key: cord-300608-eju7wnb9
authors: Sheervalilou, Roghayeh; Shirvaliloo, Milad; Dadashzadeh, Nahid; Shirvalilou, Sakine; Shahraki, Omolbanin; Pilehvar‐Soltanahmadi, Younes; Ghaznavi, Habib; Khoei, Samideh; Nazarlou, Ziba
title: COVID‐19 under spotlight: A close look at the origin, transmission, diagnosis, and treatment of the 2019‐nCoV disease
date: 2020-05-26
journal: J Cell Physiol
DOI: 10.1002/jcp.29735
sha: 
doc_id: 300608
cord_uid: eju7wnb9

Months after the outbreak of a new flu‐like disease in China, the entire world is now in a state of caution. The subsequent less‐anticipated propagation of the novel coronavirus disease, formally known as COVID‐19, not only made it to headlines by an overwhelmingly high transmission rate and fatality reports, but also raised an alarm for the medical community all around the globe. Since the causative agent, SARS‐CoV‐2, is a recently discovered species, there is no specific medicine for downright treatment of the infection. This has led to an unprecedented societal fear of the newly born disease, adding a psychological aspect to the physical manifestation of the virus. Herein, the COVID‐19 structure, epidemiology, pathogenesis, etiology, diagnosis, and therapy have been reviewed.

In December 2019, a cluster of insidious Coronavirus infections was reported in the Huanan Seafood Market, located in Wuhan State of Hubei Province in China. Unlike the name, livestock animals were also traded in the market alongside their marine relatives. Days later, the cluster turned into a local network and set off the alarm for the Chinese government. It was then that a pneumonia epidemic of unknown cause became the focus of global attention (Sahin et al., 2020) . Chinese authorities announced on January 7, 2020 that a new type of CoV (novel CoV, nCoV) was isolated (Imperial College London, 2020; World Health Organization, 2020). On December 12, 2019, a pneumonia case of unknown origin was reported in Wuhan, China. Initial laboratory tests ruled out Influenza and infection with recognized CoVs.

Following the incident, 27 new cases of pneumonia of viral origin were officially reported on December 31, 2019. A week later on January 7, 2020, the Chinese authorities announced that a new species of CoV was isolated in the country (Zumla, Hui, Azhar, Memish, & Maeurer, 2020) .

Given the whereabouts of the first case ever reported, the infection was speculated to have been contracted from a zoonotic agent. Etiologic investigations on patients who had been hospitalized with a similar medical history supported the likelihood of a viral infection transmitted from animals to humans (Sahin et al., 2020; World Health Organization, 2020; Yin & Wunderink, 2018) . nCoV was duly reported to have been originated from wild bats. Falling in the category of group 2 β-CoVs, the novel Coronavirus only shares a 70% similarity in genetic sequence with its predecessor, SARS-CoV, which also belongs to the exact same family (Gralinski & Menachery, 2020) .

The tantalizing surge in the number of cases infected with SARS-CoV-2 in China, despite the closure of markets and evacuation of the vicinity, fulfilled the burden of proof that the virus can also be transmitted from human to human. Soon thereafter, peculiar cases of acute respiratory syndrome started appearing in other Asian countries, ultimately spreading to North America and Europe. (Sahin et al., 2020; World Health Organization, 2020; Yin & Wunderink, 2018) . Following an emergent briefing on January 30, 2020,

The World Health Organization (WHO) declared the outbreak of COVID-19 as a Public Health Emergency of International Concern (Organization, 2020) .

The epidemic began to emerge with the advent of the Chinese New Year, a traditionally important festival that is heavily celebrated across the country. The coincidence paved the way for SARS-CoV-2 to turn into an unprecedented massive Coronavirus outbreak, which required extensive measurements to be contained. With a population of 10 million, Wuhan City also served as an important pathway for millions of people traveling in celebration of the Spring Festival.

Accordingly, the number of cases to be diagnosed with showed an overwhelming increase between January 10-22, 2020 .

Despite the arbitrary speculations, not only did the recent outbreak of COVID-19 egress the country of origin, it also proceeded to become a global concern in the form of a pandemic . COVID-19 is an acute self-resolving respiratory disease in most of the cases, however, it can also be fatal in some cases. The disease was initially reported to have a mortality rate of 2%. If severe, COVID-19 might result in death as a result of the preceding extensive alveolar damage, and failure of the lungs . As of February 15, 2020, a total of 66,580 cases had been confirmed, with over 1,524 deaths. However, there have no specific reports on pathology, as performing an autopsy or biopsy was not possible in most of the cases (Chan et al., 2020; Huang et al., 2020) . Table 1 

March 24, 2020 (www.WHO.int).

