Characteristics of the included studies and reports
Most of the records were retrieved from WHO, CDC reports and Global health. Out of the 70 included articles (Figure 1) more than half were reports and expert opinions.
Three months Global burden of SARS-CoV-2 in terms of total confirmed cases and deaths
The confirmed cases of SARS-CoV-2 are increasing. In the first two months, the numbers of cases were higher among countries in the west pacific Asian region than other regions with the lowest cases were reported in Africa. As of 21 May 2020, the number of cases were exponentially increased among countries in the European, American, and Eastern Mediterranean regions (Figure 2). Furthermore, the number of deaths were higher in the western pacific Asian region in January and February 2020. However, the reported deaths outnumbered among countries in the European region by since March 2020 up to date (Figure 3).
Virology, pathogenesis, and clinical syndrome of SARS-CoV-2
SRARS-CoV-2 is an RNA virus, with a typical crown-like appearance under an electron microscope due to the presence of glycoprotein spikes on its envelope that is caused by SARS-CoV-2 [12]. Even though its origin remains vague, it was isolated in environmental samples of the Huanan seafood market by China center for disease control and prevention, implying the origin of the outbreak [13]. SARS-CoV-2 was first isolated in the Broncho alveolar lavage fluid of three suspects in Wuhan Jinyintan Hospital during the late 2019 and later considered 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]. Possesses a nucleocapsid composed of genomic RNA and phosphorylated nucleocapsid protein. 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 COVID-19 presented with early symptoms of high fever (390c), headache and abnormal respiratory findings such as cough, and difficult breathing. The virus is theorized to pass through the mucous membranes, especially nasal and larynx mucosa entering the lungs through the respiratory tract [17]. After the virus reaches in the lung it spreads to peripheral blood, causing viremia. Then the virus would adhere and express 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-inflammatory cytokines [14, 18, 19-]. The main pathogenesis of COVID-19 infection as a respiratory system targeting virus was severe pneumonia, viremia, combined with the incidence of acute cardiac injury [13].
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 and the pattern recognition receptors. Usually, Toll-like receptor (TLR) 3, TLR7, TLR8, and TLR9 sense viral RNA and DNA in the endosome [21, 24]. 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 [23, 24]. This complex signaling recruits adaptors, including TLR domain-containing adaptor protein, mitochondrial antiviral-signaling protein [25] and stimulator of interferon genes protein [26] 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-inflammatory cytokines [27,28].
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. In the innate immunity there is activation and regulation of the immune system to eliminate the virus, otherwise results in immunopathology. A few plasma cytokines and chemokines like IL-1, IL-2, IL- 4, IL-7, IL-10, IL-12, IL-13, IL-17, GCSF, macrophage colony-stimulating factor, IP-10, MCP-1, MIP-1α, hepatocyte growth factor, IFN-γ and TNF-α were abnormally high among SARS-CoV-2 infected individuals [13-29]. SARS-CoV-2 causes lung injury due to an inflammatory response in the lower respiratory tract that induces cytokine storm. This is associated with the critical and life-threatening conditions among cases [30].
Like SARS-CoV and MERS-CoV, early high rise in the serum levels of pro-inflammatory cytokines occurred among SARS-CoV-2 infected individuals [31], suggesting a cytokine storm-mediated disease severity [32, 33]. 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
Unlike the other coronaviruses, limited serology details of SARS-CoV-2 were reported. In a previous study, peak IgM antibodies were observed after day 9 of disease onset. Additionally, sera from 5 patients of confirmed cases showed some cross-reactivity with SARS-CoV. Furthermore, SARS-CoV-2 is suggested to be neutralized by the antibodies produced against SARS-CoV in an in vitro plaque assay, suggesting a possible 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 triggers S and N-specific IgM response. This humoral response reached peak and isotype switching to IgG 3 weeks of post symptoms onsets. After 3 weeks IgM decreases and IgG increases [34]. Another study reported that CD8+ T cell responses were more frequently observed than CD4+ T cells. Generally, the virus-specific T cells were the central memory phenotypes with a significantly higher frequency of polyfunctional CD4+ T cells (IFNγ, TNFα, and IL-2) and CD8+ T cells (IFNγ and TNFα). Previously published report revealed that a strong T cell response was correlated significantly with higher neutralizing antibodies [35].
