COVID-19 ‘The Pandemic’: An Update on the Present Status of the Outbreak and Possible Treatment Options

1Department of Pharmaceutical Sciences, Indira Gandhi University, Meerpur, Rewari – 123401, India. 2School of Medical and Allied Science, GD Goenka University, Sohna-Gurgaon Road, Sohna -122103 Haryana, India. 3Faculty of Engineering (Biotechnology), Lunds University, Lund, P.O. Box 118, 22100, Sweden. 4Department of Pharmaceutical Sciences, Maharshi Dayanand University, Rohtak -124001, India. 5Department of Biochemistry and Biochemical Engineering, SHUATS, Naini, Pryagraj-211007, UP-India. 6Shri Baba Mastnath Institute of Pharmaceutical Sciences and Research, Baba Mastnath University, Rohtak – 124001, India. *Corresponding Author E-mail – parijatpandey98@gmail.com

As of late, a worldwide danger to human wellbeing has risen as Coronavirus Disease 2019  in December 2019, which is an outbreak of the respiratory. It has been reported to be caused by a novel virus, named coronavirus (SARS-CoV-2 or 2019-nCoV) having structural similarity with the virus causing severe acute respiratory syndrome (SARS). According to the reports of World Health Organization Situation Report-141 (WHO), till 9 June 2020, the different regions of world have reported cases of COVID-19 was 7,039,918 (108,918 cases within one day) and 404,396 deaths (3,539 within one day) globally 1 . The timeline of early outbreak of COVID-19 has been shown in the Fig. 1 2 .
The study reported that the Human corona viruses (HCoVs) as one of the viruses that has evolved most rapidly due to its high rates of recombination and genomic nucleotide substitution 3 .
Still, researchers have named six HCoVs, namely HCoV-NL63, HCoV-229E, HCoV-HKU1, HCoV-OC43, middle east respiratory syndrome coronavirus (MERS-CoV) and severe acute respiratory syndrome coronavirus (SARS-CoV). Among these HCoVs, four HCoVs (HCoVNL63, HCoV-229E, HCoV-HKU1 and HCoV-OC43) have been accounted to be circulated in the humans around the globe and have been found to contribute towards about one-third of the infections due to cough and cold in humans 4 . When infection gets severe, these four reported HCoVs were responsible for causing life-threatening disease like bronchiolitis and pneumonia especially,noticed in immune incompetent patients, children, and elderly 5,6 . According to the WHO report, the first trial for vaccine started within 60 days after receiving the viral genetic sequence shared by China. For ensuring the clear evidence of which treatments are most effective, WHO and its accomplices have composed an enormous worldwide examination, called the Solidarity Trial in many countries to differentiate the diagnosing the treatment methodology 7 against the COVID-19. On the basis of information available from the literature survey and research experience, that is, vital for treatment of other viral infection like Ebola, Malaria, MERS and SARS, while the drugs being used for treating COVID-19 include antiinflammable and anti-viral drugs, anti-malaria drugs and other agents 8 . Several efforts are also being made all around the world for understanding the clinical efficacy of hydroxychloroquine as postexposure prophylaxis of COVID -19 9 . Recently, plasma therapy is emerging as a new hope towards treatment of COVID-19 patients 10 . In this review, the authors aim to summarize the details regarding history and outbreak of COVID-19 along with various diagnostic and therapeutic approaches effective and preventive in this early stage of the outbreak.

