key: cord-0870278-m7jmkjr4
authors: Lotfi, Melika; Rezaei, Nima
title: SARS‐CoV‐2: A comprehensive review from pathogenicity of the virus to clinical consequences
date: 2020-06-03
journal: J Med Virol
DOI: 10.1002/jmv.26123
sha: f27b702373a44d64b274b4036cb7c97ed7fec8ea
doc_id: 870278
cord_uid: m7jmkjr4

Nowadays, severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2), which caused novel coronavirus disease (COVID‐19) pandemic, is the worldwide challenge. The virus is highly contagious, and clinical consequences were very divers. It is estimated that if no effective action is taken, COVID‐19 could plague 90% of the world's population and kill over 40 million people. So, it is essential to understand the virus pathogenicity and follow the preventive methods to control the high morbidity and mortality rates. Meanwhile our current knowledge of COVID‐19 is still limited, despite hard efforts of scientists and clinicians during last few months. In this review article, we have collected the latest data about characteristics, pathogenesis, clinical manifestations, and diagnostic methods of SARS‐CoV‐2. This article is protected by copyright. All rights reserved.

Entrance and replication of SARS-CoV-2 Coronavirus S protein has been shown as a remarkable determinative of virus entry into host cells (23) . The entrance of SARS-CoV into cells is primarily performed via direct membrane fusion between the virus and plasma membrane (24) like MERS-CoV (25) , which has evolved an abnormal two-step furin activation for membrane fusion as well.

Belouzard et al. (26) reported that a significant proteolytic cleavage event happened at SARS-CoV S protein at position (S2′) mediated the membrane fusion and viral infectivity. Alongside the membrane fusion, the clathrin-dependent and -independent endocytosis mediates the SARS-CoV entry as well (27, 28) . After the virus entrance to the cells, the viral RNA genome is unleashed into the cytoplasm and is translated into two polyproteins and structural proteins, after which the viral genome initiates replication (29) . It must be mentioned that like human immunodeficiency virus (HIV), SARS-CoV-2 contains a potential cleavage site for furin proteases for activating the polyproteins (30) .

The newly formed envelope glycoproteins are inserted into the membrane of the endoplasmic reticulum or Golgi, and the nucleocapsid is created through the combination of genomic RNA and nucleocapsid protein. Then, viral particles germinate into the endoplasmic reticulum-Golgi intermediate compartment (ERGIC) . Eventually, the vesicles containing the virus particles fuse with the plasma membrane to release the virus (23) .

Quantitative real-time PCR (RT-qPCR) test has prevalently been applied for the identification of causative viruses from respiratory secretions and final pathogenic This article is protected by copyright. All rights reserved.

diagnostics of COVID-19. At present, the mentioned technique is considered as a practical approach for confirming the diagnosis in clinical cases of COVID-19 (31) , and more than seven types of SARS-CoV-2 nucleic acid test kit have been developed and approved rapidly (31, 32) . Like the supreme Pure Viral RNA Kit (Roche), HiScript® II, and one Step qRT-PCR SYBR® Green Kit (Vazyme Biotech Co., Ltd) (33) .

The diagnosis of COVID-19 based on the stage of infection can be made through detecting nucleic acids of SARS-CoV-2 in specimens like nasopharyngeal and oropharyngeal swabs (34) , sputum, lower respiratory tract secretions, stool, and blood (35) . It was found that the anal swabs gave more positive results than oral swabs in the later stages of the infection (33) . Hereupon, the clinicians have to be cautious while discharging any COVID-19 infected patient based on negative oral swab test results due to the possibility of fecal-oral transmission. Recently, the live virus was detected in the self-collected saliva of patients infected with COVID-19. These findings were confirmative of using saliva as a non-invasive specimen for the diagnosis of COVID-19.

However, due to the restriction of sampling materials, specifically in the early stage of the disease, the positive rate is relatively low. Also, these techniques are associated with unnecessary risks to healthcare workers due to close contact with patients (36) .

The patients infected with COVID-19 had elevated plasma angiotensin2 levels. The level of angiotensin2 was found to be linearly associated with the viral load and lung injury, indicating its potential as a diagnostic biomarker (37) .

In-house anti-SARS-CoV IgG and IgM ELISA kits were extended applying SARS-CoV Rp3 NP as an antigen, that portioned above 90% amino acid identity to all SARS-CoVs This article is protected by copyright. All rights reserved. Accepted Article (7) . For the IgG test, MaxiSorp Nunc-Immuno 96 well ELISA plates were coated (100 ng/well) overnight with recombinant NP, and the IgM test, MaxiSorp Nunc-Immuno 96 well ELISA plates were coated (500 ng/well) overnight with anti-human IgM (µ chain) (33) . Also, there is a clinical trial for serological detecting of SARS-CoV-2 named, Clinical Performance of the VivaDiag ™ COVID-19 IgM / IgG Rapid Test in Early Detecting the Infection of COVID-19 (NCT04316728).

