COVID-19 Pandemic: A Pragmatic plan for Therapeutic Intervention

Atanu Bhattacharjee¹, Nongmaithem Randhoni Chanu², Kunal Bhattacharya^3,4*

¹Royal School of Pharmacy, Royal Global University, Guwahati, Assam – 781035.

²Faculty of Pharmaceutical Science, Assam Downtown University, Assam – 781026.

³NETES Institute of Pharmaceutical Science, Mirza, Kamrup, Assam – 781125.

⁴Pratiksha Institute of Pharmaceutical Sciences, Guwahati, Assam-781026.

*Corresponding Author E-mail: kunal22101994@gmail.com

ABSTRACT:

The prevalence of the Novel Coronavirus Covid-19 pandemic is growing worldwide and the third phase of this deadly flu has already been started across the globe. COVID-19 has already been emerged as one of the most devastating epidemics throughout the world with the highest rate of mortality and has become the most important health challenge in developed and developing countries. This paper totals and solidifies the study of disease transmission, clinical signs, finding, medications and counteractions of this new sort of COVID-19. Data were collected from the articles published in various electronic databases such as Elsevier, Science Direct, Scopus, PubMed between 2010 and 2020. Existing literature, news and media, a various statutory body of the Health Ministry of various countries, World Health Organization (WHO) has said that there is no particular medicine to prevent or treat coronavirus disease till date. Few antiviral drugs combination of lopinavir and ritonavir, antimalarial drugs like chloroquine and hydroxychloroquine are widely used as an effective medicine to treat COVID-19 to date. A search vaccine is in progress up to the clinical trial stage in many countries including China, the USA and India. Need of the hour is high-quality clinical data from different geographic areas to develop the vaccine and safe drugs.

Figure 1. Graphical Abstract

KEYWORDS: SARS-CoV-2; COVID-19; Coronavirus; Disease transmission, Clinical signs, Treatment.

1. INTRODUCTION:

On December 31, 2019, China informed the World Health Organization (WHO) about a cluster of cases of contagious pneumonia of unknown explanation in Wuhan City in Hubei locale^1,2. WHO, on 9^th January 2020, gave a declaration saying Chinese researchers have made identification of the contamination as a completely new form of coronavirus³. At the beginning of 2021, the second phase of COVID-19 had been accounted for more than 180 countries, including India and with a higher rate of mortality compared to its first phase. Lockdowns, curfews, home and social isolates, and quarantine have become the standard over the globe. After examination on human respiratory samples clinicians and health care professionals from the Centres for Disease Control (CDC), China confirmed for the first time this novel Covid pneumonia which was caused by coronavirus⁴. Subsequently, WHO confirmed the infection COVID-19. World Committee on Taxonomy of Viruses (ICTV) termed the disease as serious intense respiratory disorder coronavirus 2 (SARS-CoV-2). Coronaviruses belong to a virus family whose infection severity ranges from mild to severe. SARS-CoV-2 is a coronavirus fundamentally similar to the one responsible for SARS. Coronaviruses are zoonotic, which means their route of transmission is from creatures to people⁵. WHO has already declared the outbreak of this SARS CoV-2 related COVID-19 disease as a global pandemic which has reached the stage of a public health emergency. The ongoing research studies on SARS-CoV-2 are progressing rapidly. Relying on the newest evidence, we summed up the genetic information, the study of disease transmission, clinical attributes, treatment and avoidance of information encompassing COVID-19. This review is in the desire for helping people, in general, to successfully perceive and manage the COVID-19 and giving a reference to future research⁶.

A closer look at SARS-CoV-2: its genetic structure and pathogenic mechanism:

