COVID-19: A review on molecular basis, pathogenic mechanisms, therapeutic aspects and future projections

The SARS-CoV-2 is a recently identified positive sense single stranded RNA virus and member of the coronavirus family of viruses. It is thought to be the etiological factor for the ongoing COVID-19 pandemic. This virus is thought to have originated from bats and acquired ability of human-to-human transmission. While SARS-CoV-2 is relatively benign, it has infected more than half a million people (as of March 29 2020) worldwide and the number of infected people continues to rise. More than 170 countries have reported COVID-19 positive cases. With a mortality rate of less than both the previous coronavirus outbreaks, COVID-19 has (conversely) caused the death of over 33,980 (as of 29 March, 2020 at 22.00 hours EDT) people worldwide and the number is increasing. Given the enormous impact of this virus on human health and wellbeing and consequent devastating impacts on world trade, economics and quality of life, it is important to understand this virus better and get insight into its pathogenic mechanisms which will aid in devising effective measure to curb its spread and predict future pattern of its interaction with humans. Though very little is known about this SARS-CoV-2 but its mechanisms and patterns of spread can be speculated (with caution, nevertheless) from what we know about its closest relatives SARS-CoV-1 (responsible for SARS-2002 epidemic) and MERS-CoV (responsible for MERS-2012 epidemic). In the present review, we aim at bringing together the coherent and peer reviewed literature about the SARS-CoV-2 and its close relatives and try to understand its infection patterns and reconstruct its pathogenic mechanisms with anecdotes on diagnosis and future directions. We hope that this paper will serve the purpose of being a reliable source of information to scientists, clinicians and general public. Introduction In the last two months of 2019, some healthcare facilities in Wuhan province of China witnessed the inflow of patients with a collection of symptoms that resembled pneumonia (Chen et al., 2020; Wu et al., 2020; Chand et al., 2020, Huang et al., 2020). Their clinical presentation was similar to the that of severe acute respiratory syndrome coronavirus (SARS-CoV) that affected around 8,000 cases worldwide back in 2002-2004 (Wilder-Smith et al., 2020; Meo et al., 2020). A novel strain of coronavirus 2 (SARS-CoV-2) was subsequently isolated on January 7, 2020 and its spread as a respiratory illness was reported (Huang et al., 2020; Zhu et al, 2020; Li et al., 2020). The disease was referred to as coronavirus disease-2019 (COVID-19) (WHO Report 11 Feb). Some evidence suggests that the virus originated from the wholesale seafood market (Phelan et al., 2020) named Huanan which was subsequently closed on January 1, 2020. It was later reported that individual greater than 60 years of age and those with other comorbid conditions are susceptible to severe disease and may even die (Cascella et al., 2020). The emergence of *Correspondence: Muneeb A. Faiq Email: muneeb1983@gmail.com Preprints (www.preprints.org) | NOT PEER-REVIEWED | Posted: 7 April 2020 doi:10.20944/preprints202004.0091.v1 © 2020 by the author(s). Distributed under a Creative Commons CC BY license. 2 coronavirus (SARS-CoV-2) outbreak in December 2019 which causes the disease known as the COVID-19 (CO-VI-D-2019 or CoronavirusDisease-2019) initially turned out to be an epidemic and was later declared a pandemic by the World Health Organization (WHO) on 11 March, 2020 (Cascella et al., 2020; Cucinotta et al., 2020). It is believed that this outbreak originated from Wuhan, the capital of Hubei province in China (Phelan et al., 2020) with a population of around 11 million people. Wuhan has been a manufacturing hub owing to which it was designated as a creative city by UNESCO in the field of design in 2017 and has, therefore, been witnessing a substantial international visitorship. Being an active exporter city with a massive footfall might have been one of the reasons for the metamorphosis of COVID-19 epidemic into a pandemic. However, most of what we know about this virus is highly speculative so the claims about the origin of SARSCoV-2 are not confirmed (yet there is some reasonable evidence to support this premise). Since COVID-19 has now inflicted more than half a million people worldwide with more than 37,000 deaths (as of 30 March, 2020) and negative impact on world economy, it has also led to panic and misinformation only to exacerbated fear and mismanagement (Mia & Khan, 2020). The overall status quo of various aspects of COVID-19 is given in Figure 1. It is pertinent to mention that our group reported the mechanism of action of one of the positive sense RNA viruses (Zika virus) during the 2016 epidemic and implicated retinoic acid response elements in the etiopathogenesis of microcephaly (Faiq et al., 2016; Kumar et al., 2016). Hence, it appears that an all-inclusive review is needed that serves scientists and clinicians relatively coherent information on various aspects of COVID-19. This paper will also serve as an educational tool for general public who are perplexed by the contrasting reports that are coming from information sources that are not peer reviewed. SARSCoV-2 being similar to SARS-2002 virus (Wilder-Smith et al., 2020; Meo et al., 2020), we will aim at reconstructing the pathogenic mechanisms, symptomatology, clinical features, possible treatment regimens, measures of prevention, diagnostics and prognostic aspects in this write up. We will also try to provide relevant inputs from our research findings wherever possible. As a result, this manuscript will serve as an educational manual (not clinical advice) for healthcare workers and a reliable source of information for researchers and as well as general public. Figure 1: This figure displays the graphical representation of the status of reported, dead and treated cases worldwide. It shows country wise trend in comparison to the scenario worldwide. This graph represents total number of positive cases, new cases as on 30 th March, 2020, total number of deaths, total number of deaths reported within previous 24 hours, the number of cases recovered in each country, total number of active cases, and death normalized to each country’s population. Each country represents its own percentile which can be compared to any other country around the world. Data source (https://www.worldometers.info/coronavirus/ and https://coronavirus.jhu.edu/). It must be understood that as new information comes in, data is subject to change. Epidemiology and Demographics The SARS-CoV-2 (novel Coronavirus-2019) described as the causative pathogen for the pandemic COVID-19 is thought to have originated in China (Chen et al., 2020; Wu et al., 2020) and new information is perpetually coming up to complete the mosaic of the picture of its various aspects. Multiple peer reviewed reports are rapidly being published, it turns out to be imperative to practice caution as the information about SARS-CoV-2 and COVID-19 is being updated fast (Mia & Khan, 2020). Since SARS-CoV-2 is a recently identified virus and much is still not known about it, we felt that there is an ardent need of a comprehensive and all-inclusive overview that is scientifically accurate and relatively lucid. In addition to providing upto-date correct information and putting the subject into context (in terms of latest clinical research), such an endeavor would also help in addressing misinformation that is currently being circulated. This misinformation has been the source of panic and has presumably misled general public causing unnecessary stress and, in many cases, led to insensitivity towards the potential dangers posed by this virus Preprints (www.preprints.org) | NOT PEER-REVIEWED | Posted: 7 April 2020 doi:10.20944/preprints202004.0091.v1