Chest computed tomography (CT) is a perfect diagnostic implement for recognizing viral pneumonia as the sensitivity of chest CT images was 97% with reference RT-PCR (38) , and the sensitivity of chest CT is far more superior to the x-ray.

Moreover, in asymptomatic patients of COVID-19, lung CT scans have shown pneumonia (39) . Thus, for early diagnosis of the virus, chest CT is preferable (40) .

Chest CT findings (41) are as follow: Ground-glass opacity (86%), Consolidation (29%), Crazy-paving (19%), Linear (14%), Cavitation (0%), Discrete nodules (0%), pleural effusion (0%), Lymphadenopathy (0%), Bilateral distribution (76%), and Peripheral distribution (33%). Moreover, the primary focal unilateral ground-glass opacities may progress to diffuse bilateral ground-glass opacities and will further progress to or co-exist with lung consolidations changes within 1-3 weeks (42) .

CoVs induce inflammation in lung tissue. The histological examination of lung biopsy specimens received from COVID-19 infected patients revealed diffuse alveolar damage, desquamation of pneumocytes, hyaline membrane formation, and cellular fibromyxoid This article is protected by copyright. All rights reserved.

exudates connotative of acute respiratory distress syndrome (ARDS) (43) . The latest autopsies have confirmed that lungs are filled with clear liquid jelly, much like the lungs of wet drowning (43) . Although the nature of the crystal clear jelly has not yet been recognized, there is a connection between it and ARDS (44) , which is the potential of death.

In the healthy human lung, the ACE2 receptor is expressed on type I and II alveolar epithelial cells. Not only 83% of the type II alveolar cells have ACE2 receptor expression, but men also had a higher ACE2 receptor level in their alveolar cells than women. Moreover, the level of ACE2 receptor expression in Asians' alveolar cells is higher than that of white and African American populations. So, it is why Asian men are at high risk of the infection.

The binding of SARS-CoV-2 to the ACE2 receptors causes an elevated expression of ACE2, which can lead to alveolar cell damages and, in turn, trigger a series of systemic reactions and even death. For preventing the alveolar cell damage and death, pulmonary mechanisms would be compromised via bronchoconstriction, airway congestion, secretions, and decreased mucociliary clearance (45) .

Lymphopenia, along with/without leukocyte abnormalities (40) and "cytokine storm," may have a crucial role in the pathogenesis of COVID-19 (46) (47) (48) (49) . The investigation of 41 hospitalized patients with high-levels of pro-inflammatory cytokines consists of IL-2, IL-7, IL-10, G-CSF, IP-10, MCP-1, MIP-1A, and TNF-α were reported cytokine release syndrome (CRS) or cytokine storm in the COVID-19 severe cases (50) . Cytokine storm This article is protected by copyright. All rights reserved.

could inchoate viral sepsis and inflammatory-induced lung injury, which results in other complications, including pneumonitis, ARDS (51), respiratory failure, shock, organ failure, and potentially death. ARDS is the prevalent immunopathological event for SARS-CoV-2, SARS-CoV, and MERS-CoV infections.

One of the principal mechanisms for ARDS is the cytokine storm, the deadly uncontrolled systemic inflammatory response resulting from the release of large amounts of pro-inflammatory cytokines (IFN-α, IFN-γ, IL-1β, IL-6, IL-12, IL-18, IL-33, TNF-α, and TGFβ) and chemokines (CCL2, CCL3, CCL5, CXCL8, CXCL9, and CXCL10) through immune effector cells in SARS-CoVs infection (50, (52) (53) (54) . So, blocking IL-6, IL-1, and TNF may be useful for COVID-19 patients.

Moreover, lymphopenia is often reported in the severe stage of patients infected with COVID-19. The cytokine made through SARS-CoV-2 must be mediated via leukocytes other than T cells, as in patients getting CAR-T cell therapy, a high WBC-count is prevalent along with lymphopenia, which is as a differential diagnostic criterion for COVID-19.

The host innate immune system identifies viral infections by applying pattern recognition receptors (PRRs) to detect pathogen-associa ted molecular patterns (PAMPs) (55) .

