key: cord-296986-8fuj072z
authors: Kumar, Manish; Taki, Kaling; Gahlot, Rohit; Sharma, Ayushi; Dhangar, Kiran
title: A chronicle of SARS-CoV-2: Part-I - Epidemiology, diagnosis, prognosis, transmission and treatment
date: 2020-05-15
journal: Sci Total Environ
DOI: 10.1016/j.scitotenv.2020.139278
sha: 
doc_id: 296986
cord_uid: 8fuj072z

Abstract In order to benefit the public, community workers and scientific community, we hereby present a chronicle of SARS-CoV-2 that leads to the unseen precedent of social distancing and lockdown owing to coronavirus disease (COVID-19). Information on this life-threatening pandemic of COVID-19 is sparse and discrete; and the urgency is such that the dissemination of information is increasing with numerous daily publications on the topic. Therefore, we developed a comprehensive review on various aspects of SARS-CoV-2 and COVID-19. We scientifically compiled published research, news, and reports from various sources to comprehend and summarize the information and findings on Coronaviruses. The review explicitly covers the aspects like genome and pedigree of SARS-CoV-2; epidemiology, prognosis, pathogenesis, symptoms and diagnosis of COVID-19 in order to catalog the right information on transmission route, and influence of environmental factors on virus transmissions, for the robust understanding of right strategical steps for proper COVID-19 management. We have explicitly highlighted several useful information and facts like: i) No established relationship between progression of SARS-CoV-2 with temperature, humidity and/or both, ii) The underlying mechanism of SARS-CoV-2 is not fully understood, iii) Respiratory droplet size determines drop and airborne-based transmission, iv) Prognosis of COVID-19 can be done by its effects on various body organs, v) Infection can be stopped by restricting the binding of S protein and AE2, vi) Hydroxychloroquine is believed to be better than chloroquine for COVID-19, vii) Ivermectin with Vero-hSLAM cells is able to reduce infection by ~5000 time within 2 days, and viii) Nafamostat mesylate can inhibit SARS-CoV-2 S protein-initiated membrane fusion. We have also suggested future research perspectives, challenges and scope.

J o u r n a l P r e -p r o o f 8 Overall, WHO defines COVID-19 patient as: i) An individual with acute respiratory illness like fever and/or any sign of respiratory ailments like cough, sore throat, and/or has a travel history to locations reported community COVID-19 spread during the 14 days prior to the onset of symptoms. OR (2) An individual with any acute respiratory illness and/or been in contact with a confirmed or probable COVID-19 individual in the last 14 days. OR (3) An individual with severe acute respiratory illness with unexplained clinical diagnosis of alternate reasons for the problem. The central idea is to consider even a slightest probable case as a suspected patient based on above points with inconclusive or awaiting test results. While, a laboratory confirmed case is a person with a laboratory confirmation i.e. tested positive for COVID-19, irrespective of clinical signs and symptoms (asymptomatic patient). The trickiest feature of COVID-19 has lately been identified as being the asymptomatic (up to 60% in India). The risk is so heavy, spread is so fast and symptoms are of so varying nature that even travelling to a community spread country or being a physical contact of an infected person are being treated as symptoms.

Diagnostic testing for the SARS-CoV-2 is currently undertaken using two approaches: whole genome sequencing and real-time reverse transcriptase-polymerase chain reaction (rRT-PCR, Nucleic Acid Testing). Table 1 compiles the emerging diagnostics techniques being used/developed for SARS-CoV-2. The sequencing approach was used primarily in the early days of the outbreak, almost all diagnostic testing for SARS-CoV-2 is done using rRT-PCR . Many companies also launched RT-qPCR test kits to assist clinical diagnosis Chu et. al. (2020) described two 1-step RTqPCR assays to detect two different regions (ORF1b and N) of the viral genome. Saliva serves as a promising non-invasive specimen for the J o u r n a l P r e -p r o o f 9 diagnosis of COVID-19 patients with a high positive rate of 91.7% (11/12) in determining the disease using RT-qPCR (non-probes SYBR based fluorescence signal) . Though this technique has a sensitivity of 50%-79% of detection, depending on the protocol used and the sample type; the number of clinical specimens collected (Yam et. al., 2020) , safety hazards and detection time are some issues. CT scan is suggested as an auxiliary diagnostic method to avoid reporting false results and to increase sensitivity . Early diagnosis and evaluation of disease severity of COVID-19 patients can be performed using high-resolution CT (HRCT) scan of the chest . However, inability to differentiate from other viral pneumonia makes the interpretation of the hysteresis of abnormal CT imaging tedious and inadequate . Nevertheless, the chest CT had a very low misdiagnosed rate (3.9%, 2/51) in comparison with any other method.

