updated: 8 July 2020
Disclosure: I am not a medical doctor. However, I do have domain knowledge of human biology, genetics and biochemistry. I have written this article after going through authentic research papers and researchers' interviews published on the web.
COVID-19 pandemic was likely to peak sometime in May but it has not yet peaked in July. In some countries, its growth has come down but new waves of infection are appearing; in others, it is growing at alarming rates. Strict social distancing is the mantra that seems to be working in containing its fast spread, but there is no standard treatment for it so far. Researchers are working overtime to find a drug or a combination of drugs that work against the infection, and of course a vaccine.
Why is COVID-19 so dangerous?
COVID-19 is a very fast-spreading virus, more than most other known viruses. Among the coronaviruses (the family of viruses causing flu), COVID-19 or the one that originated in Wuhan in late 2019, spreads extremely fast. Within 6 months, nearly 11.7 million people have tested positive for the virus worldwide, while many times more number of people might be harboring it without symptoms and/or would have recovered on their own. The fast spread itself makes COVID-19 so much dangerous.Once COVID-19 virus infects, what makes it extremely dangerous is that it triggers over-activity in the body's immune system. When that happens, the body releases too much cytokines - chemicals that are meant to marshal fighting forces within the body but when too active, they lead to inflammation or swelling. This hyper-inflammation causes respiratory distress and organ failure. [This type of over-secretion of cytokine (called cytokine storm) has also been seen in complications arising due to flu, SARS and MERS.] This is why patients often need life-support system including ventilators, and why there is so much fatality. As of now, 540 thousand people have succumbed to the pandemic and the number is only rising.
If a person is already suffering from severe illness of lungs, kidneys and other organs, that makes him/ her highly vulnerable to organ distress. The medicines they might have been taking against existing illnesses can make them vulnerable. That also is a reason why people above 65 years or so are more vulnerable to develop complications than the younger ones.
Fatality from COVID-19 is a matter of huge concern. The rate of fatality among people testing positive for the virus is different among different populations, partly because of sampling differences. The global rate seems to be around 4%, which is big though much less than the earlier corona epidemics (MERS, SARS). Thus, though its fatality is lower, its enormously fast spread has seen that many times more people have died due to COVID-19 than other such epidemics.
How actually does COVID-19 attack human cells?
Most viruses are pieces of a strand of RNA covered with a sheath of proteins. RNA is a nucleic acid somewhat like the more well-known DNA. [Some viruses have DNA instead of RNA.]You would know that the genetic material (DNA/ RNA) has the potential to recreate (replicate) itself and produce proteins based on what is coded inside it. All living beings live because of interplay of proteins in cells; all types of chemical coordination and control in multi-cellular organisms including humans happens due to thousands of proteins. The enzymes and hormones that lead to numerous biochemical reactions in our bodies are all complex proteins.
In COVID-19, there are 29 proteins in its shell, which are used for attaching the virus to human cells and compromising the body's immune system. In a study of 26 out of these 29 proteins, it was found that they are able to target 332 human proteins to get favorable entry into human cells and then subjugate the human cells into submission.
The 'corona' or crown/ covering of the virus has spikes, whose tips bind to human cells through receptor proteins found in human cells. Then a human enzyme unwittingly helps the spike proteins to activate. That allows virus entry into human cells.
Once the viral RNA enters human cell, it orders the cell to make proteins of its own type, which then spawn more viral RNAs and associated proteins. Thus, numerous new coronaviruses replicate in each cell and infect nearby cells. They are all there in infected person's saliva and mucus, which act as agents to infect other humans.
When the virus replicates furiously and attacks other cells, about half of humans are able to ward it off but the rest succumb to it. Fine; that happens with other flues also. However, in the case of COVID-19, about 15% patients' bodies over-react to the infection. Their auto-immune system gets into over-drive, as if soldiers going mad. Many types of fighter cells come into chaotic action. As mentioned above, one set of chemicals, cytokines, is secreted. These directly or indirectly damage own cells and then spread to other parts of the body, damaging cells there - leading to swelling of lung lining and other organs, and other serious symptoms.
The biochemistry/ pathology associated with virus attack and how human body reacts to it is much more complex than outlined here. Dozens of chemicals react, dozens of them trigger other reactions.
In the case of viruses, a quick mutation (=change in genetic composition) is also a big problem. All genetic material is known to change in minute dozes after many generations, and in the case of viruses, a hundred thousand generations happen within no time. Luckily, COVID-19 is found to mutate much less as compared to other flu viruses.
