The new coronavirus SARS-CoV-2 continues to challenge the wisdom of healthcare specialists and biologists. Its estimated basic reproductive ratio, which is the number of susceptible people each infected person can pass the virus to, is approximately 2.9. This allows the virus to infect people in a geometric progression, where each step of infection 2.9-times as many people more.
Many people are dying, so COVID-19 is a ‘deadly’ disease.
Well, it isn’t a deadly disease. It is highly transmissible and the fact that our immune system is naïve to SARS-CoV-2 makes it a double whammy. It is quite possible that at some point, many of us would be infected by this virus and could get away with just flu-like symptoms. However, there is an unfortunate lot, the vulnerable section of our society – the geriatric people, patients with diabetes, hypertension, and those with lung disorders which could be affected by a severe form of the disease, and require hospitalisation. A study based on the largest cluster of cases (n=1099) from mainland China reported ~6% of laboratory-confirmed COVID-19 patients required either intensive care or ventilator, and 1.4% of patients died. The exceptional fatality rates in Italy have a lot to do with the demographic distribution of that country. In 2019, while 23% of Italy’s population were aged 65 years or older, 37.6% were accounted for patients aged 70 years or older. In addition, a substantial number of cases (n=687) were aged 90 years or older, in which a very high fatality rate (22.7%) has been reported.
If the virus is not highly virulent, why are hoards of apparently well, young, and bright healthcare personnel succumbing to this virus?
We still allude to our assertion that this virus isn’t ‘deadly’. But, there is a slight caveat here. Exposure to large doses of the virus coupled with protracted stressful hours while tending to the COVID-19 patients and sleep deprivation impinges upon the immune system. These are the reasons why healthcare workers are at risk of acquiring the disease.
Why are these ‘draconian’ measures in place if the disease is not deadly?
The essence of the social distancing, coughing & sneezing etiquette, and hand-hygiene continually remind us to conform to break the multiplicity of this virus within the community. If we don’t adhere to these norms, our hospitals will be inundated with infected patients for which our healthcare system is not prepared yet.
Is this God’s fury or a consequence of our fiddling with nature?
Let’s not wade in the realm of conspiracy theories about the origin of this virus as some laboratory-engineered subversive bioweapon, designed by our neighbour China, to advance its geopolitical goals. Let’s also not get into the diabolical verbal war going on between US and China, propaganda and counter-propaganda over the origin of this virus.
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SARS-CoV-2 belongs to a clan of six other viruses, which primarily derive their name from the structural similitude of the virion (infectious viral particle) to ‘corona’ or the crown. While four members of this family of coronaviruses (OC43, HKU1, NL63, and 229E) have been irritating human beings with a common cold, two others (SARS-CoV-2002, MERS-2013) caused far more severe diseases but were either restricted mainly to their country of origin or didn’t become a pandemic. Why did this seventh member, SARS-CoV-2, of the family go berserk and bizarre? This question is still shrouded in mystery, and scientists are scrambling to find an answer to it.
Large-scale environmental changes and increased human contact with wildlife acts as the pre-emergence niches of many pathogens. It is believed to be responsible for these pathogens securing a foothold in human society. Does this hypothesis hold for COVID-19too? Probably, yes.
Many biologists believe that SARS-CoV-2 breached the species boundary and made a jump into human beings, ‘possibly’ via an intermediary host, the pangolin which kind of amplified the virus. However, its efficient human-to-human transmission suggests that the virus in itself may have evolved the tropism, virulence and the necessary wherewithal ready to infect its new host. It just needed access for human dwelling. This is what the wet market in Wuhan might have provided to SARS-CoV-2.
The genetic material of the virus is garbed in a concentrically arranged shell of lipids (essentially a fat bilayer derived from the human cell itself) which is homogeneously studded with pin-head shaped Spike protein coded by the viral genome that imparts a crown-shaped appearance to these viruses.
The Spike protein is what makes the virus latch on to the human airway epithelial cells, a prelude to the infection process. One remarkable feature of this virus is its avid binding to host cell receptors, ACE2 (angiotensin-converting enzyme 2) receptors via Spike protein. A genetic mutation in the receptor-binding domain (RDB) of Spike protein-coupled with an efficient cleavage site for an enzyme, furin which is present on our cells is believed to have enhanced the ability of the virus to bind to the human cells and cause infection.
Why are patients with diabetes and hypertension at increased risk of COVID-19?
