key: cord-289114-ifnk41oq
authors: Singh, Angaraj; Kumar, Manoj; Dubey, Ashutosh Kumar
title: Effect of pre‐existing diseases on COVID‐19 infection and role of new sensors and biomaterials for its detection and treatment
date: 2020-10-28
journal: Med Devices Sens
DOI: 10.1002/mds3.10140
sha: 
doc_id: 289114
cord_uid: ifnk41oq

The entire world is suffering from a new type of viral disease, occurred by severe acute respiratory syndrome coronavirus‐2 (SARS‐CoV‐2). The present article briefly discussed the genome sequencing and interaction of host cells with SARS‐CoV‐2. The influence of pre‐existing diseases such as diabetes, heart disease and age of the patients on COVID‐19 infection is reviewed. The possible treatments of SARS‐CoV‐2 including antiviral drugs, Chinese traditional treatment and plasma therapy are elaborately discussed. The proper vaccine for COVID‐19 is not available till date. However, the trials of pre‐existing antiviral vaccines such as, chloroquine/hydroxychloroquine, remdesivir, ritonavir and lopinavir and their consequences are briefly presented. Further, the importance of new materials and devices for the detection and treatment of COVID‐19 has also been reviewed. The polymerase chain reaction (PCR)‐based, and non‐PCR based devices are used for the detection of COVID‐19 infection. The non‐PCR based devices provide rapid results as compared to PCR based devices.

Coronavirus is a member of family Coronaviridae and subfamily Coronavirinae, which is large and enveloped RNA virus having the largest genomes (25-32 kb) among RNA viruses (Richman et al., 2016) . The genome sequence of human coronavirus (HCoV) has four genera as Alphacoronavirus (α), Betacoronavirus (β), Gamacoronavirus (γ) and Deltacoronavirus (δ). Among all four HCoV, α and β coronaviruses are pathogenic (Woo et al., 2012) . The domestic mammals (swine, mice, bat etc.) and

humans are suggested to be the origin and host for α and β coronaviruses, respectively (Lim et al., 2016) . However, γ and δ coronaviruses are originated from birds and beluga whale, respectively (Geng et al., 2013) . There are six β coronaviruses which infect the human respiratory system. Severe acute respiratory syndrome (SARS-CoV) and Middle East respiratory syndrome coronaviruses (MERS-CoV) are very infectious among the six existing HCoV [HCoV-229E, HCoV-NL63, HCoV-OC43, HCoV-HKU1 SARS-CoV, and MERS-CoV] (Li et al., 2005) . The SARS-CoV was originated from bats and birds in China, in 2002, with the common cold as a general symptom (Kuiken et al., 2003) . A report suggested that approximately 8000 patients were infected by SARC-CoV, worldwide (Gual et al., 2003) . However, the mortality rate due to SARS-CoV infection was found to be ~ 10 % . In 2014, in Saudi Arabia, new HCoV, MERS-CoV, similar to SARC-CoV was reported with a mortality rate of 35 % (Morra et al., 2018; Terada et al., 2014) . The MERS-CoV was originated from bats similar to SARS-CoV, later camels become an intermediate host (Crossley et al., This article is protected by copyright. All rights reserved similarity with RaTG13 CoV. In another study, it has been reported that the genome of SARS-COV-2 is ~ 87.6-87.7 % similar to ZC45 and ZXC21 (Woo et al., 2005) . The bats are suggested to be the natural reservoir of SARS-CoV-2. The genome size of SARS-CoV-2 has been reported to be 29.9 kb . However, this value for SARS-CoV and MERS-CoV are 27.9 and 30.1 kb, respectively (Wit et al., 2016) . The genome of COVID-19 has more similarity with SARS-CoV with a few changes. The amino acid substitution is not observed in COVID-19, which is there in NSP7 and NSP13 (Lam et al., 2020) . The infection and transportation of COVID-19 depend on the mutation of NSP2 and NSP3 (Li et al., 2016) . Both SARC-CoV and SARS-CoV-2 induces inflammatory cytokines which is the main cause for the damage of human organs . [Guo et al., 2020 (Open access) ].