What types of treatments for COVID-19 are being looked at?
As would be clear from the above, if we have to treat COVID-19 infection, the approach has to be to attack/ inactivate the virus and also to help the human system to respond properly.For tackling the virus, either the body's immune system is to be made strong or a drug may be introduced which can act at molecular level to achieve one or more of the following:
- stopping viral proteins from attaching to human cells and getting activated;
- stopping viral proteins from compromising internal anti-viral system from working;
- stopping processes that lead to human enzymes obeying commands of viral RNA.
On human side, these areas need medical attention:
- comforting the body: dealing with symptoms;
- strengthening the immune system of the body to fight the virus;
- moderating the reaction of the body so that it does not harm itself;
- dealing with side-effects of medicines;
- finding ways to improve immunity in the population against the virus
It is clear that a combination of drugs has to be used, to manage infection as well as serious symptoms. Since the spread is fast and fatality is high, there is no time to depend on academic research and procedures that take years to develop one single drug molecule. A faster way out seems to be to examine drugs that are in use against other diseases or are in advance stages of trials. It is reported that about a hundred drugs in use or in advance trials have been identified and are being tested for COVID-19 treatment.
Scientists are also looking deeper into the working of viral RNA and proteins, which will help in attacking the virus in its vulnerable spots and not allowing it to exploit vulnerabilities in the human system.
As expected, one branch of research is focusing on stopping the viral protein from attaching and getting activated. That is leading to a vaccine that was useful against SARS and MERS - whose viruses also have corona and spikes; the vaccine is in fact in a very advanced stage of testing.
One branch of study is looking at tempering the auto-immune system so that it does not over-react. Drugs that are in use for calming down auto-immune system during cancers, rheumatic arthritis etc are potential candidates. These include anakinra, tocilizumab and ruxolitinib. They inhibit production or activity of some proteins in the chemical chain that causes hyper-activity. Some of these have already been authorized for use in case of Covid-19 and have shown good results.
Hydroxychloroquinine, an anti-malaria drug, is also supposed to inhibit cytokine storm. However, its actual efficacy has come into question following extensive use in the first phase of the disease.
Anti-viral drug remdesivir - the one now being widely used for COVID-19 - stops one step in the replication process of viral RNA within human cells.
Anti-viral drug remdesivir - the one now being widely used for COVID-19 - stops one step in the replication process of viral RNA within human cells.
Dexamethasone has been found to be much more effective than remdesivir in reducing death among serious COVID patients. A study on 6000 patients found its effect 'significant'.
However, there was no benefit in administering it to those with milder symptoms. Since it suppresses cytokine activity so that it does not go out of control, giving dexamethasone to those who are not very sick could impair their immune system from functioning properly.
However, there was no benefit in administering it to those with milder symptoms. Since it suppresses cytokine activity so that it does not go out of control, giving dexamethasone to those who are not very sick could impair their immune system from functioning properly.
An Indian research team is working on Sepsivac, a commercially available drug against sepsis caused by gram negative bacteria. That infection also causes cytokine storm, and so the drug has high potential in moderating the cytokine action in COVID-19 patients.
It has also been found that blood transfusion from recovered patients (=plasma therapy) is effective in treating others. This is because this blood has developed antibodies that can stop the corona spikes from being received by human cells, much like vaccines. In a number of top hospitals in India, this therapy is being put under trial; the results have been found to be encouraging. However, due to risk of allergies and lung injury, it is not yet being recommended as a proven therapy.
As of now, many of these drugs have been approved for clinical trials and some are actually being administered to patients. Some of them have toxicity and side effects, and therefore cannot be given to all patients. In some cases, a drug effective on some patients has been seen to be ineffective on others, partly because the stage of infection and overall medical condition of each patient play a major role in determining how he/ she responds to infection and to medical treatment. In many cases, some drugs have been taken back after being found ineffective or harmful.
WHO and national health authorities have been updating their guidelines almost on weekly basis, regularly revising them based on recent studies done and evidences collected as the disease progresses.
A completely different set of studies are being done on which chemicals or devices can neutralize the virus in air or on surfaces where virus-laden droplets fall. Also being studied are whether it can be transmitted through stool or blood, whether transfer from humans to other animals can occur, methods of quick testing and so on. After insisting that the virus does not spread through air except for some minutes after coughing or sneezing by the infected persons, scientists are now saying, the virus is mildly airborne too. I have excluded these from the present discussion so as to focus on finding a drug for treating COVID-19 patients.