Up until now, PRRs are divided into three types based on their forms of existence (55, 56) . The membrane type consists toll-like receptor2 (TLR2), TLR4, mannose receptor, scavenger receptor (SR); the secretory type contains mannose-binding lectin (M BL) and Accepted Article C-reactive protein (CRP); and the cytoplasmic type comprising TLR3, TLR7/8, cGAS, IFI16, STING, DAI, and NOD-like receptor (NLR) . It must be noticed that the JAK-STAT signaling pathways induce downstream interferons (IFNs) production, and the interferon production-related PRRs are TLRs, RLRs, and NLRs (57) . Upon infecting plasma-like dendritic cells (pDCs), the viral nucleic acids are detected through TLR7/TLR9 to stimulate the construction of inflammatory cytokines and type I IFNs (58, 59) . The complement system has a crucial role in the host immune response, which prepares a way for the innate immune system to detect and respond to foreign antigens, especially CoVs (65) . It is firmly controlled through inhibiting proteins in the serum, as it has the This article is protected by copyright. All rights reserved.

potential to damage host tissues. However, SARA-CoV s encoded proteins that inhibit the detection of the complement system through inhibiting proteins in the serum (66) , indicating that complements are essential to the antiviral response as C3a and C5a have strong pro-inflammatory properties and could induce inflammatory cell recruitment and neutrophil activation. So, their blockade acts as a therapy for acute lung injury as anti-C5a antibody reveals to protect mice from infection with MERS-CoV (67).

Antigen presentation stimulates the body's humoral and cellular immunity, which are mediated by virus-specific B and T cells.

In SARS-CoVs, both T and B cell epitopes were extensively mapped for the structural proteins, including S, N, M, and E protein (68) . Although only minimal percentages of monocytes/macrophages in the lung expressed ACE2 receptors (1), SARS-CoV-2 directly infects macrophages and T cells (69) . Other receptors may exist, if the ACE2 receptor is minimally expressed in the potential target immune cells, or another cellular entry mode is applied, like antibody-dependent enhancement.

Cytokine microenvironment produced via antigen-presenting cells commands the direction of T cell responses, which is very important. Although helper T cells attune the overall adaptive response, CD8 + or cytotoxic T cells are essential in the killing of virally infected cells response, so they need to be well controlled in order not to cause lung pathology. Generally, the T helper1 (Th1) immune response has a critical role in adaptive immunity against viral infections. Current pieces of evidence strongly indicated that Th1 response is a vital key for successful control of SARS-CoV and MERS-CoV and This article is protected by copyright. All rights reserved.

probably for SARS-CoV-2 as well. However, SARS-CoV-2 reduces the number of Th1 cells. The latest report demonstrated that not only the number of CD4+, and CD8+ T cells in the peripheral blood of SARS-CoV-2-infected patients is dramatically reduced especially among elderly patients (over the age of 60) and in patients needing intensive care unit (70) , but also the surviving T cells are functionally exhausted (70) . Additionally, Non-ICU patients, with total T cells, CD4+T cells, and CD8+T cells counts lower than 400/μL and 800/μL, 300/μL subsequently, might still require aggressive intervention even in the immediate absence of more extreme symptoms due to a high risk for more deterioration in condition (71) . Besides on April 30th, 2020, a phase III study to evaluate the efficacy and safety of Lenzilumab (a humanized class IgG1 kappa mAb that targets colony-stimulating factor 2 (CSF2)/granulocyte-macrophage colony-stimulating factor (GM-CSF)) in hospitalized This article is protected by copyright. All rights reserved. Chloroquine and hydroxychloroquine inhibit major histocompatibility complex class II expression and reduce CD154 expression by T cells via Toll-like receptor signaling and cGAS stimulation of interferon genes, which leads to inhibition of antigen presentation and immune activation. Moreover, both can decrease the production of various proinflammatory cytokines, like IL-1, IL-6, interferon-α, and tumor necrosis factor (TNF) (79) . However, several times, it has been reported that using hydroxychloroquine or This article is protected by copyright. All rights reserved.

chloroquine with or without macrolide increases both cardiac death and cardiac arrhythmia in COVID-19 patients, and they are not effective against the disease (80, 81) .

The recent multinational registry analysis of the use of hydroxychloroquine or chloroquine on 14,888 patients in 671 hospitals in six continents was also in agreement with these findings, and showed an increased risk of ventricular arrhythmias (82) .

Therefore WHO recommended temporary pause of the use of this drug in trials for COVID-19.

It should be mentioned that numerous antiviral drugs, like lopinavir/ritonavir, have demonstrated no benefits (83) . However, the combination of an immunomodulatory agent to decrease the cytokine storm with an antiviral agent might give doctors more time to make supportive therapy for COVID-19 patients.

