nCOVID-19: Its diagnosis, possible preventive measures, therapeutic interventions and management

Novel coronavirus (nCOVID-19) is a current global threat causing severe infections to millions of people throughout the world. WHO has reported in their case-based surveillance that the aged and male populations are most vulnerable to this recent coronavirus infection. This disease-causing virus, named as SARS-CoV-2, is a respiratory coronavirus that probably originated from the bat with a substantially different genetic makeup concerning the other known coronaviruses. Structurally SARS-CoV-2 is a diverse single-stranded RNA virus having spike (S) glycoprotein in its envelop that is associated with the transmission of the virus by binding with the host target receptor. The principal target site of nCOVID-19 is angiotensin-converting enzyme 2 (ACE2) in the host receptor. The expression of ACE2 target site varies according to the genetic susceptibility and ABO blood group locus causing variation in the severity of the infection. The virus usually affects the infl ammatory pathways, responsible for white blood cell activation and clot formation after interacting with pathogen pattern recognition receptors. The major pathological symptoms of severe nCOVID-19 are mild to severe respiratory and bowel syndromes. Prevention of infections has been achieved by social distancing depending on the concept of aerosolized/droplet transmission of virus and by maintaining personal hygiene. Remedies like ayurvedic, homeopathic, micronutrients such as vitamins and minerals along with regular physical exercises like yoga and meditation are also found to be helpful in disease prevention. The treatments that have been applied so far with some positive responses are antimalarial chloroquine and hydroxychloroquine, antivirals, plasma therapy, steroids, omega-3-fatty acid derivatives, vitamin C infusion, etc. Some global healthcare bodies are also in action for the development of vaccines therapy against nCOVID-19. Apart from the infection control, some other associated issues like long term social distancing, constant stress, anxiety, change in lifestyle are affecting adversely the aged populations and also the other part of the society. There is no doubt that government bodies from various countries throughout the world are taking extreme measures to control and mitigate the pandemic, but this untoward situation is still far from the control of human races and supposes to take more time and further scientifi c interventions and management are needed to be continued. Review Article nCOVID-19: Its diagnosis, possible preventive measures, therapeutic interventions and management Mrinal Kanti Poddar* and Apala Chakraborty Department of Pharmaceutical Technology, Jadavpur University, 188, Raja S. C. Mallick Road, Kolkata-700032, India Received: 15 June, 2020 Accepted: 06 July, 2020 Published: 08 July, 2020 *Corresponding author: Prof. Mrinal Kanti Poddar, Department of Pharmaceutical Technology, Jadavpur University, 188, Raja S. C. Mallick Road, Kolkata-700032, India, Tel: +91-33-2442-2490; E-mail:


Introduction
The novel coronavirus, nCOVID-19, also named as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is a zoonotic virus causing mild respiratory tract infections to unusual fatal pneumonia in humans upon exposure [1]. In the recent past, the deadly infection due to nCOVID-19 has been fi rst identifi ed in Wuhan City, China on 29 th December 2019 and rapidly takes a shape of a global pandemic by increasing exponentially during the last 7 months [2]. WHO has reported (as mentioned in the report released on 28 th May 2020) that there are more than 10.1 million nCOVID-19 positive cases globally with almost 0.5 million deaths [3]. WHO has also claimed, based on their case-based surveillance that the occurrence of infection is age and gender-based ( Figure 1). As per their report, the ratio of the rate of infection in males and females is 1.03:1 with a median age of 51 years (i.e. interquartile range, IQR: 36-65 years) [4]. The most common symptoms of the nCOVID-19 positive patients are mild to moderate in nature like nasal secretions, cough, fever, dyspnea, myalgia, and occasionally diarrhea [5]. Around 17% of the cases are developing acute respiratory distress syndrome (ARDS), among which 65% cases are deteriorated to the extent of septic shock and/or multiple organ failure [5]. It is also evident that patients with underlying medical conditions such as cardiovascular diseases, diabetes mellitus, renal failure, respiratory diseases are more susceptible to nCOVID-19 infections [6,7]. So far, symptomatic therapies along with some nonspecifi c antiviral therapies have been tried as a therapeutic regimen of nCOVID-19 positive cases as the development of nCOVID-19 specifi c therapies (including vaccines) are still under clinical trials and yet to be available for the treatment purpose.
The ongoing worldwide investigations on nCOVID-19 have highlighted many insights into this infection like viral structure, immunopathology, associated symptoms, diagnostic approaches, possible preventive measures, and control, etc.
The impacts of this pandemic over the global socio-economic condition, mental health of the society, etc., have also been studied [8]. In this context, it may be mentioned that social distancing, long term lockdown, discontinuation of personal work routine, the constant fear of the infection, concern for family and friends, fear of losing fi nancial independence are collectively affecting badly the mental health of a large section of the population [8]. This leads to an increase in the level of stress followed by anxiety, depression, sleeplessness, and more chances to expose in the diseased conditions [9].
Many misconceptions and unauthentic information related to nCOVID-19 are circulating in the social media platform which causing more panic among the masses [10]. In this review, the characteristics of nCOVID-19, its possible diagnosis, preventions, therapeutic interventions, and management have been discussed in detail based on the recent investigations going on worldwide. This summarized yet informative content of the review article will help to get an overall impact on the idea of the entire status of this ongoing nCOVID-19 pandemic at a glance which will help the mass to get a clear cut knowledge about this current pandemic in our belief.