A total of 8,096 SARS cases and 774 deaths across 29 countries were reported for an overall case-fatality rate (CFR) of 9.6%. MERS is still not contained and is thus far responsible for 2,494 confirmed cases and 858 deaths across 27 countries for a CFR of 34.4%. Despite the much higher CFR of 9.6% and 34.4% for SARS and MERS, the novel Coronavirus epidemic has led to a larger death toll. The Chinese government had reported 72,528 confirmed cases, with 1,870 deaths, as of February 18, 2020. These statistics yield a crude CFR of 2.6%. However, one should not haste to generalize this number, as most possibly the total number of patients with COVID-19 is much higher. That is, because the cases are not readily identifiable, as many asymptomatic patients are missed during the process Yan et al., 2020) . Despite the higher transmissibility than SARS and MERS, COVID-19 is still a relatively unknown disease and requires further investigations to be fully understood (Yan et al., 2020) . After making a successful entry, the RNA-based genome starts replicating itself, and expressing specific sequences that results in production of useful accessory proteins; facilitating the adaptation of CoV to its human host (ViralZone., 2019). Alterations in genetic make-up that result from recombination, exchange, insertion, or deletion of genes, are frequently reported among CoVs; a phenomenon that might have played a part in the past epidemics (Sahin et al., 2020) . Therefore, the classification of CoVs is continuously being changed. Based on the most recent classification provided by The International Committee on Taxonomy of Viruses, there are four genera of CoVs, that comprise a total of 38 unique species (Subissi et al., 2014) . Thus, variable mechanisms could be involved in the process of pathogenesis. For instance, SARS-CoV binds to angiotensin I converting enzyme 2 (ACE2). On the other hand, MERS-CoV is more inclined to attach the cellular receptor of dipeptidyl peptidase 4 (Lambeir, Durinx, Scharpé, & De Meester, 2003) . Following a cascade of signals after binding, the viral genome is successfully injected into the target cell. The genomic RNA that regulates the expression of structural and nonstructural polyproteins, is polyadenylated and encapsulated.

These proteins are then cleaved by certain proteases that exhibit chymotrypsin-like activity (Lambeir et al., 2003; ViralZone, 2019) .

Through replication and transcription, the resulting protein complex drives the production of negative-sense RNA or (−) RNA. Full-length (−)RNAs produced by replication are ultimately used as templates for generation of positive-sense RNA or (+) RNA (Luk, Li, Fung, Lau, & Woo, 2019; ViralZone, 2019) . All of the structural proteins are then translated from a subset of 7-9 subgenomic RNAs, which are products of discontinuous transcription. The resulting protein complex is the assembled together to envelope the viral genome, making a nucleocapsid in the process, that will bud into the lumen of the endoplasmic reticulum to finally complete the intracellular cycle. Newly formed virions are then expelled from the infected cell through exocytosis. The CoVs released thereafter are now capable to infect a wide spectrum of human cells, including lung, renal, hepatic, intestinal, and lower respiratory tract cells, as well as T lymphocytes (Chhikara, Rathi, Singh, & Poonam, 2020; Lambeir et al., 2003) . 2.1 | Respiratory system SARS-CoV-2 tends to infect the respiratory tract, thus, pneumonia is a primary clinical finding in patients with COVID-19 Li, Guan, et al., 2020; Zhu et al., 2020) . However, pneumonia is only a component of the SARS that might develop in some cases. The resulting SARS may then be aggravated and lead to serious conditions that are extremely difficult to control, for example, septic shock, metabolic acidosis, and coagulation dysfunction (Kofi Ayittey, Dzuvor, Kormla Ayittey, Bennita Chiwero, & Habib, 2020) .

Investigation on the radiological findings of COVID-19associated pneumonia have yielded little, if any, information that are mostly unspecific. Progressive lung lesions are usually detected in patients with COVID-19, about 1 week after the onset of signs and symptoms (Ooi et al., 2004) . The lesions then become aggravated during the 2nd week, and lead to formation of irregular reticular opacities mixed with ground glass opacities (GGOs), which can be detected by CT at the fourth week. In a recent cohort study, 85.7% (54/63) of subjects with COVID-19-associated pneumonia showed disease progression, defined by an increased extent of GGO, on early follow-up CT . Pulmonary fibrous cords was reported in one particular patient that displayed signs of improvement, as the inflammatory secretions had been absorbed . Long-term complications of COVID-19 in patients with severe pneumonia might include an array of fibrotic changes often observed in the late stages of lung injury, for example, reticulation, interlobular septal thickening, and traction bronchiectasis (Kim, 2020) .

There have been several reports that indicated meager Cytolethal Distending Toxin-induced lymphocytes, with a density as low as 200 cells/mm 3 in three patients with SARS-CoV infection Zhou et al., 2014) . As in the case of SARS-CoV-2, it has been suspected that infection with this type of CoV might lead to F I G U R E 1 Presents a schematic of viral structure and the entry mechanism of SARS-CoV-2 SHEERVALILOU ET AL. | 3 inflammatory cytokine storm Zumla et al., 2020) ; a life-threatening condition characterized by elevated levels of interleukin 6 (IL-6) in plasma. A number of investigations recently conducted on COVID-19 have reported that IL-6 levels was actually higher in the patients with severe disease (Cai, 2020; Chen, Liu, et al., 2020; Xiang et al., 2020) . This could highlight the importance of IL-6 as a biomarker for evaluation of disease severity .

Impaired liver function tests have been reported for a number of patients with SARS-CoV-2 infection, suggesting hepatic damage as an extrapulmonary complication of COVID-19 in almost one half of the patients (Chen, Zhou, et al., 2020; Wang, Hu, et al., 2020) . A recent study has concluded that liver function abnormality might stem from infection of bile duct cells with SARS-CoV-2. Nonetheless, the alkaline phosphatase value, which is an index of bile duct damage, were not specific in patients with COVID-19 (Chen, Zhou, et al., 2020; Wang, Hu, et al., 2020) . Investigation of liver biopsy specimens was accompanied by new pathological findings. Scientists have reported moderate microvascular steatosis, and mild lobular and portal activity in these patients, that suggests liver damage may have arisen from either SARS-CoV-2 infection or drug-induced liver .