History and Virology of 2019-nCoV
Initially, it was thought that palm civets were the natural reservoir for coronaviruses. Though, in later phylogenetic studies, it has been reported that bat is the origin of SARS-CoV. Similar clinical manifestations were observed during the MERS-CoV epidemic, it affects the Saudi Arabia in the year 2012. However, the MERS-CoV transmission is geographically limited with cases within the Middle Eastern countries; it is not the case with SARS-CoV 11 .The historical backdrop of human corona viruses (HCoVs) started in the year 1965, when the two scientists "Tyrrell and Bynoe" observed that they could passage a virus named as B814. This viral infection was found in the tracheal organ and their culture is collected from the respiratory tract of an adult suffering from common cold. They also demonstrate the infectious agent existence by inoculating the culture intranasal in human volunteers. Prior investigation reports suggested that the occurrence of flu upon infection with virus, but previously, the Tyrrell and Bynoe couldn't culture the infective agent 12 .
At about a similar time, in another examination, the researchers Hamre and Procknow gathered the examples from clinical understudies experiencing colds and effectively developed a virus having uncommon properties in tissue culture of those samples and named them as 229E.The report suggested that the both B814 and 229E viruses,were sensitive to ether and that's why, they probably required a lipid-containing coating surfaces required for infectivity 13 .
In another study, McIntosh et al., who were working at the National Institutes of Health in Robert Chanock's laboratory, reported that the recovery of multiple strains of ether-sensitive agents residing in the human respiratory tract. For this recovery purpose, they were used the similar technique as used by Tyrrell and Bynoe, therefore they named these viruses "OC", where OC reflects the culture of viruses in organ 14 .
In the late 1960s, Tyrrell leads a group of virologists working simultaneously with various animal viruses and the human strains. Their study includes an infectious transmissible gastroenteritis virus of swine, mouse hepatitis virus and bronchitis virus, having similar morphological and physiological character as revealed after carrying out intensive observation study in electron microscopy. This novel group of viruses was termed as a Corona virus (the term corona meant appearance like a crown of the surface projections), that was, later offcially announced as another family of infections 15,16 . Since 2003-present, five newly identified Human Corona viruses species come into existence, as listed in a (Table 1).
Structurally, Corona viruses can be described as a group of RNA enveloped viruses belong to Corona viridae family 25 . Related to Roniviridae and Artierivirdae, Coronaviridae is likewise arranged under the same order Nidovirale 26,27 . The structure of coronavirus has been examined under the electron microscope and was found to be roughly spherical with spike protein forming distinct "club-like" projections 28,29 . The interior of the virion has been found to contain a positive sense, single-stranded RNA viral genome enclosed in a helically symmetrical nucleocapsid with size (26-32 kilobases) 27 . The positive-sense messenger RNA (mRNA), containing a 51 terminal cap structure and a 3'poly-Atail. The Apo form of protease enzyme present at viral envelop,present in protein data bank (PDB ID: 6M03), Fig. 2 30 .

COVID-19 and SARS-CoV-2 -Epidemiology and Pathology
All CoVs identified till now,a pleomorphic RNA virus with a very high rate of recombination on account of continuously developing RNA dependent-RNA Polymerase. COVID-19 mainly attacks on the respiratory system by following the entry into the lungs. Coronavirus reaches to lungs alveoli, and starts damaging them 31 . Normally,human lung alveoli have two types of pneumocytes, distinguished as Type-1 Pneumocytes andType-2 Pneumocytes. The functional role of Type-1 pneumocytes and Type-2 pneumocytes, incorporates the gaseous exchange of CO 2 and O 2 , and also had role in the production of surfactants, respectively 32 . This virus affects the Type-2 pneumocytes after entering into the lungs. This virus contains a S-Spike protein and a single stranded RNA as a genetic material. These Stype-spike proteins are attached with the Angiotensin Converting Enzyme-2 (ACE-2) receptors. These receptors permits the viral infection to enter inside the host cell, which leads to a release of single-stranded RNA (ss-RNA), and binds to the ribosomal machinery of the host cell and initiates the protein synthesis of viral structural proteins. Its ss-RNA help to synthesize the additional RNA molecules in the presence of RNA-Dependent RNA-polymerase (RDRP), that has a role to synthesize the viral structural protein components such as Spikes, Capsids, and various kinds of cellular enzymes etc. All of these structural components and synthesized RNA together constitutes the virus cellular machinery. This process of RNA replication repeatedly occurred to make up the viral copy in a huge amount 31,33 .
Following a different route of entry inside the host cells, Coronavirus specifically, damaged the Type-2 pneumocytes, leading to a decreased or with no surfactants production, resulting into an increased surface tension. Because of increased surface tension, it causes a collapsing of lung alveoli, raised the detrimental effect of hypoxia (in which less gaseous exchange occurred). Due to this event, neutrophils becomein active mode, initiates the proteases to activate the reactive oxygen species (ROS) to kill the virus and infective species. Activated ROS, also damaged the normal Type-1 and Type-2 pneumocytes raising the critical complications of lesser exchange of O 2 in respect to CO 2 , which ultimately decrease the oxygen concentration in a blood. Meanwhile, cellular signaling component, i .e. cytokines secreted from lung alveoli and transmit their signals to the hypothalamus, which stimulates the release of prostaglandin, a hormone, which raised the body temperature 31 of an infected host. A schematic diagram of pathophysiology pathway of COVID-19is displayed in a Fig.3.
SARS-CoV-2 displayed the high rate of mutation, that's why, diversified in nature, it is found in a diverse array of animals and humans with different state of clinical manifestations ranging from asymptomatic infections to need of hospitalization, leading to series of infections aroused in neurological, gastrointestinal, respiratory and hepatic systems 34 .