Respiratory viruses
Some major viral pathogens such as infl uenza virus, rhinovirus, adenovirus, respiratory syncytial virus (RSV), and coronavirus are responsible for maximum cases of morbidity and mortality due to the development of acute respiratory diseases (ARD) [11,12]. The clinical manifestations of respiratory infections generally help to characterize the pathogens such as rhinovirus can be characterized by typical common cold and RVS by bronchiolitis [13]. But the common viral respiratory syndromes are often associated with more than one viral infection which is presented in Table 1.

Coronavirus
As described in Table 1, Coronavirus is a class of respiratory viruses belongs to the coronaviridae family. The main vector of this virus is the bat and the infections occur to the human Citation: Poddar [34].
In 2002, SARS-CoV, the novel human Coronavirus, has been fi rst recognized as a cause of atypical pneumonia mostly in older adults and a probable cause of epidemic which affects around 8000 humans worldwide after originating from Guangdong Province, China [35]. SARS-CoV is a subclass of Zoonotic virus having horseshoe bats as reservoir hosts [36]. The important traits of SARS-CoV are (a) potentially high RNA mutation rates (2×10 -6 ) in contrast to other RNA viruses and also being able to encode 3"-5" exonuclease RNA proof-reading activity within nonstructural protein 14 (nsp14) [37,38] [37].
MERS-CoV infection, causing respiratory disease in humans, has been reported fi rst in June 2012 [40]. Human MERS-CoV is a 30 kb positive single standard RNA genome that closely resembles to lineage C -coronaviruses of Tylonycteris bat CoV HKU4 and also with the MERS-CoV derived from camels with whom it has >99.5% identical nucleotides [41,42]. MERS-CoV infection has been reported to cause around 851 deaths in 27 countries due to a lack of commercial vaccines and therapeutic interventions as reported by WHO until September 2019 [43].