An essential player in maintenance of electrolyte balance and blood pressure, ACE2 is regarded by many as the principal counterregulatory arm in the axis of renin-angiotensin-aldosterone system (RAAS; Santos, Ferreira, & Simões e Silva, 2008) . Upon infection, SARS-CoV-2 binds ACE2. This results in degradation of ACE2, which subsequently dampens the counter-effect of ACE2 on RAAS.

The final effect of ACE2 in an otherwise healthy adult is to increase reabsorption of sodium and the reciprocal excretion of potassium ions (K + ). The concomitant re-uptake of water with sodium reabsorption prompts an increase in blood pressure (Weir & Rolfe, 2010) . Potassium is the predominant intracellular ion, that is majorly involved in regulation of cell membrane polarity. Too low levels of K+ in blood, known as hypokalemia, can result in cellular hyper-polarity. A hyper-polarized cell membrane tends to be depolarized faster than normal, causing aberrancy in the function of cardiac cells (Bielecka-Dabrowa et al., 2012) .

In a recent cohort study, patients diagnosed with COVID-19 were categorized into three groups: severe hypokalemia, hypokalemia, and normokalemia. The study reported that 93% of patients with a severe clinical condition had hypokalemia. Scientists did not find a direct link between gastrointestinal symptoms and hypokalemia among 108 patients with both severe or moderate hypokalemia.

Further investigations established an association between parameters such as body temperature, creatine kinase (CK), creatine kinase myocardial band (CK-MB), lactate dehydrogenase (LDH), and C-reactive protein (CRP) with the severity of hypokalemia. Reportedly, hypokalemia was most often observed with patients who had elevated levels of serum CK, CK-MB, LDH, and CRP. Potassium (K + ) loss in the urine was determined to be the primary cause of hypokalemia.

Hypokalemia requires strenuous efforts to be corrected. This is chiefly due to the incessant loss of K + in the urine, as a result of ACE2 degradation. In the case of COVID-19-associated hypokalemia, however, the patients seemed to respond well to potassium supplements when the critical phase had passed [49] . Therefore, one should consider the impact of hypokalemia in COVID-19 morbidity, and its effect on the outcomes of treatment. This is a condition that must be carefully addressed for, as patients with COVID-19 are more inclined to develop dysfunctions in heart, lungs, and other vital organs (Li, Hu, Su, & Dai, 2020) .

Several studies have sought to compare the sex differences in the clinical findings of severe COVID-19. In one study, scientists investigated 47 patients with COVID-19, 28 (59.6%) of whom were men. Procalcitonin (PCT) level was reported to be higher in men than in women. The results also showed higher amounts of serum N-terminal-pro brain natriuretic peptide, as increased levels of the molecule were detected in men 57.1% than women 26.3%. Furthermore, 17.9% of male patients were reported test-positive for influenza A antibody, whereas no such records were registered for female patients. During a 2-week stay at the hospital, 17.9% of male, and 5.3% of female patients deteriorated, and hence were reassigned to the critical-type group. There was no mortality reports among women, whereas 3.6% of male patients had deceased due to COVID-19 complications. A total of 21.1% and 3.6% of female and male patients successfully recovered, and were discharged from the hospital. Based on the current evidence, men are more likely to develop complications, and experience worse in-hospital outcomes compared with women .

A group of researchers led by Chen investigated the clinical characteristics of SARS-CoV-2 infection in nine pregnant women. Their aim was to evaluate the likelihood of intrauterine/vertical transmission of SARS-CoV-2 from mother to baby. All of the women who were being investigated had cesarean section in the third trimester of their previous pregnancies. Seven patients were febrile, and variably presented other symptoms such as cough, sore throat, myalgia, and malaise. Fetal distress was reported in two cases. Lymphopenia and increased aminotransferase activity were observed in five and three patients, respectively. There was no mortality cases, as none of the patients in the study developed severe COVID-19-associated pneumonia. Nine livebirths were recorded. The newborns displayed no signs of asphyxia. A 1-min Apgar score of 8-9, and a 5-min Apgar score of 9-10 were calculated for all nine newborns. Samples collected from six patients, including amniotic fluid, cord blood, neonatal throat swab, and breastmilk proved test-negative for SARS-CoV-2.

The clinical features of COVID-19-associated pneumonia observed in these pregnant women shared a great similarity to characteristics reported for COVID-19-associated pneumonia in nonpregnant adult patients .

In a recent investigation, scientists in China looked into the pattern of blood type distribution in 2,173 patients in three hospitals, who had been confirmed to have SARS-CoV-2 infection. Accordingly, they compared their findings regarding the blood type of patients with that of the healthy population who lived in the same area as the patients in the study. Apparently, there was a higher prevalence of blood type A among the patients with COVID-19 than in the normal population. On the contrary, it seemed that individuals with O blood type were spared somehow, as there were fewer patients with this blood type in this study (both p < .001). A series of meta-analyses on the available data indicated a significantly higher risk for COVID-19 in people with blood type A, relative to individuals with non-A blood types. However, an opposite scenario seemed to be true for the blood type O community, since, according to the literature, are less susceptible for contracting infectious diseases such as COVID-19 .