It must be taken into account that enhanced levels of inflammatory cytokines, including IL-6, IL-1, and TNF-α in the lungs of COVID-19 cases, can lead to hyaluronan or hyaluronic acid (HA) production by inducing the HA-synthase-2 (HAS2) and following ARDS and death (84, 85) . So, suppressing HA production through hyaluronidase, 4-Methylumbelliferone (4-MU), and blocking the inflammatory cytokines can be useful for reducing the mortality rates and shortness of breath in COVID-19 patients (86).

Among the immunomodulatory treatments, corticosteroids are commonly used in the clinic. Although the application of corticosteroids in COVID-19 patients can lead to host immune suppression and delay viral clearance, a recent study at Xi'an Jiaotong-Liverpool University revealed that the application of corticosteroids did not affect viral clearance time and length of hospital stay in mild COVID-19 cases (87) . Thus, based on this study, This article is protected by copyright. All rights reserved.

the use of corticosteroids is effective in severe cases of COVID-19, especially in cases with ARDS (88).

Colchicine is an immunomodulatory drug used in the treatment of gout, in which there are more than ten clinical trials for evaluating its effectiveness against COVID-19, like NCT04392141, NCT04375202, and NCT04355143 (89).

Furthermore, other immunomodulatory therapies like intravenous immunoglobulin (IVIG) and Janus kinase inhibitors have been proposed for treating severe COVID-19 (90) . However, it should be mentioned that the National Institutes of Health (NIH) does not recommend the use of Janus kinase inhibitors like Baricitinib (91) against COVID-19 due to their broad immunosuppressive effect (92) .

Moreover, in early March 2020, Chinese clinicians studied the use of Ulinastatin, which is a serine protease inhibitor with anti-inflammatory properties (including inhibition of IL-6), against COVID-19 to reduce cytokine storm (93) .

It should be mentioned that the result of using triple combination therapy with interferon beta-1b, lopinavir-ritonavir, and ribavirin in a phase II clinical trial demonstrated its effectiveness against COVID-19 (94) .

In one study, researchers concluded that the coronaviruses could often present itself as a common cold. Consequently, it has been suggested that the current definition of COVID-19, which emphasizes lower respiratory tract infection, might need to be changed (95) .

The incubation period for COVID-19 is supposed to be within 14 days following exposure and after active or quarantined monitors (96) , with most cases occurring almost four to five days after exposure (97, 98) . Besides, the Mid-incubation period was 1/2 day, the average incubation period was 1.5 days, and Mid-term incubation until the fever was 2.5 days. Besides, less than 1.2% of patients are symptomatic within 2.5 days, and in 1.2% of affected people, symptoms appear for up to 2.5 days.

A meta-analysis study of the new coronavirus with eight studies and 5732 patients found that the incidence of fever was 90.9%, cough 70.8%, fatigue 41%, ARDS equal to 14.8%, abnormal lung CT scan 95.6%, and the mortality rate was 6.4% (99) . In another study, of 1099 patients with COVID-19 (98) findings were as follow:

The most common clinical symptoms included fever (present in 4.9% of cases at admission and 5.9% of cases at admission), dry cough (in 1/2 of cases), nausea and vomiting (in 2% of cases), and diarrhea (in 1.5% of cases). Moreover, the most common radiology findings on CT at admission included Ground-glass view (at 1/8) and patchy bilateral shadowing (view at 1/8). Also, laboratory findings consisted of lymphopenia (in 1.2% of cases), thrombocytopenia (in 1.5% of cases), leukopenia (in 1.5% of cases), and most patients had high CRP. Besides, five percent of patients are admitted to the ICU, This article is protected by copyright. All rights reserved.

It must be taken into account that other symptoms like sore throat, nasal congestion, malaise, headache, muscle pain, severe dyspnea, respiratory distress, tachypnea more than 30 breaths per minute, hypoxia less than 90% of SpO2 on room air, and cyanosis have been reported in COVID-19 patients (100, 101) .

Interestingly, viral conjunctivitis and rash on the skin or discoloration of fingers or toes should be regarded as a possible early manifestation of COVID-19 (102, 103) . Moreover, it has been reported that chilblain-like lesions in the toe are a sign of COVID-19, especially in young patients with a mild infection that goes away on its own (104) .

It should be mentioned that the American Academy of Otolaryngology has indicated the loss of sense of smell and taste disorder (anosmia and dyspepsia) in some patients who were positive for COVID-19. Even in some, the loss of a sense of smell has been the only sign (105) .