The new virus SARS-CoV-2
The new coronavirus isolated in January 2020 is SARS-CoV-2, a diverse single-stranded RNA, probably originated from the bat with a substantially different genetic sequence concerning the other known coronaviruses [44,45]. Unlike SARS which has a shorter incubation period of 1-4 days, nCOVID-19 has a latency of up to 14 days under which the virus can infect an average of 3.77 numbers of other people [44,46]. The infection mechanism is dependent on the envelope spike (S) glycoprotein which facilitates receptor binding, membrane fusion, host tropism as well as transmission power of the virus [45]. This trimeric S protein cleaved in S1 and S2 subunit during viral infections [47]. S1 consists of the receptor-binding domain (RBD) and S2 is responsible for membrane fusion. S1 directly binds to the peptidase domain (PD) of angiotensinconverting enzyme 2 (ACE2) in the host receptor and host protease cleaved the S2 cleavage site and initiate the critical process of viral infections [47][48][49]. In recent research, it has been established that the ectodomain of the S glycoprotein of SARS-CoV-2 binds with the PD of ACE2 with a dissociation constant (Kd) of~15nM [50]. ACE2 in human physiology is a type I membrane protein expressed in the lungs, heart, kidneys, and intestine which helps in the maturation of peptide hormone angiotensin that controls the vasoconstriction and blood pressure [51,52]. The reported cryoelectron microscopy (cryo-EM) structures suggest that two S proteins of SARS-CoV-2 trimers can simultaneously bind to an ACE2 homodimer [53]. This binding of S protein of SARS-CoV-2 with ACE2 is 10to 20-fold greater in attraction than with S protein of SARS-CoV virus, which may be a reason behind the rapid human to human transmission worldwide [54,55]. In this context, it may be mentioned that this ACE2 expression rate is higher in less effected X-heterozygous females compared to males, as the ACE2 gene lays on the X-chromosome. Further, several genes involved with infl ammation and immune response (ABO locus, SRY, SOX3, ADAM17) are also located on the X-chromosomes and directly or indirectly plays an impact on the ACE1/ACE2 balance. Rebalancing of this ACE1/ACE2 ratio or higher level of ACE2 might reduce the infl ammation, thrombosis, and death related to nCOVID-19 [56]. The monoclonal antibodies (mAbs) S230, m396, and 80R showing cross-reactivity with SARS-CoV RBD have no possible binding affi nity towards SARS-CoV-2 RBD despite the structural homology between SARS-CoV and SARS-CoV-2 [50]. It may further suggest that SARS-directed mAbs will not necessarily cross-reactive with SARS-CoV-2 and this information will help in antibody isolation and therapeutic design for SARS-CoV-2 [50]. It is also evident that SARS-CoV-2 employs transmembrane protease serine 2 (TMPRSS2) for S protein priming. S protein priming by TMPRSS2 is found to be essential for the entry of the virus into the target cells as well as the spreading of infections [57][58][59]. Like many other infectious diseases such as infl uenza A viruses and coronaviruses, this TMPRSS2 is the critical factor for spreading of SARS-CoV-2 and thus a convenient drug target to combat SARS-CoV-2 [57][58][59][60][61][62]. In this context, it may be mentioned that camostat mesylate a serine protease inhibitor has blocking The X-ray crystallographic study of SARS-CoV-2 RBD as demonstrated by Lan, et al. (2020) has shown loops forming core along with short connecting helices with twisted fi vestranded antiparallel  sheet (1, 2, 3, 4, and 7) [60][61][62][63]. An extended insertion formed with short 5 and 6 strands, 4 and 5 helices and loops forms receptor-binding motif (RBM) is the main contacting residues for ACE2 binding. The  sheet structure is stabilized by three pairs of a cysteine residue. This extended concave outer surface in RBM of SARS-CoV-2 RBD gets an attachment to the bottom side of the N-terminal helix ACE2 small lobe Figure 2.

