COVID-19 and the race for a cure

Dr. Dharmakanta Kumbhakar

(The writer can be reached at drkdharmakanta1@gmail.com)

The year 2020 will be remembered as a dark year by everyone around the world for the Covid-19 pandemic. Due to the pandemic, the whole world was under the shadow of fear of death in 2020.The whole world fought a battle against Covid-19 in the year. Globally, over 80 million people were infected across 218 countries and 1.78 million lost the battle in 2020. India also recorded 1.02 crore confirmed Covid-19 cases of which 1.48 lakh died in 2020.

The world had no idea how to respond to an unknown deadly novel corona virus. Neither a vaccine to prevent SARS-CoV-2 infection nor appropriate medicine to cure Covid-19 patients was available. Antipyretic and cough syrup was only medicine for symptomatic treatment. Due to lack of proper medicines, a large number of Covid-19 patients lost their lives per day globally. This led to research about newer medicines to treat Covid-19 patients during the pandemic.

In the initial period of the pandemic, there was a lot of confusion regarding use of drugs like hydroxychloroquine, doxycycline, azithromycin and ivermectin for treatment of Covid-19 patients. The drug hydroxychloroquine was in the news for many weeks for its possible use in curing Covid-19. The US Food and Drugs Administration (FDA) identified the drug hydroxychloroquine as a possible treatment of Covid-19 and tested it on more than 1,500 Covid-19 patients in New Work. Anticipating that the drug hydroxychloroquine would work in the treatment of Covid-19, given the initial results, the then US president Donald Trump bought more than 29 million doses of hydroxychloroquine calling it as a "game changer" for potential treatment of Covid-19. The US FDA even gave emergency use authorization to hydroxychloroquine to treat adult and adolescent Covid-19 patients who cannot participate in a clinical trial. Many US hospitals used hydroxychloroquine as the first-line therapy for hospitalized Covid-19 patients despite extremely limited clinical data supporting its effectiveness. The Brazilian President Jair Balsonaro even compared hydroxychloroquine to "Jeevan Dayani" for Covid-19 patients. Hydroxychloroquine is an inexpensive anti-malarial drug similar to chloroquine, one of the oldest and best known anti-malarial drugs with lesser side-effects. It is an anti-inflammatory drug also; hence it has been used to treat rheumatoid arthritis and lupus, apart from malaria, for decades. Various studies claimed that hydroxychloroquine demonstrated anti-viral activity and has an ability to reduce the immune system's response (as hydroxychloroquine acts as an interferon blocker) and hence may be useful in the treatment of Covid-19. Moreover, the drug hydroxychloroquine shot to fame as it showed to have shortened the time to clinical recovery of Covid-19 patients. A few studies even claimed that hydroxychloroquine alone or in combination with antibiotic like azithromycin and doxycycline appeared to reduce viral load quicker and hence can reduce the duration and severity in Covid-19 illness. Gradually a clear picture emerged regarding the pathophysiology of the Covid-19 disease process and these drugs were no longer accepted in the treatment module of Covid-19. Moreover, a few Covid-19 patients on hydroxychloroquine with azithromycin developed lethal cardiac side-effects. The role of steroids to stabilize the excessive immune response as evidenced by the rise of IL-6 was widely discussed and was accepted as a part of standard regime for the treatment of Covid-19 patients. Moreover the role of low molecular weight heparin to combat intravascular coagulation was established and it was also accepted as a part of standard regime for the treatment Covid-19 patients. Antiviral like Remdesivir was routinely used in many centres for treating Covid-19 patients. A few centres even used antiviral Lopinavir, Ritonavir and HIV Protease inhibitor for treatment of Covid-19. Monoclonal antibody like Tocilizumab was administered to Covid-19 patients with good results to combat cytokine storm. But, the drugs Remdesivir, Lopinavir, Ritonavir and Tocilizumab are too costly. Of course, high flow oxygen therapy essentially remained the primary treatment for Covid-19 patients once the oxygen saturation started falling.