Introduction
In the last two months of 2019, some healthcare facilities in Wuhan province of China witnessed the inflow of patients with a collection of symptoms that resembled pneumonia Chand et al., 2020. Their clinical presentation was similar to the that of severe acute respiratory syndrome coronavirus (SARS-CoV) that affected around 8,000 cases worldwide back in 2002Meo et al., 2020). A novel strain of coronavirus 2 (SARS-CoV-2) was subsequently isolated on January 7 th , 2020 and its spread as a respiratory illness was reported Zhu et al, 2020;. The disease was referred to as coronavirus disease-2019  (WHO Report 11 Feb). Some evidence suggests that the virus originated from the wholesale seafood market (Phelan et al., 2020) named Huanan which was subsequently closed on January 1 st , 2020. It was later reported that individual greater than 60 years of age and those with other comorbid conditions are susceptible to severe disease and may even die (Cascella et al., 2020). The emergence of coronavirus (SARS-CoV-2) outbreak in December 2019 which causes the disease known as the COVID-19 (CO-VI-D-2019 or Coronavirus-Disease-2019) initially turned out to be an epidemic and was later declared a pandemic by the World Health Organization (WHO) on 11 th March, 2020 (Cascella et al., 2020;Cucinotta et al., 2020). It is believed that this outbreak originated from Wuhan, the capital of Hubei province in China (Phelan et al., 2020) with a population of around 11 million people. Wuhan has been a manufacturing hub owing to which it was designated as a creative city by UNESCO in the field of design in 2017 and has, therefore, been witnessing a substantial international visitorship. Being an active exporter city with a massive footfall might have been one of the reasons for the metamorphosis of COVID-19 epidemic into a pandemic. However, most of what we know about this virus is highly speculative so the claims about the origin of SARS-CoV-2 are not confirmed (yet there is some reasonable evidence to support this premise). Since COVID-19 has now inflicted more than half a million people worldwide with more than 37,000 deaths (as of 30 th March, 2020) and negative impact on world economy, it has also led to panic and misinformation only to exacerbated fear and mismanagement (Mia & Khan, 2020). The overall status quo of various aspects of COVID-19 is given in Figure 1. It is pertinent to mention that our group reported the mechanism of action of one of the positive sense RNA viruses (Zika virus) during the 2016 epidemic and implicated retinoic acid response elements in the etiopathogenesis of microcephaly (Faiq et al., 2016;Kumar et al., 2016). Hence, it appears that an all-inclusive review is needed that serves scientists and clinicians relatively coherent information on various aspects of COVID-19. This paper will also serve as an educational tool for general public who are perplexed by the contrasting reports that are coming from information sources that are not peer reviewed. SARS-CoV-2 being similar to SARS-2002virus (Wilder-Smith et al., 2020Meo et al., 2020), we will aim at reconstructing the pathogenic mechanisms, symptomatology, clinical features, possible treatment regimens, measures of prevention, diagnostics and prognostic aspects in this write up. We will also try to provide relevant inputs from our research findings wherever possible. As a result, this manuscript will serve as an educational manual (not clinical advice) for healthcare workers and a reliable source of information for researchers and as well as general public. in comparison to the scenario worldwide. This graph represents total number of positive cases, new cases as on 30 th March, 2020, total number of deaths, total number of deaths reported within previous 24 hours, the number of cases recovered in each country, total number of active cases, and death normalized to each country's population. Each country represents its own percentile which can be compared to any other country around the world. Data source (https://www.worldometers.info/coronavirus/ and https://coronavirus.jhu.edu/). It must be understood that as new information comes in, data is subject to change.

Epidemiology and Demographics
The SARS-CoV-2 (novel Coronavirus-2019) described as the causative pathogen for the pandemic COVID-19 is thought to have originated in China  and new information is perpetually coming up to complete the mosaic of the picture of its various aspects. Multiple peer reviewed reports are rapidly being published, it turns out to be imperative to practice caution as the information about SARS-CoV-2 and COVID-19 is being updated fast (Mia & Khan, 2020). Since SARS-CoV-2 is a recently identified virus and much is still not known about it, we felt that there is an ardent need of a comprehensive and all-inclusive overview that is scientifically accurate and relatively lucid. In addition to providing upto-date correct information and putting the subject into context (in terms of latest clinical research), such an endeavor would also help in addressing misinformation that is currently being circulated. This misinformation has been the source of panic and has presumably misled general public causing unnecessary stress and, in many cases, led to insensitivity towards the potential dangers posed by this virus (Mia & Khan 2020;Geldsetzer, 2020). We assert what we know about this virus could change rapidly and, hence, it is important to look into the latest literature before making an opinion or suggesting any recommendations. However, given our understanding of virology and SARS-2002 and MERS-2012 epidemics we can make reasonable conclusions/hypotheses that would help us to contain this virus and bring down its fatality (Barry et al., 2002;Wilder-Smith et al., 2020;Peeri et al., 2020). It is important to be mindful of the misinformation and myths that have been spreading (as is always the case with epidemics and pandemics) and the need to educate not only patients, but caregivers, those in quarantine as well as the general public. In addition, clinicians are at high risk of catching SARS-CoV-2 infection as they are in regular contact of patients a vast majority of whom may be infected. This is particularly true with ophthalmologists Wan et al., 2020) and otorhinolaryngologists.