Immunopathology of nCOVID-19
The SARS-CoV-2-induced immune responses are occurred in two phases [64]. During the fi rst phase of incubation, the specifi c adaptive immune response gets activated to eliminate the virus and to mitigate the disease progression [64]. The development of this endogenous protective immune response during the early phase solely depends on the health of the patients and the immune-boosting approaches are helpful in this phase only. In this context, it may be mentioned that genetic differences are strong contributors to the variation in the immune response to pathogens in individuals [64]. A recent investigation of Ellinghaus, et al., (2020) have shown a 3p21.31 gene cluster as a genetic susceptibility locus for the nCOVID-19 patients as a reason for respiratory failure. The ABO blood group system has a potential involvement in this risk as locus 9q34.2 coincided with the ABO blood group locus. The study further revealed that blood group A has a higher and blood group O has lower chances of respiratory failure during nCOVID-19 infection in comparison to the other groups [65]. Impairment of immune response initiates the viral attack to the high ACE2 expressed organs such as intestine and kidney. In the second phase of the disease, cytokine release syndrome (CRS) or increased level of pro-infl ammatory macrophages and granulocytes are observed followed by infl ammation of lungs, respiratory distress, and associated disorders in severe stage [66]. Lagunas-Rangel and Chávez-Valencia (2020) have reported that severe nCOVID-19 patients have higher IL-6/ IFN- ratio than moderate nCOVID-19 patients which could be the possible reason behind the cytokine storm followed by lung damage [67]. Cytokine storm syndrome is a resultant effect of excessive release of pro-infl ammatory stimuli and/ or deregulation of infl ammation due to host-derived or environmental causes and associated with severe systemic infl ammation, hemodynamic instability, multiple organ failure, and fi nally death [68]. These proinfl ammatory stimuli are superantigens (causing massive activation of T-cell receptors), antigens, toll-like receptor (TLR) ligands, allergens, or proinfl ammatory cytokines [68]. The lack of capacity to induce an immune response in the patient of SARS-CoV-2 may be the reason behind the remaining or returning of viruses after the complete cure of the patients [67]. In severe nCOVID-19 patients, lymphocytopenia is also observed with a signifi cant reduction in B cells, natural killer (NK) cells, CD4+ T cells, and CD8+ T cells, monocytes, eosinophils and basophils along with an increase in neutrophil count [66,69,70]. The upregulation of exhaustion markers such as NKG2A on cytotoxic lymphocytes (such as NK, CD8+ T cells) is observed in nCOVID-19 positive activity against TMPRSS2 [57,58].

Structural elucidation of the receptor-binding domain of SARS-CoV-2
Citation: Poddar  patients [71][72][73][74]. SARS-CoV-2-specifi c antibodies have been detected from the plasma of convalescent patients and used to treat SARS-CoV-2 positive with acute respiratory distress syndrome (ARDS) patients [75]. Another pathological condition of nCOVID-19 is thrombocytopenia which has been observed in 36.2% of cases of severe nCOVID-19 positive cases and also carrying the risk of developing disseminated intravascular coagulation (DIC) [76][77][78]. It has been reported as per the International Society on Thrombosis and Haemostasis diagnostic criteria that DIC has been observed in 15 out of 21 non-survivors of the nCOVID-19 patients [79]. Some other reports have shown by a meta-analysis that the presence of thrombocytopenia increases the chance of severe diseases up to fi ve folds whereas in severe disease the platelet counts decrease (mean difference: −31×10 9 /L, 95% CI: −35 to −29×10 9 / L) [80]. The occurrence of thrombocytopenia and elevated D-dimer are probably due to the over activation of coagulation cascade and platelets as the procoagulant and anticoagulant homeostatic mechanisms get disrupted during viral infections [81]. This phenomenon also involves endothelial dysfunction, Toll-like receptor activation, von Willebrand factor elevation, and tissue-factor pathway activation [80,81]. It is also known that platelets, the key mediator of infl ammatory pathways, are responsible for white blood cell activation and clot formation after interacting with pathogen pattern recognition receptors or immunoglobulin Fc receptors and complement receptors (pathogen recognition) [82]. Disruption of this mechanism has a major role in viral infections associated procoagulant effect [82,83]. One rare pathological condition of nCOVID-19 is viral encephalitis which has been found in one nCOVID-19 infected patient in Beijing, China. The study with cerebrospinal fl uid (CSF) of nCOVID-19 infected patients has revealed the presence of SARS-Cov-2 in the central nervous system (CNS) and showing the symptoms of encephalitis [84].