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The SARS-CoV-2 has 6-11 open read frames (ORFs) (Paraskevis et al., 2020) . Two-third of the viral RNA is found in the first ORF (ORF1a/b), which encode 16 non-structural proteins (NSP) and also convert two polyproteins, pp1a and pp1ab (Li et al., 2016) . However, the structural proteins such as spike glycoprotein, envelope protein, matrix protein, and nucleocapsid protein are translated by the rest of ORFs . These four structural proteins are responsible for the functioning of COVID-19. The spike glycoprotein binds the virus with receptor angiotensin converting enzyme . The transport of nutrients and development of envelope is associated with membrane proteins . However, nucleocapsid and envelope protein is responsible for the host immune function (Cui et al., 2019) . Fig.1 demonstrates the origin, host and structural layout of SARC-CoV-2 . The genomes of SARS-CoV-2 from USA, Italy and India are ~ 99 % similar to Chinese SARS-CoV-2, while Nepal SARS-CoV-2 genomes are 100 % similar to that of the Wuhan (Sardar et al., 2020) . The genome mutation of SARS-CoV-2 from USA, Italy, India, China and Nepal has been carried out using real-time (rRT-PCR) method to understand the effect of genome sequence on the transmission of SARS-CoV-2. The sample for gene sequencing was taken from SARC-CoV-2 infected patients of Jin Yintan Hospital (Wuhan, China) for analyses of open read frame ORF1b and N genes (Thompson et al., 1994) . The sequence of both, ORF1b and N genes are represented in Table 1 (Chu et al., 2020) . The expected amplicon sizes for ORF1b and N genes were calculated to be 132 and 110 bp, respectively. The amplification efficiency of both, ORF1b and N genes were calculated to 99.6% and 95.4%, respectively. The reported gene was a perfect match with the available standard data for gene sequencing (Accession number: MN908947) (Kumar et al., 2018) . Table 1 . Genome sequence of SARS-CoV-2 (Chu et al., 2020) Gene Sequencing

Probe 5'-GCAAATTGTGCAATTTGCGG-3' b .

The novel SARS-CoV-2 has a similar interaction with host cells as observed in SARS-CoV. The contact of host cells initiates the attachment of the cellular receptor (ACE-2) with spike proteins . The virus comes into the contact of the host cell and stimulates endocytosis (Kumar et al., 2018) . The S-glycoprotein is divided into two subunits S1 and S2. The main function of S1 subunit is to determine the host range of virus and cellular tropism (by RBD). However, the membrane fusion occurs in the endosome, which is determined by S2 subunit (Zhang et al., 2014) .

Following this, the genomic RNA (gRNA) released into the cytoplasm. However, the main function of uncoated RNA is to convert ORF1a and ORF1ab into polyproteins pp1a and pp1ab (Xia et al., 2020) . The 16 non-structural proteins are produced by ORF1a, which form replication-transcription complex (RTC) in double-membrane vesicle (DMV). Besides, the gRNA started replication and form nucleocapsid (Sawicki et al. 2005) . It is collected in Endoplasmic Reticulum Golgi Intermediate Compartment (ERGIC) and budded into the lumens. Finally, the plasma membrane combines with

This article is protected by copyright. All rights reserved virion and releases the HCoV virus (Hussain et al., 2005) . The interaction and replication of SRS-CoV-2 are schematically represented in Fig. 2 . The attachment of S-protein with ACE-2 is one of the major factors for the interaction of SARS-CoV-2 (Aniket et al., 2020) . There are several host factors such as, inter feroninducible transmembrane proteins (IFITMs), which inhibit the attachment of HCoV. The attachment with previously existing HCoV such as SARS-CoV, HCoV-NL63 and HCoV-229E is inhibited by IFITMs protein due to its antiviral resistance against RNA viruses . Recently, the binding efficiency of SAR-CoV-2 is reported to be approximately 10-20 times higher than that of SARS-CoV (Letko et al.,

This article is protected by copyright. All rights reserved 2020). The research outcome suggested that SARS-CoV-2 attach more easily than other HCoV (Shereen et al., 2020) .

The innate immunity of human being is one of the influencing factors to transmit the HCoV. The innate immune system of the host has main function to use to sense the virus (Akira et al., 2011) .

Pathogen associated molecular patterns are identified using Pattern recognition receptors (PRRs).

Currently, toll like receptor (TLR), C-type lectin-like receptors (CLmin), and free-molecule receptors in cytoplasm, such as IFI16, DAI, are recognized PRRs .

In extracellular interaction, macrophages are infected by HCoV, followed by T cells, presents in macrophages by CoV antigens (Shereen et al., 2020) . The activation and differentiation of T cells generate cytokines from different T cell subunits. These cytokines are responsible for stimulation of immune response (Akira et al., 2011) . However, the higher production of these cytokines can damage the CD8 T and NK cells (Ermolaeva et al., 2008) . Also, in the intracellular host, HCoV interact with 

This article is protected by copyright. All rights reserved The extracellular cytokines are produced through the interaction of HCoV with macrophage, followed by T cells which produce the cytokines. In the intercellular region, spike proteins interact with HCoV which shows genomic RNA in the cytoplasm. The drRNA interacts with toll-like receptors (TLR-3 and TLR-4) which produce the antiviral proteins. The antiviral proteins enhance the immunity of host cells via protecting the uninfected cells.

The patients of COVID-19 increases very rapidly throughout the world. The SARC-CoV-2 is highly transmissible among previously existing HCoV. The latent and infection periods of SARC-CoV-2

This article is protected by copyright. All rights reserved have been reported to be 4.6 and 5 days, respectively (Ferguson et al., 2020) . The COVID-19 has an impact on pre-existing diseases such as cardio, diabetes, as well as age.