According to the literature, the pathogen and area of origin were similar in both SARS and COVID-19 outbreaks. However, despite this similarity, the raised public awareness and extensive interventional procedures that might have once proved effective for SARS containment, have been rendered ineffective against the 2019 novel Coronavirus; as the disease is already more widespread than SARS (Liu, Gayle, Wilder-Smith, & Rocklöv, 2020) . A large family of viruses, CoVs are common among many different animal species, including cattle, civets, camels, and bats. However, these CoVs are not solely restricted to animal populations, as they can occasionally infect humans, bringing epidemics such as SARS, MERS, and in recent memory, COVID-19 (Sahin et al., 2020) . Recent investigations conducted on the origins of CoVs responsible for the past epidemics have reported bats as the primary reservoir for both SARS-CoV and MERS-CoV; suggesting that other animal species were involved in the process merely as intermediate hosts. Accordingly, the majority of batassociated CoVs belong to α-CoV and β-CoV genera, while almost all of the avian CoVs fall in the other two genera; γ-CoVs and δ-CoVs (Yin & Wunderink, 2018) . It has been suggested that species responsible for the recent epidemic is reminiscent of the CoV isolated in bats. Trafficking of wild animals in Huanan Seafood Market, located in Wuhan State of Hubei Province in China, where the first cases were reported, further supports this finding. Only 10 days following the first outbreak, secondary cases started emerging. Although the new cases had no contact with the marketplace, they did have a history of social contact with the salesmen and people who had previously been there. The growing pile of confirmed cases from healthcare workers in Wuhan City is an strong indicator of human-tohuman transmission in the case of SARS-CoV-2 (Sahin et al., 2020) .

Transmission of the virus from human to human occurs mostly with close contact. The short distance between individuals in close social contacts makes it possible for respiratory droplets of the infected person, released by coughing and sneezing, to reach other people in the proximity. This is similar to the transmission of Influenza and other respiratory infection. It still remains unclear if the virus can be contracted by touching surfaces, and then touching mouth, nose, or even eyes (WHO, 2020). Apparently, COVID-19 is considered most contagious when individuals infected with the virus is symptomatic. However, there have been cases who reportedly had contracted the disease from asymptomatic patients in the prodrome period of COVID-19. Transmission of the novel Coronavirus has yet to be clarified by more investigations. (Rothe et al., 2020) .

Investigation on a familial cluster of five patients concluded that SARS-CoV-2 might have actually been transmitted by an asymptomatic carrier in the family (Bai et al., 2020) . Surprisingly, the first reverse transcription polymerase chain reaction (RT-PCR) test of the asymptomatic family member was reported negative; a noteworthy example of a false-negative result. Unwanted false-negative results are inevitably reported due to a number of factors, for example, quality of the test kit, sufficiency of the collected sample, or performance of the test by clinicians. To this date, RT-PCR has widely been used as a reliable diagnostic method (Corman et al., 2020) .

Thus, her second RT-PCR result, reported positive, was unlikely to have been a false-positive result; hence, it was accepted as the definite evidence that the suspected person had indeed been infected with SARS-CoV-2 (Bai et al., 2020) .

There was also another study that reported an asymptomatic young boy with COVID-19 infection. However, CT scans obtained from the subject exhibited abnormalities, indicative of an on-going pulmonary pathology (Chan et al., 2020) . If we presume that the findings regarding asymptomatic carrier-based transmission of COVID-19 can be replicated, this would prove COVID-19 an overwhelmingly challenging issue to be controlled (Bai et al., 2020) .

The incubation period for the asymptomatic patient in the case of familial cluster was 19 days. Despite being a long period, it still perfectly falls in the suggested incubation period of 0-24 days (Bai et al., 2020; Guan et al., 2020) .

A proper diagnosis of COVID-19 is made based on the following criteria, which have been recently suggested based on the initial investigations:

(a) clinical signs and symptoms, (b) history of traveling or close contact with people suspected to be infected, (c) positive test result for the pathogen, and (d) pathologic findings on CT images. The key clinical features of COVID-19, though nonspecific, include fever, dry cough, dyspnea, and pneumonia (Chen, Zhou, et al., 2020; Huang et al., 2020; Li, Guan, et al., 2020; Wang, Hu, et al., 2020) . Rapid screening of patients with acute respiratory symptoms, initiation of an appropriate quarantine program, and development of therapeutic measures have been suggested as a top-priority strategy to control the spread of COVID-19 Wang, Kang, et al., 2020) . According to the data gathered by individual-level surveillance, it is strongly recommended that the elderly and male patients should be diagnosed in a timely manner, as progression of the respiratory pathology to pneumonia might result in catastrophic outcomes (Jian-ya, 2020).

Understanding the otherwise nonspecific clinical signs and symptoms of COVID-19 is a crucial step toward appropriate management of the disease. Patients mostly complain of fever, non-productive cough, and body ache or extreme tiredness. In some cases, diarrhea and nausea precede fever by a few days, suggesting that fever might not be the initial manifestation of infection. A small number of patients reportedly had headache, or even developed hemoptysis Wang, Hu, et al., 2020) . Some patients remained asymptomatic, despite being tested positive for the disease (Chan et al., 2020) . According to several studies, infection with SARS-CoV-2 in the elderly, especially the male community, is more likely to result in severe alveolar damage and respiratory failure (Chen, Zhou, et al., 2020) . Occasionally, the disease may be demonstrated with a fulminant natural history, rapidly progressing to organ dysfunction, and even death in critical cases. Organ dysfunction includes conditions such as shock, ARDS, acute cardiac injury, and acute kidney injury Wang, Hu, et al., 2020) . From a laboratory point of view, lymphopenia, thrombocytopenia, impaired prothrombin time (PT), and elevated serum levels of CRP stand among the findings that can be reported for patients with COVID-19 (Chen, Zhou, et al., 2020; Guan et al., 2020; Huang et al., 2020; Wang, Hu, et al., 2020) . Overall, any patient with fever and acute respiratory symptoms, who is reported to have lymphopenia or leukopenia on lab examination, should be suspected. A history of travel to Wuhan or having close contact with local residents is a strong indicator for careful management of the patient (Zu et al., 2020) . 