Symptoms of nCOVID-19
The nCOVID-19 is mainly transmitted through the respiratory droplets from coughing and sneezing and the common symptoms are fever and respiratory symptoms like cough and dyspnoea, and also there is evidence of bilateral atypical pneumonia during infections. It has also been observed that aerosolized SARS-CoV-2 particles remain for hours in the air and are able to transport over a usual distance (6 feet) like outside of rooms and intra building [85]. WHO has also reported the existence of this virus in stools of the patient in 30% cases which persist up to 4-5 weeks, although not known whether it signifi es the presence of an infectious virus or not [2,86,87]. It has been found that nCOVID-19 also present in the glandular cells of the rectum along with interstitial edema and lymphoblasts-cytosis, although their association with pathological evidence such as diarrhea during nCOVID-19 infection has not been clear yet [2,88]. The increased level of proinfl ammatory cytokines (IL-1B, TNFalpha) has an association with infl ammatory bowel diseases (IBD), characterized by fever, abdominal pain, and diarrhea, during relapse and remission phases of nCOVID-19 [86,89].  have investigated by using single-cell transcriptomic analysis that the digestive system is also a potential route of SARS-CoV-2 infections along with the respiratory tract [90]. Zhang, et al. have also suggested that this may be a possible reason behind symptomatic diarrhea as an enteric symptom of nCOVID-19 as the sites of enterocytes are highly expressed with ACE2 and TMPRSS2 [89]. The rare case of nCOVID19 associated encephalitis has shown meningeal irritation signs in the patients along with low WBC count (3.3 × 10 9 /L) and lymphopenia (0.8 × 10 9 /L) [91].

Diagnosis of nCOVID-19
Globally, RT-PCR is recognized as an only validated tool for the confi rmation of nCOVID19 cases to verify the asymptomatic cases (those who have been in close contacts of nCOVID-19 positive cases) and also to differentiate nCOVID-19 from the other respiratory infections [92][93][94]. As suggested by WHO, various RT-PCR protocols are examining the amplifi cation of nCOVID-19 specifi c genes i.e. (a) envelope protein (E); (b) RNA-dependent RNA polymerase (RdRP); (c) open reading frame 1a and b 226 (Orf1a,b) ; (d) nucleocapsid protein; (N) genes of SARS-CoV-2; or (e) combination of those genes (two or more), for screening and identifi cation of nCOVID-19 positive cases. At least one of these genes should be detected by RT-PCR for interpreting the result as positive as per the guideline of WHO [94][95][96][97][98]. At present, the knowledge regarding nCOVID-19 is not fully proved, so it has been recommended to collect the specimen from the upper respiratory tract (Nasopharyngeal swab, oropharyngeal swab, nasopharyngeal aspirates, etc.) and also from the lower respiratory tract (Sputum, bronchial washing, tracheal aspirates, transtracheal aspirates, bronchoalveolar lavage, transbronchial lung biopsy, etc.) within seven days of symptoms onset [99]. Reports are available regarding the possibilities of transmission of nCOVID-19 via the fecal-oral route [100][101][102]. SARS-CoV-2 viral nucleotide detection has been found to be positive in anal swabs but negative in nasopharyngeal swabs even after 42 days of infections suggesting the requirement of resting the fecal specimen of the nCOVID-19 patients also [103].
Due to the shortage of laboratory-based molecular testing capacity and reagents, diagnostic test manufacturers are now more focused on manufacturing easy to use devices to expedite the testing process in less time [104]. The test kits are mainly able to detect (a) viral protein fraction from the human respiratory sample or (b) human antibodies generated in response to infection. For the detection of the target antigen, the testing kit usually contains specifi c antibodies fi xed paper strip or plastic casing that can give visual signal upon antigenantibody reactions [104]. The testing process usually takes 30 mints of time and the accuracy rates varying from 38% to 80% in different kits [104,105]. The testing is only able to detect in acute or early infection time when the target antigens are present in suffi cient concentration [104]. The limitation of such a test is the specifi city of antibodies towards nCOVID-19 antigen as antibodies on the test strip may also be able to recognize the human coronavirus that causes the common cold. In that case, the test should be performed only in those patients whose symptoms are very likely to nCOVID-19. Due to this reason WHO has not recommended these types of antigendetecting rapid diagnostic tests for patient care. The other Citation: Poddar   5. Consumption of milk with turmeric powder.
6. Application of sesame oil, coconut oil, or ghee in both the nostrils twice a day (in morning and evening).
7. Inhalation of steam with mint leaves or caraway seeds.
8. Application of clove powder with honey in a sore throat or cough.
9. Practicing the oil pulling therapy by swishing 1 tablespoon sesame or coconut oil in the mouth for 2 to 3 minutes and then rinsing the mouth with warm water for once or twice a 10. Naturopathic nutrition (balanced diet with fruits and vegetables) is important for improving innate immunity, especially in comorbid patients. 11. Intermittent fasting or lemon juice fasting helped in boosting the immune system; reduce oxidative stress as well as may improve autophagy in comorbid patients.  [126]. Vitamin D, which is likely to synthesized less in the body during quarantine due to lack of exposure in sunlight, able to protect the respiratory tract by preserving tight junctions and also helps to decrease the level of pro-infl ammatory cytokines followed by reducing the risk of cytokine storm leading to pneumonia [127]. It is also evident that zinc has the potential to inhibit severe acute respiratory syndrome (SARS) coronavirus RNAdependent RNA polymerase (RdRp) template binding [128].