COVID-19 vis-à-vis other Coronavirus Outbreaks
We know that the SARS-CoV-2 has significant similarities with the SARS-CoV-1 virus in many respects (Barry et al., 2002;Wilder-Smith et al., 2020;Peeri et al., 2020). The SARS-CoV-1 coronavirus was etiological basis of the outbreaks that led to SARS-2002(de Wit et al., 2016. This outbreak generally identified as 2002 outbreak was an epidemic that originated from Foshan area in China and was characterized by severe acute respiratory syndrome (SARS) and led to the death of approximately 800 people worldwide. It is believed that 2002 coronavirus had bat as the original reservoir (probably a primary host) from where it is believed to have acquired the ability (most likely through mutations in its genome) to infect the intermediate host-Civet (a nocturnal mammal which was sold for meat in the markets of Yunnan province in China) where from the virus acquired the ability (most likely due to mutations in its genome) to be able to infect humans van Staden, 2020;.
At the outset, it is important to mention that coronaviruses are relatively benign, but they do show some significant respiratory effects (like viral rhinitis etc.) in humans (due to certain anatomical and physiological reasons explained later in this paper) and in certain cases they cause severe acute respiratory syndrome (SARS) Huang et al., 2020). SARS is name given to a collection of conditions (usually caused by SARS-CoV) accompanied with severe systemic symptoms including muscle pain, headache, and fever, followed by the onset of respiratory symptoms (within 2 to 14 days), including cough, dyspnea and pneumonia with decreased number of lymphocytes in blood (Cleri et al., 2010;Darnell et al., 2004;Vijayanand et al., 2004). So, it appears that the virus often mutates (Denison et al., 2011;Holmes et al., 2004;Parvin et al., 1986) in certain imperative ways (owing to its highly dynamic RNA based genome and relatively low fidelity of the RNA-dependent-RNA polymerase (Elena et al., 2005;Venkataraman et al., 2018;Cameron et al., 2016) which is the enzyme it utilizes to replicate its genome) so as to be able to infect another host (an animal which serves as an intermediate host) other than its primary host. In case of SARS 2002 there was some evidence to show that the intermediate host was Civet (Hu et al., 2015;Chan & Chan, 2013;Bolles et al., 2011;Wang et al., 2006;Tu et al., 2004;Xu et al., 2004). Why was Civet an intermediate host is not known but there seems to be a peculiar pattern that SARS-CoV-1 (SARS 2002) as well as SARS-CoV-2 (causative for  both have nocturnal mammals (though this is based on speculations) an intermediate hosts indicating that humans might have to practice caution in future about the trade and use of nocturnal mammals, which in all possibility may be reservoirs of potentially dangerous viral pathogens (Shi & Hu 2008) and in some cases may turn out to be fatal in the long run. There is every chance that we may be seeing epidemics and pandemics more frequently in the near future where more fatal pandemics might come from these intermediate nocturnal mammalian hosts. Is coronavirus a regular pathogen in nocturnal mammals is a question that needs to be pursued rigorously and might also hold answer to questions about the previous epidemics (SARS-2002, MERS-2012, the present one as well as those that are awaiting us in the future. From Civet (an intermediate host for SARS-2002), SARS-CoV-1 mutated enough to be able to infect humans van Staden, 2020;Zhang et al., 2020). This is not an isolated case in the history of human-virus interaction but has happened multiple times (through a process called zoonosis) (Weber & Rutala, 1999;Salata et al., 2019;Rodriguez-Morales et al., 2020;Li & Du, 2019;Chan et al., 2015;Huynh et al., 2012;Vijgen et al., 2005) and it did happen afterwards and is probably going to be a regular pattern in future (unless we develop necessary measures to curb the spread).
Almost a decade after the 2002 coronavirus SARS outbreak; in 2012 another similar eruption took place; the so-called Middle-Eastern Respiratory Syndrome (MERS) (Fehr et al., 2017;Sharif-Yakan et al., 2014;Milne-Price et al., 2014). MERS is also called the camel flu because its intermediate host was camel (Dawson et al., 2019;Bhatia et al., 2016). It was an epidemic caused by MERS-coronavirus (MERS-CoV) and its symptoms (fever, cough, diarrhea, shortness of breath or increased work of breathing) were similar to SARS-2002 but the mortality was significantly higher in comparison to COVID-19 (Cascella et al., 2020). The mortality rate of MERS was around 35 percent which means one third of the infected individuals died. By comparison COVID-19 is relatively benign with a mortality rate of 1 to 3 percent (though this percentage is changing with time and might actually be lower than the cited value). In case of MERS-2012, the origin (the primary host or the primary animal reservoir) is thought to be bat (again a nocturnal mammal) from where the virus acquired the ability to infect camel (the intermediate host which is not typically nocturnal but given the environment it lives in, it is also active during the nighttime). From camel it then mutated enough to be able to infect humans (Banerjee et al., 2019;Lau et al., 2018).

Hosts and Infection Patterns
From the above mentioned two major outbreaks, we arrive at the December-2019 outbreak which is referred to as COVID-19. In this case also the general belief again is that the virus originated from bats Singhal et al., 2020) (primary host reservoir) where from it acquired the ability to infect pangolins (a nocturnal mammal of the order Pholidota generally known as scaly ant eater) as the intermediate hosts Fisher et al., 2020;Prompetchara et al., 2020;. Investigators are not yet sure if the intermediate host is pangolin indeed but this possibility seems to be highly likely Fisher et al., 2020;Prompetchara et al., 2020;. Again, from pangolin, this virus is thought to have mutated to the extent so that it acquired the ability to infect humans Murdoch et al., 2020).
A relevant aspect here is that these viruses (in addition to acquiring the ability to infect humans from the intermediate hosts) also acquire the ability for human-to-human transmission , Lai et al., 2020Velavan et al., 2020;Mandal et al., 2020;Riou & Althaus, 2020;Kakimoto et al., 2020). That is where the reason of the infection turning into an epidemic/pandemic comes from (Mandal et al., 2020;Riou & Althaus, 2020) and that is where the philosophy and recommendation for quarantine is justified (Lewnard & Lo, 2020;Parmet & Sinha, 2020;Tang et al, 2020;Anderson et al., 2020). This might be one of the important areas of research to explore whether zoonosis has a parallel effect of human-to-human transmission and how can that be tackled in terms of vaccine development and/or by other means. In addition to human-to-human transmission, one of the major reasons for COVID-19 to transmogrify into a pandemic may be that pangolin (which is believed to be the intermediate host of the virus) is highly trafficked around the world for medicinal purposes as its scales are thought to possess some healing properties .
But pangolin being the intermediate host of SARS-CoV-2 is not confirmed (though there is evidence). This frequent trafficking of the intermediate host complemented with frequent international air-travel in the modern world (Craig et al., 2020Wells et al., 2020) (Wang & Wu, 2018;Ameli, 2015;Erdem & Unal, 2015;Quinn & Kumar, 2014;de Almedia 2013;Howard & Fletcher, 2012;Goldenthal et al., 1996;Aitken & Jeffries, 2001). It is not sufficient to understand only the zoonosis though zoonosis might provide important clues about the spread of the virus and might also aid in prediction, and therefore, development of protocols to prevent outbreak of infective diseases in the future.