WHO Regional Director for Europe stated that the "Older people are at highest risk from COVID-19, but all must act to prevent community spread". The worldwide COVID-19 patient report suggested that old age people have more chances to infect as compared to youngster .

According to the available reports from federal centers for disease control in China, approximately 80 % of died patients are more than 60 years old. However, in Italy, it was ~ 81 years old (Aronson et al., 2020) . It has been reported that one-third of died American patients are about 65 years old. In Italy, higher fatality rate (~ 20 %) has been reported for older (< 80 years) patients;

however, China has ~ 14 % for the same (Grasselli et al., 2020) . Elderly people are more likely to experience a condition of acute respiratory failure, an acute lung infection that causes many deaths (Gerst et al., 2015) . However, it also appears that the virus is more likely to damage the heart, and people may die from heart attacks with COVID-19 (WHO Team et al., 2020).

The cardiovascular patients have higher risk of SARS-CoV-2 infection as reported for SARS-CoV and MERS-CoV. The heart patients have reported more cases with MERS-CoV infection as compared to SARS-CoV (Badawi et al., 2016) . In addition, approximately 30 % of the patients have heart disease that was infected with MERS-CoV (Wu et al., 2017) . Recently, a report on sever COVID-19

infected patients suggested that ~ 58 % of patients had hypertension and 25 % of patients had heart diseases (Chan et al., 2020) . The initial reports on COVID-19 suggested that approximately 12 % of COVID-19 patients have acute cardiac injury . However, these patients have high risk of death . The Chinese report on 99 patients suggested that ~ 40 % of COVID-19 patients had cardiovascular disease (CDC 2020) However, another study reported that approximately 10.5% of died patients have cardiovascular disease (Hi et al., 2020) . Several reports indicated that cardiac arrhythmias in critical COVID-19 patients have significantly higher than that of in mild and moderate cases . 

This article is protected by copyright. All rights reserved to the heart. The virus can cause heart muscle inflammation called myocarditis, making it more difficult for the heart to pump (Burrell et al., 2005) . The heart attack can be one of the reasons for the deaths of COVID-19 patients (Christopher et al., 2020) . Generally, ACE inhibitors are prescribed for hypertension (Ge et al., 2013) . Therefore, the dose of ACE has to be stopped for cardio patients infected with COVID-19 (He et al., 2006) . Cardiovascular patients need more attention during the treatment of SARS-CoV infection. In another study, it has been recorded that the use of antiviral medicines can cause heart failure and other cardiovascular problems (Sakabe et al., 2013) . The SARS-CoV-2 infected patients with the cardiovascular problem have a higher fatality rate as compared to general COVID-19 patients. In another study, it has been reported that the use of ACE for cardio patients increases fatality. The fatality rate for COVID-19 patients using ACE is higher (~ 36.8 %)

than that of without ACE (25.6 %) .

Diabetes is an incurable disease with numerous molecular and vascular anomalies which can change the pathogenic response (Knappet, 2013) . It has been reported that the mortality of diabetes patients was significantly higher in previously emerged viruses (Influenza A (H1N1), SARS-CoV and MERS-CoV) of complication such as high blood sugar, diabetic ketoacidosis, pneumonia and dehydration. These people have higher stress conditions that increases the release of hyperglycemic hormones which raises the level of blood glucose and abnormal glucose variability . However, approximately 10 % of type-2 diabetic patients, infected with SARS-CoV-2, have been observed to suffer from hypoglycemia (< 3.9 mmol / L) . Hyperglycemia and insulin resistance facilitates enhanced production of end-products of glycosylation and inflammatory cytokines that can

This article is protected by copyright. All rights reserved change the immune response of T-cells (Petrie et al., 2018) . Besides, higher level of glucose can inhibit the antiviral activity. Therefore, the control of blood glucose level in diabetes patients can improve the antiviral activity (Michael et al., 2020) . Blood sugar level may increase in diabetic patients which reduce the production of insulin, resulting in diabetic ketoacidosis (DKA). The body begins breaking down energy fats, resulting in an accumulation of blood ketones, which make the blood more acidic resulting in the serious heath complications. The diabetic patients have a higher risk of pneumonia such as COVID-19 as it causes due to inflammation of the air sacs of the lungs.

Therefore, diabetes patients (above 2 years) have been advised to have pneumococcal and annual influenza vaccines.

