COVID-19: A scoping review

Background: Globally, the novel coronavirus, SARS-CoV-2, has led to a pandemic in which individuals may experience severe and life-threatening complications. Methods: A scoping review was conducted following the methodological framework. In this scoping review, 70 records as of May 21, 2020, were included and discussed to better understand the current updates of the virus. PubMed, BioRxiv, MedRxiv, Global Health and google scholars were searched comprehensively for articles, preprints, grey literature, reports, conference proceedings and expert information. Studies conducted in human and published in the English language were included in the review. All the �ndings and statements of the review regarding the outbreak are based on published data. Results: We identi�ed 624 records, of which 70 studies met the inclusion criteria. We synthesized the data from the included records and deep insights were extracted. It was observed that the impact of the outbreak is worsening due to overcrowding, presence of asymptomatic carriers, scarcity of test kits, the immune escaping ability of the virus and lack of community awareness. Conclusions and recommendations: Due to the fast-spreading nature of the SARS-CoV-2 the prevention and control strategies become challenging. It is imposing social, psychological, and socio-economic impacts. Adherence to physical distancing, quarantining suspects, using personal protective equipment, health education and introducing appropriate handwashing practices, avoiding contact with animals, improved control, and prevention strategies are recommended.


Introduction
Globally, the novel coronavirus, SARS-CoV-2, is causing a pandemic respiratory syndrome (COVID-19) that needs urgent attention [1].Coronaviruses were not reported to cause serious and life-threatening respiratory complications in humans until the outbreak of severe acute respiratory syndrome (SARS-CoV) that occurred early in 2003 which had infected 8000 people, with a death rate of 9.5% [2].This was followed by middle east respiratory syndrome (MERS-CoV) occurrence during 2012-2015 that infected 2500 people with a case fatality rate of 35% [2,3].COVID-19 is a new disease caused by the strain severe acute respiratory syndrome 2 (SARS-CoV-2) that has been identi ed to cause serious infection among humans [4] and has now become a pandemic with up to 4,789,205 con rmed cases and 318,789 deaths as of 20 May 2020 [5].SARS-CoV-2 is a viral agent in the family of corona-viridae which are positive sense, enveloped, nonsegmented RNA viruses.SARS-CoV-2 is classi ed under the genus of beta coronavirus that has a zoonotic origin whereby rst isolated from humans in 1960s [1].The virus has human and animal host.Hence, it has a zoonotic transmission [6].The novel coronavirus, previously designated 2019-nCoV, caused a cluster of pneumonia-like infections in China during late 2019.On 31 December 2019, four cases of an acute respiratory syndrome with unknown etiology were reported in China among people linked to a local seafood market [1,3].From 31 December 2019 to 3 January 2020, a total of 44 pneumonia cases with unknown etiology were reported to world health organization (WHO) from China.Within one month of the outbreak a total of 11, 791 con rmed cases and 213 deaths were reported from 19 countries [4,5].
WHO declared SARS-CoV-2 as a global public health emergency on 11 March 2020 [7] after about 118,598 con rmed cases were reported from more than 100 countries [7,8].As of 21 May 2020, SARS-CoV-2 affected 213 countries and 2 territories [9].As per the report from a previous study the median age of the con rmed cases was 59 years (range: 15 to 89 years) with the majority being males [8].The incubation period of SARS-CoV-2 is from 2 to 14 days (sometimes ranging up to 27 days) [10,11].WHO and national guidelines have endorsed preventive strategies for the current outbreak.However, the current prevention, control strategy and treatment option of SARS-CoV-2 is facing challenges.Hence, we conducted this scoping review to assess the epidemiology, transmission, treatment and current interventions, syndromes, risk factors, future prevention strategies and immune response towards SARS-CoV-2 pandemic.

Methodological framework
We used the following methodological framework to conduct this scoping review.( 1

Search strategy and searching sources
A search strategy was developed using MeSH terms in our research question: "SARS-CoV-2", "nCoV-19" and "COVID-19".We have also utilized free keywords like "Epidemiology and Pathogenesis of SARS-CoV-2", "Immune-response of SARS-CoV-2", "Prevention of SARS-CoV-2", "Treatment of COVID-19", "Challenges of SARS-CoV-2" and "future prevention strategies of SARS-CoV-2".We comprehensively searched PubMed, Cochrane, Global Health and google scholars.To avoid missing relevant studies we included preprints and grey literature using BioRxiv, MedRxiv, World Health Organization and Centers for Disease Control and Prevention reports, conference proceedings and expert information.

Study selection and data extraction
After the literature search, all the references were imported to Zotero.Four researchers (BB, HD, HL and HN) independently screened studies for eligibility and relevance.A fth researcher (GA) was consulted for discrepancies.We resolved differences through discussion.

Inclusion criteria
Articles, reports and preprints published in English language were included.