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 [36]. 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 signaling, immune modulation including membrane or nonstructural proteins (NS4a, NS4b, NS15), viral mutations and immune exhaustion [37-9]. Furthermore, in the adaptive immune response, the evasion mechanism is due to downregulation of antigen presentation via MHC class I and MHC class II [40].
Suggested strategies to trigger immune system
In the presence of controversial ideas between the immune system and SARS-CoV-2, some scientist and reports suggested that taking items listed below are some supplements to trigger the immune system.
- Reducing stress: Stress has negative impact on the production of lymphocytes. As stress increases the risk of viral disease increases [41, 42].
- Exercise: Regular exercise promotes cardiovascular health, lowers blood pressure, helps control body weight, and offers protection against diseases. Exercise also improves blood circulation, allowing immune system cells to move through the body more freely and do their job more effectively. Exercise also helps to improve cholesterol and lowers blood pressure and the risk for heart disease [41-43]
- Eat a balanced diet with fruits, vitamins, and vegetables: Previous evidence suggested that a lack of these nutrients can alter the immune response [42, 44].
- Get enough sleep: Studies showed that people who get an optimal sleep (sleeping 7-8 hours for adults and up to 10 hours for children and teenagers) are less likely to be at risk of viral infections [42, 44].
- Nutritional supplements: Such as Vitamin A, B, C and D, Zinc Selenium and iron can boost the immune system against SARS-CoV-2 [45, 46].
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 [47] 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].
Laboratory diagnosis
The following laboratory diagnostic techniques are used to detect SARS-CoV-2.
- Viral nucleic acid test: Is the routine confirmation test for COVID-19 based on detecting a unique sequence that shows the presence or absence of the virus. The sensitivity and specificity of real-time RT-PCR is greater than 90%. Some factors like contamination, mutations in the primer and probe-target regions of SARS-CoV-2 indicated to have false results [48, 49]. Another study revealed that RT-PCR is a gold standard with 100% sensitivity and specificity [50].
- Serology 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 Specific antibody of SARS-CoV-2. Diagnosing SARS-CoV-2 with serology lies with 65-80% sensitivity and 93-100% specificity [51].
- Viral sequencing: After the virus is detected by nucleic acid test viral sequencing is important for monitoring genome mutation [52, 53].
- Viral culture: It is not a routine test but used for further investigation [52, 53].
- Haematological test: Is a supportive test to the routine tests for screening the distribution of complete blood cells [52, 53].
- Chest CT Scan: It aids as a supportive diagnostic method to show pneumonia. This test should be considered to confirm COVID-19 when we are under investigating of this virus [52, 53]. It has higher sensitivity (86-98%) and low specificity (25%) because the imaging features overlap with other viral pneumonia [54, 55].
- Blood oxygen saturation test: This test also uncommon and not routinely applied as a confirmatory test rather used as further investigation of the virus [52].
- Detecting Indicators of the inflammatory 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, TNF-α, INF-γ and other indicators of inflammation and immune status, which can help evaluate clinical progress, alert severe and critical tendencies, and provide a basis for the formulation of treatment strategies [56].
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. Rapid public health interventions with antibodies, anti-viral or novel vaccine strategies are highly essential. As per previous reports, passive antibody therapy limits SARS-CoV-2 pandemic which can recognize epitope regions in the foreign virus particle and reduce the virus replication [57, 58]. Although there is no specific treatment, some reports recommended that using some anti-bacterial or antimalarial and antiviral drugs are important as pre or shortly after the onset of the virus as prophylaxis to reduce infectiousness to others by reducing viral shedding in the respiratory secretions [57]. Some of the prophylactic drugs are listed below.
