SARS-CoV-2 pandemic: causes and current situation, historical lessons, and strategical therapeutic interventions

Use your smartphone to scan this QR code and download this article ABSTRACT The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which caused an initial outbreak in China, now has 40 strains with infections in more than 200 countries worldwide, according to scientists. To date, 4,121,777 people have become infected and 280,868 people died as a result of coronavirus disease 2019 (COVID-19), with many patients still under critical condition. The SARS-CoV-2 is phylogenetically similar to SARS-like bat viruses and, thus, bats can be a key host for SARS-CoV-2. Many viruses have been transmitted to humans due to the consumption of wild birds and animals as a food source. The lack of vaccine, improper containment, and diagnostic strategies by various countries have converted COVID-19 into a global pandemic. The lockdown conditions in developing countries may produce economic crises. COVID-19 patients can suffer from mental distress, partly resulting from quarantine restrictions, and therefore, there is dire need for mental counseling. The combination of previously used broad-spectrum antibiotics, antiviral and anti-parasite agents, and interferon have reduced viral infection at higher and frequent doses. Many patients have been discharged after clinical recovery, though COVID-19 can still leave severe adverse effects on p atients. The use of traditional Chinese medicines ( TCMs) has led to recovery of 90% of COVID-19 patients in China. The current review article highlights the current situation, the major causes which have led to the COVID-19 pandemic, as well as strategical interventions to control the pandemic and cure infected patients.


INTRODUCTION
When an emerging epidemic in a region or country is not actively controlled, and spreads widely to other areas, it becomes pandemic. In history, the world has witnessed numerous epidemics which have turned into pandemics because of failure in quick response action. In some cases, treatment and vaccines are not available at the time. Thus, controlling the wide spread of infection, effective quarantine, proper diagnosis, hospitalization, and safety measures are key factors to successful deal with the epidemic.
Infectious diseases have long been the cause of global pandemics. The first time the quarantine strategy was used to control infectious disease outbreak was in Italy (and followed by other countries) during the Black Death in 1346 1 . Moreover, this was one of the top worst outbreaks in history; it was an epidemic caused by Yersinia pestis (bacteria) in China and Russia during the spring season of 1346, which later developed into a pandemic and became known as the "Black Death". Of note, 75 million people died from the Black Death in Europe and Asia 2 . Later on, another epidemic, named as "smallpox" and caused by variola virus, became pandemic and killed 2 million people 3 . Moreover, while various strains of influenza virus still infect millions of people around the world today, the major flu-related pandemic (termed the "Spanish flu") initiated in 1918 and infected 500 million individuals, with 30 million deaths across the globe 4 . Human immunodeficiency virus (HIV) which causes acquired immunodeficiency syndrome (AIDS) emerged during 1920 in Africa; it later spread worldwide. HIV still infects people in many countries including, Canada, India, United States, Mexico, Germany, Brazil, Indonesia and Iran. To date, HIV has infected 75 million people; 32 million have died and many are still dying each year 5,6 . The details of viruses which have previously caused global pandemics and which are still infecting world population are outlined in Table 1.     14,15 . The human-to-human transmission of the virus is very rare, although there have been a

REASON OF VIRAL SPREADING IN REST OF THE WORLD
The main reason behind the viral transmission in many countries is due to the evacuation of their nationals from the epicenter of SARS-CoV-2 (Wuhan, China) without proper screening and quarantine procedure. The individuals traveled from infected countries were not fully aware of or underestimated the risk of viral transmission 18 . Isolation wards for confirmed infected patients near the quarantine centers of suspected people (or people coming from infected areas) could further limit the risk for exposure to infected patients. Residents from countries like Pakistan, Bangladesh, India, Afghanistan, and Iran typically already have strong immune systems, often ac-quired in the state of war, against common pneumonia, HIV, flu, and other endemics/epidemics. These countries also face poverty, political instability, terrorism, and lack of diagnostic and research laboratories which limit public health resources. Moreover, infectious viruses are also frequently mutating and adapting to the environment, thereby enhancing viral pathogenicity, which have led to worsening conditions in Europe and the US. To date, 40 strains of a single SARS-CoV-2 have been discovered across the globe 11 .

THERAPEUTIC STRATEGIES
At present, no specific vaccine or anti-viral drug is available to treat COVID-19, though the combination of anti-viral and anti-bacterial drugs, as well as inhibitors, have significantly reduced the viral load in infected patients and animal models 19 . High doses of Remdesivir, Chloroquine salts, Arbidol, Nafamostat, Nitazoxanide, Ribavirin, Penciclovir, Favipiravir, Ritonavir and Baricitinib, either alone or in combination, have efficiently reduced viral load in infected patients 8,20,21 . High dose of antiviral and antibiotics have help patients to recover from COVID-19 but have also caused severe adverse effects in elderly patients. Higher doses of antiviral agents have caused mental, hepatic, cardiac and renal complications in many patients [22][23][24] . Plasma isolated from recovered patients have also been used to treat infected patients, resulting in production of antibodies against SARS-CoV-2 and clinical recovery of infected patients 25 .