Interestingly, recently a novel multisystem inflammatory syndrome has been related to COVID-19. The WHO recently introduced this COVID-19 related syndrome in children and adolescents. Some of the features of this syndrome are said to be similar to those of Kawasaki and toxic shock syndrome.

The WHO criteria for diagnosing this syndrome are as follow: All people between the ages of zero to 19; and the existence of fever for at least three days; and increased inflammatory markers such as ESR, C-reactive protein, or procalcitonin; and lack of other microbial evidence; and evidence for the presence of a COVID-19 infection or close contact with an infected person; and two of the following: Rash or non-purulent bilateral conjunctivitis, or inflammatory symptoms of Moko Kotanus (mouth, hands, and This article is protected by copyright. All rights reserved. Accepted Article feet), hypotension or shock, features of myocardial dysfunction, pericarditis, valvular inflammation, coronary vascular abnormalities, evidence of coagulopathy (according to PT, PTT, and D-dimer levels), and acute gastrointestinal problems (abdominal pain, diarrhea, and vomiting) (106).

As mentioned above, the COVID-19 symptoms have reportedly ranged from mild to severe that can eventually lead to death. Although diffuse alveolar damage and acute respiratory failure were the main characteristics of COVID-19 (107) , the severe cases demonstrated respiratory, hepatic, gastrointestinal, and neurological complications that can lead to death. So, we have investigated the effects of SARS-CoV-2 on various vital organs in the following:

CVMs could be the initial presentation or appear throughout the whole course of COVID-19. Two studies have reported that patients with COVID-19 and hypertension or coronary artery disease had worse in-hospital outcomes (108, 109) . The initial report of 

COVID-19 and figured out that 7.3% of patients complain of palpitation as an early symptom (112) .

A vast number of studies have shown that the gastrointestinal tract tropism of SARS-CoV was verified through viral detection in biopsy and stool specimens even in discharged patients, which may partially explain gastrointestinal symptoms, potential recurrence, and transmission of the virus (113) . In particular, in the first corroborated case of the COVID-19 in the United States, a 2-day history of nausea and vomiting on admission and then passing a loose bowel movement on hospital day two was reported. Moreover, the viral nucleic acids in loose stool were detected, and both respiratory samples later tested positive (114) . Besides, the 2019-nCoV sequence can also be identified in the collected saliva of the most COVID-19 patients (36) .

The viral infection of liver cells might directly cause liver injury in patients with COVID-19 infection. Almost 2-10% of patients with COVID-19 present with diarrhea, as mentioned before, and SARS-CoV-2 RNA has been detected in stool and blood samples (115) . These documents revealed the feasibility of viral exposure in the liver and intestine. It has been reported in one study that more than one-third of 148 COVID-19 patients admitted to the hospital had an abnormal liver function and were hospitalized for a more extended period (116) . Although pathological analysis of liver tissue from a patient died from COVID-19 demonstrated that viral inclusions were not observed in the liver (43) , pathological studies in patients infected with SARS-CoV confirmed the This article is protected by copyright. All rights reserved.

presence of the virus in liver tissue. Also, the viral titer was relatively low because viral inclusions were not observed (117) . So, it is feasible that the liver impairment is due to drug hepatotoxicity and cytokine storm and pneumonia-associated hypoxia in patients with the severe stage of COVID-19. Besides, liver damage in mild cases of COVID-19 is often transient and can return to normal without any special treatment.

Although human tissue RNA sequencing data revealed that the ACE2 receptor expression in urinary organs (118) was much higher (nearly 100-fold) than that in respiratory organs (lung) (119) , after lung infection the infiltrated virus might enter the blood circulation (as RT-PCR of the urine and plasma sample in some COVID-19 patients were positive (107) ), accumulate in the kidney, and cause damage to renal cells. Thus, the kidney impairment probably happened through coronavirus entering cells by the ACE2 receptors. Indeed, It has been reported that 6.7% of patients with the severe acute respiratory syndrome (SARS) developed acute renal impairment, and the mortality of patients infected with SARS-CoV with AKI or acute kidney injury was 91.7% (120) . Therefore, the kidney impairment and outcome in patients infected by SARS-CoV-2, which is similar to SARS-CoV in 2003, were ensured. AKI is a syndrome of abrupt loss of kidney function that is strongly associated with higher mortality and morbidity (121) , which defined as an enhancement in serum creatinine (122) by 0.3 mg/dl within 48 hours or a 50% increase from the baseline within seven days (118) .