Shortly after the onset of the epidemic, The National Health Commission of China (Committee, 2020a; Organization, 2020a) initiated the Diagnosis and Treatment Program of COVID-19-associated pneumonia, following the guidelines provided by WHO on SARS and MERS (Azhar & EI-Kafrawy, 2014; Organization, 2017 Organization, , 2020b .

According to the newly formulated criteria, a "suspected case" is defined as a patient with epidemiological history, that is traveling and contact, and two clinical findings pertinent to the disease. If, however, an epidemiological history is not confirmed, then the patient must present at least three clinical findings to be considered as a Edition, the term "clinical diagnosis" was removed and replaced with "etiological diagnosis" (Organization, 2020a). According to the recent revision, it is imperative that an etiological diagnosis of COVID-19 is made at first, which can then be complemented by a positive real-time RT-PCR assay for SARS-CoV-2, which is duly performed on the sputum or blood sample of the patient. After the final diagnosis is made, confirmed patients are categorized into mild, moderate, severe, and critical types, based on the severity of disease (Zu et al., 2020). 5.3 | COVID-19 detection tests: Pathogenic laboratory testing, real-time RT-PCR, and sequencing of nucleic acid Table 3 (Ai et al., 2020; Bai et al., 2020; Chen, Zhao, et al., 2020; Shi et al., 2020; Tian et al., 2020; Wang, Kang, et al., 2020; Wu & McGoogan, 2020; Yan et al., 2020; Yang et al., 2020) and Table 4 represent 2020 studies on diagnosis of COVID-19 infected patients and related clinical trials, respectively.

Despite being the diagnostic gold standard, pathogenic lab testing is a rather time-consuming procedure, with unavoidable false-positive results (Wang, Kang, et al., 2020) . It is recommended that lab testing should be performed, as soon as the patient is identified as a "person under investigation" (PUI). Viral nucleic acid required for an RT-PCR test is usually extracted from secretions of the lower respiratory tract, for example, bronchoalveolar lavage; however, tracheal aspirate or sputum can also be used Corman et al., 2020) . Since the onset of the epidemic, several factors have been found to affect the final efficiency of nucleic acid testing, that is, availability, quality, stability, and reproducibility of detection kits. In most of the cases, the tests need to be repeated for several times (Wang, Kang, et al., 2020) , as the estimated detection rate of the test falls in an underwhelming range of 30-50% Corman et al., 2020; Zhang et al., 2020) . In spite of being a valuable asset, the undesirable false-negative results of RT-PCR have prompted careful clinical and etiological evaluation of COVID-19 in suspected cases as the first-line diagnostic method (Zu et al., 2020) .

CT has proved to be of great value in diagnosis of the COVID-19associated pneumonia, as it provides major evidence, that cannot readily be obtained with alternative methods. It is true that CT is a reliable imaging modality in subtle detection of viral pneumonia and screening of suspected cases; however, it should be noted that many pulmonary diseases of inflammatory nature share similar radiographic findings (Wang, Kang, et al., 2020) . The majority of patients with COVID-19 present with GGO in their chest CT, which later progress into multilobar consolidations. There have been several reports of rounded opacities, which are sometimes peripherally distributed in the lung (Chung et al., 2020; Huang et al., 2020) .

In contrast to CT, plain chest radiography (CXR) has not been recommended as a first-line imaging method, because this modality does not provide the clarity viewed on CT scans, especially in the early stages of pulmonary infection (Ng et al., 2020) . Nevertheless, CXR is capable of recording pathologic changes in patients with severely progressed COVID-19, as the bilateral multifocal consolidations present in these patients are too dense to be missed. The notorious "white lung" appearance can be optimally viewed on CXRs of critically ill patients (Zu et al., 2020) . CT resulted in diagnosis of 14,840 new cases as of February 13, 2020 (Zu et al., 2020) . Therefore, slice chest CT is an adequately sensitive and reliable method in early detection of pneumonia in patients with COVID-19 (Chan et al., 2020; Ng et al., 2020) .

Depp learning, as a novel AI-based modality might be able to analyze radiographic features of COVID-19, and help clinicians provide an accurate clinical diagnosis based on a precedented pattern (Wang, Kang, et al., 2020) . As part of recent advancements, Convolutional Neural Network (CNN), a class of deep neural networks, has been shown to be capable of medical image analysis. To this date, CNN has been successfully employed in investigations on the nature of pulmonary nodules reported in CT images, diagnosis of pneumonia in children based on CXR, and image recognition in cystoscopy videos (Choe et al., 2019; Kermany et al., 2018; Negassi, Suarez- The 21st century has seen many AI-based models to be incorporated in several scientific fields, particularly imaging studies.

Diagnostic AI-based models might actually be a forward leap in tasks that simply cannot be handled by manpower, especially risk prioritization, that can greatly help improve patient turnaround time.