Azithromycin: This antibacterial drug acts by down regulating inflammatory responses and reduces the excessive cytokine production associated with respiratory viral infections [58].
Chloroquine: This anti-malarial drug with anti-inflammatory and immunomodulatory activities, has gained significant interest as a potential therapeutic option for the management of COVID-19 which acts by inhibiting the viral enzymes or processes such as viral DNA and RNA polymerase, viral protein glycosylation, virus assembly, new virus particle transport, and virus release. It also involves angiotensin-converting enzyme 2 (ACE2) cellular receptor inhibition, acidification at the surface of the cell membrane inhibiting fusion of the virus, and immunomodulation of cytokine release [58].
Lopinavir and Ritonavir: These ant viral drugs act by binding to Mpro, a key enzyme for coronavirus replication [59].
Alpha interferon: It is used during immunomodulation as an adjuvant treatment [60].
Acetaminophen: It is a temperature controller [61].
Serum therapy: It is the use of monoclonal antibodies with serum therapy and intravenous immunoglobulins preparations as passive immunization [59, 62]. 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 [60-63].
Antithrombotic treatment
SARS-CoV-2 has been associated with inflammation and a prothrombotic state, with increases in fibrin and fibrin degradation products which are currently added to the treatment guidelines. This treatment is recommended for careful monitoring, evaluating, and treating hospitalized patients with COVID-19 [64].
Drugs under investigations
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 [64, 65, 66]
Hydroxychloroquine: Have better tolerability than chloroquine but the FDA precautioned that should not be used outside the hospital [67].
Immune globulin administration: Administration of convalescent plasma is recommended therapy which is currently under trial for COVID-19 treatment options [55, 64].
Interleukin inhibitors: To limit the cytokine storm following the immune response against SARS-CoV-2 interleukin inhibitors are undergoing phase trial for treatment option [55, 64].
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 their border, 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 financial markets [68, 69]. Besides this, the outbreak leads to psychological trauma like fears, sadness, anxiety, and depression of the people [70].
Risk groups: Individuals with obesity, cardiovascular disease, respiratory diseases like chronic obstructive pulmonary disease, asthma, bronchitis, sinusitis, seasonal allergies/toxic mold exposure, dysbiosis, auto-immune diseases, fibromyalgia, neuro-degenerative disease, cancer, fatty liver, biotoxin illness and diabetes are highly susceptible to SARS-CoV-2 due to the depletion of immunological barrier mechanisms and cellular dysfunction [60].
To minimize the risk of vulnerable individuals, preventative strategies like cleaning and disinfecting in home and areas that people touch the most should be used. Adhering the same preventive measures as people went out and contacting healthcare providers are very crucial to minimize the risk of getting infected. Furthermore, individuals must limit shared spaces when having guests and keeping recommended physical distancing [71].
Challenges and future prevention of SARS-CoV-2
Challenges: The challenges for the effective controlling of SARS-CoV-2include absence validated vaccine and treatment [60, 72], ability of the viral antigen to stay hours and even longer in the air, socio-cultural behaviour of people, lack of awareness, viral capacity to stay in inanimate objects for weeks [73], overcrowding environment, presence of asymptomatic carriers [74], presence of wide host range [61], lack of adherence to the recommended physical distancing protocols, variation of interpreting physical distancing, unclear infective dose of the viral agent, unclear duration of infectiousness prior the onset of clinical manifestation and after recovery [65, 67].
Future preventions and recommendations
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 [75].
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 [75, 76], avoiding over-crowding [75], avoiding intimate contact with animals [76] and applying hand glove to protect touching different contaminates [75] should be practiced.
At churches and University levels: Minimizing conferences and Sunday schools, avoiding movement along with different places, avoid lecturing in classes and replace with alternative lecture methods, creating awareness using posters, preparing and distributing handwashing jars for the university community at the entry and exit and empowering the community on the usefulness of social distancing and handwashing practices.
For upcoming researchers: Researchers should develop validated vaccine and treatment.