Moreover, Kaplan-Meier analysis revealed a significantly high in-hospital death rate for patients with kidney impairments, including increased baseline serum creatinine, This article is protected by copyright. All rights reserved.

increased baseline blood urea nitrogen (BUN), proteinuria, hematuria, and AKI. In one cohort study (123) , the detection rate of AKI in COVID-19 patients was 3.2%, which was similar to that reported in previous studies with small patients numbers (107, 111, 124) and higher than 0.5% in a large observational study (125) . Although the data of kidney specimens from SARS patients demonstrated normal glomerular histology (the possibility of active immune-mediated glomerulonephritis was low) along with the absence of electron-dense deposits and, deposition of immune complexes of viral antigen or virus-induced specific immunological effector mechanisms (specific T lymphocyte or antibody) might damage the kidney. Moreover, virus-induced cytokines or mediators, which have indirect influences on renal tissue, such as hypoxia, shock, and rhabdomyolysis, might damage the kidney. Therefore, the etiology of kidney impairment in COVID-19 patients is probably diverse and multifactorial, and not only early prevention of kidney impairment, including adequate hemodynamic support and avoiding nephrotoxic drugs, is particularly remarkable, but also early renal replacement treatment in patients with damaged kidney may improve the patients' prognosis.

CoVs infection can affect the nervous system through various ways like direct infection injury by blood circulation pathway and neural pathway, hypoxic injury, ACE2 receptor, and immune injury. It is believed that CoV, in coordination with the host's immune system, may turn these infections into persistent infections that can lead to neurological diseases. Therefore, patients with coronaviruses infections should be appraised early for neurological symptoms, such as headache, consciousness disorder, paresthesia, and other pathological signs (126, 127) . This article is protected by copyright. All rights reserved.

It should be mentioned that COVID-19 can lead to necrotizing hemorrhagic encephalopathy as well (128) . Besides, as some coronaviruses can spread via a synapseconnected route to the medullary cardiorespiratory center from the mechanoreceptors and chemoreceptors in the lung and lower respiratory airways, regarding the high similarity between SARS-CoV and SARS-CoV -2, it is not clear whether the potential invasion of SARS-CoV-2 is partially responsible for the acute respiratory failure of patients with COVID-19 (129) . Moreover, as mentioned above, SARS-CoV-2 can cause anosmia and dyspepsia.

So, Health care workers should be aware that patients with COVID-19 can present with encephalopathy in the acute phase of the disease and during hospitalization.

The timely evaluation of cerebrospinal fluid, awareness, and management of neurological complications associated with infection is essential to improve the prognosis of patients with a critical illness (126) . Moreover, during the COVID-19 pandemic, when seeing individuals with neurologic manifestations, clinicians should suspect SARS-CoV-2 infection as a differential diagnosis to avoid delayed diagnosis or misdiagnosis and lose the chance to treat and prevent more contagion (130) .

Age, the most common comorbidities (131), diabetes, hypertension, cardiovascular disease, endocrine, and respiratory diseases, have been recognized as the common mortality risk factors (132) . Although the lymphopenia and coronary artery disease were not the risk factors of death, D-dimer more than one and higher sequential organ failure assessment (SOFA) score were the risk factors of death (131) . Moreover, patients with shortness of breath, confusion, chest pain at admission and older men with underlying disease are also more likely to die (132, 133) and the inadequate response of immune cells (especially the elderly patients), as well as inhibition of the essential stat1 protein (which enhance this response), is one of the crucial causes of suboptimal responses and mortality in COVID-19 patients. So, the use of interferons in the early stage of the disease has been emphasized as a control (134) . In the meanwhile, it must be mentioned that, based on the recent reports, obesity was reported to increase the vulnerability to infection (135 

March. They took into account the period of illness incubation as well as the interval between onset of symptoms and ICU admission (138) .

Four factors could predict the progression of the disease to severe infection, including the existence of comorbid diseases, the age of more than 50 years, lymphopenia less than 1500 /μl, and serum ferritin more than 400 ng/mL (139) .

In one study, which investigated 201 patients with a mean age of 51, 84 patients eventually developed ARDS, of which 44 died. In this study, risk factors for death-related ARDS were: older age, neutrophilia, organ failure, and coagulopathy (higher LDH and D-dimer level) (88) . The vital point in this study is that higher fever (equal to or greater than 39) increases the risk of ARDS but lower the risk of death.

Besides, the degree of lymphopenia and high concentration of cytokines or cytokine storm give an idea about the disease prognosis as it is found positively correlated with the disease severity (40, 50) . Also, platelet to lymphocyte ratio and neutrophil to lymphocyte ratio (patients over the age of 50 years with a ratio of more than 3/13 must be treated promptly) are valuable prognostic factors (140, 141) .