COVID-19 Outbreak in China
Wuhan, Hubei province, China, recognized a sudden outbreak of pneumonia among the people. The reported unknown cases in China and across the world had attracted the world. These cases of pneumonia were later demonstrated to be related with a novel coronavirus which was named as 2019-nCoV, that was identified by scientists in China by 7 January 2020, from infected patients in Wuhan. By January 30, 2020, the reported number of confirmed cases was reached to 9692 out of 15,238 suspected cases, it has prevalence in around 31 cities and prominently exists in a China. Out of 15,238 confirmed cases, about 1527 cases were severe. The disease existence is because of contact and respiratory droplets as reported by National Health Commission of People's Republic of China. The 2019-nCoV genetic sequence empowered the advancement of point-of-care real-time diagnostic tests explicit for COVID-19 at a beginning phase of the outbreak [35][36][37] . The COVID-19 Cases were no longer limited to Wuhan city. A great increment in COVID-19 Cases has been reported till date, already reported by WHO (28 th May 2020), a region wise details of which has been summarized in the Table 3 below. At present the United States of America has been found to have the maximum number of COVID-19 cases (3,366,251 cases) till now, reported by WHO 1 . Globally situation of COVID-19 cases existing is presented in a Table.3.

Clinical Manifestations for COVID-19 cases
Doctors and hospitals all around the world are testing the decades-old antimalarial drugs for the treatment of COVID-19 patients by applying drug repurposing technique on already existing therapies in a race for developing an effective treatment option. Antimalarial drugs chloroquine phosphate and hydroxychloroquine have given an early indication of progress in manifestations of patients with COVID-19 positive status, in light of the reports by specialists and scientists of South Korea, France and China, and other U.S. Physicians are also using the drugs 38 . On the basis of currently available epidemiological information, the initial symptoms after infected with COVID-19 includes cough, fever, dyspnea, sputum production, fatigue, hemoptysis and headache 39 . while less common symptoms of red or irritated eyes, no taste or sore throat sense, no smell sensation was seen, even diarrhoea, stuffy and running nose with aches 40 was not clearly observed in positive patients The currently available data suggested that the age of disease onset in pediatric patients has been 1.5 months, that is, ranging to 17 years 41,42 . Children infected with 2019-nCoV may have asymptomatic infection or may have minor symptoms of fever, dry cough, and fatigue, or in some cases upper respiratory symptoms can also registered in some cases, which includes the running nose with nasal congestion 43 . But in some cases, this disease may also cause the lower respiratory tract infection. The reported data of COVID-19 severe cases obtained from adult patients has revealed that, predominantly observed dyspnea symptoms arises within one week after the onset of disease. In such cases, if it is remained untreated then it may lead to a rapid progression of refractory metabolic disorders like acidosis, septic shock, coagulation dysfunction and acute respiratory distress syndrome (ARDS) 44 . And it characterized the COVID-19 clinical manifestations elaborately in a Table 4 45 .