In previous studies on SARS or MERS, lung parenchymal irregularity was reported in the central and bilateral upper lobes of lungs (Das et. al., 2016; Paul et. al., 2004) . However, Li and Xia (2020) showed that the peripheral (sub-pleural), and middle and lower zones of lungs showed an abnormality at the initial stages, followed by affecting the upper lobes, and in severe cases, all five lobes of both lungs were affected. Recently, the Center for disease control and prevention (CDC) is working on Serologic (Antibody) immunoassays (IAs) testing i.e. Protein testing, for diagnosis of COVID-19 (Vashist, 2020 (Vashist, 2020) . Further, wastewater based epidemiological (WBE) surveillance for the genetic material of SARS-CoV-19 has drawn loads of attention that can be helpful in early detection as well as resurgence of COVID-19 (Kumar et al., 2019a,b; Kumar et al., 2020a,b,c; Kitajima et al., 2020) . WBE surveillance are expected to become handy for the potential eradication of the virus in a community.

SARS-CoV-2 moves from the back of the throat to the lungs and then ultimately into the blood.

All coronaviruses contain specific genes in downstream regions of ORF1 that encode proteins for viral replication, nucleocapsid, and spikes formation (Van et. al., 2012) . SARS-CoV-2 and SARS-CoV binds with a receptor called angiotensin-converting enzyme 2 (ACE-2) found on the respiratory cells with the help of S protein, which helps in entry and replication for further spreading the infection. The receptor-binding domain (RBD) is loosely attached among viruses leading to infection of multiple host (Raj et. al., 2013; Perlman and Netland, 2009 ). Fig. 4 (a) demonstrates the interaction of viral S protein with ACE-2 on the host cell surface which is highly significant being an initiation step of infection/pathogenicity. Cryogenic Electronic

Microscopic structure analysis revealed that the binding affinity of S protein to ACE-2 is about 10−20 times higher for SARS-CoV-2 than that of SARS-CoV, which is the reason for the higher transmissibility and contagiousness of SARS-CoV-2 as compared to SARS-CoV. After , however, there still exists a lack of information about the antigen presentation of SARS-CoV-2. Therefore, till date, no SARS-CoV-2 specific antiviral agents could be discovered for a possible treatment to save lives and to produce an effective vaccine for future prevention.

demonstrates the progression of SARS-CoV-2 inside the host body. Inflammatory response of ARDS is mainly caused by the release of large amounts of pro-inflammatory cytokines known as 'cytokine storm' . SARS-CoV-2 infection undergoes 'cytokine storm' that triggers viral sepsis and inflammatory-induced lung injury leading to complications like pneumonitis, respiratory failure, ARDS, shock, organ failure, and potentially death , Prompetchara et. al., 2020 . During the cytokine storm mechanism in the body a wide variety of cytokines (IFN-α, IFN-γ, IL-1β, IL-6, IL-12, IL-18, IL-33, TNF-α, TGFβ, and others) and chemokines (CCL2, CCL3, CCL5, CXCL8, CXCL9, CXCL10, and J o u r n a l P r e -p r o o f 12 others) are released William and Chambers, 2014; Cameron et al., 2008) .

Although, the detailed beneficial role of cytokines is unclear currently due to the recent progression of the disease, there are already clinically tested drugs available which may add value to the current treatment process of cytokine storm. Interleukin-6 inhibitors, or IL-6 inhibitors drugs, which were found to be helpful in patients of France, China, and New York works based on blocking a specific cytokine associated with inflammation. Further,

Supplementary Table-2 shows various supporting statements given by doctors and researchers regarding 'cytokine storm' mechanisms and response in our body. Overall, understanding of immuno-pathological mechanism of SARS-CoV-2 infection has great potential to develop therapeutic strategies to contain the pandemic.