Therapeutic interventions of nCOVID-19
The in-vitro activity and clinical applications of some drugs  [140,144].

Antivirals other than antiretrovirals:
Ribavirin is an RNA polymerase inhibitor and effective against other coronaviruses [129]. However, information related to its activity against SAR-CoV-2 is limited and so far only extrapolated from results against other coronaviruses [129]. A high dose of ribavirin or in combination therapies has shown in vitro activity against SARS-CoV but that is also associated with several side effects and toxicities such as hematologic and liver toxicity [146].
This substantial teratogenicity and toxicity is the limitation of Ribavirin as a potential therapeutics of nCOVID-19 [147].
Infl uenza-like symptoms have been treated with Oseltamivir like neuraminidase inhibitor but it has no in-vitro activity against SARS-CoV-2 [148]. So far none of the clinical trials have included oseltamivir as proposed therapeutic interventions [149]. Recently, China and Russia have approved umifenovir as a potential antiviral against SARS as this drug can target S protein/ACE2 interaction and inhibit the membrane fusion of the viral envelope [150,151]. A nonrandomized clinical data has recently established that the use of umifenovir for a median duration of 9 days in nCOVID-19 patients shows a lower mortality rate and higher compared to those who not receiving this drug [152]. Anti Ebola virus drug remdesivir or GS-5734 is a monophosphate pro-drug which converted Citation: Poddar  into active C-adenosine nucleoside triphosphate analog after metabolism, is now in limelight as a potential candidate for nCOVID-19 therapy due to its anti-RNA virus activities against coronaviridae and fl aviviridae [153]. Similarly, another anti-Ebola analog favipiravir or T705, a purine nucleotide which after activation inhibits the RNA polymerase and halt the viral replication, has shown a broad activity against RNA viruses [154]. EC50 of favipiravir against SARS-CoV-2 is 61.88 μM/L in Vero E6 cells [155]. For the treatment of the SARS-CoV-2 higher range of dosing has been proposed such that the recommended loading dose is 2400mg to 3000mg every 12 hours/day followed by a maintenance dose of 1200mg to 1800mg every 12 hours per day considering its mild side-effects in comparison to other antiviral drugs [156]. which is a polypeptide that helps to stabilize a surface protein and improves antigen recognition proving a stronger immune response [162]. Other than the subunit vaccine, DNA vaccines can also be served by direct injection of plasmids encoding the antigens followed by a wide range of immune responses [163].
The DNA vaccine development is focused on the improvement of the effi cacy by using electroporation to deliver plasmids [164]. External respiratory support: Studies suggest that respiratory failure is the main reason behind nCOVID-19 death [173,174]. The patients with respiratory distress and/or hypoxemia transnasal high-fl ow oxygen, endotracheal intubation, and invasive mechanical ventilation should use the external respiratory support as and when necessary if standard oxygen therapy does not function properly. In severe cases, a fi beroptic bronchoscope may be required for high-density sputum suction or bronchoalveolar lavage for their relief [175].
Myocardial protection: Vasoactive drugs like norepinephrine or dopamine, dobutamine for increasing the systemic functions, creatine sodium phosphate, vitamin C, coenzyme Q for avoiding comorbid myocardial injury during severe nCOVID-19 infections, conservative fl uid treatment for fl uid resuscitation and to improve oxygen supply to tissues are also sometimes needed to the patients in severe conditions [176,177].
Artifi cial liver support therapy: Treatments like plasma replacement, blood adsorption, perfusion, artifi cial liver blood purifi cation system should be carried out in the severe nCOVID-19 patients with excessive infl ammatory responses and failure of the liver. It may help to reduce the level of excess cytokines [175].
Steroids: Low doses of glucocorticoids for the short term could be a possible therapy for excessive infl ammatory responses, progressive worsening of oxygenation markers, and rapid progressive imaging. Glucocorticoids can be considered in severe nCOVID-19 cases to prevent the progression of ARDS [175]. of debris and also found to counteract the pro-infl ammatory cytokine production by the process, infl ammation resolution [178]. Thus, SPMs affect viruses in a very low dose (in nanogram level) without being an immunosuppressive. SPMs also promote various anti-viral B cell antibodies and lymphocytes, making it a potential candidate for the treatment of nCOVID-19 [178].