Auxiliary Examinations of infected with COVID-19
The auxiliary examinations for COVID-19 include both laboratory examination and chest imaging examination. Both these examinations helped in determining the disease severity and recommended treatment commenced, in order to, save the life of the patients.

Laboratory examination 41 Recommended Potential Treatments Upon Infected with COVID-19
Unfortunately, a very little or no treatment options are available today, for suddenly occurring viral diseases and being the similar case, still no effective treatment or vaccine developed to prevent from the infection caused by 2019-nCoV. Several molecules are being studied in-vitro, they are proven to effectual for the treatment of COVID-19, but these are also based upon the previous trials on human MERS-Cov and SARS-CoV infections 46 . Some featured medications are accounted for in this examination, as an antiviral medication, Remdesivir has been effectively actualized in first announced instance of COVID-19 found in the United States of America, albeit, more contextual investigations are expected to show the medication efficacy to affirmed as a treatment against the COVID-19 46, 47 infection. Some of the drugs/molecules are still being to be evaluated as treatment of COVID-19, that is, already summarized in a Table 5. Furthermore, additional observational and clinical studies are being conducted to illustrate a potential treatment against the COVID-19 infection. Table 6, summarized a few clinical trials are being conducted at different stages in order to develop the possible effective therapy against this pandemic as obtained from clinicaltrials.gov 48 .

Plasma Therapy
Recently, plasma therapy appears to be a promising development in the race to signify a treatment against the viral infection. Researchers all around the globe tested this experimental therapy, depicting the transfusion of antibody-rich blood serum of recovered COVID-19 patients into those people who are struggling with this serious illness. In the underlying preliminary period of the investigation around 5,000 seriously ill patients have received the blood plasma transfusions, and it was noted during the plasma therapy there is less chances of side effects occurred occasionally while observing the significant improvement signs 10 . Based on the ailments of the people suspected to have the disease, disconnection must be done in a solitary room or self-confinement at home be followed according to the specialists' recommendation. The patients with confirmed infections can be admitted in the same isolation ward as for suspected patients. While, the reported critical cases should be immediately admitted to an ICU as earliest as possible. The general and symptomatic treatments presently reported for COVID-19 already described in a Fig. 5 66 .
The specialists everywhere throughout the world have distinguished the treatment or discover alternatives treatment and adjuvant treatments which can be utilized and are being utilized for the treatment of COVID-19 in this beginning stage. These are discussed here in this study report:

Oxygen therapy
In COVID-19 cases where hypoxia appears, the patient should be given effective oxygen therapy immediately using mask oxygen and nasal catheter. In extreme cases, obtrusive or non-intrusive mechanical ventilation and nasal high-stream oxygen treatment ought to be given if important. 67 .

Antiviral therapy: Lopinavir and Remdesivir
L o p i n a v i r o r L i t o n a v i r a r e t h e recommended anti-viral drug, tried to evaluate its effectiveness against COVID-19 in adult patients, but no successful data has been reported yet 47,68 . Recent report declares the Japanese organization (Gilead sciences) had approved, a drug named Remdesivir to manufacture in the country, a first officially authorized drug to tackle the disease. On account of this, Japan had reached the decision within three days after the US drug organization has filed for fast-track approval of the drug 69 .

Ivermectin
Ivermectin is an anti-parasitic drug with antiviral potential against a number of viruses like dengue, HIV, influenza and Zika. The drug acts by inhibiting the interaction of viral protein

Interferon á
Interferon-á have been found to decrease the viral load at the initial stage of infection and thus, it helps in relieving the symptoms and to reduce the disease progression. Based on accessible information on clinical examination and the prior consequences of utilizing interferon-á for the treatment of intense viral contamination of upper respiratory, pneumonia, SARS, bronchiolitis, hand foot mouth sickness, and different diseases brought about by the infection in youngsters, the recommended interferons practices aresuggested 74 .