ACE-2 has been recognized as the potent receptor of SARS-CoV-2. The ACE-2 has been suggested as a medicine for the treatment of diabetes because it reduces inflammation .Therefore, the diabetes and COVID-19 patients treated with ACE-2 have higher risk of infection (Zachary, 2020) . Dipeptidyl peptidase-4 (DPP-4) has been reported as the receptor for MERS-CoV (Letko et al., 2020) . In addition, DPP-4 is used for reducing the blood glucose level and therefore, DPP-4 can protect the SARS-CoV-2 infection (Fadinil et al., 2020) . Another research outcome suggested that diabetes patients are not susceptible towards SARS-CoV-2 infection, while the fatality rate is quite higher than that of normal SARS-CoV-2 patients (Zoppini et al., 2018) . In summary, the diabetes patients have a higher risk of complications due to the lower immune system which increases the fatality rate. Several reports suggested that old age diabetes patients have a higher risk of COVID-19 infection as compared to young diabetes patients. It is important to notice that COVID-19 patients display symptoms very similar to flu and in many cases, it results in death of the patients in a very short time. Therefore, better treatment initially requires accurate disease diagnosis.

Due to very fast disease progression, non-specific symptoms, and death of the patient in the short duration requires detection scheme sensitive and selective enough to accurately indicate this disease.

Importantly, the COVID-19 virus is a single-stranded and fast mutating, which requires sensors to be robust, insensitive to mutation, rapid and very sensitive to viral detection on the onset of the diseases with minimal false positive results. For this reason, PCR based detection kits are the best suited.

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The development of a specific vaccine for the treatment of pandemic SARS-CoV-2 is under progress.

As COVID-19 infected patient has major problem in the respiratory system. Therefore, the treatment of COVID-19 patients is mainly focused on symptomatic and respiratory support (Colson et al., 2020) . Initially, the oxygen therapy is given to all COVID-19 patients (Marmor et al., 2016) .

Although, the specific drug for SARS-CoV-2 is not discovered till date, the medical observers are attempting with different antiviral drugs for the treatment of COVID-19 infection .

Various The active triphosphate nucleoside in remdesivir binds with RNA. This RNA polymerase and act as RNA chain terminator (Sheahan et al., 2020) . The remdesivir (EC 50 = 0.07% μM) was applied for medicinal of SARS-CoV and MERS-CoV . In addition, EC 50 = 0.77% μM of remdesivir is used for in-vitro analyses of SARS-CoV-2 for the duration of 48 h in Vero E6 cell lines (Gordon et al., 2020) . Recently, a young COVID-19 infected patient in Snohomish County in Washington was treated with remdesivir and recovered on the next day .

However, the Californian COVID-19 patient report suggested that the use of the remdesivir is not helpful (Michelle et al., 2020) .

In past few decades, chloroquine (4-amino-quinoline) and hydroxychloroquine have been adopted as major vaccines to prevent malaria, rheumatoid arthritis and lupus erythematosus as well as SARS-CoV due to its antiviral and anti-inflammatory activity, respectivel . Apart from its antiviral ability, chloroquine has ability to modulate the immunity which enhances in-vivo antiviral impact after oral administration. Therefore, chloroquine can be adopted as a vaccine to reduce SARS-CoV-2 infection (Touret et al., 2020) . However, another study conducted on Chinese COVID-19

This article is protected by copyright. All rights reserved patients demonstrated that the combination of a new antiviral drug remdesivir and chloroquine slowed down the growth of SARS-CoV-2 (Abdul et al., 2017) . The mechanism for the effectiveness of chloroquine against COVID-19 is still unclear. However, few reports suggested that chloroquine increases the pH of endosome which can inhibit the spread of SARS-CoV (Abdul et al., 2017) .

However, another report suggested that chloroquine and hydroxychloroquine inhibit the generation of sialic acid biosynthesis by inhibiting quinone reductase 2, which affect the ACE-2 glycosylation in human cells. In addition, the immune module of chloroquine and hydroxychloroquine has anti-viral property (Tricou et al., 2010) . In contrast, high dose of chloroquine increases the toxicity which 

This article is protected by copyright. All rights reserved infection. The trial of chloroquine and remdesivir has been performed on Vero E6 cells. During the trial, chloroquine and remdesivir were pretreated with the drugs for 1 h (Full time) [Fig. 5 ]. Following this, the virus was introduced (2 h). The mixture of the viral drug was extracted and cells were cultured in the medium containing drug. However, for "Entry" treatment, the drugs were applied to cells for 1 h prior to viral attachment. Drugs were introduced for 2 h for the "Post-entry" trial and retained until the end of the experiment (Fig. 5 ).

This article is protected by copyright. All rights reserved Therefore, previously developed antiviral drugs can be used for the treatment of COVID-19. Error! Bookmark not defined. Table 2 summaries the antiviral drugs, used for the treatment of viral decease. 

The use of the antiviral drug causes adverse effect on human health. Therefore, various conventional treatments have been adopted to treat COVID-19 infection. The recent Chinese report suggested that traditional Chinese medicines have been a potential alternative to reduce SARS-CoV-2 infection (Ren et al., 2020) . It has been found that the lung is the main infected organ (~ 90 %) for COVID-19

patients. However, damp and toxin plague are the main cause of infection. The traditional Chinese medicines aim to treat the damaged organ through conventional methods (National Health

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Commission of the People's Republic of China; 2020) This medicine was also used to treat SARS-CoV patients. The SARS-CoV-2 patients were treated with traditional decoctions such as qingfeipaidu decoction (QPD), gancaoganjiang decoction, sheganmahuang decoction, qingfeitouxiefuzheng recipe, etc . Chinese government treated approximately 60,000 COVID-19 patients using these conventional decoctions (Publicity Department of the People's Republic of China; 2020). This treatment is helpful for the treatment of mild cases .