Of late, remdesivir is in high demand because it has been found to be effective in patients with serious symptoms. Some countries are even making political statements regarding monopolisation of the drug by others. Now that dexamethasone is found to be much more effective in serious patients, there is likelihood that this one displaces remdesivir from the top slot.
The top organizations that fund research have also been showing flexibility. Some of them have extended grants to on-going projects, some have increased stipends and added funds for providing kits to researchers against COVID-19. Some of them have given quick approvals for projects specifically on coronavirus. I have seen report of such promising news coming from funds in the US, UK, France, Germany, Australia and India.
However, it is also apprehended that many labs and manufacturers will keep close to their heart the molecules they discover as potent. Some may not be cooperating with international effort, only paying lip service. Even when a drug is found effective, its supply in a large scale at a short notice may not be easy. Authorities are also known to be slow in granting permissions, especially for trials, for fear of negative consequences and ethical concerns. COVID-19 has generated a sense of urgency and collaboration among international and national health and medical research authorities that was not seen before.
The shortest timelines towards finding focused cure against COVID-19 look like this:
A completely different set of studies are being done on which chemicals or devices can neutralize the virus in air or on surfaces where virus-laden droplets fall. Also being studied are whether it can be transmitted through stool or blood, whether transfer from humans to other animals can occur, methods of quick testing and so on. After insisting that the virus does not spread through air except for some minutes after coughing or sneezing by the infected persons, scientists are now saying, the virus is mildly airborne too. I have excluded these from the present discussion so as to focus on finding a drug for treating COVID-19 patients.
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| Stages in which virus needs to be attacked (pic courtesy: advancedsciencenews) |
Scientists see vaccines as the ultimate cure against the pandemic. Reports say that as many as 150 different vaccines are under
development. Over a dozen of them have already been put on human trials
while others are yet being administered to animals. Different
approaches are being used, starting from injecting weakened virus so
that antibodies are formed to using some type of proteins to bind with
virus proteins and make them inactive. You may like to visit the
linked detailed article on how vaccines are developed and the progress of vaccine development.
Why was hydroxychloroquine (HCQ) so much in demand at one time? Is the same happening with remdesivir now?
As explained above, HCQ was supposed make it difficult for virus to enter human cells and also calm down the auto-immune system. It also has fewer and more sober side effects than other similar drugs. When no other treatment was in sight, many countries gave permission for its trials and use on COVID-19 patients. However, many studies have found that it is not significantly and universally effective in the case of COVID-19.Of late, remdesivir is in high demand because it has been found to be effective in patients with serious symptoms. Some countries are even making political statements regarding monopolisation of the drug by others. Now that dexamethasone is found to be much more effective in serious patients, there is likelihood that this one displaces remdesivir from the top slot.
How soon can you expect a proven treatment against COVID-19?
It is good to know in such dire situation when thousands of people are dying every day from this virus, that international organizations, countries, research labs, institutions and drug manufacturers have joined together to come out with treatments against the virus. Research coalitions and a genome sequencing alliance have been formed for collaboration and exchange of research data. Funds have been flowing from public and private organizations, governments and international bodies. Trial periods of drugs and vaccines have been shortened, many countries have given permission for clinical trials, and large number of trials on volunteers have started. Hospitals are creating data on progression of disease, symptoms, use of different drugs on patients, etc and sharing that with research bodies.The top organizations that fund research have also been showing flexibility. Some of them have extended grants to on-going projects, some have increased stipends and added funds for providing kits to researchers against COVID-19. Some of them have given quick approvals for projects specifically on coronavirus. I have seen report of such promising news coming from funds in the US, UK, France, Germany, Australia and India.
However, it is also apprehended that many labs and manufacturers will keep close to their heart the molecules they discover as potent. Some may not be cooperating with international effort, only paying lip service. Even when a drug is found effective, its supply in a large scale at a short notice may not be easy. Authorities are also known to be slow in granting permissions, especially for trials, for fear of negative consequences and ethical concerns. COVID-19 has generated a sense of urgency and collaboration among international and national health and medical research authorities that was not seen before.
The shortest timelines towards finding focused cure against COVID-19 look like this:
- More effective, experience-based, use of medicines already being administered: on-going; may reach near-satisfactory levels by early winters.
- Wide-spread use of blood plasma from recovered patients if proves effective: in the coming months.
- Identification of existing drug(s) as effective against COVID-19: already in progress; improving every month.
- Vaccine: the first set of vaccines might come out for large-scale cure by September '20.
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