The data which has emerged from China and other hard-hit countries reveals that patients with diabetes and hypertension could be at heightened risk of contracting coronavirus. Although, it is controversial or not known as to why people with these comorbidities are at increased risk of developing a severe form of infection. Many argue that anti-hypertensive regimen commonly used to treat these patients: ACE-1 inhibitors and angiotensin II type I receptor blockers (ARBs) lead to the upregulation of ACE-II receptors, which necessarily would mean providing more binding sites for the virus. But, should then such patients discontinue their anti-hypertensive medication? A joint statement by the American Heart Association (AHA) and Heart Failure Society of America (HFSA) on March 17, recommends continuation of ACE-I inhibitors and ARBs in those patients who are currently prescribed these agents. However, in COVID-19 patients with cardiovascular illnesses, the decision to continue the anti-hypertensive treatment will be the sole prerogative of the treating physician who only can take a final call after making a due assessment of the hemodynamic status and the clinical presentation of the patient.
For heaven’s sake, why don’t scientists come up with a vaccine?
Vaccines can pre-empt an infectious disease and confer immunity to people at risk of acquiring an infection. However, the process of developing a versatile vaccine and bringing it into clinical use takes years, if not decades. The method of designing a vaccine begins with the identification of a stable, immunogenic (ability to evoke antibody formation) and clinically safe antigen. It is quite challenging because the virus can evade immunological assault by either embedding the antigen through conformational changes or by sugar-coating its antigens, a process called glycosylation. Fortunately, the advancement in medical technology and in-silico methods (reverse vaccinology) have made it easy to pick potential vaccine candidates among a repertoire of proteins of the pathogen. It could then be taken up for wet-lab experiments. The second stage of vaccine development is pre-clinical testing of the vaccine (testing in animals). The selection of animal models depends upon existing knowledge about the pathogen, pathogenesis of infection, genetic–relatedness of the model to humans, etc. SARS-CoV-2 virus is brand new, so the selection of the model is another challenge for COVID-19. After passing pre-clinical testing, the potential vaccine candidate goes into clinical trials (testing on the human).
Another challenge for the development of a vaccine is the lack of interest of pharmaceutical companies. Bringing the vaccine from development to clinical use needs an investment of millions of dollars, and companies do not want to invest in infections of outbreak nature or rare diseases. When the outbreak recedes, these products won’t fetch profit for the companies. In the end, everything boils down to money for these firms.
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Why is there a clamour for Hydroxychloroquine & Trump’s conjecture on Hydroxychloroquine?
Donald Trump recently touted hydroxychloroquine as a game-changer in our fight against COVID-19. His tweet was a reference to a study from France in which the therapeutic efficacy of a combination of hydroxychloroquine and azithromycin was evaluated in 24 COVID-19 patients. However, the scientists suggest, hold on!
Although, the study which Trump mentioned, found 100% viral clearance in the combination group as compared to 57.1% in the hydroxychloroquine alone group, and 12.5% in the control group. A small study in China also found chloroquine reduced viral load and improved clinical condition of COVID-19 infected patients. Also, a team of doctors in India administered a combination of Lopinavir, Ritonavir, and Hydroxychloroquine to three COVID-19 patients. They claimed an incredible response in terms of clinical outcome, as all the three patients got hale and hearty. But, all these isolated, small-scale studies are anecdotal evidence and not enough for any approval of any definitive clinical armory against COVID-19. A well-established evidence for any drug to be incorporated in a therapeutic modality requires a rigorous evaluation: a meta-analysis of the previous literature on the medicine followed by randomised controlled trials (RCT). All the studies related to the repurposing of some existing drugs have adopted prospective cohort design, which is considered a weak testimony in evidence-based medicine as compared to the RCT.
Can we use other antiviral drugs to treat COVID-19 patients?
Till now, there is no specific antiviral for COVID-19, but the repurposing of a few old drugs is under consideration. Repurposing is better than developing a new drug in pandemic situations because we have prior knowledge of the safety profile, side effects, and drug interactions. After the outbreak of SARS in 2003, some studies reported good efficacy of Lopinavir in combination with Ritonavir for SARS-CoV-2 in the pre-clinical phase. However, when this combination was evaluated for COVID-19, it showed no positive effect in terms of the reduction in the viral load and mortality as compared to the standard of care. The data on the efficacy of Remdesivir, an investigational nucleoside analog which is in phase III clinical trial, is expected to come by April 2020.
Will this virus go into oblivion in the coming months, or is it a long haul?
Well, the scientific community seems to be clueless about whether we will be able to relegate this virus. At present, the virus refuses to budge. If COVID-19 becomes a seasonal affliction, designing a vaccine makes sense. But if the infection goes into oblivion like its predecessors, SARS and MERS, that would be a major discouraging factor for pharmaceutical and biotech companies. Even if we come up with a vaccine for this virus, whether the virus will go away for all time is not clear.
Medical Disclaimer: The information provided in this article is just for awareness of the readers about the disease and its agent. No portion of this article should be deemed as a prescription.
Authors’ note: The views expressed by authors are their own and in no way represent the views of the departments or of the Institute they are associated with.
Raees ul Hamid Paul is a senior research fellow in the department of medical microbiology and Imran Ibni Gani Rather is a Ph.D. scholar in the department of pharmacology – both at PGIMER, Chandigarh.