Results And Discussion
Characteristics of the included studies and reports Most of the records were retrieved from, PubMed, Google Scholar, WHO, CDC reports and Global health.The records were included as per the PRISMA diagram (Figure 1).

Global burden of SARS-CoV-2
The con rmed cases of SARS-CoV-2 are increasing.In the rst two months, the numbers of cases were higher among countries in the west paci c Asian region than other regions with the lowest cases were reported in Africa.As of 21 May 2020, the number of cases was exponentially increased among countries in the European, American, and Eastern Mediterranean regions (Figure 2).Furthermore, the number of deaths was higher in the western paci c Asian region in January and February 2020.However, come to March, the prior reported deaths were outnumbered by the reported deaths in the European and American regions(Figure 3).Virology, pathogenesis, and the clinical syndrome of SARS-CoV-2 SARS-CoV-2 is an RNA virus, with a typical crown-like appearance under an electron microscope due to the presence of glycoprotein spikes [12].Even though its origin remains vague, it was isolated in environmental samples of the Huanan seafood market by China centre for disease control and prevention, implying the origin of the outbreak [13].SARS-CoV-2 was first isolated in the Bronchoalveolar lavage fluid of three suspects in Wuhan Jinyintan Hospital during the late 2019 and later determined as a member of β-CoVs [14,15].Genome phylogenetic analysis indicates that SARS-CoV-2 shares 79.5% and 50% sequence similarity to SARS-CoV and MERS-CoV, respectively [6, 14,15].The nucleocapsid is buried inside phospholipid bilayers and covered by spike proteins.The membrane and envelope proteins are located among the S proteins in the viral envelope [16].
Individuals infected with SARS-CoV-2 presented with early symptoms of high fever (39 0 C), headache and abnormal respiratory ndings such as cough, and di cult breathing.The virus is theorized to pass through the mucous membranes, especially nasal and laryngeal mucosa entering the lungs through the respiratory tract [17].After the virus reaches the lungs it spreads to peripheral blood, causing viremia.Then the virus spreads by adhering to the angiotensin-converting enzyme 2 (ACE2), of the organs like lungs, heart, renal, gastrointestinal tract.Patients infected with the virus have a higher number of leukocytes, and increased plasma pro-in ammatory cytokines [14,18,19].The main pathogenesis of SARS-CoV-2 includes severe pneumonia, viremia, combined with the incidence of acute cardiac injury [13].
Manifestations of SARS-CoV-2 are milder in children compared with adults [20][21][22].Although most infected individuals are asymptomatic, some children do require hospitalization and intensive care due to respiratory syndrome caused by SARS-CoV-2 [23][24][25][26].Recent reports from Europe and North America have described clusters of children and adolescents requiring admission to intensive care units with a multisystem in ammatory condition with symptoms like Kawasaki disease and toxic shock syndrome [27,28].
Host immune response to SARS-CoV-2 The immune system is responsible for controlling, resolution and immunopathogenesis of Coronavirus (CoV) infections.The immune system recognizes the viral agent through pathogen-associated molecular patterns (PAMPs) and the pattern recognition receptors (PRRs).Usually, Toll-like receptor (TLR) 3, TLR7, TLR8, and TLR9 sense viral RNA in the endosome [29][30][31][32].The most important recognition mechanisms of RNA viruses are viral RNA receptor (retinoic-acid inducible gene I), cytosolic receptor (melanoma differentiation-associated gene 5) and nucleotide transferase cyclic GMP-AMP synthase [31,32].This complex signalling recruits adaptors, including TLR domain-containing adaptor protein, mitochondrial antiviral-signalling protein [33] and stimulator of interferon genes protein [34] to trigger downstream cascade molecules.This will also be involved in adaptor molecule MyD88 and lead to the activation of the transcription factor nuclear factor-κB, interferon regulatory factor 3, the production of type I Interferons and a series of pro-in ammatory cytokines [35,36].