Other agents or drugs: Anti influenza drugs
Arbidol, an anti-influenza drug can be prescribed for adult patients suffering from COVID-19; however, the safety and efficacy of the drug is not much clear yet. Some other drugs of this category like Oseltamivir can be applied and tested for their efficacy 75 .

Humanized Monoclonal Antibody
Human monoclonal antibodies are also among the drugs being evaluated for the treatment of COVID-19. A Tocilizumab, a humanized monoclonal antibody, an immune suppressant drug, utilized for the treatment of rheumatoid arthritis by binding specifically to interleukin-6 (IL-6) receptors. This drug has been suggested by China for the treatment of COVID-19 just because of its safety and efficacy, as shown in clinical practices. The drug has been found to be effective in some severe COVID-19 cases reported in Naples and Italy 72 . Another known drug Siltuximab, having reaction mechanism similar to Tocilizumab, has also been evaluated in a several reported clinical studies and found to be effective against the COVID-19 76 .

Other Recommended Treatment and Precautions Psychotherapy
For a proper recovery from this disease, a psychological counseling could be effectively useful strategy. Psychotherapy is required in cases where the patients showing symptoms of psychological disorders, fear, or mood swing and for this active psychological intervention can also recommended for treatment 77 .

Release and discharge criteria
The patients with confirmed infection can be released from isolation wards or if required, they can transfer to the related departments to treat other similar kind of diseases. This can be done only if the patient meets all the following inclusion criteria 78, 79 : 1. Improvement in respiratory symptoms 2. Normalization of the body temperature longer than 3 days 3. The test reports should be negative for respiratory pathogenic nucleic acid for two times in a row with sampling interval of at least 1 day.

Prevention
COVID-19 is a novel communicable outbreak that has affected the human globally. This infection has been categorized as category-B infectious disease legally but being managed as category A. It is very important that infection control practices must be implemented for controlling the source of disease, blocking the route of transmission, and protecting the immune incompetent populations 79 .

Risk factors
As this chronic infection has emerged as a new disease, along these lines, there is restricted data with respect to hazard factors for serious illness. The currently available scientific reports and clinical expertise suggested that those individuals who are affected by infection are older aged adults or people of any ages and they have serious underlying medical conditions might be at higher risk of severe illness from COVID-19 80 . The major risk factors observed are as follows: • Age >65 years old • Open exposure to artificial environment • Patients with medical conditions (chronic lung disease or moderate to severe asthma, rheumatic diseases 81 , serious heart conditions, immune incompetent patients like HIV & AIDS infections 82 , severe obesity, diabetes, chronic kidney disease.

Risk of infection in Pets and Other Animals
The Centre for disease control and prevention (CDC) announced the alert of a small number of pets worldwide, including cats and dogs, and expected to be infected with the virus that causes COVID-19, mostly after close contact with those peoples who are infected with COVID-19. Thus, no such literature is available to date, describing the animals risk and COVID-19 transmission to people is considered to be low. It was notified in some study that the COVID-19 virus can cause and spread infection from people to animals. So, just to avoid this, pets should also be treated as other human family members, should not be allowed to come in contact with suspected people or animals outside the household. If a particular individual inside the household carried an infection, that individual should be take care of all family members and remain isolated from everyone else in the family, including pets 83 .