The latest addition in the treatment of Covid-19 was convalescent plasma therapy (CPT). The US FDA authorized CPT for people with Covid-19 during the pandemic as there was no approved treatment for Covid-19. India's Central Drugs Standard Control Organization (CDSCO) and the Indian Council of Medical Research (ICMR) permitted CPT for the treatment of Covid-19. Convalescent plasma therapy is a strategy for passive immunization which uses the plasma from people who've recently recovered from a viral illness to help others recover from the same viral illness. The concept of CPT is not a newer one. It is one of the century old treatment modalities. Over 100 years ago, Emil Behring was awarded first Nobel Prize for physiology and medicine for using convalescent plasma for treating diphtheria. CPT has been shown to be effective against other infections, all the way back to the 'Spanish flue', which struck the world as a pandemic in 1918. Then, the USA military used convalescent plasma to treat flue patients. In 1934, convalescent plasma was used for treating measles. More, recently the WHO approved convalescent plasma as empiric treatment against Ebola virus infection in 2015, and it was deployed with success against SARS and MERS corona virus as well (whose outbreaks occurred in 2002-2003 and 2012 respectively).

Convalescent plasma for Covid-19 refers to plasma obtained from an individual who has recuperated from SARS-CoV-2 infection. During the infection period, the individual's immune system would have mounted an attack on the foreign SARS-CoV-2. By the time the virus is vanquished, the body of the Covid-19 individual would have developed ammunition specially to beat the virus, which will be a type of antibody (IgG and IgM).

These antibodies are suspended in the circulating plasma of the recovered Covid-19 individual. The plasma containing these antibodies called convalescent plasma is separated by an automatic aphaeresis machine. The collected convalescent plasma containing these antibodies can be administered to people with Covid-19 to boost their ability to fight the virus (passive immunisation). This is the basic principle of CPT in the treatment of Covid-19 which can reduce mortality in Covid-19 patients by increasing neutralizing antibodies, clearing viruses and reducing clinical symptoms. In theory, convalescent plasma is likely to be more effective in the early stages of SARS-CoV-2 infection, when the viral load is lower, and the Covid-19 patient can be saved from more severe stages. Convalescent plasma can be used as prophylactic treatment for Covid-19 also.

The advantage of CPT is that preparation of convalescent plasma is not costly and eligible donors are locally available. Moroever, transfusion of convalescent plasma to Covid-19 patients may provide further benefits such as immunomodulation via amelioration of severe inflammatory response as convalescent plasma contains other proteins such as anti-inflammatory cytokines, clotting factors, natural antibodies, defensins, pentraxins, and other undefined proteins in addition to the viral neutralizing antibodies. The negative aspect of CPT are- adverse reaction from mild fever to allergic reaction to life like bronchospasm, transfusion related acute lung injury, circulatory overload, etc. As transfusion of convalescent plasma that contains antibody is a form of passive immunity, and in doing so we interfere with the Covid-19 patient's normal immune response. As a result, even if the Covid-19 patient recovers, he/she could still be at risk of re-infection. Moreover, a few studies want to say that CPT has no role in critically ill Covid-19 patients. Hence, more research is necessary to establish the role of CPT in the treatment of severe COVID-19 cases.

An individual, irrespective of sex, of ages between 18 and 50 years with weight more than 45 kilogrammes, haemoglobin level more than 12.5 gram per decilitre of blood, platelet count more than 1.5 lakh per decilitre of blood, serum protein more than 6.5 gram per decilitre of blood, blood pressure, body temperature and plasma sugar within normal range, free from transfusion transmitted infections (HIV, HBV, HCV, malaria and syphilis), who have recovered from symptomatic Covid-19 infection for at least 28 days, free from symptoms and have tested negative in RT-PCR for the virus at least 14 days before the plasma donation is an eligible donor up to 3 months from the first donation. Perouse women are not eligible for convalescent plasma donation. The donor must be negative in RT-PCR for the virus and must have sufficient neutralizing factor, IgG antibody titre more than 1:640 at time of convalescent plasma donation. Before collecting the convalescent plasma donor must give written consent to collect it from him and to transfuse it to other Covid-19 patients. A donor can donate his/her 400 millilitre convalescent plasma (later divided as two units of each 200 ml) in one sitting twice a week with a minimum gap of 48 hours up to 3 months from first donation. The collected convalescent plasma can be stored up to one year in minus 80 degree Celsius refrigerator. ABO group specific frozen convalescent plasma is transfused to active Covid-19 patients after thawing it. Usual dose of convalescent plasma to be transfused to active Covid-19 patient is 3 millilitres per kilogram body weight. Moreover, baseline clinical and biochemical parameters such as CRP, D-dimmer, LDH, serum protein must be monitored every 4 hours of the convalescent plasma recipient. CPT is contraindicated in immune depressed patient. Till date no major adverse effect is recorded in CPT.