Innate immunity
To mount an antiviral response, innate immune cells need to recognize the invasion of the SARS-CoV-2.The recognition is through PAMPs and PRRs.Innate immunity will be activated to limit the virus.A few plasma cytokines and chemokines like IL-1-17, GCSF, IP-10, MCP-1, IFN-γ and TNF-α were abnormally high among SARS-CoV-2 infected individuals [13,37].SARS-CoV-2 causes lung injury due to an in ammatory response in the lower respiratory tract that induces a cytokine storm.This is associated with the critical and life-threatening conditions among cases [38].
Like SARS-CoV and MERS-CoV, early high rise in the serum levels of pro-in ammatory cytokines occurred among SARS-CoV-2 infected individuals [39], suggesting a cytokine storm-mediated disease severity [40,41].The effective innate immune response against SARS-CoV-2 involves the action of interferon responses and its downstream cascade that controls viral replication and induction of effective adaptive immune response [15].The recognition site is present in a subset of lung cells called type 2 alveolar cells [14].
Adaptive immune response SARS-CoV-2 is suggested to be neutralized by the antibodies produced against SARS-CoV in an in vitro plaque assay, that in turn indicates a successful mounting of the humeral responses [14].Although the antibody response against SARS-CoV-2 is currently under investigation, the previous study revealed that humoral immunity was mounted against the spike glycoproteins (S) and nucleoproteins (N).This humoral response peaks and undergoes isotype switching to IgG 3 weeks post-onset of symptoms [42].
Another study reported that CD8+ T cell responses were more frequently observed than CD4+ T cells.Generally, the virus-speci c T cells were the central memory phenotypes with a signi cantly higher frequency of polyfunctional CD4+ T cells (IFNγ, TNFα, and IL-2) and CD8+ T cells (IFNγ and TNFα).A previously published report revealed that a strong T cell response was correlated signi cantly with higher neutralizing antibodies [43].

Immune Evasion Mechanisms
Current observations indicate that coronaviruses are particularly adapted to evade immune detection and dampen human immune responses.This partly explains why they tend to have a longer incubation period, 2-14 days [44].Hence the viral antigen can escape host immune detection at the early stage.The immune evasion mechanism is potentially like SARS-CoV and MERS-CoV.The other immune escaping mechanism is inhibition of innate immune responses, inhibition of interferon recognition and signalling, immune modulation including membrane or nonstructural proteins (NS4a, NS4b, NS15), viral mutations and immune exhaustion [45][46][47].Furthermore, in the adaptive immune response, the evasion mechanism

Laboratory diagnosis
The following laboratory diagnostic techniques are used to detect SARS-CoV-2.
A. Diagnostic laboratory tests 1. Viral nucleic-acid test: Is the routine con rmation test for COVID-19 based on detecting a unique sequence that shows the presence or absence of the virus.The sensitivity and speci city of real-time RT-PCR is greater than 90%.Some factors like contamination, mutations in the primer and probetarget regions of SARS-CoV-2 indicated to have false results [50,51].Another study revealed that RT-PCR is a gold standard with 100% sensitivity and speci city [52].Serum therapy: It is the use of monoclonal antibodies with serum therapy and intravenous immunoglobulins preparations as passive immunization [61,64].This can be achieved by using peptide fusion inhibitors, anti-SARS-CoV-2 neutralizing antibodies, anti--ACE-2 and protease inhibitors.The spike protein present on the viral membrane plays a vital role in virus entry and is the principal antigenic component responsible for inducing immune response [62-65].
Antithrombotic treatment SARS-CoV-2 has been associated with in ammation and a prothrombotic state, with increases in brin and brin degradation products which are currently added to the treatment guidelines.This treatment is recommended for careful monitoring, evaluating, and treating hospitalized patients with SARS-CoV-2 [66].

Drugs under investigation and trials
Remdesivir: This is not approved therapy by the Food and Drug Administration.However, it available through an FDA emergency use authorization for the treatment of hospitalized clients with COVID-19.It is suggested to be highly selective for viral polymerases, low toxicity and have a high genetic barrier to resistance with a long half-life that allows for once-daily dosing [66][67][68].This drug is under trial (GS-5734) to evaluate its safety and antiviral activity among participants with moderate and severe coronavirus diseases comparing.
Immune globulin Administration of convalescent plasma is recommended therapy which is currently under trial for SARS-CoV-2 treatment options [57,66].
Interleukin inhibitors: To limit the cytokine storm following the immune response against SARS-CoV-2 interleukin inhibitors are undergoing phase trial for treatment option [57,66].
Lenzilumab: This drug can alleviate the immune-mediated cytokine release syndrome and prevents respiratory failure.This is under clinical trial (CLS-20486775) [69].
Ravulizumab: This is also under clinical trial for safety and effectiveness with a registration number of CLS-20488594 [70].
The economical and psychological impact of SARS-CoV-2 Following the index case of SARS-CoV-2 infected individual in China by December 2019 it started to spread to the rest of the world.It is then declared as a pandemic outbreak by WHO.Since the declaration of the outbreak, it leads to several economical and psychological problems.Some of the impacts include disruption of the global chain supply due to the closing of borders, a slowdown of the investment, loss of revenue due to debt, increment in health spending cost, shortage of food and drugs, decrement of business travel and tightening domestic nancial markets [71,72].
Risk groups: Individuals with obesity, cardiovascular disease, respiratory diseases, cancer, and diabetes are highly susceptible to SARS-CoV-2 due to the depletion of immunological barrier mechanisms and cellular dysfunction [62,73].
To minimize the risk of vulnerable individuals, preventative strategies like cleaning and disinfecting inhome and areas that people touch the most should be used.Furthermore, individuals should limit shared spaces when having guests and keeping recommended physical distancing [74].
Challenges and future prevention of SARS-CoV-2 Challenges: The challenges for the effective controlling of SARS-CoV-

