|Ahead of print
|COVID-19 pandemic: A story of helpless humans, confused clinicians, rudderless researchers, and a victorious virus!
Pankaj Chaturvedi1, Aditi Chaturvedi2, Arjun Gurmeet Singh1
1 Department of Head and Neck Oncology, Tata Memorial Hospital, Mumbai, Maharashtra, India
2 NMIMS School of Law, Mumbai, Maharashtra, India
Click here for correspondence address and email
|Date of Submission||23-Dec-2020|
|Date of Decision||27-Dec-2020|
|Date of Acceptance||13-Jan-2021|
|Date of Web Publication||18-Feb-2021|
|How to cite this URL:|
Chaturvedi P, Chaturvedi A, Singh AG. COVID-19 pandemic: A story of helpless humans, confused clinicians, rudderless researchers, and a victorious virus!. Cancer Res Stat Treat [Epub ahead of print] [cited 2021 Feb 28]. Available from: https://www.crstonline.com/preprintarticle.asp?id=309749
The coronavirus disease 2019 (COVID-19) vaccine can turn people into “crocodiles” or “bearded ladies”– a bold statement by the Brazilian President, Jair Bolsonaro. A week before this, the United Kingdom (UK) Health Secretary, Matt Hancock, declared December 8, 2020 as the “V-Day”– an expression of their success in World War II. This was also the day when the 90-year-old Margaret Keenan became the first person in the world to receive the Oxford-AstraZeneca vaccine outside of a trial following its rapid clinical approval. The next day, the United States (US) reported more than 3100 deaths in a single day. With the unending spell of disease, despair, disability, and death, humankind has been hoping that a vaccine will bring an end to the COVID-19 pandemic. This hope was shattered when the top coronavirus advisor in the US, Dr. Anthony Fauci, warned that the vaccine that appears to be on the horizon may not be enough to help eradicate the disease. The despair continued after the former Vice President and Chief Scientist of a large pharmaceutical company stated that, “There is absolutely no need for vaccines to extinguish the pandemic. You also don't set about planning to vaccinate millions of fit and healthy people with a vaccine that hasn't been extensively tested on human subjects.” This makes us ponder on what the world has been up to during the last nine exhausting months of the COVID-19 pandemic.
The storyline thus far mimics a classic Hollywood nail-biting thriller about a genetically altered bat virus, the Chinese wet market theory, conspiracy to topple the world's economies, rising tensions between superpowers, unprecedented lockdowns, rising death tolls, doctors working in personal protective gears, research misconducts, etc.,, What is likely to make it worthy of an Oscar nomination is the fact that some of the most protected people such as the President of the United States, Prime Ministers of Russia and the UK, and other powerful politicians across the world contracted the infection just as easily as the common man did. Ironically, this lethal virus gets killed in 20 s when exposed to regular soap. Given the kind of medical advances that developed countries boast about, it is perplexing that we have not found any treatment so far.
Early in the year 2020, the world witnessed an ugly spat between the USA and China. The US President blamed the prestigious World Health Organization (WHO) for colluding with China and suppressing facts that delayed the declaration of the emergency. By this time, a plethora of treatment options were available in the market based on the traditional wisdom and the opinions of wise men, including the presidents and leaders. But, what followed in the subsequent months was a dizzying academic roller coaster. As the pandemic surged menacingly, physicians were faced with the harsh reality that none of the treatments were backed by robust evidence and only the best speculation seemed to benefit the patients. This prompted a mad scramble of clinical trials, with almost all meeting a similar trajectory – optimism, acceptance, criticism, and subsequent dismissal.
Incarcerated in their labs, hospitals, and houses, the researchers created an equally staggering wave of publications. As per a recent study, 23,634 related articles on COVID-19 were published between January 1, 2020 and June 30, 2020. Statisticians, mathematicians, and epidemiologists were left with nothing but to predict, forecast, or draw impressive curves to keep everyone on tenterhooks. Journal editors, locked in their home-offices, alarmingly shortened the publication pipeline to just 7 days. About 2 months into the mess, the health-care community witnessed another drowning flood caused by the wave of webinars, that was fueled by the conference-addicted globetrotting clinicians who could not survive otherwise. At any given point, as someone lightly said, more doctors were attending webinars than treating patients!
