Updated: Aug 1, 2020
Covid-19 is a disease related to SARS-Cov2 virus which enters the body through many cells that have an ACE2 receptor. It may enter by other means but this seems to be the dominant entry path. Once inside the cell it multiplies and may cause cell death. It also enhances ACE2 expression in these cells which means that more viruses can now enter the cell. Following entry, the body produces Interferon to kill the virus. While interferon is known to peak within the first week or two, it starts diminishing or exhausting after that thus allowing the virus to create havoc and damage. Most common symptoms include dry cough, fever, shortness of breath, loss of smell, sore throat, upset stomach or diarrhea, malaise,or just a feeling of unwellness or fatigue. While most individuals are without symptoms or have mild disease from which they recover, a small proportion (10-15%) of those infected do go onto develop a chemokine and cytokine storm. These “kines” and other substances include CCL2, CCL3, CCL5, CXCL9, IL1, IL2, IL6, IL8, TNF alpha along with active expression of many genes involved in the immune pathway. Release of chemokines results in activation of white blood cells and other cells within the body which then get transported to the affected parts of the body and along with cytokines result in massive inflammation of the organ such as lung, kidney, heart, liver, even the brain, etc. This is called a hyperactive immune response or cytokine storm. Once the cytokine storm hits, antiviral drugs (those that directly kill the virus) have minimal effect on the disease. Because the virus causes a cytokine storm and clotting problems, quite different from influenza, it is much more deadly than influenza. Not only that, it’s R0 value (number of people that get infected from one individual) exceeds 1.5 to 2.0, therefore people are at higher risk of getting infected as opposed to influenza which has a R0 value of 0.5
The best time for antiviral drugs to work is during the first week or 10 days after symptoms have begun. Interferon either by IV or by nasal inhalation has shown improvement in this disease. Remdesevir, another antiviral has shown benefit in mild to moderate disease but not so much when the disease is severe to critical. Favipiravir, another direct antiviral, is now in phase III trials having shown some benefit in China and Europe. The early data on hydroxychloroquine seemed encouraging but the total data is quite controversial. While observational studies (studies without controls or placebo) showed benefit in preventing progression of disease in some, randomized control trials in general have not shown much benefit and have shown some side effects. A randomized trial from China suggested that hydroxychlorquin in addition to other antivirals is beneficial. However, the general impression from treating many many patients in NYC and other places is that hydroxychloroquin with Azithormycin and zinc is not be the drug of choice in cytokine storms. The most important intervention in patients with symptoms is to provide patients oxygen, symptomatic relief and ensure their vitamin D is normal and that those infected do not develop cytokine storm or clotting within the blood vessels that could cause stroke or heart attacks. Pneumonia with shortness of breath remains the dominant features of moderate to severe disease with some patients progressing to ARDS. Chest Xray abnormality is noted even in asymptomatic individuals. Newer treatments such as convalescent plasma (or plasma from blood of recovered patients) are showing encouraging signs and reducing mortality at least based on observation. However, results from randomized control trials are necessary to confirm that. Some of the early data on convalescent plasma were controversial but later data may perhaps show more benefit. Tocilizumab, an antibody that blocks the actions of IL-6 cytokine, was very successful in observational studies in Italy but randomized control trials (RCT) did not show statistical benefit and it had some side effects. So, it currently remains an experimental drug with larger data and results to be released later this year. The results of Leronlimab from its phase II trial should be coming out next week for the mild to moderate disease trial. In another 8 weeks, it should come out with its 195 patient interim analysis of phase III trial in severe to critically ill. This drug has shown early promise but the RCT results will show if indeed its success is durable. A number of other drugs including Lenzilumab, Remestemcel, CAP-1002, baricitinib, etc are also in trials currently as well as a trial on Remdesevir + Tocilizumab and Remdesevir + baricitinib. Dexamethasone was shown to effective in preventing the deterioration of disease and is now up for approval in Covid-19. In India, Itolizumab, a new drug, showed that 20 treated patients with severe disease did not advance to death while 3/10 patients in the placebo arm did end up dying. This drug has been approved in India.
In terms of the vaccine status, the two front runners are Moderna Therapeutics and Pfizer /BioNtech, which start their phase III trials this month. Each company plans to recruit 30,000 individuals; 20,000 in the vaccine set and 10,000 in the placebo set to understand the vaccine’s efficacy, safety and their ability to create a lasting immune response to the virus. Astra Zeneca vaccine and Johnsons and Johnson vaccines are next and then Novavax, Regeron and Inovio Pharmaceuticals and others. The Chinese vaccine companies including Sinovac are already ahead in the race for vaccines and Sinovac is using an inactivated virus vaccine with an adjuvant that helps potentiate its’ action. Chinese vaccine is being tested in the Chinese military personnel now. At least a 100 companies or Governments are going after a vaccine treatment and at least 30 companies have drugs/therapeutics they are trying to bring forth including antibodies by Regeneron and Sorrento Pharmaceuticals.
That we did not mandate masks right from the onset is coming to haunt us.
We did not focus on developing a large-scale accurate testing focus with extensive contact tracing. Wearing a mask has become a partisan issue despite scientific data suggesting it’s benefit in preventing and reducing case numbers. That self-distancing rules are still not being followed and that Covid parties are still held is a shame. Whether or not a lockdown was necessary or will become necessary again will be debated for a long time. Some smaller countries have managed without draconian lock downs including Vietnam, South Korea and Singapore. Unfortunately, we now have over 140,000 dead and more than 4 million cases while Vietnam had only 412 cases. And about half or more of our dead are the elderly.
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