Coronavirus (family: Coronaviridae) comprises of a, b, d, and g coronaviruses (COV) with positive-sense single-stranded RNA⁷ of an approximate size of 27-32 kb⁸. Like other COVs, SARS-CoV-2 are spherical and consists of proteins called S-proteins. S-proteins contains spikes that protrude out of the surface providing an appearance similar to the crown. The mentioned S-proteins bind to human host cells and fuse which gives the virus access to human cell^9,10. There are six coronaviruses already reported previously and SARS-CoV-2 is the seventh member of the COVs family after SARS and MERS¹¹. Myung-Guk Han et al., have isolated COVID-19 (denoted name: Beta CoV/Korea/KCDC03/2020) from lower and upper respiratory tract secretion samples from putative patients with the disease and reported full genome sequencing through real-time RT-PCR technique. The acquired gene was compared to 57 animal and human coronaviruses and showed high homology of > 99.5% with other isolated SARS-CoV-2 sequences¹². Further, it is reported that the homology of the genome sequence of SARS-CoV-2 and SARS is about 7 per cent and is closer to the MG772933 which are SARS-like bat CoVs than the SARS-CoV. The S-protein of SARS-CoV-2 shares ~98% genetic sequence similarity with that of Bat-SARS-like CoV. National Institute of Virology (NIV), Pune in India successfully sequenced the genome of SARS-CoV-2 which was obtained from two patients hailing from Kerala. Researchers observed that similar to the SARS virus, spikes from the SARS-CoV-2 also attach themselves to the angiotensin-converting enzyme 2, a cellular receptor that opens to door for the virus to gain access to a human cell.

With 10 to 20-fold much higher affinity¹³, Coronavirus mainly recognizes the ACE2 receptor on the target cell through the S-protein on its surface and penetrates the cell, replicate rapidly and causes the occurrence of infection¹⁴. As SARS-CoV-2 has a high partiality for binding with ACE2, soluble ACE2 may be a significant possibility for COVID-19 treatment. Moreover, mapping of the 3D atomic structure of S-protein of SARS-CoV-2 will help the researchers to find the clue to create immunizations and antivirals against the infection and far better diagnostics (figure 2).

2. Prevalence of SARS-CoV-2:

In epidemiology, in a population where everyone is susceptible to infection. R₀ is the basic reproduction number for an infection which is the possible number of cases directly caused by one case where no other individuals are infected or immunized (naturally or through vaccination)^15,16.

Figure 2. Possible Pathogenic mechanism of SARS-CoV-2 (Adapted and modified from Bonnie and Douglus 2020)

Wu JTL et al. of York University estimated the R₀ of novel coronavirus is ~2.47-2.86 while Majumder et al., of Boston Children’s Hospital, reported R₀ to be ~2.0-3.3. Earlier it was reported that the R₀ value of SARS and MERS 2.2-3.6 and 2.0-6.7 respectively. These show that SARS-CoV-2 has generally higher contagiousness^17,18. The population falling in the age of around 47 years were more susceptible. 87 per cent of the patients were found in the age bracket of 30-79 years among which around 41.9 per cent were female patients. The case fatality rate, in general, was found to be 2.3 per cent¹⁹. This infers older male residents are increasingly helpless to this crown infection and this infection is bound to influence old male residents with co-morbidity like diabetes, hypertension, coronary illness etc). With the objective that short measures should be taken to control the spread of the infection WHO data (up to July 26, 2021) is furnished beneath.

Table1. Regions with reported laboratory-confirmed COVID-19 cases and deaths. Data as of 26th July 2021 (WHO data)

Region	Total Confirmed Cases	Total Death
Western Pacific Region	4245918	62141
European Region	59115914	1212703
South East Asia Region	37641711	550934
Eastern Mediterranean Region	12191288	231466
American Region	76090220	1992005
African Region	4794204	113034
Global	130459184	2842325

3. Transmission modes of the COVID-19 virus:

It spreads through the respiratory droplets of contaminated individuals. People may get affected by the SARS-CoV-2 virus when they come in contact with objects or surfaces having the presence of virus and later touch their parts of the face like nose, eyes or mouth. COVID-19 virus is primarily transmitted among the population via different routes of contact and respiratory droplets (particle size is > 5-10µm)²⁰. Transmission of respiratory droplets may occur to healthy individuals within a range of 1metre distance through sneezing or coughing or via fomites present in the immediate surrounding around the person infected.^21,22.