Nutritional supplements for gut microbiota:
The intestinal barrier can be disrupted by the high infl ammatory responses during nCOVID-19 infection-causing bacterial translocation and secondary infections [179]. This phenomenon further increases the lipopolysaccharides infl ux which takes part in the release of TNF, IL1, and IL-6, causing further exacerbation of systemic infl ammation [180]. Gut and respiratory tract fl ora interact and it has been found that gut microbiota can reduce enteritis and ventilator-associated pneumonia [179,181]. Administration of probiotics, energy source(s), amino acid, and trace elements are thus essential for the nCOVID-19 patients for maintaining the equilibrium of the gut microfl ora [175]. been applied for trial [183]. The study is most likely to be ended by the month of September 2020. The patients are assessed based on the requirement of ventilation, organ failure score, length of stay in ICU, and also the rate of 28 days mortality [183].

Treatment with the plasma of recovered patients:
From the experience of SARS and MERS, it is evident that plasma of recovered patients can be effective as a treatment of nCOVID-19 [184,185]. This is currently under clinical trial but it is expected to be effective on severe nCOVID-19 cases before applying any non-specifi c antiviral drugs although a very dynamic evaluation is needed [186,187].

nCOVID-19 and global mental health
Although the prevalence of nCOVID-19 is uncertain in the community there is no doubt that older persons are at much higher risk than the younger generation especially those with comorbidity [188,189]. The primary prevention for the aged generation is social isolation which is highly associated with depression, cognitive damage, cardiovascular, and other aging-related diseases ultimately leading to an increased rate of mortality. It is a well-known fact that people with mental illness have a lower expectancy of life than the general population [190]. A large group of populations is psychologically venerable due to poor physical and mental health, impaired access to services, and losing control over day-to-day normal lives. A greater focus is needed for the mental health of society during this lockdown phase [191]. Otherwise, anxiety, panic-like mental issues will worsen the outbreak of nCOVID-19 among the public. Retrospective case studies have shown that severe nCOVID-19 patients are showing neurological disorders like cerebrovascular diseases, consciousness impairment, and skeletal muscle symptoms [192]. The uncertainty of infection, their growth rate, and the corresponding mortality, etc. create a psychological disturbance in the population [193]. Meng and his team have conducted a survey in china with a total of 1556 samples and have observed that 37.1% of the seniors are experiencing depression and anxiety due to nCOVID-19 [194].
Qiu and others have recently shown that aged individuals are more prompt to emotional reactions [192]. They [195]. The India based survey on the younger generation has shown that 80% of the educated young generation is preoccupied with the thought of the pandemic situation and 12.5% are facing sleep diffi culties, 37.8% are going through paranoia and 36.4% of the participants are in distressful condition [8]. Even the academicians and researchers are also going through the same stressful situation due to lack of access to the university and their respective professional fi elds of activities [196]. The only option is to withdraw the social isolation as soon as the infection is under control and enough treatment is available in the market.

Conclusion
The global threat of nCOVID-19 has declared as pandemic but this global pandemic also has a huge impact over, social, economic, cultural as well as psychological damages [198]. One thing that cannot be ignored is the chances of the reoccurrence of this disease condition soon after nCOVID-19 with the same or some other infections and therefore, control is needed from every part of the society. It is important to understand and reorganized global healthcare policies and management.
Clinicians also need to be trained with updated interim guidance on the effective, safe, effi cient and prompt supportive