However, it has been reported that sever cases were recovered 2 days earlier than that of treated with hydroxychloroquine. It has been reported that the oral liquid of Shuanghuanglian can be used to inhibit the SARS-CoV-2 infection (Lin et al., 2002) . However, another report suggested that the oral liquid of baicalin, chlorogenic acid and for sythin in Shuanghuanglian is more effective to inhibit a variety of viruses and bacteria (Lu et al., 2000) . According to the Chinese research report, both, mild and severe COVID-19 infected patients were treated with traditional medicine. However, it is more suitable for the treatment of mild cases.

In the absence of specific drugs, various antiviral drugs, therapies were applied to recover COVID-19

patients. The use of antiviral drugs has limitation due to its harmful side-effect on the human body.

However, conventional treatment was not effective for severely infected patients. Convalescent plasma therapy has been recognized as one of the most effective ways to treat critical patients (Jenkins et al., 2015) . The convalescent plasma therapy is a technique, which is applied for the treatment of virus-infected patients using antibodies from the blood of improved patients (Lai, 2015) .

In 2014, WHO declares convalescent plasma therapy as an empirical treatment during Ebola outbreak (Cheng et al., 2005) . The use of convalescent plasma therapy reduces the mortality rate for patients of MERS-CoV, Ebola, and Influenza A H1N1viruses (Arabi et al., 2015) . Convalescent plasma therapy has been observed as a better alternative for the treatment of severely infected COVID-19 patients. A COVID-19 recovered patient's blood contains unique anti coronavirus antibodies. The serum of these blood antibodies are used for the treatment of severely infected patients. These blood antibodies can stop the reproduction of the virus and also improve the immune response of patients. A research report suggested that plasma treatment is more effective at the initial stage (within 14 days of symptoms) of COVID-19 infection. The late use of plasma therapy has less effect and increases the

This article is protected by copyright. All rights reserved risk of organ damage. The plasma of recovered patients is used to make the plasma globulin, specifically for the SARC-CoV-2. However, this globulin has adverse effect to human health. It has been reported that after testing in 10 adult COVID-19 infected patients, suggested that 200 mL of convalescent plasma saturated the patient's condition after 3 days of treatment (Duan et al., 2020).

However, after 7 days high level antibodies were produced which remove the viremia. Another research report suggested that the convalescent plasma treatment improves the breathing of patients and remove the mechanical ventilator after 3 days of treatment (Shen et al., 2020) . The condition of plasma donor is an influential factor for this treatment. A generalized criteria has been adopted for the plasma donor which are as follows,

1. The body temperature of a plasma donor must be normal for more than 3 days.

2. The plasma donor has at least two consecutive negative reports of SARS-CoV-2.

3. The plasma has to be collected from the donor who has plasmapheresis in the range of 21 CFR 630.15.

4. The donor has a positive serological test report at the time of plasma collection.

The plasma therapy can be an effective treatment for COVID-19 if it is started at the early stage of infection and considering the donor and acceptor eligibility factors. In addition to the success of convalescent plasma therapy, a research report suggested the risks factor associated with plasma treatment. The plasma treatment may fail in a few patients which increases the COVID-19 infection.

It can also affect the immune system of the patient, which subsequently, causes the re-infection. Apart from this risk factor, plasma therapy has been potentially used for the treatment of COVID-19 patients worldwide.

The awareness about social distancing can be helpful to decrease the COVID-19 infection. Recently, all COVID-19 infected countries have been imposed lockdown to maintain the social distancing in public places. It has been demonstrated the effect of social distancing with and without considering the seasonal effect (Kissler et al., 2020) . The linear mathematical model was applied to estimate the transmission dynamics, as used earlier for HCoV-OC43, and HCoVHKU1 (Read et al., 2020) . The transmission rate [β(t)] is directly proportional to the basic reproduction rate [R 0 (t)] (Wallinga et al. 2007 ).

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where, γ is the individual recovered rate.

The one-time social distancing (20 weeks) data demonstrated that reproduction rate reduces by approximately 60 %. However, longer and rigid temporary social distancing was not more effective to reduce the basic production rate of COVID-19 (Lu et al., 2020) . Fig. 6 represents the dynamics of COVID-19 infection without considering seasonal effect. The reproduction rate was taken constant (2.2) during the entire scenarios. The success of social distancing ranged from zero to a 60% reduction in R 0 . The long-term (20 weeks) social distancing has the lowest average peak and total outbreak duration. The more success rate (20-40%) has been recorded in long-term social distancing as compared to temporary distancing scenarios (Lu et al., 2020) . 