MENTAL COUNSELING AND RAPID DIAGNOSIS
Those who have been kept in quarantine phase can often suffer from the unpleasant experience. Separation from family and loved ones, and loss of freedom can cause psychological effects. In a previous outbreak, suicides during quarantine were reported 26 .
To minimize the negative effects of quarantine, the phase should be reduced as much as possible. The lack of a sensitive and rapid diagnosis of COVID-18 has caused a prolonged quarantine phase for suspected patients. Mental illnesses can lead to weaker immunity, which in turn enhances the chance of being infected 27 , and can be related to morbidity and mortality. Indeed, the limited exposure to outside environment, lost income, limited access to masks and other preventive measures, fear of contracting the infection, and lack of facilities have fueled the severity of mental illnesses and led to many people suffering from xenophobia 28 . Many individuals have faced altered and negative behaviors, such as rudeness, anger and frustration, due to constant exposure to electronic devices and disturbed circadian cycle 29 . Thus, mental counseling and support for medical health workers, patients in quarantine or isolation phase, and people during lockdown are not only highly recommended but necessary. After the emergence of SARS-CoV-2, a real-time reverse transcriptase-polymerase chain reaction (RT-PCR) test has been consistently used for the detection of the virus, although it is not possible to carry out RT-PCR at people's doorsteps to conduct door-todoor detection. Currently, antibody-based (IgM-IgG) -immunochromatographic test kits (ICT Kits) 30 and droplet digital-polymerase chain reaction (dd-PCR) have shown promising sensitive and accurate results for the detection of SARS-CoV-2 31 . ICT kits are smaller in size and can provide rapid results. Therefore, use of ICT kits can be an effective tool for doorto-door and maximal detection of COVID-19 patients.

VACCINES AND TRADITIONAL CHINESE MEDICINES (TCMS)
Vaccines are the most effective and suitable solution to treat and eradicate viral infections. Unfortunately, at the current time, there is no vaccine available to treat human coronaviruses, especially SARS-CoV-2 induced COVID-19. However, some multinational pharmaceutical companies and research centers, including Johnson & Johnson, Stemirna Therapeutics, US National Institute of Allergy and Infectious Diseases, Novavax, and Sanofi are making efforts to develop an effective vaccine for COVID-19 [32][33][34] . The mortality rate from COVID-19 is steadily increasing around the world, but these companies and research centers still require 5 to 10 months to develop a vaccine. There is still doubt as to whether these vaccines will be effective against all the existing strains of SARS-CoV-2. In a recent report, the Chinese have developed a vaccine called PiCoVacc which was successful in animal trials; however, it was effective against only 10 strains of SARS-CoV-2 35 . Nature has the best remedy for microbial infections. Plants which exist in nature contain various plant-specific secondary metabolites which can have robust bioactivities including anticancer, antiinflammatory, antiviral, antibacterial and antidiabetic functions 36,37

CONCLUSION AND FUTURE PROSPECTS
The SARS-CoV-2 outbreak first initiated in China but has now spread to every country of the world. USA and European countries have become the new epicenter of COVID-19. The European countries responded late and their nationals did not effectively follow the strategies to contain the virus. Therefore, the mortality rate from COVID-19 in Europe is almost 15%, while in China the mortality rate has been limited to 4%. Chinese health authorities responded swiftly and effectively to contain the viral spreading and treated their patients with TCMs, which resulted in greater than 91% recovery. We suggest that the higher authorities of infected countries take serious action in conducting awareness campaigns to educate their nationals on how to best protect themselves and other people in their surroundings from the viral infection. Flight operations should be limited and the consumption of wild animals should be completely banned until the specific origin of the SARS-CoV-2 is confirmed. It is further suggested that isolation and quarantine wards for infected and suspected patients be built near the borders and airports, thereby restricting potentially infected individuals from entering populated cities. A psychiatrist along with doctors should be placed in isolation wards for the sake of mental counseling of infected and suspected persons. The most efficient strategies used by the Chinese government and doctors to contain and treat COVID-19 should be adopted by infected countries. ICT kits and dd-PCR should be commercialized and used for rapid and accurate detection to avoid delays of the quarantine phase. Use of TCMs should be encouraged to treat COVID-19 patients; moreover, evaluation of novel antiviral compounds from plants should be conducted. Lastly, we suggest that door-to-door rapid diagnosis and assessments should be a current priority in the fight against SARS-CoV-2.