4. Clinical characteristics of SARS-CoV-2 infection:

COVID-19 produces an acute respiratory viral disease in people with a brooding time of 3-14 days. Giddiness, dry cough and fever are the most common symptoms which may accompany nasal congestion, body aches, diarrhoea and sore throat mainly. Some infected people remain asymptomatic whereas in others affected by COVID-19 the above-mentioned symptoms may develop gradually. In a study of 393 patients in New York City, USA, the most common presenting symptoms were fever (77.1%), cough (79.4%), dyspnea (56.5%), diarrhoea (23.7%), myalgias (23.8%), nausea and vomiting (19.1%). Moreover, lymphopenia (90.0%), thrombocytopenia (27%), and hepatic inflammation were also observed. In addition, already there is evidence of infection in the ocular surface of the patients infected from COVID-19 confirmed by detection of SARS- CoV-2 virus in the ocular secretions of the patients. Some COVID-19 patients have an arrhythmia, acute heart injury, abnormal liver function (50.7%) at admission and impaired renal function. As contrasted with bacterial pneumonia, patients with SARS-CoV-2 demonstrated a lower oxygenation index. The disease progresses with aggravation of cytokine release syndrome and low levels of CD8+T, CD4+T along with high IL-10 and IL-6 levels in COVID-19 patients. SARS-CoV-2 RNA presence got confirmed by analyzing the tissue samples from the stomach, rectal mucosa and duodenum^23,24. Features of radiography for coronavirus were found in line with those seen in community-acquired pneumonia brought about by different microorganisms. A fresh study showed a sensitivity of chest to CT and bilateral chest CT findings in 90 per cent of patients to suggest COVID-19 was 97%.

Diagnosis of pneumonia caused by COVID-19 can be done early when laboratory tests & clinical symptoms are combined with features of chest CT scan. The severity levels based on clinical manifestations reported by the CDC of China are^25,26:

· Mild infection: non-pneumonia and mild pneumonia; observed in 81% of cases.

· Severe infection: respiratory frequency ≥ 30/minutes, dyspnea, blood oxygen saturation (SpO2) ≤ 93 per cent observed in 14% cases.

· Critical infection: septic shock, respiratory failure and/or multiple organ dysfunction observed in 5% cases.

5. Diagnosis of SARS-CoV-2:

The affected patient sample is generally being collected by the healthcare provider via any one of the following: i) swab your nose or the back of your throat ii) aspirate fluid from your lower respiratory tract iii) take a sample of stool or saliva²⁷. Using the Reverse transcription PCR (RT-PCR) technique, scientists extracted the viral nucleic acid from the sample from which the amplification of the genome was carried out to provide a large sample for viral comparisons. In the genome of SARS-CoV-2 two genes were found i) If the positive presence of both genes will be seen ii) If negative neither of the genes are found iii) inconclusive if only one gene is found²⁸. In India 52 laboratories of VRDL belonging to the Government under the Indian council of medical research along with 10 laboratories of the National Centre for Disease Control and authorized private laboratories are equipped to test samples of COVID-19 patients.

6. Treatment of SARS-CoV-2:

6.1 Antiviral drugs treatment:

As of now, the treatment of SARS-CoV-2 patients is done to give them relief from the symptoms. There is no current proof from randomized controlled studies to suggest a particular treatment for suspected or affirmed COVID-19 patients. Because of the absence of proof-based literature, no particular medication can be given to COVID-19 patients. However, to date, the antiviral medications utilized for the treatment of COVID-19 patients are referenced beneath:

6.1.1. Remdesivir:

It is an analogue of adenosine nucleotide, which embeds into viral RNA chains and stop replication. It is prescribed in the post-disease treatment for COVID-19. Holshue et al. unexpectedly detailed that treatment of a patient with COVID-19 who utilized remdesivir and accomplished great outcomes²⁹. At that point, Xiao et al. additionally revealed the in-vitro antiviral impact of remdesivir successfully in the control of 2019-nCoV contamination³⁰.

6.1.2. Arbidol:

It is a derivative of indole molecule, which was found to impede viral combination against influenza A and B infections and hepatitis C infections and affirmed to have an antiviral impact on SARS-CoV in the cell. Inhibition of virus entry is done by blocking the virus-mediated fusion into the target membrane. The randomized controlled examination on the treatment of COVID 19 by Arbidol is under investigation as of now³¹.

6.1.3. Lopinavir/Ritonavir/Favipiravir:

The antiviral drug Kaletra, a combination of lopinavir/ritonavir is a nucleoside analogue, neuraminidase inhibitors and the combination has generated early excitement for COVID-19 treatment. Data published in the New England Journal of Medicine from Chinese researchers found no benefit on the administration of the drug in COVID-19 patients. 199 people in total having low oxygen levels were randomized to either get a placebo or Kaletra. Few of the patients who took Kaletra died. Over time both the groups having a similar viral load. However, research is still going on in the hope of getting a positive result^32,33.

