Coronaviruses are a group of viruses that can cause respiratory infection in humans [1]. These viruses were discovered in 1966 by Tyrell and Bynoe, who cultured the viruses from common cold patients [2]. Because of their morphology as sphere-shaped viruses with a core-shell and surface projections similar to a corona (meaning “crown” in Latin), they are named coronaviruses [3, 4]. These viruses are members of the subfamily Coronavirinae in the family Coronaviridae and the order Nidovirales. This subfamily includes four groups: Alphacoronavirus, Betacoronavirus, Gammacoronavirus, and Deltacoronavirus (Figure 1). The Alpha and Betacoronaviruses infect just mammals. Although Gamma and Deltacoronaviruses infect birds, some also may infect mammals [5]. Alpha and Betacoronoviruses are usually associated with human respiratory disease and gastroenteritis disorders in animals. Middle East respiratory syndrome coronavirus (MERS-CoV) and Severe acute respiratory syndrome coronavirus (SARS-CoV) are the most pathogenic viruses which cause the intense respiratory syndrome. The other four human coronaviruses cause mostly mild to severe respiratory illnesses, (i.e. HCoV-229E, HCoV- NL63, HKU1, and HCoV- OC43) [1, 6, 7].

On New Year’s Eve 2019, a new, human-infecting coronavirus was reported in some patients with a history of contact with the Huanan seafood market, in Hubei Province, China [8]. This outbreak spurred Chinese scientists to sequence the genome of this virus immediately and raised concern about the link between this virus and wildlife, most likely from bats or pangolins, although a slew of genetic analyses has yet to find definite proof [8, 9]. Using next-generation sequencing, they reported that this virus belongs to B lineage of the Betacoronaviruses and is associated with the SARS-CoV [8, 10]. At first, the virus taxonomy was called 2019-nCoV, but, on February 11, 2020, the International Committee on Taxonomy of Viruses officially renamed the novel coronavirus responsible for the current pandemic of coronavirus disease (aka., COVID‐19), severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) [10]. Therefore, the virus is referred to as SARS-CoV-2, and the associated disease as COVID-19. At the time of last revision for this article (May 16, 2021), more than 162 million cases were reported globally with over 3.3 million deaths from 223 countries, areas or territories, mostly from the United States, India, Brazil, France, Turkey, Russia, United Kingdom, and Italy [11, 12]. As of May 12, 2021, a total of 1,264, 164, 553 vaccine doses have been administered, mostly in developed countries [11, 12]. Given the novelty and the lack of knowledge regarding the current pandemic of COVID-19, here we reviewed the existing evidence on epidemiologic, diagnostic, and treatment approaches of COVID-19.

The 2002–2004 SARS-CoV is a Betacoronavirus which first emerged in China and infected >8,000 people, leading to 774 deaths in 37 countries around the world [13, 14]. The MERS-CoV was known for the first time in Saudi Arabia in 2012 and resulted in 2,494 definite cases of infection and 858 deaths since September 2012 [15–17]. The receptor which SARS-CoV utilizes for contaminating type II pneumocytes and ciliated bronchial epithelial cells is angiotensin-converting enzyme 2 (ACE2) [18–20], while MERS- CoV employs dipeptidyl peptidase 4 [21] (DPP4) receptor and contaminates type II pneumocytes and unciliated bronchial epithelial cells [22–24]. SARS-CoV and MERS-CoV were spread to individuals from market civets and camels, respectively, and both of them are suspected of originating in bats [25–31]. Figure 2 displays the SARS-CoV-2 genome structure and virion.