Standard treatment for any disease develops following years of rigorous clinical research. This time around there was no such opportunity, and the physicians were free to choose whatever seemed useful, ranging from household remedies to exotic therapies. Most clinicians began with an array of repurposed drugs that were known to be effective against similar viruses in the past. Hydroxychloroquine (HCQ) and azithromycin were the frontrunners that had gained tremendous publicity and demand, with prominent figures supporting their efficacy. Propelled by an intense media buzz, despite the poor evidence and serious side effects, physicians promoted the use of HCQ as a wonder drug. At one point, there were more than 180 trials ongoing to evaluate the role of HCQ in the prevention and management of COVID-19. By the end of May 2020, this antimalarial fell into disrepute with the emergence of data regarding its cardiac toxicity and lack of efficacy. Few months later, preliminary results from the Randomized Evaluation of COVID-19 Therapy (RECOVERY) trial also showed no significant reduction in the mortality with HCQ usage. Finally, the WHO, National Institute of Health, and other organizations halted the HCQ trials and the Food and Drug Administration (FDA) revoked its emergency approval. At the height of this frenzy, The Lancet retracted a publication on HCQ following serious objections regarding the integrity of the data and their analyses. To add to the disillusionment of society, a lot of discussion revolved around the influence of pharma companies on the publication houses.
As we entered April 2020, increasing volumes of the contagion's prey began pouring into the emergency rooms, aggravating the helplessness of the clinicians and health-care workers. Antivirals such as remdesivir, favipiravir, oseltamivir, umifenovir, lopinavir, and ritonavir that were used for Ebola and hepatitis C gained popularity. Preliminary results of trials like the Adaptive COVID-19 Treatment Trial (ACTT and ACTT-II) and the DISCOVERY trial were portrayed as great breakthroughs that reported a reduction in the recovery time of the hospitalized patients from 15 days to 11 days.,,
Understanding the pathophysiology of the disease unraveled even more drama as time progressed. In the beginning, COVID-19 was considered a fatal, contagious, viral pneumonia that killed people by causing acute respiratory distress syndrome (ARDS). By the end of April 2020, it appeared to be a disease that triggered systemic coagulopathy affecting not only the lungs, but all parts of the body. This prompted the use of thromboprophylaxis with low-molecular-weight heparin. Around the same time, physicians started reporting a cytokine storm that triggered immune responses resulting in lung damage. And there came along cytokine inhibitors to counter this autoimmune response, a process similar to other inflammatory conditions like arthritis. Various off-label drugs such as tocilizumab, sarilumab, and anakinra were used widely by clinicians. Tocilizumab, a monoclonal antibody against the interleukin 6 receptor, was shown to reduce mortality. However, many infamous studies published at the time did not include a comparison group, leaving the door wide open to criticism on its comparative efficacy. Within a month, another well-designed randomized trial sealed the fate of tocilizumab, showing no benefit in reducing mortality.
Four months into the pandemic, an inexpensive and widely available drug, dexamethasone, a steroid used for several conditions to rein in the immune responses, stole the spotlight. As other drugs had fallen out of favor, dexamethasone became the first drug to significantly reduce the COVID-19 mortality. A study of over 6000 people found that the drug reduced the mortality by a third in severely ill patients on ventilatory support and by one fifth in those needing oxygen support. It was shown to benefit patients with moderate to severe ARDS and may have been detrimental if administered to patients at an early stage. Most guidelines have now added dexamethasone to their COVID-19 algorithm but recommend its use in combination with other drugs. The RECOVERY trial recruiting patients from major hospitals in the UK also faced a lot of criticism, as it was an open-label trial and reported its results based on only 15% of the recruited cases.
Exasperated clinicians tried convalescent plasma or passive immunotherapy that has been found to be beneficial in other infectious diseases. The filtered plasma is obtained from the blood of individuals who have recovered from COVID-19 to obtain a concentrate of their immune cells against COVID-19. Early trials studying this technique yielded promising results, and many regulatory bodies gave an emergency approval for its use in very sick patients. The contents of this plasma can also be manufactured synthetically as monoclonal antibodies. Convalescent Plasma for Hospitalized Adults with COVID-19 Respiratory Illness (CONCOR-1) and Passive Immunity Trial of the Nation for COVID-19 trials are currently underway to determine the safety and method of administering this novel treatment., However, in September 2020, a large multi-centric phase II study conducted by the Indian Council of Medical Research concluded that convalescent plasma therapy did not reduce the mortality.
