A comprehensive review and update on severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and Coronavirus disease 2019 (COVID-19): what do we know now in 2021?

Abstract

It has been more than a year since the new virus called severe acute respiratory syndrome Coronavirus 2 (SARS-CoV-2) was identified in Wuhan, China. The disease it causes was named Coronavirus disease 2019 (COVID-19), and on 11 March 2020 it was declared a pandemic. As the virus continues to spread, the number of patients worldwide has already crossed the 100 million mark with more than 2 million deaths. We sought to provide an update on the progress made in identifying the virus, its pathophysiology, risk factors such as hypertension, diabetes, and smoking, as well as various methods of treatment. Our review also provided an overview of the different vaccines.

Introduction

In early December 2019, a group of patients from Wuhan City, China reported symptoms of pneumonia of unknown origin [1]. The patients had all recently been exposed to the Huanan Seafood Wholesale Market [2]. The respective Chinese Health departments and the World Health Organization (WHO) were informed of the situation. The first report consisted of 44 patients, amongst whom 11 were severely ill. Their main symptom was fever, and some patients had difficulty breathing, with invasive lung lesions seen bilaterally [3]. Genomic sequencing was performed to identify the new agent, which was first named 2019-nCoV [4, 5]. Because the virus was closely related to severe acute respiratory syndrome (SARS) coronavirus (SARS-CoV), the name was changed to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and the disease it causes was called Coronavirus disease 2019 (COVID-19) [1, 6]. The WHO raised warning concerns and labelled it as a public health emergency of international concern on 30 January 2020. The virus started to spread, first throughout China, and then internationally. It was officially declared a pandemic on 11 March 2020 [1, 2].

Fast-forward a year, and the world is still struggling to control the spread of the virus, with many countries in lockdown or with their international borders closed. Many hospitals are overloaded with sick patients and the death toll keeps rising daily. This review aims to provide an in-depth understanding of the virus, its pathophysiology, epidemiology, as well as the clinical management while reflecting on what the future holds with the current situation.

Virology: what is SARS-CoV-2?

SARS-CoV-2 originates from the coronavirus family and is an enveloped, single-stranded RNA virus. Two other members of that family of virus include severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS) [1, 7]. SARS appeared between 2001 and 2003, causing the deaths of 774 people. Between 2012 and 2015, MERS was reported to kill 858 people [8]. Another manifestation of the coronavirus family includes the common cold. While SARS-CoV-2 has several similarities with other members of the coronavirus family, several major differences in pathology and prognosis have been reported [1, 9, 10].

An early analysis of 10 genomic sequences was obtained by Lu et al. from 9 patients who were exposed to the Huanan Seafood Market in Wuhan, China. They reported that the new virus had a similarity of 88% with two previously reported sequences of SARS-CoV, i.e. bat-SL-CoVZC45 and bat-SL-CoVZXC21, which were both bat derived. Less similar correlations were found with SARS-CoV (79%) and MERS-CoV(50%) [11]. The virus has 6 main functional open reading frames (ORFs) called Replicase (ORF1a/ORF1b), Spike (S), Envelope (E), Membrane (M), and Nucleocapsid (N) [12]. Hu et al. compared the proteins, listing more than 90% similarity in the amino acid identity between SARS-CoV2 and SARS-CoV [13]. The S gene, however, showed major differences [13–15].

Chen et al. identified the entire genome to be 29,881 bp long, which encodes for 9860 amino acids. The surface of the virus contains multiple TM protease serine 2 (TMPRSS2) glycosylated proteins called S proteins. They help the virus bind to the host receptor angiotensin-converting enzyme 2 (ACE2), which then promotes the entry of the virus into host cell via a type 2 TM serine protease called TM protease serine 2 (TMPRSS2) [16]. The viral RNA is transcribed, translated, and replicated inside the host cell [17].

Multiple variants have been reported for the virus [12]. The B.1.1.7 lineage was initially isolated in the United Kingdom in late 2020. This mutated virus has been linked with a higher risk of infectivity (50–75% higher). The presence of the strain was also eventually confirmed in other countries [18, 19]. The B.1.351 lineage was found in South Africa. It has an N501Y mutation in the spike protein [12, 20].

The main route of transmission is person-to-person via respiratory droplets. Close-range contact within 2 metres can infect another person if the droplets are inhaled or make contact with the mucous membranes [12, 21, 22]. Contaminated surfaces may also be a source of infection. The virus has also been detected in stool, blood, semen, and even ocular secretions [12]. While the virus can have an incubation period of around 14 days, many cases have been reported within 4–5 days of exposure [12, 23–25].