SARS-CoV-2 is a single-stranded, sense positive RNA virus in length around 26–32 kb with a diameter of 60–140 nm [32]. The membrane of the virus comprises the transmembrane glycoprotein (M), spike glycoprotein (S), envelope protein (E), and a flexible nucleocapsid [33, 34]. Coronaviruses have a minimum of six open reading frames (ORFs). ORF1a/b is the first which contains around two-third of the genome and codes replica proteins. The 3′-end of the genome codes structural proteins with a set of additional proteins that are exclusive for each virus species. Coronavirus cell entrance occurs by binding the S protein to a certain receptor on the cell surface, subsequent fusion is facilitated by the target cell membrane, and finally, the virus nucleocapsid enters the cell for later replication [35]. Some studies indicate that COVID-19 uses ACE2 as its receptor-like SARS-CoV, suggesting that this virus can share a similar life cycle with SARS-CoV [4]. The clinical analysis showed that the S protein of SARS-CoV-2 binds 10- to 20- fold higher affinity than the S protein of SARS-CoV to ACE2. This high affinity may explain the ease by which SARS-CoV-2 can spread among the human populations [36]. Moreover, it has been confirmed that SARS-CoV-2 shares 96% nucleotide identity with the complete genome sequence of the bat coronavirus. However, attempts to recognize intermediate hosts await future research to elucidate [4]. The physicochemical features of SARS-CoV-2 have not been defined completely yet. It is reported that SARS-CoV-2 is sensitive to heat, lipid solvents like 70% ethanol, and UV radiation [37].

In a recently published study, genetic analysis was performed on 103 genomes of SARS-CoV-2 and the results indicated that SARS-CoV-2 developed into main types, L and S. These two types are defined by two single-nucleotide polymorphism (SNP) which demonstrated nearly complete linkage across SARS-CoV-2 strains. Also, the evidence proved that type L (70%) was more prevalent and aggressive than type S, but human interference probably shifted the abundance of L and S type after the outbreak of SARS-CoV-2 [38]. Nevertheless, as highlighted by authors of this study, it is pivotal to further investigate combine genomic and epidemiological data, and chart records of the clinical symptoms of patients infected by SARS-CoV-2.

Understanding of the epidemiology of COVID-19 is evolving since its first report to the Country Office of WHO in China on December 31, 2019 [39]. The exponentially increasing number of confirmed cases and deaths reported from China and beyond spurred WHO to declare a Public Health Emergency of International Concern on January 30, 2020, which was later upgraded to a declaration of COVID-19 pandemic on March 11, 2020 [40].

Symptoms of SARS-CoV-2 differ in some respects from other betacoronavirus, (e.g. SARS-CoV, MERS-CoV). For example, unlike SARS-CoV and MERS-CoV, SARS-CoV-2 spreads rapidly [41]. Surprisingly, this virus can infect and actively reproduce in the upper respiratory tract given that its close genetic relative, SARS-CoV, lacks this ability [42]. Moreover, whereas COVID-19 patients present intestinal symptoms like diarrhea only a low percentage of SARS-CoV or MERS-CoV patients exhibited these symptoms (Table 1) [43, 44]. However, a recent study in the New England Journal of Medicine [45], concluded that the stability of SARS-CoV-2 is comparable to that of SARS-CoV under clinical conditions. The authors suggest that dissimilarity in the epidemiologic features of these two viruses arise from other aspects such as high viral loads in the respiratory tract and the potential for asymptomatic individuals to shed and transmit the virus to other people. These features facilitate the transmission of the virus during daily activities and interactions between people. Given these characteristics, and to protect the population’s health and slow the rate of transmission of COVID-19, while waiting for vaccines to reach all over the globe, WHO and public health experts are urging several simple mitigation strategies, (e.g. face-covering masks, social distancing, and cleaning hands with an alcohol-based hand rub or washing them with soap and water) to combat COVID-19 pandemic [46–49].