Another substance naturally produced by our immune systems in response to a viral infection is interferon. Injecting synthetically manufactured interferons has become a standard treatment for several different immune disorders. An open-label study from China has shown that interferon therapy can prevent healthy people from getting infected. The UK has also been working on a nebulized form of interferon, called SNG001, for airway delivery, which has been shown to lower the severity of the COVID-19 infection. While there is a widespread use of these methods, the efficacy has not been proven in any large clinical trial so far.
Traditional and alternative medicine specialists soon joined the race with their claims of cure with ginseng, ginger, garlic, cinnamon, hot pepper, eucalyptus oil, tea, alcohol, lemon, and elderberries, among others, not leaving even the sun's rays! Shuang-Huang-Lian, a Chinese herbal formula extensively used to treat a variety of ailments, was reported to be extremely beneficial. Ayurvedic medicines like arsenic album were promoted by some. “Coronil” and “Swasari”, were popularized and promoted by a group in India. Irrational and unverified claims about this miracle drug sparked a major controversy in some countries., But at least the astrologers were scurrying for their own safety rather than making predictions! Soon after, several of the much-hyped drugs started getting the boot. The WHO discontinued the use of HCQ and lopinavir/ritonavir in their 30-country wide trial in light of the evidence that these drugs cause little to no reduction in mortality. Pharma companies hit the jackpot with the industry giants such as Gilead disparately pricing drugs such as remdesivir at $520 for US private insurance companies in contrast to $390 for other countries.
For the ones who did not get infected and for those few who got re-infected, the results of the ongoing vaccine trials were the only hope. Russia won the invisible race by getting approval for the world's first vaccine against the severe acute respiratory syndrome coronavirus 2, Sputnik V. The results were heavily criticized as the phase I/II study only showed evidence of a strong immune response, that would not generally be an adequate basis for approving a vaccine by other FDAs. Even the most promising Oxford vaccine trial had to halt their accrual globally after reports of serious adverse events in few of its participants emerged. The preliminary results published by the other nascent vaccine trials now report dosing mistakes in few of their participants, further adding to the credibility of the vaccine's spectacular efficacy. Russia and China have gone a step further and are now undertaking large vaccination drives of their indigenous vaccines. Recently, the Australian government terminated their billion-dollar vaccine trial (University of Queensland and CSL) when their participants started reporting false-positive HIV test results. As time goes by, people across the world are more and more puzzled by the concept of a COVID-19 vaccine and question taking it even as more evidence surfaces.
One of the largest trials being run by the WHO, the Solidarity trial, recently reported no benefit from remdesivir or interferon, further baffling the doctors about what to prescribe and to whom. The latest efforts are to develop antiviral-antibody cocktails, currently being tested in trials such as the RECOVERY (REGN-COV2) trial. Most of the available treatment options are based on trials where at least one comparator has been studied, be it a placebo or an active control. The rest are either tentative, where the evidence is in a preclinical stage, or are based on pseudoscience. With more than a thousand collaborative trials taking place across the world, it is ironic to see that we do not have any definitive answers yet to tackle this virus. Most regulatory bodies across the world have not fully licensed any specific treatment but have granted permission for their use in emergency situations only. But who is to define these emergencies?
In the words of Aristotle, “The society that loses its grip on the past is in danger, for it produces men who know nothing but the present, and who are not aware that life had been, and could be, different from what it is.” I am afraid that we have learnt little from this pandemic except the century-old knowledge that “prevention is better than cure.” The pandemic reminds us of the words of the famous French writer, Voltaire– ”The art of medicine consists of amusing the patient while nature cures the disease.” We sincerely hope that the vaccine is safe and effective!
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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Department of Head and Neck Oncology, Tata Memorial Hospital, Mumbai, Maharashtra
Source of Support: None, Conflict of Interest: None
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