This article is protected by copyright. All rights reserved represents the cumulative infection sizes with the herd immunity threshold (horizontal black bar)

[Reproduced from (Kissler et al., 2020;  Open access].

Biomedical devices play an important role in the detection of diseases as well as drug delivery systems. The COVID-19 infections in patients can be examined by pathology, immunology and molecular biological instruments. The higher molecular weight (140 kDa) encoding 3800 DNA bp of COVID-19 suggests that it requires drug delivery system . These vaccines can be delivered through the DNA, mRNA or protein (Kowalski et al., 2019) . The materials used for protective equipment, such as protective suits, masks and gloves are also an important factor to control the COVID-19 infection. A few challenges in developing protective suits are poor antitoxicity, breathability and heat dissipation. However, low protection against aerosols, reuse of gloves and mask are its main concerns (Itani et al., 2020) . As far as the treatment of COVID-19 is concerned, the role of effective detection devices becomes important. There are several sensing devices used to detect the COVID-19 infection, as discussed in the subsequent section.

The polymerase chain reaction ( 

In RT-PCR, initially, RNA is converted to cDNA by reverse transcription (Tahamtana et al., 2020) .

The transcription of RNA to DNA entails primer design in alignment to the desired RNA target sequence, followed by addition of dNT's, reverse transcriptase (enzyme), and nuclease-free buffer, which results in conversion of RNA to amplified cDNA target ( Lu et al., 2020) . The transcription and amplification process requires heating and cooling cycles. The produced cDNA is identified either by gel electrophoresis or by gene sequencing (Baelum et al., 2020) . In RT-PCR, target amplification can be monitored and quantified with relative ease. However, the application of RT-PCR requires costly

This article is protected by copyright. All rights reserved RT-PCR machines and its post analysis is quite complex (Dharavath et al., 2020) . To reduce the post sample handling, specific target amplification and to get a reliable result, Taq Man probes are introduced in the RT-PCR systems.

It possesses fluorescent dye on 5' end and a quencher on the 3'end. The fluorescent signal is reversed when TaqMan probes anneal to the target, separating the quencher and reporter dye (Baelum et al., 2020) . In the meantime, the growing primer reaches the 3' prime end and cleaves the quencher due to endonuclease activity. This detection format allows very specific, sensitive and selective identification of the nucleic acid target. It is important to note that PCR based nucleic acid detection may require thermocyclers or quantitative PCR machine which are costly and does not provide onsite detection capability. Besides, droplet digital PCR (dd-PCR) was also adopted as a sensing device for COVID-19 detection.

The dd-PCR is a new technology, where Taq Man probes are used . The amplification is carried out in a dispersed droplet phase where dispersed phase constitutes of water-oil emulsion (Taylor et al., 2017) . Due to high surface area and a large number of droplet steps before amplification, reaction is enhanced significantly. As a case study, 336 samples from 76 patients were accurate, however, dd-PCR was found to be more accurate when viral load was low.

The non-PCR based method includes self-sustained sequence replication, isothermal multiple displacement amplification, nucleic acid sequence based amplification, the loop-mediated isothermal amplification of DNA (LAMP), real-time LAMP, and real-time quantitative LAMP (RT-q LAMP) (Zhou et al., 2019) . Among which, isothermal methods have become popular due to its simplicity.

This article is protected by copyright. All rights reserved This method uses a single enzyme and does not require thermocyclers, making it easy to use in any lab setup. The process of target amplification can be accomplished at temperature of 60-75 0 C.

Besides, it uses a single enzyme and provides detection sensitivity similar to PCR-based methods.

Liu et al. investigated 4880 nasal and pharyngeal swab samples using RT-PCR method, out of which 1875 were found to be positive. It was, therefore, concluded that nasal and pharyngeal swabs displayed poor sensitivity. Other study reported the detection of COVID-19 infection using RT-LAMP method, which is a rapid visual detection kit . The detection employed colour change of reaction mixture, from orange (negative) to green (positive) and also utilized turbidity (650 nm) measurements (Shirato et al., 2020) . Primers used for the detection of Orf2ab and spike gene segments are provided in Table 3 . The pseudo-virus, ranging from 1 copy/µL-1x10 8 copies/ µL was detected using these primers (Park et al., 2020) .

In essence, it is observed that RT-LAMP methods have been used in most of the cases for the 

Recently, various polymers such as polypropylene (PP), polyvinylidene floride (PVDF), and polytetrafluoroethylene (PTFE) are used to prepare the protecting kits (Correa et al., 2020) .The protecting kits include face mask and shields. The polypropylene is used to prepare the certified masks such as N95, FFP2, FFP3 and surgical masks . However, polycarbonate (PC) and poly (ethylene terephthalate) (PET) are used to prepare the face shields (Piedmont Plastics; 2020).

