AS of April 11, Covid-19 has killed more than 100,000 people as it continues to put 1.6 million lives at risk of life or death. The death toll is accelerating at a daily rate of between 6 to 10%, with about 7,300 lives lost every day globally. The death toll now parallels that of London’s Great Plague in the mid-1660s, which killed an estimated 100,000 people. Far from being comforted, the rate is still short of the Spanish flu of 1918 that killed more than 20 million people by the time it was over, after a harrowing two years reign of terror. There’s nothing to thank goodness for!

Ever since Covid-19 first reared its ugly head, the question of how Covid-19 kills its victims has left many medical practitioners and research scientists befuddled. It seems the virus is abetted by other factors to kill their elderly victims. Evidence has been accumulating that the host’s immune response itself is lending a hand in Covid-19 winning the battle. There’s a Brutus sort of betrayal within the already critically ill. The immune system of the patient causes the primary organs – the lungs – to become ultimately overwhelmed, resulting in malfunction and death. This fact is baffling and worrying. Indecisions hold sway whether suppressing the patient’s immune system would be beneficial and lifesaving. Any effort to dampen the immune response would also lessen the ability of the patient’s immune response in the contest to defeat the coronavirus.

This vagueness only helps to breed vacillation, possibly irreversible damage, in the treatment of those suffering critically from the disease. It is causing fractious issues in trying to stop the appetite of this highly contagious and ravenous monster of a virus. In their desperation, doctors find themselves carelessly pushing steroid treatments to restrain the immune response. Anecdotes of “successful” therapies using bizarre cocktails of unproven efficacies suddenly serve as possible alternative therapies. They find themselves checking unpublished data and inconclusive treatment procedures from all sources. Clinical trials done haphazardly now seem worth some consideration. They find themselves poring over scientific findings published in non-peer reviewed journals. Even advice of unsolicited treatment on social media are cautiously rebuffed as incredulous, even before considerable thought and weighing up. All this in their increasingly powerless and desperate bid to save lives.

Earlier reports from China touched on high blood levels of proteins called cytokines in critically ill patients. Cytokines are small molecular proteins secreted by specific cells of the immune system. Functionally, they are important as signalling molecules that serve to regulate our immune response in the face of infection. Immunologists have been studying how these chemical messengers, such as interferon, interleukin and growth factors, affect other cells in our body. In Covid-19 patients, a particular cytokine called interleukin-6 (IL-6) is massively mobilised into the lungs to be battle-ready and fight the invading virus. This is now referred to as a cytokine storm. Colossal numbers of white blood cells, the macrophages, are also marshalled in to locate and eat Covid-19 that are in the process of causing harm to the alveoli of the lungs. Dreadfully, during this inflammatory process, the macrophages also damage healthy lung cells – collateral damage galore. This is how Covid-19 tragically ends up killing its host.

The more they ask about the overactive immune response killing severely ill patients, the more complicated the whole story becomes. The next best viable option would be to turn to steroids. These are drugs capable of suppressing immune response but they do this broadly. There is no specificity towards Covid-19 or other coronaviruses. The imminent danger here is steroids can significantly reduce the patient’s whole ability to fight other infections lurking around the corner to take advantage of the patient’s already weak immune defence. Steroids are known to suppress the overall functions of macrophages and other immune cells. For examples, the CD4 T cells and CD8 T cells are two types of immune cells, known as antiviral assassins, capable of destroying cells infected with viruses. Inadvertently, supressing the beneficial effects of these CD4 T and CD8 T cells with broadly active steroids would be disastrous. What we are desperately crying for now is a substance that can specifically suppress the harmful effects of IL-6 to the lungs. Limiting the activity of IL-6 that appears to be specifically released during Covid-19 infection would be the ultimate aim.

Everyone has been thrown into a quandary. Ideally, we need a drug that can block IL-6 activity by reducing the influx of highly charged-up macrophages to an optimal, desirable level. Such IL-6 inhibitors already exist for the treatment of a variety of autoimmune diseases. A steroid – dexamethasone, for instance – has been used for rheumatoid arthritis and other inflammatory diseases with much success. But looking at the hundreds of thousands of clinically ill Covid-19 patients now, there just isn’t enough of such drugs to go round.

Previous pandemics caused by related coronaviruses, SARS and MERS, indicated that steroids on its own hold little benefit, if at all. Steroids have been shown to unexpectedly delay the elimination of viruses from the patients’ lungs. They delay recovery. This has led to clinical trials involving combination therapy aimed at eliminating damage from both the virus and the immune response. To date, we have yet to discover an IL-6 inhibitor that can partially suppress the cytokine storm to a desirous level so as to save the lives of Covid-19 patients.

How should Malaysia position itself in this frantic search for a drug to stop the killing by Covid-19? The holy grail of Covid-19 therapy is preventing a cytokine storm. There is an urgent need to develop such drugs. Malaysia’s rich and diverse marine flora would be the best bet. Not long ago, the National Cancer Institute US carried out a preclinical screening for anti-tumour potential in natural products of marine and terrestrial origins. They found that approximately 1% of marine samples have bioactive natural products, in comparison with 0.1% of terrestrial samples tested. This is a significant insight. Marine-derived natural products are not only chemically unique but are also significantly higher in biological activity. Marine biodiversity is an excellent resource for Malaysia. It  offers great opportunities for the discovery of new biopharmaceuticals, such as immunomodulators for Covid-19 therapy and other immune-mediated diseases, such as allergies, autoimmune and chronic inflammatory diseases.

Malaysia needs to venture actively into drug discovery and development programmes focused on the search for bioactive compounds obtained from marine natural sources. Such research programmes could lead to the unravelling of nature’s enormous arsenal of new bioactive compounds and natural metabolites. We need to heighten our level of preparedness in anticipation of the next brutal pandemic. – April 16, 2020.

* Ghazally Ismail reads The Malaysian Insight.

* This is the opinion of the writer or publication and does not necessarily represent the views of The Malaysian Insight. Article may be edited for brevity and clarity.