It must be mentioned that high levels of procalcitonin are associated with almost five times the severity of COVID-19 (142) . So, it has been recommended that serial measurement of procalcitonin may play a critical role in determining the severity of the disease. This article is protected by copyright. All rights reserved.

In conclusion, SARS-CoV-2 is a mysterious virus, and the contemporary pieces of knowledge are vague and inadequate. Although scientists are making an effort to develop proper preventive and therapeutic intervention strategies containing monoclonal antibodies, interferon-based therapies, peptides, vaccines, and small-molecule drugs to overcome the SARS-CoV-2 and more than 200 clinical trials of COVID-19 have been recorded in https://clinicaltrials.gov/, it might take a long time to examine their efficacy in vitro/in vivo. So, that is why the WHO is conducting the solidarity clinical trial to accelerate the process of clinical trials (143) .

The latest information on the SARS-CoV-2 vaccine is fortunately positive. It has been reported that the Ad5 vectored COVID-19 vaccine had no severe side effects and was immunogenic. Moreover, both humoral immunity and neutralizing antibodies peaked on day 28 after vaccination, and the rapid response of type T cells was observed on day 14 (144) . However, vaccine preparation for healthy individuals is time-consuming, and there is no effective therapy for infected individuals. Thus, current therapies of COVID-19 are supportive and symptomatic, and the best way to control the COVID-19 pandemic is to follow the preventive strategies.

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Coronavirus infections and immune responses

Pattern recognition receptors: doubling up for the innate immune response

Sensors of the innate immune system: their mode of action

A novel method for autophagy detection in primary cells: impaired levels of macroautophagy in immunosenescent T cells

In vitro screening platforms for identifying autophagy modulators in mammalian cells

Clinical progression and viral load in a community outbreak of coronavirus-associated SARS pneumonia: a prospective study

Interaction of SARS and MERS coronaviruses with the antiviral interferon response

Virus interference. I. The interferon

Regulation of type I interferon responses

P200 family protein IFI204 negatively regulates type I interferon responses by targeting IRF7 in nucleus

Different mechanisms of serum complement activation in the plasma of common (Chelydra serpentina) and alligator (Macrochelys temminckii) snapping turtles

Complement activation contributes to severe acute respiratory syndrome coronavirus pathogenesis

Inhibition of complement activation alleviates acute lung injury induced by highly pathogenic avian influenza H5N1 virus infection

T-cell immunity of SARS-CoV: Implications for vaccine development against MERS-CoV

Immunopathogenesis of coronavirus infections: implications for SARS

COVID-19, an emerging coronavirus infection: advances and prospects in designing and developing vaccines, immunotherapeutics, and therapeutics

Reduction and Functional Exhaustion of T Cells in Patients with Coronavirus Disease

Plasticity of mesenchymal stem cells in immunomodulation: pathological and therapeutic implications

Profile of specific antibodies to the SARS-associated coronavirus

A novel human mAb (MERS-GD27) provides prophylactic and postexposure efficacy in MERS-CoV susceptible mice

Ultrapotent human neutralizing antibody repertoires against Middle East respiratory syndrome coronavirus from a recovered patient

Tocilizumab treatment in COVID-19: a single center experience

Crossneutralization of SARS-CoV-2 by a human monoclonal SARS-CoV antibody

Interleukin-1 blockade with high-dose anakinra in patients with COVID-19, acute respiratory distress syndrome, and hyperinflammation: a retrospective cohort study. The Lancet Rheumatology

Mechanisms of action of hydroxychloroquine and chloroquine: implications for rheumatology

Hydroxychloroquine or chloroquine with or without a macrolide for treatment of COVID-19: a multinational registry analysis

Observational study of hydroxychloroquine in hospitalized patients with Covid-19

Hydroxychloroquine or chloroquine with or without a macrolide for treatment of COVID-19: a multinational registry analysis

A trial of lopinavir-ritonavir in adults hospitalized with severe Covid-19

Pathological findings of COVID-19 associated with acute respiratory distress syndrome. The Lancet respiratory medicine

Defective lung function following influenza virus is due to prolonged, reversible hyaluronan synthesis

Inhibition of hyaluronan synthesis attenuates pulmonary hypertension associated with lung fibrosis

Impact of corticosteroid treatment in patients with coronavirus disease 2019

Risk factors associated with acute respiratory distress syndrome and death in patients with coronavirus disease 2019 pneumonia in Wuhan, China. JAMA internal medicine. 2020. 89. clinicaltrials.gov. Colchicine | covid

Towards treatment planning of COVID-19: Rationale and hypothesis for the use of multiple immunosuppressive agents: Anti-antibodies, immunoglobulins, and corticosteroids