Given the shortage of human resources and inadequate number of hospital beds in a country like China, AI-based models for analysis of CXR and CT scans can be useful in ruling out irrelevant cases, and resource-wise admission of patients to the hospitals (Kim, 2020) . . Table 3 ( Chen, Zhao, et al., 2020; Yan et al., 2020) and Table 4 represent 2020 studies on prognosis of COVID-19 infected patients and related clinical trials, respectively.

Scientists have made strenuous efforts to come up with an effective regimen for successful treatment of COVID-19 (Gao, Tian, & Yang, 2020) . Table 3 Fan et al., 2020; Han et al., 2020; Lan et al., 2020; Li, Zhang, et al., 2020; Li, Hu, et al., 2020; Lim et al., 2020; Wu & McGoogan, 2020) , Tables 4 and 5 

Combination therapy is a more extensive and rigorous approach mainly aimed at correction of life-threatening events such as shock, hypoxemia, secondary or super infection, and maintenance of homeostasis, that is, electrolyte, acid and base balance. As a palliative practice, antiviral treatment in the early stages of COVID-19 might lessen the severity and prevent further progression of the disease.

Trials on combination therapy with lopinavir/ritonavir and arbidol (umifenovir) have reported satisfactory results in treatment of COVID-19. Alongside a proper antiviral treatment, patients may also benefit from an artificial liver blood purification system, which is capable of rapidly removing the inflammatory factors from blood, thus, halting the disastrous cytokine release syndrome. This system can also facilitate the sustenance of critically ill patients by preserving the balance of bodily fluid. Administration of glucocorticoids in moderate doses is another intervention that has recently been indicated for patients with severe COVID-19-associated pneumonia.

However, secondary fungal infection should be considered. Patients with an oxygenation index of less than 200 mmHg might benefit more from oxygen therapy than noninvasive ventilation. A rational prescription of antimicrobial medicines has been cautioned only for patients with remittent fever and elevated antimicrobial prophylaxis 

A new therapeutic for treating immune-mediated diseases, MSC therapy might have the capability to terminate the inappropriate release of cytokines in COVID-19. Through its anti-inflammatory effects, MSC therapy has been reported to improve respiratory function in murine models with acute lung injury. Evidence suggests that MSCs might be doing so by repressing the aberrant release of inflammatory factors (Hu & Li, 2018; Wang, Yao, Lv, Ling, & Li, 2017; Xiang et al., 2017) . In particular, a study by Chinese scientists concluded that transplantation of MSCs could be considered as a novel approach in treatment of viral pneumonia, noting promissory implications of this method in management of H7N9-induced ARDS.

Since H7N9 and SARS-CoV-2 can result in similar complications, for example, ARDS and respiratory failure, MSC-based therapy might lead to a new path in treatment of COVID-19-associated pneumonia .

It has long been known that the traditional circulation-based delivery of therapeutic agents is not as effect, prompting pharmaceutical industries to develop novel platforms for delivery of molecules to hard-to-reach tissues in human body. Conjugation of antiviral agents, particularly nucleoside analogs, with specific nanoparticles has proved to be effectual in treatment of resistant HIV infection (Agarwal, Chhikara, Doncel, & Parang, 2017; Agarwal, Chhikara, Quiterio, Doncel, & Parang, 2012) . Today, an appreciable number of drug delivery platforms based on nanotechnology are available that can be experimentally used with custom therapeutic formulations for treatment of COVID-19 (Chhikara & Varma, 2019) in hopes of shortening the course of the disease (Chhikara et al., 2020) .

Progression of COVID-19, similar to any other disease, can result in suffering of the patients, prompting psychological symptoms, which will require special interventions. It has been well-established today that individuals who fall victim to public health emergencies, for example, disease outbreaks, develop variable degrees of stress disorders. The problem persists even after the individual has recovered and discharged from the hospital (Cheng, Wong, Tsang, & Wong, 2004; Fan, Long, Zhou, Zheng, & Liu, 2015) . With that in mind, one should consider several factors for classification of patients who will most probably benefit from psychological interventions; that is overall course of the disease, severity, and quality of hospitalization (e.g., home, ordinary wards, ICU, etc.) (Duan & Zhu, 2020) .

In large-scale outbreaks such as COVID-19 epidemic, healthcare workers become the frontline at providing psychological cares for patients who battle against the disease. Primary medical and mental care should be provided for those individuals who are recognized as "suspected case" and duly quarantined at home. (Duan & Zhu, 2020) .

Interventions should be discreetly formulated following a thorough evaluation of risk factors involved in emerging of these psychological issues, including a history of impaired mental health, bereavement after a deceased family member, panic, separation from loved ones, and a low income (Kun, Han, Chen, Yao, & Anxiety, 2009 ).

The following criteria must be met in order for a patient to be discharged from hospital or released from quarantine: (a) having been afebrile for at least 3 consecutive days, (b) remission of respiratory distress, (c) regression of infiltrations/consolidations on chest CT images, and two consecutive negative reports of RT-PCR test performed at least 1 day apart (d). Despite these thoroughly formulated criteria, one study reported positive RT-PCR test results 5-13 days after hospital discharge for four patients with COVID-19, who met all of the criteria above before they were discharged. These findings are important in that they imply the slight possibility that even a fully recovered patient might still be a silent carrier of the virus. In this scenario, however, no family members were reported to be infected, since all of the four patients with bizarrely late positive tests were medical professional, and followed all of the guidelines while they were at home quarantine. With due attention to this incident, the current criteria for hospital discharge may need to be reconsidered (Lan et al., 2020) .