It has been demonstrated that the use of nano biomaterials in the drug delivery system enhances the activity of antiviral drugs (Kumar et al., 2020) . Recently, various organic nanoparticles including lipid and polymer nanoparticles were used for DNA and mRNA delivery (Yingjie et al., 2020) . Lipid nanoparticles such as liposomes are suitable for drug delivery due to its spherical structure and enhanced biocompatibility (Islam et al., 2015) . Recently, moderna use negatively charged ionized liposome to deliver mRNA for the SARS-CoV-2 spike protein (Cohen et al., 2020) . Among

polymeric nanoparticles, polyethyleneimine (PEI) with modified fat chains and Poly (b-amino) esters (PABEs) were adapted to deliver the DNA and mRNA (Sonaje et al., 2012) . In another study, it has been reported that chitosan nanoparticles were used for delivery of antiviral drugs to the infected patients. Recently, Novochizol (containing chitosan nanoparticles) is used for the treatment of infected areas, especially lungs infection due to COVID-19 . Lately, graphene has been recognized as an alternative material for the treatment of COVID-19 infection due to its antibacterial and antiviral efficiency (Palmieri et al., 2020).

COVID-19 infection is continuously increasing worldwide. The present article reviewed the genome sequence as well as host-cell interaction with SARS-CoV-2. The ACE-2 has been identified as the primary receptor of SARS-CoV-2. The influence of pre-existing diseases like diabetes, hypertension, and age factor on infection as well as the fatality rate of SARS-CoV-2 has been discussed. The pre- Accepted Article

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Vaccine designers take first shots at COVID-19 science

Chloroquine for the 2019 novel coronavirus SARS-CoV-2

Polymer Applications for Medical Care in the COVID-19 Pandemic Crisis: Will We Still Speak Ill of These Materials?

Identification of a novel coronavirus possibly associated with acute respiratory syndrome

Origin and evolution of pathogenic coronaviruses

Lopinavir/ritonavir: a review of its use in the management of HIV infection

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A one-step, one-tube real-time RT-PCR based assay with an automated analysis for detection of SARS-CoV-2

Effectiveness of convalescent plasma therapy in severe COVID-19 patients

Function of TRADD in tumor necrosis factor receptor 1 signaling and in TRIF-dependent inflammatory responses

Prevalence and impact of diabetes among people infected with SARS-CoV-2

Review of the Clinical Characteristics of Coronavirus Disease 2019 (COVID-19)

Are patients with hypertension and diabetes mellitus at increased risk for COVID-19 infection?

Impact of non pharmaceutical interventions (NPIs) to reduce COVID-19 mortality and healthcare demand

Chitosan nanoparticles potential drug delivery systems for COVID-19

Favipiravir (T-705), a novel viral RNA polymerase inhibitor

Breakthrough: Chloroquine phosphate has shown apparent efficacy in treatment of COVID-19 associated pneumonia in clinical studies

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A novel human coronavirus: Middle East respiratory syndrome human coronavirus

Loneliness as a public health issue: the impact of loneliness on health care utilization among older adults

Isolation and characterization of a bat SARS-like coronavirus that uses the ACE2 receptor

The mechanism of resistance to favipiravir in influenza

The antiviral compound remdesivir potently inhibits RNA-dependent RNA polymerase from Middle East respiratory syndrome coronavirus

Critical care utilization for the COVID-19 outbreak in Lombardy, Italy: early experience and forecast during an emergency response

Isolation and characterization of viruses related to the SARS coronavirus from animals in Southern China

Myocardial injury may be key in predicting COVID-19 fatalities

The origin, transmission and clinical therapies on coronavirus disease-2019 (COVID-19) outbreak -an update on the Status

Expression of elevated levels of pro-inflammatory cytokines in SARS-CoV-infected ACE2 cells in SARS patients: relation to the acute lung injury and pathogenesis of SARS

Radiological findings from 81 patients with COVID-19 pneumonia in Wuhan, China: a descriptive study

Clinical features of patients infected with 2019 novel coronavirus in Wuhan

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Clinical and radiographic features of cardiac injury in patients with 2019 novel coronavirus pneumonia

Identification of novel subgenomic RNAs and noncanonical transcription initiation signals of severe acute respiratory syndrome coronavirus

Hepatitis C guidance recommendations for testing, managing, and treating hepatitis C virus infection

Biomaterials for mRNA delivery

Optiazing use of theranostic nanoparticles as a life saving strategy for treating COVID-19 patients

The effectiveness of convalescent plasma and hyperimmune immunoglobulin for the treatment of severe acute respiratory infections of viral etiology: a systematic review and exploratory meta-analysis. The

Detecting the Coronavirus (COVID-19)

Press conference of the joint prevention and control mechanism of state council on

Hydroxychloroquine prophylaxis for COVID-19 contacts in India

Novel coronavirus 2019-nCoV: early estimation of epidemiological parameters and epidemic predictions

Traditional Chinese medicine for COVID-19 treatment

Clinical virology

Nitazoxanide: a first-in-class broad-spectrum antiviral agent Antiviral research

Sick sinus syndrome induced by interferon and ribavirin therapy in a patient with chronic hepatitis

Comparative analyses of SAR-CoV-2 genomes from different geographical locations and other coronavirus family genomes reveals unique features potentially consequential to host-virus interaction and pathogenesis

Effects of chloroquineon viral infections: an old drug against today's diseases?