DISCUSSIOn
The coronavirus has affected a large portion of population worldwide and have taken up lives of so many people across the globe. This is a rapidly evolving situation; so much information and clarity on the aspects are still not available. The most common clinical manifestations associated with COVID-19 involves cough, fever, sputum production, fatigue, sore throat, shortness of breath, headache, conjunctivitis, pleuritic pain, etc. 84,85 . Washing hands, wearing masks, and surface disinfection have been found contribute towards decreasing the risk of infection 86 . The countries around the globe have increased the rate of testing for potential cases and isolating the infected people in any possible way to prevent the spread of COVID-19 87 . In acute respiratory infection, reverse transcriptase based-PCR is routinely used. In this circumstance, more swab testing to distinguish infections in the respiratory discharges is required which may help in early screening of the presumed cases 88 .
It is very important to identify proper treatment against COVID-19. A number of studies for SARS-CoV-2 have sprung up since the outbreak of this epidemic COVID-19. In-depth of understanding the SARS-CoV-2 has an underlying pathogenic mechanism that is target based therapy of COVID-19. Based on the currently available literature it has been observed that different phases are associated with COVID-19 including infection, invasion and viral replication and then immune response of human body, up to hyperinflammation. As the disease is highly complex in nature, a multidisciplinary approach entangled towards its treatment can be best option. From the beginning of this outbreak, a lot of information is being published every day regarding diagnosis and treatment of COVID-19. All this information is mainly based on preliminary experiments and experiences gained from retrospective studies. Among all the proposed treatment options for SARS-CoV-2 infection, antimalarials, antivirals, biotechnological molecules, corticosteroids, interferons anticoagulants and convalescent plasma are commonest 89 .
For COVID-19, different curative factors have been recommended and evaluated, but none of factors shown proper effective in treatment. Intravenous Remdesivir, tested in 1063 COVID patients for 10 days. This study noted the time to recovery engaged either in hospitalization upon infection or discharge from the hospital. Remdesivir was only the drug, which proof to be effective in terms of time shortening to recovery 90 . The Food and Drug Administration has also made Remdesivir available under an emergency-use authorization to treat the patients with severe SARS-CoV-2 infection 91 . In a study, conducted by Wang et al. the effectiveness of remdesivir was evaluated against SARS-CoV-2. For this, time-ofaddition assay was used by implementing Vero E6 cells and remdesivir showed effectiveness as treatment option on administration after 2 hours of infection, but not as prophylactic administered prior to the SARS-CoV-2 infection 92 Recently, intravenous immunoglobulin, plasma therapy, emapalumab and etoposide have shown effectiveness for the treatment of this infection as a rescue therapy 93,94 . A clinical trial has also been registered recently in which the efficacy and safety of emapalumab and anakinra have been evaluated in COVID-19 95 . Targeting IL-1 with monoclonal antibodies like Canakinumabis another approach which has been approved by the Italian drug agency for the treatment of COVID-19 pneumonia. A phase 2clinical trial is ongoing to evaluate the effectiveness of Canakinumab in the treatment of COVID-19 pneumonia 96 .
The effectiveness of plasma therapy is associated with its low rate of causing serious adverse effects which makes is advantageous to be used over other unproven therapies for SARS-CoV-2 infection; however more evidences related to its efficacy are still required 97 . The use of immuno suppressants such as corticosteroids is very controversial, and it may be appropriate for some to mitigate the impact of the SARS-CoV-2 mediated cytokine storm. Dexamethasone is showing to reduce death rates and has shown efficacy particularly in critically ill patients. There were 2104 patients who received a dose of 6 mg per day in this study. The risk of death in ventilated patients was decreased by one third in the dexamethasone arm 98 .
Another effective drug has been found to be hydroxychloroquine alone or in combination with azithromycin which has shown effectiveness in various in vitro pre-clinical studies. Although in vitro results have been found to be efficacious, the translational value of these pre-clinical studies to clinical stage is yet to be established at a great level 99 .
The experts suggested that the if no eûective vaccine and drugs are widely implemented at early stage of this pandemicand it is expected that by the year 2022, COVID-19 cases might affect 90% of the global population and more than 40 million individuals may lose their life 100,101 . Therefore, effective and safe treatment options for COVID-19 are required to be developed as early as possible. The sooner the treatment identified and developed, the better will be the outcomes. Early diagnosis, quarantine, and supportive treatments are playing a crucial role in curing the patients. In this current study, authors aim to review and focused the available context relevant to disease parameters including the epidemiology, prevention and diagnosis, and current treatment options for this infection. Alongside that, some clinical preliminaries exploring treatment alternatives for COVID-19 have likewise been examined.