicate in primary human airway epithelial cells. Large heterogeneous pools of strains of CoV in bats in terms of their spike glycoprotein variation from 0%-35% from the original SARS CoV that emerged in 2003. SARS CoV-2 2019 has about 23% spike glycoprotein genetic variation from the SARS CoV 2003. Both SARS CoV and SARS CoV-2 S-glycoproteins use human ACE 2 receptors to enter the human cell. Features of high-risk strains CoV: Use hACE 2 receptor as docking for entry in human cells. Grow in primary human epithelial airway cells. Cause acute respiratory distress syndrome (ARDS). Severe in patients with age-related comorbidities. If >10 % spike glycoprotein variation – existing immune therapeutics – agents developed against SARS CoV will probably have limited usability against SARS CoV-2. Epidemiology Distribution of daily case reports: early in the course of the epidemic the spread of COVID-19 was limited mostly to China. Before January 2020: Most of the early cases linked to Huanan Seafood Market in Wuhan province in China. In 2020: Cases rapidly spread to persons with no known exposure to this market. Mid-January 2020: COVID-19 confirmed in almost all provinces in mainland China. February 25th: Cases outside China exceed the cases reported inside China. March 4th: Deaths outside China exceed deaths reported in China. Pathogenesis and symptoms: Predominate symptom: Fever >80% of patients eventually develop a fever during the illness, even with lower prevalence at early presentation (only 44 % of patients). 50% of patients develop a cough. 25% of patients develop myalgia/arthralgias. A small fraction develops headache or diarrhea (in some patients GI disturbances precede cough and fever). No subset of symptoms can reliably discriminate between other respiratory viral illnesses such as influenza. Median incubation period 4-6 days (range 2-14 days). Most people will recover with supportive care. In those who develop further illness, complications may include: pneumonia, respiratory failure, multiorgan system failure. The major cause of death for MERS-CoV, SARS-CoV, SARS-CoV-2: acute respiratory distress syndrome (ARDS) – end-stage lung disease with a 30% mortality rate – causes of mortality: hypoxia, oxygen insufficiency, organ failure. The virus destroys the cell-lining of the alveoli allowing the fluid to cross the interstitial barrier and fill up the alveoli causing pulmonary edema and drowning. Progress of the disease: pulmonary fibrosis – in the repair process, fibroblasts in multilayers are laid down between alveoli and capillary bed preventing oxygen diffusion leading to suffocation. Distribution of COVID-19 in relation to: AGE Most patients have been middle-aged adults (who also comprise a major proportion of the general population). Limited infections in children – may be equally susceptible to COVID-19, and data may represent underreporting of pediatric infections, with children presenting with a milder illness than adults and thus unrecognised as COVID-19. Adults over the age of 60 experience a significantly more severe illness and are more likely to die (case fatality rate (CFR) – shown orange on the graph). Exact figures of CFR depend on multiple factors such as the geographic location and local healthcare system, the group of patients affected by the illness, the number of people tested, etc. Most ill people with the highest risk of death are tested first. As more people with a less severe case of the disease are tested, the case fatality rate drops. A number of deaths are also dependent on how well the disease is recognized and managed. With all these factors considered, the current best estimate is that the CFR of COVID-19 is somewhere between 0.5% to 3.5%. By comparison, the CFR for seasonal influenza is 0.1% – COVID-19 could be 5–35 times more deadly than seasonal influenza.High-risk groups: Persons with comorbidities and advance age, CFR >5%. Immunocompromised patients: No data (but those with low CD4 count and not virally suppressed may have a greater risk). Transmission Main mode: Respiratory droplets in the air or on surfaces; viral shedding is highest at the onset of symptoms. Possible: Transmission from pre-symptomatic or asymptomatic infected persons. Unlikely: Stool – only one report of replication-competent virus cultured from stool. Not yet observed: Perinatal transmission. Hospitals are epicenters for disease expansion. Community spread due to asymptomatic cases is common, and makes SARS CoV-2 harder to contain than SARS CoV. Diagnostics PCR-based test can diagnose COVID-19 from respiratory and serum clinical samples. Therapeutics development No approved drugs, immune therapeutics, or vaccines against any group of 2b coronavirus. 261 records of clinical trials for COVID-19 at WHO clinical trial registry (as on March 3rd 2020). Vaccines and vaccine complications: Vaccine platform technologies are deployed from research centers – the time taken to first human vaccine trial injection for emerging diseases: Vaccine efficiency in aged populations could reduce performance. A vaccine tailored to a particular virus serotype will not provide protection to more variable virus strains. Original DIV SARS CoV vaccine and adjuvant S glycoprotein vaccine caused Th2 immune pathology actually increasing the pathology of the disease in animals. Experimental drugs: Remdesivir-ribonuclease inhibitors induce chain termination during RNA synthesis and inhibit replication in cell culture, and act against a range of CoV: Effective in animal models of CoV disease (mice, primates). Clinical testing of remdesivir for COVID-19 initiated in 3 controlled trials in hospitalized patients, 2 additional trials awaiting enrollment. EIDD 1931 another ribonuclease inhibitor under FDA review. Lopinavir/ritonavir (protease inhibitors) used for HIV prevention and treatment, used as investigational drug for other CoV. Broad-spectrum antiretrovirals. Monoclonal antibodies are isolated and tested. Control the outbreak! Nonpharmaceutical interventions focus on social distancing and can be applied at home, at school, at work, and at gatherings. Avoid close contact with sick people, avoid touching your face. Wash hands with soap and water for 20 seconds – this is a better option than hand sanitizing gel (use it when soap is not available). Expert commentary: “SARS is a bad virus. SARS 2 is also a bad virus. There are 1300 different bat species at least that exist on a planet and we’ve only surveyed maybe 50 to 75 total species for the presence of coronaviruses. Most people think that SARS original 2003 strain is still out there circulating in bats and it is waiting its moment in time.“ “Data suggest that as bats are becoming more compressed within the hibernacula, virus generalists exist within the population that can use ACE 2 receptor orthologs across different bat species. The zoonotic population is now seeded with preprogrammed viruses that have been designed to use multiple bat ACS 2 receptors and by random chance, some of them can directly use the human host. So you don’t need this massive mutation-driven adaptation process to initiate the infection. In some cases, these viruses are capable of programming directly into an epidemic.” – Ralph S. Baric, PhD, University of North Carolina

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