6.1.4. EIDD-2801:

EIDD-2801 a drug that is similar to antiviral drug remdesivir; functions by mimicking ribonucleosides present in RNA leading to errors when the drug gets into the path of viral RNA replication, preventing its spread in body³³.

6.2. Antimalarial drug:

For prophylaxis of malaria, the cheap drug chloroquine is being used for a long time which had shown excellent results with safety. Studies done in-vitro showed positive results against SARS CoV-2. The replication of coronavirus at an early stage is inhibited by multiple mechanisms among which, the major one is by increasing the anti-inflammatory response which is done by affecting the immune system³⁴.

6.3. Immunoenhancement therapy:

This therapy helps in the alleviation of mesenchymal stem cells which produces anti-apoptotic and anti-inflammatory effects. This helps in restoring the damage that occurred in epithelial cells and also helps in clearing the alveolar fluid. The efficacy and safety of this therapy have been confirmed using the preclinical and clinical research data. Recombinant interferon α showed successful results to SARS patients in clinical studies. For long-term intravenous use, immunoglobulin may be considered as safest in all ages. It also helps to stop cytokinin storms. Moreover, to control COVID-19 disease Thymosin alpha-1 (Ta1) can be used to boost immunity in patients affected by SARS. Ta1 and Intravenous immunoglobulin can also be used as therapeutics for COVID-19 patients^35,36.

6.4. Convalescent plasma therapy:

When there are no adequate antibodies and explicit medications, plasma treatment could be a viable method to lighten the course of ailment for seriously patients³⁷. A study by Hung and accomplices demonstrated that for patients with pandemic H1N1 influenza disease in 2009, the general risk of death was lower in patients treated with plasma therapy. By far most of the patients recovered from COVID-19 would express antibodies against the SARS-CoV-2, and their serum could be used to prevent reinfection. Hypothetically, viremia tops during the main seven day stretch of most infections, and it ought to be progressively viable to give recuperation plasma ahead of schedule in the disease. Along these lines, the plasma of certain patients recuperated from COVID-19 could be gathered to get ready plasma globulin explicit to SARS-CoV-2^38,39.

7. Prevention of SARS-CoV-2:

7.1. Vaccine development:

Researchers of the University of Southampton, UK have already proceeded for clinical trials with 510 healthy human volunteers aged 18 to 55 of a novel vaccine candidate called ChAdOx1 nCoV-19 against Covid-19. The vaccine is developed by the Oxford Vaccine Group and the University of Oxford’s Jenner Institute from an adenovirus isolated from chimpanzees. Genetical modification in this adenovirus has been done to inhibit its growth in humans. It was then combined with genes that generate Covid-19 virus proteins, known as spike glycoproteins, which is involved in the novel coronavirus infection pathway⁴⁰. This vaccine aims to target the glycoprotein spikes, against it, raising antibodies that stick to them allowing the immune system to destroy the virus. Apart from this, various countries like China, the USA, Russia and India have already developed the vaccine. To date, four vaccines have received emergency use authorisation (EUA) in India. A massive free vaccination from 18 years above people has been initiated by the Government of India and to date. Covi-shield and Covaxin, manufactured by the Serum Institute of India and the Indian Council of Medical Research (ICMR) are the two approved vaccines by the Government of India that have been administered to the people at present. Recently, Sputnik V developed in Russia is imported to India for further immunity development to the mass community.

Covishield jab (manufactured by Oxford-AstraZeneca) is an adenovirus vaccine found in Chimpanzees, ChAD0x1. It delivers spike proteins and mounts a tolerable immune response to a live virus. Covaxin, an India developed vaccine also uses a similar viral strain in its inactive form. Sputnik V, a two-dose Covid-19 vaccine was developed by Gamaleya Research Institute of Epidemiology and Microbiology, Moscow. Sputnik V used two different human adenoviruses. Moderna's COVID vaccine, which was one of the first ones to be approved for use globally, is made using an innovative mRNA technology (messenger RNA) that instructs the cells to build a harmless fragment of the spike protein, similar to the actual coronavirus and prompt an immune response. mRNA vaccines are considered a new-age technology, with its set of benefits and considered to be more successful. However, the use of traditional technology vaccine platforms makes for a safer choice at the same time, which is more reliable and hence, has a lot of takers. In near future, Indian pharma major Zydus Cadila may introduce another COVID-19 vaccine, built using a completely different platform, plasma DNA, which will be the first-of-its-kind vaccine in the world subject to approval and use.