New insights into the antiviral effects of chloroquine. The Lancet Infectious Diseases

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Coronavirus transcription: a perspective. Current topics in microbiology and immunology

Broad-spectrum antiviral GS-5734 inhibits both epidemic and zoonotic coronaviruses

Comparative therapeutic efficacy of remdesivir and combination lopinavir, ritonavir, and interferon beta against MERS-CoV

Treatment of 5 Critically Ill Patients With COVID-19 With Convalescent Plasma. The journal of the american medical association

COVID-19 infection: Origin, transmission, and characteristics of human Coronaviruses

Antiviral drugs against alphaherpesvirus

Development of Genetic Diagnostic Methods for Detection for Novel Coronavirus 2019 (nCoV-2019) in Japan

Opening of epithelial tight junctions and enhancement of paracellular permeation by chitosan: microscopic, ultrastructural, and computed-tomographic observations

Real-time RT-PCR in COVID-19 detection: issues affecting the results

Droplet Digital PCR versus qPCR for gene expression analysis with low abundant targets: from variable nonsense to publication quality data

Mechanism of inhibition of ebola virus rna-dependent rna polymerase by remdesivir

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Emergence of pathogenic coronaviruses in cats by homologous recombination between feline and canine coronaviruses

improving the sensitivity of progressive multiple sequence alignment through sequence weighting, position-specific gap penalties and weight matrix choice

Of chloroquine and COVID-19

A randomized controlled trial of chloroquine for the treatment of dengue in Vietnamese adults

How generation intervals shape the relationship between growth rates and reproductive numbers

A Melting Curve-Based Multiplex RT-qPCR Assay for Simultaneous Detection of Four Human Coronaviruses

Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro

Updated understanding of the outbreak of 2019 novel coronavirus (2019-nCoV) in Wuhan

RT-LAMP for rapid diagnosis of coronavirus SARS-CoV-2

SARS and MERS: recent insights into emerging coronaviruse

Characterization and complete genome sequence of a novel coronavirus, coronavirus HKU1,from patients with pneumonia

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Discovery of seven novel Mammalian and avian coronaviruses in the genus deltacoronavirus supports bat coronaviruses as the gene source of alphacoronavirus and betacoronavirus and avian coronaviruses as the gene source of gammacoronavirus and deltacoronavirus

Genome composition and divergence of the novel coronavirus (2019-nCoV) originating in China

A new coronavirus associated with human respiratory disease in China

Timely blood glucose management for the outbreak of 2019 novel coronavirus disease (COVID-19) is urgently needed

Secular trends in all-cause and cause-specific mortality rates in people with diabetes in Hong Kong

Preliminary exploration of the mechanism of Qingfei Paidu decoction agains novel coronavirus pneumonia based on network pharmacology and molecular docking technology

Altered lipid metabolism in recovered SARS patients twelve years after infection

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Fusion mechanism of 2019-nCoV and fusion inhibitors targeting HR1 domain in spike protein

Rapid and visual detection of 2019 novel coronavirus (SARS-CoV-2) by a reverse transcription loop-mediated isothermal amplification assay

Epidemiological and clinical features of the 2019 novel coronavirus outbreak in China

In Vitro Antiviral Activity and Projection of Optimized Dosing Design of Hydroxychloroquine for the Treatment of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2)

Biosafety materials: an emerging new research direction of materials science from the COVID-19 outbreak

Quantitative Detection and Viral Load Analysis of SARS-CoV-2 in Infected Patients

Diabetes and COVID-19

Diabetes patients with COVID-19 need better care

Clinical characteristics of 140 patients infected by SARS-CoV-2 in Wuhan

Progress and Prospects on Vaccine Development against SARS-CoV-2, Vaccines

Current advancements and potential strategies in the development of MERS-CoV vaccines

Investigating the mechanism of Qing-Fei-Pai-Du-Tang for the treatment of Novel Coronavirus Pneumonia by network pharmacology

Probable pangolin origin of SARS-CoV-2 associated with the COVID-19 outbreak

A Pneumonia Outbreak Associated with a New Coronavirus of Probable Bat Origin

A Review of the Microbial Production of Bioactive Natural Products and Biologics

Mortality from infectious diseases in diabetes. Nutrition, Metabolism & Cardiovascular Diseases

Coronaviruses -drug discovery and therapeutic options

Accepted Article

This article is protected by copyright. All rights reserved Traditional and Herbal drugs. Retried from