Infectivity, Mortality and Morbidity
One of the appropriate ways to approximate the severity of viral disease is to look into the mortality/fatality rates (Onder et al., 2020;Kelly & Cowling, 2013;Yoshikura, 2012;Dombrovskiy et al., 2005). Such an approach is crucial and pertinent as it may influence the intensity of government response at the policy level and public reaction (Lo et al., 2018;Pelat et al., 2014). This in turn determines the intensity and nature of necessary steps to taken by all the institutions that have a stake in the outcome. Misinformation about this aspect may be one of the major reasons for panic potentially doing more harm than anticipated. Case fatality rate (CFR) or case fatality ratio is an important gauge as it allows us to make proper estimates (and hence neither over react nor under react in response to an epidemic) of the severity of the problem so that sufficient level of preparedness (for future) and response is initiated (Onder et al., 2020;Kelly & Cowling, 2013;Yoshikura, 2012;Dombrovskiy et al., 2005;Lo et al., 2018;Pelat et al., 2014). By definition, CFR is an estimate of the percentage of deaths from a disease compared to the total number of people diagnosed positive for the disease during a particular time period. It is essential to present a caveat here that CFR can only be considered final when all the cases have been resolved (either died or recovered with no active cases being reported) (Atkins et al., 2015;Reich et al., 2012;Hop et al., 1997). By that definition, the CFR we are talking about COVID-19 in this paper is the preliminary CFR which may substantially change as the situations evolves. In the light of this, COVID-19 appears to pose some concerns with regards to the consensus on actual figures that are being reported by different research groups. The CFR can be estimated by the following equation: For the SARS-2002, the CFR was estimated to be approximately 11 percent (Xu et al., 2004;Chan-Yeung & Xu, 2003 (Shim et al., 2020;Wilson et al., 2020;Dong et al., 2020;Porcheddu et al., 2020). This is much lower than the CFR of the previous coronavirus outbreaks and hence should be mentioned whenever a comparison of COVID-19 is made with previous coronavirus outbreaks. Nevertheless, it is vital to point out that the estimate of 4.2 CFR for COVID-19 may actually be significantly lower than what it appears at the outset. This is because we don't, as of now, have any reliable estimates of the total number of people infections by this virus. This is due the fact that many SARS-CoV-2 infected individuals are asymptomatic and never get tested Lu et al., 2020;Mizumoto et al., 2020;Lin et al., 2020). The number of people who are infected with SARS-CoV-2 may be notably higher than the actual confirmed cases indicating that the CFR of COVID-19 may be notably less than the estimated rate. A critical dimension to note here is that most of the SARS-CoV-2 infections either present with mild symptoms or generate no symptoms at all meaning many individuals might have the infection which spontaneously gets healed without even the person having realized it Lu et al., 2020;Mizumoto et al., 2020;Lin et al., 2020). This phenomenon has both positive as well as negative effects.
The positive aspect is that the virus is benign and, in many cases, does not require any intervention and/or hospitalization. This is in addition to having lower than estimated CFR. The negative aspect, conversely, is that an infected asymptomatic person can co-infected (unknowingly) many people who may develop symptoms and might require clinical attention. In this case we miss the opportunity to quarantine the asymptomatic carrier. Furthermore, many flu-like symptoms appear to be similar to COVID-19 (Cascella et al., 2020, Fisher et al., 2020Guo et al., 2020;Bordi et al., 2020) which is an additional reason for general public to be apprehensive and a technical challenge for clinician to rule out parallel illness (for differential diagnosis) (Bordi et al., 2020). It remains the prerogative of the clinician to decide whether a particular set of symptoms in a patient presenting in the clinic looks like a  Ridenhour et al., 2014;Hefferman et al., 2005;Dietz, 1993). The RO of SARS-CoV-2 ranges from 2 to 3.5 (again this number is based on some initial reports when the actual number might change with time as new reports and epidemiological data become available) . This indicates that if an infected person comes in contact with many people in a gathering (room, hall, office, public transport etc.) where the distance with other people is less than two meters, and if the person happens to sneeze or cough (thereby release respiratory droplets which contain the virus), there is a possibility that an average of approximately three persons will acquire the infection (though the actual number may vary vastly). It is to be borne in mind that this is a probabilistic case and the actual infectivity and the number of secondary infections may vary from situation-to-situation, society-tosociety, population-to-population, and age group-to-age group. If the people around are immunocompromised, then the infectivity and hence and hence different estimates. If we compare this number with influenza, the RO of influenza virus is around 1.3 (meaning that one infected person generally infects slightly more than one person in turn) (Biggerstaff et al., 2014). This gives rise to a dynamic picture of COVID-19 with an exponential rise as shown by Figure 2. One of the major strategies to control the epidemic (now declared a pandemic by WHO) is to target the RO and thereby bring down the spreading ability. It appears that epidemiologists and clinical microbiologists have to pay attention to the strategies that affect RO. Given the three major stages of the infection viz. exposure, latent infection and isolation after diagnosis, a mathematical model can also be applied to know how to curb the spread (Mandal et al., 2020;Kucharski et al., 2020;Choi et al, 2020;Hellewell et al., 2020). Also, if we have a list of factors that affect (increase or decrease) the RO then we may be able to bring down the number of cases and halt the spread of the virus by curbing the factors that increase RO while enhancing those that decrease RO washing hands regularly, by social distancing, staying away from crowds, sneezing in a proper way, coughing in a proper way (there are many instruction manuals available and many YouTube videos also). A list of such the factors that may potentially help in reducing the frequency of new infections and is given in Table 1. This list is in no way exhaustive.