Baricitinib as potential treatment for 2019-nCoV acute respiratory disease. The lancet

Cytokine storm and immunomodulatory therapy in COVID-19: role of chloroquine and anti-IL-6 monoclonal antibodies

Triple combination of interferon beta-1b, lopinavir-ritonavir, and ribavirin in the treatment of patients admitted to hospital with COVID-19: an open-label, randomised, phase 2 trial

Clinical presentation and virological assessment of hospitalized cases of coronavirus disease 2019 in a travel-associated transmission cluster. medRxiv

The incubation period of coronavirus disease 2019 (COVID-19) from publicly reported confirmed cases: estimation and application

Early transmission dynamics in Wuhan, China, of novel coronavirus-infected pneumonia

Clinical characteristics of coronavirus disease 2019 in China

Clinical Characteristics of 5732 Patients with 2019-nCoV Infection. Available at SSRN 3539664

Di Napoli R. Features, evaluation and treatment coronavirus (COVID-19)

The continuing 2019-nCoV epidemicthreatof novel coronaviruses to global health: the latest 2019 novel coronavirus outbreak in Wuhan, China

Novel Coronavirus disease 2019 (COVID-19): The importance of recognising possible early ocular manifestation and using protective eyewear

Q&A on coronaviruses (COVID-19

What Is 'Covid Toe'? Maybe a Strange Sign of Coronavirus Infection

Multisystem inflammatory syndrome in children and adolescents temporally related to COVID-19

Detection of 2019 novel coronavirus (2019-nCoV) by real-time RT-PCR

ACE2 expression in kidney and testis may cause kidney and testis damage after 2019-nCoV infection. medRxiv

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

Presumed asymptomatic carrier transmission of COVID-19

Clinical characteristics of novel coronavirus cases in tertiary hospitals in Hubei Province. Chinese medical journal

Enteric involvement of severe acute respiratory syndrome-associated coronavirus infection

Enteric involvement of coronaviruses: is faecal-oral transmission of SARS-CoV-2 possible?

Clinical Features of COVID-19-Related Liver Damage

SARS-associated viral hepatitis caused by a novel coronavirus: report of three cases

KDIGO clinical practice guideline for the diagnosis, evaluation, prevention, and treatment of Chronic Kidney Disease-Mineral and Bone Disorder (CKD-MBD)

Caution on kidney dysfunctions of 2019-nCoV patients

Acute renal impairment in coronavirus-associated severe acute respiratory syndrome

Management of patients at risk of acute kidney injury. The lancet

Differential maturation and subcellular localization of severe acute respiratory syndrome coronavirus surface proteins S, M and E

Kidney impairment is associated with in-hospital death of COVID-19 patients. medRxiv

Pandemic potential of 2019-nCoV. The Lancet Infectious Diseases

Nervous system involvement after infection with COVID-19 and other coronaviruses

Central nervous system involvement in COVID-19. Archives of Medical Research

COVID-19-associated acute hemorrhagic necrotizing encephalopathy: CT and MRI features

The neuroinvasive potential of SARS-CoV2 may play a role in the respiratory failure of COVID-19 patients

Neurologic Manifestations of Hospitalized Patients With Coronavirus Disease

Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. The Lancet

The Risk of Death in 2019 Novel Coronavirus Disease (COVID-19) in Hubei Province. Available at SSRN 3539655

Clinical characteristics of 82 death cases with COVID-19. medRxiv

Therapeutic approaches for COVID-19 based on the dynamics of interferon-mediated immune responses

Obesity Expands a Distinct Population of T Cells in Adipose Tissue and Increases Vulnerability to Infection

Characteristics of and important lessons from the coronavirus disease 2019 (COVID-19) outbreak in China: summary of a report of 72 314 cases from the Chinese Center for Disease Control and Prevention

Characteristics and Outcomes of 21 Critically Ill Patients With COVID-19 in Washington State

Real estimates of mortality following COVID-19 infection. The Lancet Infectious Diseases

Clinical Characteristics Predicting Progression of COVID-19

Neutrophil-to-Lymphocyte Ratio Predicts Severe Illness Patients with 2019 Novel Coronavirus in the Early Stage

Platelet-to-lymphocyte ratio is associated with prognosis in patients with Corona Virus Disease-19

Procalcitonin in patients with severe coronavirus disease 2019 (COVID-19): a meta-analysis. Clinica chimica acta; international journal of clinical chemistry

Solidarity" clinical trial for COVID-19 treatments 2020

Safety, tolerability, and immunogenicity of a recombinant adenovirus type-5 vectored COVID-19 vaccine: a dose-escalation, open-label, non-randomised, firstin-human trial