In the absence of an effective and specific antiviral therapy for Covid-19, every one worldwide was waiting for an effective Covid-19 vaccine from the beginning of the pandemic. Several pieces of research and clinical trial were on the run in various research centres worldwide for an effective Covid-19 vaccine during the pandemic. As on today, several Covid-19 vaccines are developed worldwide (e.g. Pfizer-BioNTech Covid-19 vaccine, Moderna's Covid-19 vaccine, Oxford-AstraZeneca's Covid-19 vaccine, Janssen's Covid-19 vaccine, Novavax's Covid-19 vaccine, etc.) and most of the countries have started Covid-19 vaccination drive. All the Covid-19 vaccines show an acceptable safety profile, increased antibody response, and T-cell immune response against SARS-CoV-2. Currently Pfizer-BioNTech Covid-19 vaccine and Moderna's Covid-19 vaccine are authorized and recommended to prevent Covid-19 in the US. South Africa has started administrating the Janssen's Covid-19 vaccine to health workers. The Drugs Controller General of India (DCGI) V.G. Somani approved two Covid-19 vaccines, Oxford-AstraZeneca's Covishield, developed by the Pune-based Serum Institute of India and Bharat Biotech's Covaxin for restricted emergency use in India on January 3, 2021. The DCGI granted the approval on the basis of recommendations by a Covid-19 Subject Expert Committee (SEC) of the Central Drugs Standard Control Organizations (CDSCO). As per DCGI both vaccines are 110% safe and Covishield is 70.42% effective while Covaxin provides a robust immune response. The DCGI gave permission for restricted use of both vaccines in emergency situations in public interest only as there should be more options for vaccinations, especially in case of infection by mutant strains. The DCGI approval paved the way for a massive inoculation drive in India and currently Government of India is running the world's largest immunization drive against Covid-19 in India. In the first phase of the Covid-19 vaccination drive almost 30 crore prioritized beneficiaries will be vaccinated free across the country. It will be offered to one crore healthcare workers along with two crore frontline and essential workers, and 27 crore elderly, mostly above the age of 50 years with comorbidities. Taking the Covid-19 vaccine in India is voluntary. Both the vaccines are to be stored at a temperature between 2 and 8 degree Celsius. One needs to take two doses of one type of vaccines at 4 to 12 weeks apart as different Covid-19 vaccines aren't interchangeable. One needs to take at least half an hour rest after getting vaccinated and should inform the authority for any discomfort. Like other vaccines, it has also some degree of side-effects like mild fever, pain, allergy, etc. Medicines used for cancer, diabetes, hypertension don't affect the Covid-19 vaccine efficacy. In fact, they should take the vaccine as early as possible as they are high-risk group for Covid-19. Generally the protective level of antibody develops two weeks after receiving the second dose of the Covid-19 vaccine. A Covid-19 recovered individual also can receive Covid-19 vaccine. However, people with active and symptomatic Covid-19 should not go to the vaccination sites as they may spread the infection in the site. They should defer vaccination for at least 14 days after the symptoms resolved. Moreover, India is supplying Covid-19 vaccines to several countries. The Covid-19 vaccination drive worldwide will intensify and strengthen global fight against the ongoing pandemic. To end the pandemic all countries must receive the vaccine doses in a fast and fair manner.

The pandemic is not yet over. The threat of Covid-19 is not yet over in 2021. Majority of the European countries are still getting severely affected. Maharashtra, Kerala are continuing to be the worst-hit state in India till date. Moreover, confirmed cases of infection caused by the new strain of SARS-CoV-2, first detected in the UK, which is more contagious and severely infectious than the previous one, is also increasing in India. Of course, India has recorded one of the lowest new cases per million populations in the last seven days, while Brazil, Russia, France, Italy, the USA and the UK have much more higher new cases per million populations reported in the last seven days. It is seen that most of the people are thinking as if Covid-19 pandemic has ended. At the present moment, the number of positive Covid-19 cases has declined but that doesn't mean that there is no possibility of a sudden increase of Covid-19 cases in future. Though vaccination against Covid-19 is going on all over world including India, people shouldn't drop the safety guard. Till an effective medicine develops for treatment of Covid-19 and complete coverage of population by Covid-19 vaccination, the use of mask and hand sanitizers, frequent hand washing with soap, maintaining respiratory hygiene and physical distancing should be followed strictly. We remember that, when the Covid-19 pandemic was in its initial stages in 2020, we didn't adhere to the safety norms issued by the Government. The results were devastating. Hope the mistakes will not be repeated.