Although understanding COVID-19 transmission risk is in its infancy, as the outbreak progressed, human-to-human spread was identified as the main mode of transmission [50]. The United States Centers for disease Control and Prevention (CDC) report shows that the major route of transmission of this virus is through respiratory droplets generated when an infected individual coughs or sneezes [51]. Additional evidence shows that close social interaction and touching the eyes, nose, or mouth with a contaminated hand, are sources of transmission [50, 52]. Whether transmission may happen via mother-infant or breast milk is not fully known yet [37]. For example, WHO scientific report (June 23rd, 2020) highlighted that the data are not enough to conclude vertical transmission of COVID-19 through breastfeeding [53]. Also, as of May 13, 2021, the United States Center for disease Control and Prevention (CDC) maintains that breast milk is not likely to spread the SARS-CoV-2 to babies [54]. A comprehensive review article published in the International Breastfeeding Journal on September 14, 2020, concluded that breastfeeding must be encouraged, mothers and newborns dyads should be cared for together, and skin-to-skin contact ensured throughout the COVID-19 pandemic [55]. Nevertheless, an earlier study from China concluded that vertical maternal-fetal transmission cannot be ruled out since three of 33 infants (9%; in their study sample) presented with early onset SARS-CoV-2 infection [56]. They suggested that it is critical to screen pregnant women and implement strict infection control procedures, quarantine mothers who are COVID19 positive, and closely monitor neonates at risk of COVID-19 [56]. Moreover, a recent case study concluded that transplacental transmission of SARS-CoV-2 infection is possible during the last weeks of pregnancy [57]. Although future longitudinal studies are warranted to better understand mother-to-child transmission, US CDC recommends sevral precautions while newborn is rooming-in with infected mother in the hospital [54]; they include wearing mask, washing hands with soap, keeping newborn more than 6 feet away from mother as much as possible, and using a physical barrier, (e.g. placing the newborn in an incubator).

As discussed earlier, the number of confirmed cases is increasing exponentially worldwide. As shown in Table 2, according to the WHO, as of May 16, 2021, the top 10 countries that are contributing to the ongoing global pandemic of COVID-19 reported case fatality rate (CFR) between 0.87% in Turkey to 2.99% in Italy, with global CFR of 2.07% (Table 2) [12, 40]. In comparison, the 2002–2004 outbreak of SARS had a CFR of around 10%, while MERS killed 34% of infected people between 2012 and 2019 [58].

Appropriate case definition is critical in recognizing and responding to infectious outbreaks, as well as for clinical diagnosis and public health surveillance [59]. According to WHO [60], the case definitions of COVID-19 are as follow:

1) “A suspected case is: A. a patient with acute respiratory illness (that is, fever and at least one sign of respiratory disease, for example, cough or shortness of breath) AND with no other etiology that fully explains the clinical presentation AND a history of travel to or residence in an area that has reported local transmission of COVID-19 during the 14 days prior to symptom onset.” Or “B. a patient with any acute respiratory illness AND who has been a contact of a confirmed or probable case of COVID-19 during the 14 days prior to the onset of symptoms (see the definition of contact below).” Or “C. a patient with a severe acute respiratory infection (that is, fever and at least one sign or symptom of respiratory disease, for example, cough or shortness breath) AND who requires hospitalization AND who has no other etiology that fully explains the clinical presentation.”

According to the existing evidence, the incubation period for COVID-19 varies from 2 to 14 days with a median of ∼5 days, which is similar to SARS [37, 61–65]. The most important clinical symptoms of the disease are fatigue, fever, and dry cough. Regardless of the atypical symptoms that were reported, fever was cited as the typical sign of COVID-19 infection (Table2) [66]. The disease severity ranges from mild self-restricting flu-like ailment to fulfillment pneumonia, respiratory failure, and death.

As reported by WHO [12], 80% of COVID-19 infections are mild or asymptomatic, 15% are severe, requiring oxygen, and 5% are critical infections, requiring ventilation. Risk of acquiring virus and severity of COVID-19 differs by sex, age, and other factors such as severe obesity [67, 68]. A study based on publicly released data from 1,212 confirmed patients infected with COVID-19 in Henan of China, showed that a majority of infected cases were among males (55% vs. 45%) [69]. The results highlighted two probable factors that lead to this gender difference including 1) The high expression and distribution of COVID-19 receptor (ACE2) in male patients and 2) The tendency for males to engage in wider social activities than females [69]. Additionally, the reduced vulnerability of women to COVID-19 infections may be related to the protection from sex hormones and X chromosome, which have a key function in immunity [70]. Nevertheless, to explore more precise gender differences of COVID-19, future studies are warranted. A recent retrospective cohort study of 6,916 patients with COVID-19 in the US, found severe obesity as a profound risk for death from COVID-19, particularly in male patients and younger populations [67]. Severe obesity is an intractable problem in the United States and many western nations and little likely can be done in the short-term to reduce its effects on COVID-19 progression except to recognize the increased risk of obesity and target obese patients early for stepped up care.