7.2. Protecting yourself against COVID-19:

Guidelines by the WHO emphasizes maintenance of personal hygiene is of utmost importance to reduce the risk of infection. As the virus remains alive and infective till more than a day on different objects and surfaces it is advised to wash the hand with soap or rinse the hand with alcohol-based sanitiser to minimize the risk of infection as we always tend to touch our face after touching different objects and surfaces throughout the day.

7.3. Washing with soap:

Washing the hand alone with soap will decrease the amount of virus present in our hands but will not be effective in preventing the viral infection as a single virus is enough to infect the human body. Soap is made up of a hydrophilic head and lipophilic tail which increases the affinity of the soap molecules towards the virus cells as they are encapsulated in the lipophilic coating. The lipophilic pin-shaped tail makes it easier for the soap molecule to enter into the virus and destroy it. Therefore, it is recommended to wash hands with soaps to avoid and prevent any kind of microbial infection⁴¹.

7.4. Alcohol-based hand sanitisers:

Like soap, alcohol-based sanitisers inactivate the virus by dissolving the envelope made by lipid and disrupting the spiked protein running of the lipid envelope. The alcohol content in the sanitisers should be 60% to be effective in destroying the virus.

7.5. Using a mask:

As the transmission of the virus occurs primarily through droplets from coughing and sneezing wearing a medical mask is very essential to prevent the spread of coronavirus infection. As India is an overpopulated country, it is difficult to maintain social distancing always. The virus affects the people even before showing any symptom, therefore it is advised to wear a mask so that there is no exchange of infected respiratory droplets between individuals through oral or nasal routes⁴¹.

7.6. Social distancing:

The WHO recommends that one ought to keep up in any event 1metre (3 feet) separation while coughing, wheezing or talking. Try not to contact eyes, nose and mouth; Hands can get incredibly in contact with numerous surfaces. It would then be able to move the infection to your eyes, nose or mouth. From that point, the infection can enter your body and can make you sick⁴¹.

8. Adjuvant therapy:

Adjuvant therapy allows primary therapy to maximize its effectiveness. Various studies reported the effectiveness of corticosteroids, interferons, monoclonal antibodies, etoposide, ruxolitinib, anticoagulants, natural killer (NK) cells, inhaled Nitric Oxide (NO), melatonin, plant-based Rasayana drugs, hydrogen, vitamin C etc. improve the patient compliance as adjuvant therapy along with primary treatment (figure 3). However, toxicity profile, safety and efficacy of adjuvant therapy are necessary to be analyzed ^42,43.

Figure 3: Adjuvant therapies of Covid-19 treatment

9. CONCLUSION:

Although massive vaccination program has been initiated by various state Government across the globe, still a considerable number of people have not fortunate enough to receive the same. To date, in India, only about 40 million people have been vaccinated and the rest of the population are yet to receive. Covid-19 patients are currently treated with antiviral drugs targeting the SARS CoV-2 virus along with adjunctive therapies to ease the symptoms associated with the disease. The COVID-19-associated complications such as cytokine storm, Acute Respiratory Distress Syndrome (ARDS), respiratory failure, cardiac problem, coagulopathy, and multi-organ failure could be managed by adjuvant therapies. In conclusion, it remains a challenging task for medical professionals to fight against the SARS CoV-2 virus as it has tremendous mutation properties to adapt to environmental and host environments. Increasing knowledge about the SARS CoV-2 virus will aid in earlier recognition and more effective therapy.

10. DECLARATIONS:

10.1. Competing Interests:

The authors report no conflicts of interest in this work.

10.2. Author contributions:

All authors contributed to data collection, drafting or revising the article, gave final approval of the version to be published, and agree to be accountable for all aspects of the work.

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Received on 18.04.2021           Modified on 05.06.2021

Accepted on 02.08.2021         © RJPT All right reserved

Research J. Pharm. and Tech. 2022; 15(6):2862-2868.

DOI: 10.52711/0974-360X.2022.00478