Deemed a global health emergency, COVID-19 outbreak has continued to be the headline of the news. The number of confirmed cases is on the rise, and the seamless spread of the virus has become a plight for general population, and the entire medical community. In spite of the extreme preventive measures while near a patient, clinicians are still at great risk for contracting the disease from the visitors. Else, it is vividly known that quarantine alone is not the optimal choice for containing of the virus.

On the other hand, the devastating potential impact of the outbreak is a much feared topic around the world. Science has always been the ultimate arsenal of weaponry when it comes to battling obstinate pathogens; however, time is needed for conduction of proper investigations on human-to-human and animal-to-human transmission of SARS-CoV-2.

With no access to requisite information on the structure and life cycle of the novel Coronavirus, research and development programs on therapeutic agents become a far-fetched milestone, rendering the tried-and-true primary prevention measures the only proper means to confront SARS-CoV-2. As of today, few existing drugs have been considered for treatment of COVID-19, with scant reports on benevolence of the results. As our meager knowledge of SARS-CoV-2 is advancing, one may speculate the advent of an effectual vaccine, alongside treatment options that might include antiviral agents, and even monoclonal antibodies. At the time of writing this manuscript, no definitive treatment option has been known for COVID-19; however, the unabating flow of investigations and clinical trials may soon lead us to the optimal therapy for COVID-19-associated pneumonia.

Needless to say, the fascinatingly high transmissibility of COVID-19 demands meticulous monitoring of the transmission routes and patterns to a reach a firm theory on adaptive mechanisms wielded by SARs-CoV-2, thus, making an accurate prediction about the future outcomes regarding pathogenicity, transmissibility, and evolution of the virus. These efforts will hopefully result in better prognosis and fewer mortalities.

Synthesis and anti-HIV activities of unsymmetrical long chain dicarboxylate esters of dinucleoside reverse transcriptase inhibitors

Synthesis and anti-HIV activities of glutamate and peptide conjugates of nucleoside reverse transcriptase inhibitors

Correlation of chest CT and RT-PCR testing in coronavirus disease 2019 (COVID-19) in China: A report of 1014 cases

Evidence for camel-to-human transmission of MERS coronavirus

Presumed asymptomatic carrier transmission of COVID-19

The meaning of hypokalemia in heart failure

An Insight of comparison between COVID-19 (2019-nCoV) and SARS-CoV in pathology and pathogenesis. 1-23

The convalescent sera option for containing COVID-19

A familial cluster of pneumonia associated with the 2019 novel coronavirus indicating person-to-person transmission: A study of a family cluster

Clinical characteristics and intrauterine vertical transmission potential of COVID-19 infection in nine pregnant women: A retrospective review of medical records

Clinical study of mesenchymal stem cell treating acute respiratory distress syndrome induced by epidemic Influenza A (H7N9) infection

Analysis of clinical features of 29 patients with 2019 novel coronavirus pneumonia

Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: A descriptive study

Detectable serum SARS-CoV-2 viral load (RNAaemia) is closely associated with drastically elevated interleukin 6 (IL-6)

Human infections with the emerging avian influenza A H7N9 virus market poultry: Clinical analysis and characterisation of viral genome

From SARS-CoV to Wuhan 2019-nCoV outbreak: Similarity of early epidemic and prediction of future trends

Psychological distress and negative appraisals in survivors of severe acute respiratory syndrome (SARS)

Corona virus SARS-CoV-2 disease COVID-19: Infection, prevention and clinical advances of the prospective chemical drug therapeutics

Nanochemistry and nanocatalysis science: Research advances and future perspectives

Deep learning-based image conversion of CT reconstruction kernels improves radiomics reproducibility for pulmonary nodules or masses

Role of lopinavir/ritonavir in the treatment of SARS: Initial virological and clinical findings

Molecular diagnosis of a novel coronavirus (2019-nCoV) causing an outbreak of pneumonia

Productive replication of Middle East respiratory syndrome coronavirus in monocyte-derived dendritic cells modulates innate immune response

CT imaging features of 2019 novel coronavirus (2019-nCoV)

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

Treatment of COVID-19: old tricks for new challenges

Psychological interventions for people affected by the COVID-19 epidemic

Longitudinal trajectories of post-traumatic stress disorder symptoms among adolescents after the Wenchuan earthquake in China

Clinical features of COVID-19-related liver damage

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

Office of State Administration of Traditional Chinese Medicine. Notice on the issuance of a program for the diagnosis and treatment of novel coronavirus (2019-nCoV) infected pneumonia

Office of state administration of traditional Chinese medicine. Notice on the issuance of a programme for the diagnosis and treatment of novel coronavirus (2019-nCoV) infected pneumonia

Return of the coronavirus: 2019-nCoV

Clinical characteristics of 2019 novel coronavirus infection in China. MedRxiv

A new virus isolated from the human respiratory tract

The course of clinical diagnosis and treatment of a case infected with coronavirus disease 2019

Preconditioning influences mesenchymal stem cell properties in vitro and in vivo

Clinical features of patients infected with 2019 novel coronavirus in Wuhan

Report 2: Estimating the potential total number of novel coronavirus cases in Wuhan City

Clinical characteristics of 51 patients discharged from hospital with COVID-19 in Chongqing. China. medRxiv

Identifying medical diagnoses and treatable diseases by image-based deep learning

Outbreak of novel coronavirus (COVID-19): What is the role of radiologists?