The prognosis of COVID-19 can be done by its effects on various body organs. The recovery rate from the infection of COVID-19 is varying based on its severity. People with mild condition (with few or no symptoms having a resemblance to some upper respiratory diseases such as common cold) are recovering within two weeks, the recovery duration can go up to six weeks for severe or critical disease cases. Two to eight weeks of duration from the symptoms onset has 16-24 February 2020). Various complications and health issues associated with COVID-19 have been reported, like Pneumonia affecting lungs, ARDS which may lead to respiratory and multiorgan failure (Cascella et. al., 2020; Heymannand and Shindo, 2020) , abnormal clotting, sepsis and damage to kidney, liver, and heart . In order to understand the severity of the virus outbreak, it is crucial to focus on the population groups which are at high risk, which will allow them to direct the resources towards the most vulnerable. high variance among the age groups. The age group of >80 years is considered a vulnerable age group due to highest death risk associated with it in all the countries. However, the age group below 50 years, and children can have mild symptoms, but the risk of death is low. The CFR caused by COVID-19 is distinctive than the other historical pandemics like malaria and Spanish flu, where the most vulnerable age group was children or young adults. However, in the case of COVID-19, along with the age group the underlying health conditions also have a significant impact on the death risk ( Fig. 5(b) ). The early-stage CFR data of China shows that people with underlying health conditions such as cardiovascular disease, cancer, hypertension, chronic respiratory disease, and diabetes, are at higher risk (WHO, 23 rd January 2020). The CFR due to COVID-19 was highest for those underlying cardiovascular disease (10.5%), followed by diabetes (7.3%), chronic respiratory disease (6.3%), hypertension (6.0%), and cancer (5.6%). A comparison suggests that people with no previous underlying health condition had ten times lesser CFR (0.9%) and thus the elderly age group with pre-existing health conditions are more.

J o u r n a l P r e -p r o o f 14 Overall, the susceptibility and recovery of the disease is highly dependent upon the innate immunity of the person. transmission. However, to date, no such study has been conducted that could establish a relationship between the fecal−oral transmission of the SARS-CoV-2. Zhou et. al., 2020b reported that viral shedding is one of the most significant ways of transmission and observed that the viral shedding was found to last for 37 days in survivors. The amount of viral load contributed to the environment by asymptomatic and symptomatic patients was conducted by Bai et. al., 2020 and Zou et. al., 2020a . The authors reported that transmission was possible even in the case of asymptomatic patients, but in the case of symptomatic patients increase in viral loads was observed.

As of now, the environmental factors that has been studied to understand the COVID-19

transmissions, are the ambient environmental temperature, humidity but still, no authenticity on the relationship is confirmed yet Kumar et al., 2020a ; Tobias and Molina 2020). Apart from climatic conditions (temperature and humidity), the transmission may be further triggered by population and medical facility (Dalziel et. al., 2018; Hemmes et. al., 1960) .

Based on the assumption that the SARS-CoV-2 is similar to SARS-CoV, it has been hypothesized that the SARS-CoV-2 may not survive at high temperature and humidity (Chan et. al. 2011 , Kumar et al., 2020 Tobias and Molina, 2020) The underlying hypothesis of decrease in the spread of viruses during warmer seasons is higher vitamin D levels, resulting in better immune responses (Aranow, 2011; Kumar et al., 2020) .

Interestingly, a common man notion is that in cold weather, people tend to stay inside, often in a closed room, at times close to each other, and that enhances the infection probability. A study confirmed a strong relationship does exist between the reported cases, temperature, and absolute with the findings for the influenza virus (Park et. al., 2020; Steel et. al., 2011; Lipsitch and Viboud, 2009; Shaman and Kohn, 2009) , where the high temperature and high humidity leads to a significant reduction in transmission of the influenza virus. This might be due to the following reasons: (i) Cold and dry weather might cause weakness in the immunity of the host (Kudo et. al., 2019; Eccles, 2002) , (ii) unlike influenza virus they might be more stable in lower temperature and within the respiratory droplets (Lowen and Steel, 2014; Tellier, 2009) . Also, the observations made for SARS CoV for temperature and humidity (Chan et. al., 2011; Yuan et. al., 2006) were inconsistent with the findings of Wang et. al., 2020.

Li et. al., 2020 reported at present, there is no proven antiviral agent that can control the COVID-19 outbreak and inactivate SARS-CoV-2. By 29 th April 2020, no drug has been approved by US food and drug administration that can prevent COVID-19. Currently, management strategies for COVID-19 patients with mild symptoms include infection prevention by using oseltamivir/ intravenous antibiotics, clinical supportive measures for severe patients such as oxygen and mechanical ventilator support . Some of the therapeutics drugs and therapy reduction in viral RNA (Caly et. al., 2020) . Another drug, Nafamostat mesylate (Fusan) as demonstrated by Japanese researchers can inhibit the fusion of SARS-CoV-2 (S) protein and initiated membrane at achievable and safe concentrations in the patients (Hannah, 2020) .