21
All forms of public transport Avoid using public transports if possible, or use proper gears, as masks and gloves, for protection. Sanitize yourself following that.

22
Air around the infected person Virus is not known to pass in air but infected droplets can transmit it.
Keep a safe distance (about 6 feet).

23
Clothes of the infected person May contain virus. Avoid touching or sharing, or sanitize your hands following that. surfaces have come in contact with an infected person in the past 24 to 48 hours. It must be understood that such surfaces do not normally contain the virus. These points of contact harbor the virus only and only if they have come in contact with an infected person. If that is the case, then it might be expedient to avoid coming in contact with these surfaces. It might also be a good idea to try to disinfect these surfaces (wherever feasible) and also was your hands with soap immediately in case the individual comes in contact with infected surfaces. *There are many online resources that show how hands should be washed in order to effectively neutralize a pathogen. Few important reliable sources are the Johns Hopkins video (https://www.youtube.com/watch?v=IisgnbMfKvI) and WHO tutorial (https://www.youtube.com/watch?v=3PmVJQUCm4E).
One of the major ways to target RO is to quarantine the infected and Another critical aspect that warrants our attention is the Serial Interval (SI). SI may be defined as the time between successive cases (usually number of days) in a chain of infection transmission (Huber et al., 2016;Vink et al., 2914;Leevy et al., 2013;Donelly et al., 2011;Cowling et al., 2009;Vynnycky & Fine, 2000;ten Asbroek et al., 1999). It is vital to analyze RO in relation to SI because SI also has a major role to play in infection spread and also in certain important  (Vink et al., 2014;Levy et al., 2013;Cowling et al., 2009). This indicates that the time interval from onset of symptom in P1 and the time of onset of symptom in P2 is 7.5 days (as against 2.5 days for influenza). A comparison of the SI of various viruses is given in Table   2.
It can now be concluded that high RO and low SI is indicative of high pace of a viral infection turning into an epidemic (or pandemic). In case of COVID-19 it can be roughly estimated that the infection from one person infecting other person takes around 7.5 days so on and so forth.
By almost 22 days this single person become the source of 27 infections and the pattern follows an exponential curve as shown in Figure 2. It looks like that the SI of COVID-19 is significantly larger than influenza which may be one of the reasons that it took a considerably longer time for people and authorities around the world to realize how severe the threat is. At the same time, this must be borne in mind that owing to this significantly longer SI, the disease may peak months after the expected peak time which, in turn, indicates that we have to be cautious of any silent, asymptomatic infections apart from the relapse cases .

Modes of Transmission
Coming to the modes of transmission, it must be understood that we don't know much about the routes through which this virus gets transmitted but extrapolating from SARS-2002 experience fecal-oral Gu et al., 2020;Han et al., 2020;Yeo et al., 2020) and respiratory routes (Yang and Wang, 2020;Qu et al., 2020;Pend et al., 2020;Lai et al., 2020) can be hypothesized. An infected person touching surfaces without proper precautions and then another person coming in contact with such surfaces is one of the major routes of transmission , Frieden & Lee, 2020 have the potential to travel in air some distances without settling down (Liu et al., 2017;Stikianakis & Drossinos, 2010;Xie et al., 2009;Li et al., 2009;Xie et al., 2007;Hogg & Hustan, 2006;Duguid, 1946). In most of the cases the distance these respiratory droplets are able to move without settling are 3 to 6 feet (1 to 2 meters) (Duguid, 1946;Stikianakis & Drossinos, 2010). This distance immediately sets the optimum length for social distancing. It is to be understood that the distance is not everything. These respiratory droplets can settle on surfaces where they can survive for 24 hours or more (Marr et al., 2019;Warnes et al., 2015;Nikitin et al., 2014;Fernstrom et al., 2013;Greatorex & Goldbatt, 2011;Rapport 1991;van Doremalen et al., 2020;Roosa et al., 2020;Duan et al., 2003). If these surfaces come in contact with a healthy person, in that case the person may get infected.
Again, it is worth mentioning that such a possibility is not absolutely inevitable but is highly probable. Such surfaces include tables, computer keyboards, chairs, handles, clothes, etc. This list can be enormous and hence a clinician needs to make a comprehensive list of these potential surfaces and have it circulated (or at least displayed in the clinics). We have made a list of the possible points of contact for coronavirus (SARS-CoV-2) with the hope that this might serve some purpose to clinicians and the relevant healthcare workers. It will also be useful for the general public.  , 2020) indicating that the volume around the infected person who releases droplets (after coughing and/or sneezing) in the air is potentially infective within two meters radius for about three hours. If this principle is understood, a majority of the problem is likely tackled. It is important to mention here that asymptomatic person infected with SARS-CoV-2 is also capable of producing these cough droplets containing the virus and also has the same ability to infect other people as that of the infected person with symptoms of the disease.

Pathogenic mechanisms
Once the virus makes its way to the respiratory tract, it reaches the alveoli where its primary target are the type II pneumocytes (Cascella et al., 2020;Gralinski & Baric, 2015;Qian et al., 2013;Mossel et al., 2008). Type I pneumocytes play role in gas-exchange (Ward et al., 1984) while as the type II pneumocytes produce an important substance called surfactant (a substance that reduces the surface tension within the alveoli and hence contributes to the elastic properties of the lungs thereby making breathing relatively easy and effortless) (Sugahara, 1994;Helewski & Preprints (www.preprints.org) | NOT PEER-REVIEWED | Posted: 7 April 2020 doi:10.20944/preprints202004.0091.v1 Konecki, 1989). Type II pneumocytes are the primary targets of the virus which infects the cells and initiates its multiplication inside the body. The S-spike of the virus binds with the angiotensin converting enzyme 2 (ACE-2) on the surface of the pneumocytes type 2 (Ortega et al., 2020). ACE-2 is a member of the ACE family and a type I transmembrane metallocarboxypeptidase and a regulator of the Renin-Angiotensin system and hence an important target for management of hypertension. It is distributed in many tissues in the body including lung, kidney, gastrointestinal (GI) tract, and cardiovascular system Roca-Ho et al., 2017;Varagic et al., 2014;Tikellis & Thomas, 2012;Ocaranza & Jalil, 2012;Hamming et al., 2007). This