Presentation of COVID-19 in children presents somewhat differently from adults. Although earlier in the pandemic it was recognized that children have milder symptoms (compared to adults) and are less likely to be hospitalized [71], several studies reported a multisystem inflammatory syndrome in children (MIS-C) associated with COVID-19 [72–74]. Available data by the American Academy of Pediatrics shows that, as of May 6, in 46 states of United States, over 3.85 million children have tested positive for COVID-19 since the onset of the pandemic, and children represented 14.0% of all cases in the Unites States by May 6, 2021 [75]. Although children were 0%–0.4% of all COVID-19 deaths, and 19 states reported zero child deaths, the United States CDC’s report highlights that children are at risk for severe COVID-19 and public health authorities and clinicians should continue to track pediatric COVID-19 infection [76].

As shown in Table 3, three major forms of the clinical courses of COVID-19 have been recognized by the Chinese CDC:

• Mild form: patients have asymptomatic upper respiratory tract infection (URI) with minor pneumonia, this usually occurred in approximately 80% of COVID-19 patients [77, 78].

The United States CDC recommends the collection of specimens for COVID-19 examination from the respiratory tract [70]. Other specimens such as urine or stool can also be collected for diagnostic purposes. Following collection, specimens are tested in the form of reverse transcription-polymerase chain reaction (RT-PCR), which can determine results in 4–6 h [79, 80].

The WHO released a rapid advice guide on using chest imaging in COVID-19 patients on June 11, 2020 that highlights several points:

• “No study evaluated the diagnostic accuracy of chest imaging in asymptomatic patients possibly infected with SARS-CoV-2.”

Health providers collect serum samples for COVID-19 that may show virus spreading from the infected lung into the blood circulation, as formerly observed in SARS patients [81]. However, in the first infected case in the United States, it was reported that the stool and respiratory specimens were positive by RT-PCR for COVID-19, while the serum examination was negative [82]. Notably, in some patients, the ground-glass opacity (GGO) variations on CT scan revealed earlier than the positive for RT-PCR test [83, 84]. Thus, repeating sputum or nasopharyngeal swab test are suggested in suspected cases with an initially negative lab result taken from these samples [82, 85–87].

In the current situation, controlling the infection is the best way to tackle the pandemic of SARS-CoV-2 [102]. Some non-pharmaceutical strategies, including early diagnoses, isolation, and supportive treatments and protective measures, (e.g. wearing masks, improving personal hygiene, and keeping rooms ventilated) can efficiently break the SARS-CoV-2 transmission chain [103].

Overall, treatment approaches are classified into three stages related to the severity of the disease:

1) Mild phases of the disease: symptomatic support treatment [104].

Analysis of the SARS-CoV-2 RNA genome indicated that this virus has differences in sequence. These differences are typically single nucleotide variations. The preliminary data from samples suggest that SARS-CoV-2 is actively evolving through various mutations which can lead to a major challenge in developing effective drugs and vaccines [106].

At the time of writing this review, no definite cure has been provided for COVID-19. Some drugs, however, are prescribed by health providers, such as nucleoside analogs, lopinavir/ritonavir (LPV/r), umifenovir (Arbidol), neuraminidase inhibitors, remdesivir, DNA synthesis inhibitors (like Disoproxil, tenofovir, and Lamivudine), Hydroxychloroquine/Chloroquine (HCQ/CQ), and favipiravir [107, 108]. There are some positive reports that these antiviral drugs may have clinical efficacy against COVID-19 [109].

For patients with severe signs, antibiotics (Tazobactam sodium, Moxifloxacin, Piperacillin sodium, and Meropenem) and methylprednisolone (1–2 mg per kg weight per day) also have been utilized, according to the physicians’ decision [70]. In low immune function cases, like diabetics, older people, HIV infected persons, individuals with long-term use of immunosuppressive drugs, and pregnant women, early prescribing of antibiotics to inhibit infection may decrease morbidity and mortality [70].

Since the start of the COVID-19 pandemic, corticosteroid use has been the subject of debate.

Previously, it has been recommended that immune-modulating drugs such as corticosteroids be utilized in some special situations, including: in quickly deteriorating chest imaging and ARDS, in encephalitis, hemophagocytic, septic shock, and in apparent wheezing symptoms. Intravenous methylprednisolone (one to two mg/kg/day) usage is suggested for 3–5 days [37, 110].