Future preventions and
At government level: International, National, regional governments should participate by allocating budget for training, isolation of suspects, testing and supportive cares and awareness creation.
At health institutions: Health institutions should also screen and early detection, giving supportive care and treatment, distributing medical protective equipment, give health education and introducing handwashing practices to customers and preparing isolation rooms [79].
At the community level: Creating community awareness on the transmission and early prevention, active case detection, distribution and preparing handwashing jars, utilization of hand sanitizers and respirators [79,80], avoiding over-crowding [79], avoiding intimate contact with animals [80] and applying glove to protect touching different contaminates [79] should be practiced.
At churches and University levels: Minimizing conferences and Sunday schools, avoiding large group gatherings, avoiding class lectures are recommended.Alternative lecture methods like online lectures and video conferences have to be implemented.
For upcoming researchers: should develop validated vaccine and treatment.

Conclusion
Due to the rapidly spreading nature of SARS-CoV-2, the prevention and control strategies become challenging.Generally, the SARS-CoV-2 pandemic is imposing social, psychological, and socio-economic impacts.Curative treatments and vaccines are trying to be administered to humans and some are on clinical trials.Moreover, the most important preventing strategies for the pandemic up to date are ) Identi cation of review question (what is the known about SARS-CoV-2?), (2) Developing review objectives (to assess epidemiology, transmission, treatment and intervention, risk factors, future prevention strategies and challenges of SARS-CoV-2), (3) Developing search strategy and identi cation of search sources, (4) Screening records and data extraction and (5) Setting eligibility criteria.
is due to downregulation of antigen presentation via MHC class I and MHC class II [48].Transmission, laboratory diagnosis and current treatment Transmission: The virus has two main transmissions, zoonotic transmission like the outbreak of SARS-CoV in 2003 and MERS-CoV in 2012/2015.Though there are ongoing researches on the origin of SARS-CoV-2, it is thought to be transmitted from animals.It has not yet been known which animal has caused the pandemic.It showed 96% genotypic and phenotypic similarity of SARS-CoV-2 with the Bat coronavirus [49] and anthroponotic, via direct contact or through droplets spread while coughing or sneezing.Moreover, there is no evidence of congenital transmission for SARS-CoV-2 [16].

4 .
Detecting Indicators of the in ammatory response: It is recommended to conduct tests of C-reactive protein, procalcitonin, ferritin, D-dimer, total and subpopulations of lymphocytes, IL-4, IL-6, IL-10, TNFα, INF-γ and other indicators of in ammation and immune status, which can help evaluate clinical progress, alert severe and critical tendencies, and provide a basis for the formulation of treatment strategies [58].Current treatment Neither an effective vaccine nor anti-viral therapeutic agent is approved to treat SARS-CoV-2.Hence, we mostly focus on supportive care.Development of interventions with antibodies, anti-viral or novel vaccine strategies is highly essential.As per previous reports, passive antibody therapy is observed to reduce the replication of SARS-CoV-2 [56, 60].A previous report suggested using some anti-bacterial, antimalarial, or antiviral drugs are important to limit the viral antigen by reducing viral shedding in the respiratory secretions [60].Some of the antimicrobials which are suggested to have anti-SARS-CoV-2 activities are listed below.Azithromycin: This antibacterial drug acts by regulating in ammatory responses and reduces the excessive cytokine production associated with respiratory viral infections [60].Lopinavir and Ritonavir: These antiviral drugs act by binding to Mpro, a key enzyme for coronavirus replication [61].Alpha interferon: It is used during immunomodulation as an adjuvant treatment [62].Acetaminophen: It is used to manage fever [63].

Figures Figure 1 PRISMA diagram of included records Figure 2
Figures
[54]erology test: Used for outbreak investigation.These serological tests play a role in research and surveillance which includes antigen and antibody testing.Serum antibody can be detected using ELISA coating a 3. Blood oxygen saturation test: This test also uncommon and not routinely applied as a con rmatory test rather used as further investigation of the virus[54].
[77]75]de absence validated vaccine and treatment[62,75], the ability of the viral antigen to stay hours and even longer in the air, sociocultural behaviour of people, lack of awareness, the viral capacity to stay in inanimate objects for weeks[76], overcrowding environment, presence of asymptomatic carriers[77], presence of wide host range [63], lack of adherence to the recommended physical distancing protocols, a variation of interpreting physical distancing, the unclear infective dose of the viral agent, unclear duration of infectiousness prior the onset of clinical manifestation and after recovery[67].The other main challenge of SARS-CoV-2 prevention is social stigma[78].