Many of the COVID-19 cases present with extra-pulmonary
symptoms. This is presumably because ACE-2 is expressed in many cell types in the body. ACE-2 mediated functions imbibe a wide array of physiological events that can serve as an integrative model to reconstruct the COVID pathology. Figure 4 shows  As already mentioned that SARS-CoV-2 is a positive sense single stranded RNA virus (Fehr & Perlman, 2015;Yuen et al., 2020;Khan et al., 2020, Lai et al., 2020. It requires RNA-dependent-RNA polymerase to multiply its genetic material. This may provide rationale for the potential use of Remdesivir for treatment of COVID-19 and studies are, therefore, underway (Elfiky, 2020;Dong et al., 2020;Al-Tawfiq et al., 2020;Gordon et al., 2020). Ramdesivir was also used in the treatment of Ebola -virus infections (Mulangu et al., 2019;Tchesnokov et al., 2019). The multiplication of COVID-19 virus does not depend on a DNA phase and hence the DNA phase may not exist.
Although we have produced some evidence that certain positive sense Preprints (www.preprints.org) | NOT PEER-REVIEWED | Posted: 7 April 2020 doi:10.20944/preprints202004.0091.v1 RNA viruses may act through activation of endogenous reverse transcriptase to archive their genome in the host genome in the form of DNA (Faiq et al., 2018;Kumar et al., 2016) but that does not seem to be the case with SARS-CoV-2. This is perhaps the reason that antiretroviral therapy may be thought of some potential to manage COVID-19.
Once the RNA is released into the cytoplasm of type 2 pneumocytes, it acts as a messenger RNA and utilizes the host cell ribosome machinery to translate the polyproteins which are cleaved by specific enzymes (proteases) into active protein particles including the S-spike (against which antibodies are being designed for therapeutic/vaccination purposes) (Ibrahim et al., 2020;Ahmed et al., 2020;Liu et aal., 2020;, the capsid and various other protein moieties (Vankadari & Wilce, 2020;Kim et al., 2020) requisite for the assemblage of the active and viable virus (Mclntyre et al., 2018;Poltronieri et al., 2015;Hyodo & Okuna, 2016;Richards & Jackson, 2013;Wang & Li, 2013;Ahlquist et al., 2003). It appears that certain protease-inhibitors can have potential to inhibit this step and, therefore, may act as potential drugs for COVID-19 treatment (Martinez, 2020).
Ritonavir, a potent protease inhibitor (which has been used to treat HIV infection) may serve as a potential candidate for such investigations Yao et al., 2020;Lim et al., 2020). One of the translated proteins of SARS-CoV-2 is the RNA-dependent-RNA polymerase which leads to the synthesis of multiple RNA copies (which are the genome of the virus). Given the enough copies of the RNA being produced within the cytoplasm of the host cells (which in this case are pneumocytes), and the enough proteins important for the viral structures, these two moieties combine to give rise to hundreds and thousands of viral particles within the cell (Zinzula & Tramontano, 2013). Once that occurs, the cell either activates its apoptotic mechanism or is being destroyed by the macrophages. This leads to the release of the multiple copies of the viable virus into the extracellular matrix and interstitial fluid where the new/amplified progeny of the virus has now the opportunity to infect other type 2 pneumocytes.
Given the enough number of viruses being produced, they infect type 2 pneumocytes of other alveoli and also enter the blood circulation to invade other cell types (particularly those expressing ACE-2). Then the coronavirus mediated pathophysiology (Freeman, A. M., & Leigh, 2020) potentially leading to pneumonia sets in.
Once the type 2 pneumocyte gets ruptured, it may (in all possibilities) attract macrophages through the production of inflammatory mediators. The so activated macrophages (Naeem et al., 2020;Herbert et al., 2010;Losa et al., 1999;Driscoll et al., 1995)  Apart from macrophages, the inflammatory mediators released by the demise of type 2 pneumocyte tends to bring in neutrophils which cross the alveolar membrane and start concentrating within the alveolar sac to neutralize the viruses released into the alveolar space. One of the major mechanisms through which neutrophils act on viruses is to release reactive oxygen species (ROS) and proteases which in certain quantities neutralize the virus but in overwhelming proportions may lead to an excess ROS and proteases. Such a condition, not only neutralizes the viruses but also destroys the cells lining the alveoli (including both type1 and type 2 pneumocytes). As a result, the structure and therefore the function of the alveoli is disturbed. Since type1 pneumocytes play important role in gas-exchange (Ward et al., 1984;Powers & Dhamon, 2020), there is a significant drop in gasexchange and hence it precipitates severe hypoxemia (and a consequent drop in the partial pressure of oxygen ensues). As the cells lining the alveoli get destroyed and as the infiltration of neutrophils and macrophages (as a result of inflammatory mediators released by the rupture of pneumocytes) leads to increase in the cell debris within the alveolar space; the alveoli, as a result, have accumulated cell debris, degraded protein, neutrophils, macrophages. This condition (referred to as consolidation) severely hampers gas-exchange at the level of the alveoli again leading to drop in partial pressure of oxygen and hypoxemia.
The release of immense quantities of IL1 and IL6 seep into the bloodstream. Since this release of TNF-α, IL1 and IL6 comes from a vast number of alveoli within the lungs, it may lead to a significant increase of these compounds in the blood and hence travel to the central nervous system. The hypothalamus, in response to the increased concentration of these mediators responds by releases prostaglandins thereby resetting the body thermostat leading to increase in body temperature (fever; an important presenting symptom of . That is how the two important features (respiratory distress and fever) may be generated in the SARS-CoV-2 infection (Cascella et al., 2020;Wan et al., 2020;He et al., 2020). The consolidation (of the cellular debris in the alveoli) needs to be moved out of the lungs and one of the mechanisms of throwing such debris out in humans is coughing.
Hence, this debris may cause cough (initially dry cough but can be productive cough also) and the COVID-19 patients present with this as one of the symptoms. Hence another symptom in these patients (dry and subsequently productive cough). It is worth mentioning that though there are certain symptoms and clinical features that are frequently associated with COVID-19 but the actual symptoms/clinical features may vary and there are numerous permutations of symptoms and clinical features that a patient can present with. These symptoms range from asymptomatic to cough, sneezing, sore throat, fever, pneumonia (hence need for ventilator), lymphopenia, drop in pO2, hepatic dysfunction, pH dysregulation, renal compromise, cardiovascular manifestations (tachycardia), GI upset, inflammatory phenotype, etc (Cascella et al., 2020;Wan et al., 2020;He et al., 2020).
The low pO2 in the blood may trigger a peculiar chemo response or stimulation of chemoreceptors which, in turn, can initiate a reflux to stimulate the sympathetic nervous system (SNS) to increase the heart rate. This way the patient might also present with increase in pulse rate.
The COVID-19 patient might also present with tachycardia. Drop in pO2 and subsequent SNS response precipitate an increase in respiratory rate which may also be one of the symptoms in the presenting patient.
Till now we were discussing the situation when the disease is still under control. Now let us see when all these issues enter into the severe category. As more and more alveoli get involved and increasing number of alveoli witness consolidation, most of the inflammatory markers (IL1, IL6 and TNF-α) seep into the blood stream and there may be an upsurge of battery of inflammatory markers in the blood. As a result, the inflammation within the lungs (pulmonary inflammation) can now lead to systemic inflammatory response which is a potential for sceptic shock. A condition that started off with pneumonia may harbor the potential to culminate at the multiple system organ failure.