However, according to the latest evidence corticosteroids do not appear to play a main role in treatment of ARDS [111, 112]. Despite improved cardiopulmonary physiology, routine use of methylprednisolone for persistent ARDS is not recommended [112].

According to a meta-analysis of COVID-19 patients, mortality was higher among patients receiving corticosteroids than among patients who were not receiving corticosteroids [113]. In contrast, a cohort study of 1444 COVID-19 patients found that treating with corticosteroids had no effect on hospital mortality [114]. As a result, corticosteroids seem to be a double-edged sword in the battle against COVID-19 and should be used cautiously, considering the risk–benefit ratio [115].

These recommendations are supported by WHO guidance suggesting that corticosteroid regimens should not be routinely used in the treatment of COVID-19 except in certain scenarios such as treatment of exacerbated asthma attacks, COPD, or septic shock [110, 116].

On September 2020 Public Health authorities in South East region of England detected a new SARS-CoV-2 variant as a lineage B.1.1.7, aka Variant of Concern 202,012/01 (VOC-202012/01), 20I/501Y.V1, or more commonly known as the British variant or United Kingdom variant [193]. Seventeen mutations in the viral genome occurred in this variation, eight of which are localized in the spike (S) protein of the virus. Two significant characteristics of lineage B.1.1.7 are the N501Y mutation and the 69–70 deletion of the S protein. The 69–70 deletion reduce sensitivity to neutralization by convalescent serum samples [194]. The N501 is one of the six amino acids interacting with ACE-2 [195], and the tyrosine substitution could increase binding affinity to the ACE-2 [196]. These variations have led scientists to be worried about high contagiousness, rapid spread, and possibly augmented mortality.

Variant B.1.351 has appeared in South Africa over the last several months, and similar to the B.1.1.7 raised transmission rates and higher viral load following infection have been reported [197]. Mutations in the S protein are more extended than variant B.1.1.7. Three of these mutations are found in the RBD (E484K, K417N, N501Y). Since RBD is the dominant target for neutralizing antibodies, these mutations might affect the effectiveness of previously approved monoclonal and polyclonal antibodies elicited by vaccination or infection in neutralizing the virus [198, 199].

An additional independent lineage of SARS-CoV-2 (named P.1 variant or 20J/501Y.V3) was identified in Brazil. Variant P.1 is a branch of lineage B.1.1.28 that was initially reported by the Japanese National Institute of Infectious Diseases (NIID) in four travelers from Brazil. It contains three mutations in the spike protein receptor binding domain (E484K, N501Y and K417T) [200]. Existing evidence suggests that some mutations in the P.1 variant can affect its transmissibility and antigenic profile, that may affect the ability of antibodies produced by a previous infection or vaccination [201].

Globally, researchers constantly working hard to gain knowledge and richer understand the variations of virues alluded to above in order to provide information to public health authorities like WHO to prevent more infections and save lives.

It is critical not to neglect the mental health issues associated with the COVID-19 outbreak. Patients, family members, and healthcare workers who treat viral outbreak patients are all at increased risk of developing mental health problems. For example, the 2002–2003 global SARS epidemic was labeled a “mental health catastrophe” [202]. Health care workers on the front lines of patient care during viral outbreaks experience a whole host of stressors, such as long shifts, difficulty balancing professional and family responsibilities, dealing with inadequate equipment and the fear for personal and family safety, and having to make ethically challenging decisions about the allocation of treatment resources. As a result, healthcare workers are at increased risk of experiencing psychological distress and post-traumatic stress disorder (PTSD) [203]. Additionally, COVID-19 patients, those patients who recovered but still have some symptoms like shortness of breath, high risk populations, (e.g. the elderly, people living with HIV, and those living or receiving care in crowded locations), and people with preexisting medical conditions such as psychiatric or substance use problems are at increased risk for adverse psychosocial consequences [204–206]. Therefore, providing psychosocial support and regularly monitoring mental health needs of those at higher risk necessitate activities that need to be integrated into the general pandemic healthcare system, especially for those nations that are hard hit by this novel disease.