The first case of 2019 novel coronavirus pneumonia imported into Korea from Wuhan, China: Implication for infection prevention and control measures

Updates on Wuhan 2019 novel coronavirus epidemic

Inhibition of human coronavirus 229E infection in human epithelial lung cells (L132) by chloroquine: Involvement of p38 MAPK and ERK

Prevalence and risk factors for posttraumatic stress disorder: A cross-sectional study among survivors of the Wenchuan

Dipeptidylpeptidase IV from bench to bedside: An update on structural properties, functions, and clinical aspects of the enzyme DPP IV

Positive RT-PCR test results in patients recovered from COVID-19

Sex differences in clinical findings among patients with coronavirus disease 2019 (COVID-19) and severe condition

Early transmission dynamics in Wuhan, China, of novel coronavirusinfected pneumonia

Hypokalemia and clinical implications in patients with coronavirus disease 2019 (COVID-19)

Case of the index patient who caused tertiary transmission of Coronavirus disease 2019 in Korea: The application of lopinavir/ ritonavir for the treatment of COVID-19 pneumonia monitored by quantitative RT-PCR

Therapeutic effects of dipyridamole on COVID-19 patients with coagulation dysfunction

The reproductive number of COVID-19 is higher compared to SARS coronavirus

Molecular epidemiology, evolution and phylogeny of SARS coronavirus

Application of artificial neural networks for automated analysis of cystoscopic images: A review of the current status and future prospects

Imaging profile of the COVID-19 infection: Radiologic findings and literature review

Severe acute respiratory syndrome: Temporal lung changes at thin-section CT in 30 patients

Imaging changes in patients with 2019-nCov

Initial CT findings and temporal changes in patients with the novel coronavirus pneumonia (2019-nCoV): A study of 63 patients in Wuhan

Transmission of 2019-nCoV infection from an asymptomatic contact in Germany

2019 Novel Coronavirus (COVID-19) Outbreak: A Review of the Current Literature

Recent advances in the angiotensin-converting enzyme 2-angiotensin (1-7)-Mas axis

Radiological findings from 81 patients with COVID-19 pneumonia in Wuhan, China: A descriptive study. The Lancet Infectious Diseases

One severe acute respiratory syndrome coronavirus protein complex integrates processive RNA polymerase and exonuclease activities

Inhibitors of RAS might be a good choice for the therapy of COVID-19 pneumonia

Characteristics of COVID-19 infection in Beijing

The human microbiota in health and disease

Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in Wuhan

Development and validation of a deep-learning algorithm for the detection of polyps during colonoscopy

A deep learning algorithm using CT images to screen for Corona Virus Disease (COVID-19)

Potassium homeostasis and reninangiotensin-aldosterone system inhibitors

Middle East respiratory syndrome case definition for reporting to WHO

Clinical management of severe acute respiratory infection when novel coronavirus (2019-nCoV) infection is suspected

WHO guidelines for the global surveillance of severe acute respiratory syndrome (SARS)

World Health Organization. Coronavirus Disease 2019(COVID-19): Situation report-28

statment-on-the-second-meeting-of-the-international-health-regulations-(2005)-emergency-committe-regarding-of-outbreak-of-novel-coronavirus-(2019-nCoV World Health Organization. (2020e). Emergencies preparedness, response. Pneumonia of unknown origin -China. Disease outbreak news

Clinical characteristics of imported cases of COVID-19 in Jiangsu province: A multicenter descriptive study

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

Transplantation of menstrual blood-derived mesenchymal stem cells promotes the repair of LPS-induced acute lung injury

Integrative bioinformatics analysis provides insight into the molecular pechanisms of 2019-nCoV

Management of corona virus disease-19 (COVID-19): The Zhejiang experience

Pathological findings of COVID-19 associated with acute respiratory distress syndrome

Prediction of criticality in patients with severe Covid-19 infection using three clinical features: A machine learning-based prognostic model with clinical data in Wuhan

Clinical characteristics and imaging manifestations of the 2019 novel coronavirus disease (COVID-19): A multi-center study in Wenzhou city

MERS, SARS and other coronaviruses as causes of pneumonia

Clinical, virological, and histopathological manifestations of fatal human infections by avian influenza A (H7N9) virus

Isolation of a novel coronavirus from a man with pneumonia in Saudi Arabia

Potential interventions for novel coronavirus in China: A systematic review

Recent advances in the detection of respiratory virus infection in humans

Relationship between the ABO Blood Group and the COVID-19 Susceptibility. medRxiv

Active replication of Middle East respiratory syndrome coronavirus and aberrant induction of inflammatory cytokines and chemokines in human macrophages: Implications for pathogenesis

A novel coronavirus from patients with pneumonia in China

Coronavirus Disease 2019 (COVID-19): A Perspective from China. Radiology

Reducing mortality from 2019-nCoV: Host-directed therapies should be an option

COVID-19 under spotlight: A close look at the origin, transmission, diagnosis, and treatment of the 2019-nCoV disease

This review was conducted under supervision of Zahedan University of Medical Sciences and Iran University of Medical Sciences.

The authors declare that they have no conflict of interest.

All authors contributed to different parts of the study.

http://orcid.org/0000-0001-7996-845XMilad Shirvaliloo https://orcid.org/0000-0001-5122-1274Habib Ghaznavi http://orcid.org/0000-0002-4629-1697Samideh Khoei http://orcid.org/0000-0001-9357-0229