Diagnostics
In the light of the above given mechanism, it can be understood that a patient might present with fever, cough, shortness of breath and sometimes with upper respiratory tract infection symptoms (sore throat, headache etc.) and also with GI symptoms (nausea, vomiting, and diarrhea). According to our studies (our unpublished data), all these symptoms can be explained in terms of the ACE-2 mediated pathogenic mechanism of COVID-19. However, it must be understood that the primary symptoms are the triad of fever, cough and shortness of breath (Cascella et al., 2020;Wan et al., 2020;He et al., 2020). This is despite the fact that the patient may present with symptoms other than this trial. In that case, the clinician faces a strong diagnostic challenge with a high risk of misdiagnosis or delay in differential diagnosis. It may, therefore be advisable to order radiological examinations like chest X-ray and CT (Bai et al., 2020;Yoon et al., 2020) and look for signs of consolidation (the so-called ground glass patter) while the other diagnostic test results are awaited.
Sometimes the whole set of clinical features looks like a flu and in most of the cases it is a flu indeed. Asking a few questions to the patient might help the clinician navigate through the differential diagnosis.
Some of the questions that need to be asked are: 1.
Have you been in contact with any person who has been diagnosed positive for COVID-19?

2.
Have you travelled recently?

3.
Have you recently been to some country where there was an outbreak of coronavirus?
All these questions (and many others) are likely to aid the clinician to figure out the clinical history that might prove to be vital for establishing the diagnosis. After asking the questions, it appears to be coherent to run a flu test. The test for influenza is straightforward. Just taking a nasopharyngeal swab and testing for influenza A and influenza B (or as might be the WHO recommendation in different countries) is all that is needed to rule out influenza. So, one of the first steps in the differential diagnosis of COVID-19 arguably be ruling out influenza.
The realtime polymerase chain reaction (RT-PCR) is a sophisticated test which needs to be done by a highly competent person who is well trained and experienced to run the test otherwise there is always chance of having high number of false positive and/or false negative results.
The RT-PCR based diagnostic methods have a varied sensitivity indicating that we can very well have false positive and false negative cases. But this test is still the gold standard for the diagnosis of COVID-19 Lan et al., 2020;. Another issue with RT-PCR is that this test involves a number of steps and hence takes a lot of time (a few days in most of the cases). Since the results come after some time, the severity of the symptoms (in certain cases) might worsen in the interim. The selection of the sample to be harvested for RT-PCR is also a challenge. However, many kits come with detailed and precise instructions about the nature (nasopharyngeal swab, glossopharyngeal swab, aspirate, blood or sputum) and amount of sample to be taken. The instructions about the method of harvesting sample, is however, lacking in the manual of many of the available kits. Another related test that can be done which is relatively expensive is the Nucleus Acid Amplification Test (NAAT). The principle of this test is similar to RT-PCR but it gives results relatively earlier than RT-PCR.
It is important to know the patient status in terms of various aspects and hence would be critical to evaluate the markers that are associated with high mortality rate. Figure 6   though the mortality rate increases with age but younger individuals may also progress to intense disease severity and death. Masculine gender appears to have higher mortality rates than the feminine gender. Also, cardiovascular comorbidity has been found to be highly associated with high mortality (Data source: https://coronavirus.jhu.edu/data/mortality and https://www.worldometers.info/coronavirus/). It is also pertinent to evaluate the patient's general inflammatory markers. Though these markers may have limited role in diagnosis but they do have a significance in understanding the prognosis. These markers are c-reactive protein (CRP) and erythrocyte sedimentation rate (ESR). Both of these might be elevated. Levels of IL1, IL6, and TNF-alpha can also be evaluated to get an idea about the severity of the proinflammatory phenotype. Elevation in lactate dehydrogenase can also be an additional finding (this can be elevated in response to hypoxemia), so can be the elevation of D-dimer. There may even be an elevation in ferritin levels. All these markers may be elevated in COVID-19 patients and their elevation may be associated with relatively higher mortality rates. However, this is not always the case.
Continued hypoperfusion to cardiac muscles due to drop in blood pressure (secondary to vasodilation and hyperpermeability of the endothelial cells) might also cause the elevation of troponin I, troponin C and CK-MB in the blood. This also is an indicator of a relatively higher mortality rate. All these conditions are associated with hemodynamic instability.
There are some imaging tests that might also be helpful in understanding the patient's condition and consequently managing the disease better. These tests can be chest X-ray, CT scan (Bai et al., 2020;Yoon et al., 2020;Dai et al., 2020) and USG (Moro et al., 2020;Soldati et al., 2020;. To this effect, CT might be the most important and the most sensitive. Though CT is not specific to COVID-19 but it is highly sensitive Ai et al., 2020). In a chest X-ray, a characteristic picture of a ground glass opacity might be visible. In a CT, the ground glass opacities are also visible in the peripheral lung fields but there are two additional features that can be picked up by CT. One of these features is the areas of alveolar consolidation indicating pneumonia. In addition to this the unique pattern called the 'crazy paving pattern' (associated with interstitial fluid accumulation, membrane thickening compounded with alveolar interstitial edema) can also be seen. In addition to these tests, point of care ultrasound can also be done where a pleural line thickening can be observed. In this case the ultrasound may also be associated with lines of pulmonary edema (also called the B lines). The consolidation with air bronchograms is also visible on the ultrasound.
In this context radiological consultation might prove to be very helpful Yu et al., 2018;Gao et al., 2017;Kobayashi & Mitsudomi, 2013)