Remdesivir is an antiviral drug that is intravenous and inhibits the synthesis of viral RNA by preventing the replication of RNA by early termination of RNA transcription . Lo et. al. (2017) successfully demonstrated that Remdesivir is a potent antiviral towards SARS and MERS-CoV. As per the CDC, "Remdesivir has in-vitro activity against SARS-CoV-2 and in-vitro and in-vivo activity against related beta coronaviruses".

Hydroxychloroquine and chloroquine are anti-malarial drugs that are taken through oral administration, and both of the drugs belong to the quinolone family. Yazdany and Kim (2020) demonstrated that both the medicines have a potent antiviral property that can control SARS-CoV-2 in-vitro. Roque (2020) reported that the use of hydroxychloroquine is much safer and has more potential of inhibiting SARS-CoV-2. Hydroxychloroquine has been proven more successful than chloroquine (inhibition rate did not exceed 50% ) at inhibiting SARS-CoV-2 . Paton et. al. (2011 ), Ooi et. al. (2006 reported negative results of hydroxychloroquine and chloroquine during random testing for influenza in random patients.

Henceforth, there is lack of report, facts and figures to support the use of hydroxychloroquine and chloroquine as an efficient treatment mechanism (Yazdany and Kim, 2020) .

J o u r n a l P r e -p r o o f 19 Early signs are that convalescent plasma therapy can reduce the mortality rate in SARS-CoV-2 patients (Cheng et. al., 2005; lai, 2005; Soo et. al., 2004) . Mair-Jenkins et. al., 2015 showed recovery from SARS-CoV-2 at early-stage of treatment with convalesced plasma therapy.

Unlike SARS-CoV (Mair-Jenkins et. al., 2015) and MERS-CoV (Koenig et. al., 2015 , many patients are donating plasma with SARS-CoV-2 antibodies to control COVID-19. Duan et. al., 2020 demonstrated the potential of convalescent plasma therapy to treat the severe COVID-19 patients. 10 patients were treated with plasma therapy, a 200 ml of convalescent plasma neutralize with antibody titers above 1:640 was given to the patients who showed rapid improvement in symptoms with three days of convalescent plasma transfusion. However, treatment by convalescent plasma therapy is still questionable .

COVID-19 is a severe global health issue which is caused by SARS-CoV-2. The genomic study revealed that the phylogeny of the SARS-CoV-2 is very similar to SARS-like bat/Pangolin. The disease result in respiratory illness like SARS-CoV and MERS-CoV and may cause death in severe cases. The mortality is significantly higher in the elderly age group, mostly having preexisting health conditions. At the initial stage the disease may be identified by symptoms such as fever, dry cough, muscle pain and fatigue but challenge of identifying the asymptomatic patient is huge. The transmission is mainly through the respiratory droplets and their diameters, and through direct contact with an infected surface. In the case of airborne transmission, the probability of being infected is very less and case-specific. The higher transmissibility and contagiousness of SARS-CoV-2 may be attributed to the high binding affinity of SARS-CoV-2, S protein to ACE2. The rapid transmission is due to the weak linkage between the receptor-J o u r n a l P r e -p r o o f 20 binding domain (RBD) of SARS-CoV2 and the host cell. Some of the profound drugs available to control cytokine storm are Interleukin-6 inhibitors or IL-6 inhibitors, but for older people or people with past medical histories inhibiting the immune system may result in severe health issues. One of the probable ways to curb the infection is to restrict the binding between S protein of SARS-CoV-2 to ACE2. Though the cause and effects are known still the transmission mechanism is not fully understood. [CFR is based on Actualización nº 67, 5 th April, 2020; COVID-19 in Denmark, 6 th April, 2020; Epidemia in Rome COVID-19, 6 th April, 2020; COVID-19 in Korea, 5 th April 2020; Epidemiologische situatie COVID-19, 3 rd April 2020; Surveillances, V., 2020] 

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We acknowledge the moral support of various initiatives started by the administration of IIT Gandhinagar. We also acknowledge the help received from Ms. Payal Mazumder, Dr. Arbind Patel, Mr Alok K Thakur and anonymous referees.

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