Future Directions
In terms of the management, the first and foremost thing that should be done is to get proper education and clear doubts. To this effect Table 3 provides probable answers to certain frequently asked questions that might help in clearing doubts. Second is the recommendation for a person suspected of having COVID-19 (even if the results of the test are not yet confirmed) is to self-quarantine. It might be a good idea to give a phone call to the healthcare provider rather than personally visiting the clinic (Telemedicine services, 2020; Portnoy & Elliot 2020;Smith et al., 2020;Hollander & Carr, 2020). The clinician might then decide if the patient should arrive physically in the clinic. Also, the airline industry has to be prepared for future epidemics and they have to be mindful of their role in the transmission of critical and highly infective human pathogens (Wilf-Miron et al., 2003;Craig et al., 2020). The personnel working with the aviation industry need to be especially trained to be able to curb any epidemic and keep it from spreading to international and global levels. Can a person stay protected from SARS-Cov-2 by swallowing or gargling bleach, or taking acetic acid or steroids, or using essential oils, saline water, or any other substance?

No
There is no evidence that these practices help to prevent or treat COVID-19. On the contrary, such practices may prove to be harmful.

21
Was new coronavirus actually deliberately created or released by some people to infect masses?

No
Viruses can change over time and outbreak occur when the virus acquires the ability to infect humans and also has human to human transmission ability. 22 Can ordering or buying products that are shipped from China infect a person with COVID-19?

No
Coronaviruses do not stay alive for very long on surfaces. So, it is not likely that a person gets infection from a package which was already on transit for weeks. The most frequent route of transmission is through droplet infection. In fact, kids in schools also need to be trained about different ways to quarantine and about ways to help in such situations.
While the COVID-19 pandemic has brought life to a halt globally, this does not seem to be the status quo for long-term future (Petropoulos & Makridakis, 2020;Santacrose et al., 2020;Prompetchara et al., 2020). Many speculations have already been made as to how to end this pandemic (Guest et al., 2020;Peto et al., 2020). Given the R0 (3.7) and SI (7.5 days) values of the virus along with the timeline of recovery (and the proportions thereof), the time-course of vaccines development and improved management strategies; it appears that COVID-19 might follow one of the two patterns with regards to its pathogenic interaction with humans.
One is that the infection will eventually pacify and we might not see more cases once the pandemic is over and no active case is reported. The second path is that SARS-CoV-2 becomes a regular part of human viral pathogen repertoire and we may either have to vaccinate our population on regular basis (like flu shots) or once in a life time (a rare possibility). In any case, it might take a year or two for the pandemic to subside to levels that warrant a complete return of normal life. The optimism that the pandemic will die down in a matter of two to three months is not a realistic outlook, nevertheless. Since very little is known about SARS-CoV-2 and the body's immune response against this virus, it might be early to make sweeping statements and strong predictions about the dynamics of the pandemic. But reasonable guesses by experts should be acknowledged given the fact that the possibility of an outbreak was also indicated through an expert guess at least one year before the onset of COVID-19. In a scenario when a significant proportion of the population contracts the infection, a majority of the infected individuals develops resistance (immunity) against the virus. This immunity may be long-lived or may reduce down in a small period of time. In case of long-term immunity, it will become difficult for the virus to maintain its inter-human transmission and hence the society will eventually recover. This is an ardent possibility but there is no way as of now to know the timeline of such a scenario. It appears that either a vaccine will be developed and we may achieve population level immunity (or what we refer to as herd immunity) or the virus infects (and in the process kills) a significant number of people thereby rendering those who recover as immune. The caveat here is that it is too early to claim that those recovering from COVID-19 are immune to SARS-CoV-2. With regards to the timeline the harmonogram appears to be a year or two long. While in the meantime slowly and steadily life will return back to normalcy. where everyone is waiting for a vaccine desperately, it is possible that certain downsides or harmful effects of a potential vaccine (or treatment regimen) might be overlooked and that might itself present as a hazard immediately or in the long run. Vaccination of hundreds of millions of people seems to be extremely difficult task at the outset and WHO has a momentous task ahead to this effect.
World charities need to come forward to raise funds for WHO so that unanimous and authentic body of experts take care of threats like this. Also, availability if subsidized vaccines (or cost-effective vaccines) is another issue that we may be facing in a few months from now. In the light of this, it appears that return of the normal life does not seem to be plausible at least for a few months from now. Onset of summer may or may not bring down the infection rates. Even if the pandemic pacifies significantly, public health experts, governments, healthcare establishments and general public have to be cautious about the resurgence and authorities would have to consider reopening every institution in phases with comprehensive deliberation on expert recommendations.

Conclusion
COVID-19 has been declared a pandemic by WHO and it is spreading very fast. This pandemic has impacted many areas of human health and has led to crisis in the medical management worldwide. It appears that the virus mediates its pathogenic effects through binding with ACE-2. In certain cases, the infection turns out to be fata (particularly in elderly and those with comorbid conditions). While the virus has high infectivity, the infection can be avoided and hence the spread can be halted. With increasing number of deaths, rigorous research studies are being conducted to get insights into this disease and to develop vaccine and effective treatment regimens. Diagnostic kits are also being developed but have not yet been distributed widely. Even there has been an acute shortage of personal protective equipment (like face masks) worldwide. This has given us an idea about the preparedness of human all over the globe for pandemics like this. Additionally, a lot of misinformation is being spread about COVID-19 which has led to panic. In a world where we have guidelines in place to meet even aliens, this pandemic is a reminder of our humble preparedness towards any global pandemic that might occur in future. Therefore, recommendations should be developed and guidelines issued with international cooperation to curb this disease and the pandemics that we are likely to face in near future.

Funding
There was no dedicated funding for this project.