Epidemiology of COVID-19

By 10 March 2020, there had been 113,702 reported cases of COVID-19 in the world, and 4012 patients had died. At that time, the United States had only had 472 cases with 19 deaths, and South Korea, Japan, and Italy were the countries outside of China with the highest incidence of the disease [1]. However, as of 1 February 2021, there are now 103,741,860 confirmed cases of COVID-19 across the world and 2,243,354 people have died of the virus [26]. Cases of COVID-19 have been reported across all continents except for Antarctica, and it is believed that the actual number of infected individuals might be as much as 10 times higher than the reported number [12, 27, 28]. The United States currently has the highest number of total reported cases of COVID in the world with 26,796,980 infected Americans. It also has the highest total deaths due to COVID-19, as 452,921 have died since the virus was first confirmed in the country on 20 January 2020 [29]. India has the second-highest number of total cases with 10,767,159 confirmed cases, while Brazil is third with 9,204,731 patients [26].

Clinical findings

The range of clinical symptoms can vary from asymptomatic to severe or even death. Diagnosis can be made via nucleic acid-based tests, and the use of reverse-transcriptase polymerase chain reaction (RT-PCR) from various samples is a gold standard method of confirming an infection [30]. As per the Centers for Disease Control and Prevention (CDC) in the United States, the common symptoms can include fever (43%), chills, cough (50%), shortness of breath (29%), headache (34%), new loss of taste or smell (< 10%), sore throat (20%), diarrhoea, nausea/vomiting (12%), congestion, muscle ache (36%), and fatigue [31, 32]. Eighty-nine percent of patients who lost their sense of smell or taste reported that it improved over the next 4 weeks [33]. An early report by the Chinese Centre for Disease Control and Prevention showed that 81% of patients had mild disease, which may or may not include mild pneumonia. Fourteen per cent showed several severe symptoms such as dyspnoea, hypoxia, or at least 50% of lung involvement on imaging after 1–2 days. Five percent of those affected in their report had critical disease, which included respiratory failure, shock, or multiple organ dysfunction. They also reported a fatality rate of 2.3% [12, 34]. In a meta-analysis conducted by Meyerowitz-Katz et al., the infection fatality rate (IFR) was estimated at 0.68% [35]. An overall infection fatality risk of 0.8% was reported in Spain [36].

Several possible risk factors such as a history of hypertension, diabetes, smoking, previous cerebrovascular disease, acute or chronic kidney injury, and chronic obstructive pulmonary disease have all been linked with severe COVID-19 [37–42]. Several laboratory findings such as thrombocytopaenia, low haemoglobin value, and elevated red blood cell distribution width (RDW) have also been associated with a more critical prognosis of the disease [43–47]. Some clinical symptoms such as myalgia and headache do not predict severity [48, 49]. While COVID-19 can present in people of all ages, middle-aged and older adults were more commonly affected than children. Older age was associated with a higher hospitalization rate and also a higher risk of mortality [34, 50–52]. Men have a higher risk of developing a critical outcome or death than females [50–61]. Several ethnic differences linked with socio-economic and social determinants of health have also put African Americans, Hispanics, and South Asians in the high-risk group [12, 50, 57–61].

Some rare cases of multisystem inflammatory syndrome in children (MIS-C) have been reported by the CDC in children who have been exposed to COVID-19 or have been around someone with the disease. MIS-C has several similarities and differences with Kawasaki disease [62, 63]. It can affect the heart, lungs, kidneys, as well as the gastrointestinal system and present with a myriad of symptoms [64]. The CDC has established the definition for MIS-C as a patient of age less than 21 years, having a fever of at least 38.0°C for at least 24 h or subjective fever lasting more than 24 h, as well as evidence of inflammation such as “an elevated C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), fibrinogen, procalcitonin, d-dimer, ferritin, lactic acid dehydrogenase (LDH), or interleukin 6 (IL-6), elevated neutrophils, reduced lymphocytes, and low albumin”. These individuals should also be ruled out for any other possible cause, and they should have a positive current or recent SARS-CoV-2 infection confirmed via RT-PCR, serology, or antigen test. Alternatively, they should have been exposed to someone who is a confirmed or suspected case of COVID-19 within the last 4 weeks before the onset of their clinical findings [65].

The most common symptoms in pregnant women are cough and fever, and they have a mild course of illness that will not affect their delivery. However, pregnancy increases the risk of a more severe outcome of COVID-19 that may require intubation or mechanical ventilation. Boushra et al. found that pregnant women are at the highest risk of critical outcome needing intensive care admission or mechanical ventilation during their third trimester. This puts the foetus at a risk of miscarriage, foetal growth restriction, or even prematurity [66]. In the study conducted by Kotlyar et al., the risk of vertical transmission during the third trimester was found to be 3.2% [67].

Management of COVID-19-positive patients

There are multiple guidelines for the management of COVID-19 based on symptoms and severity [68, 69]. The guidelines by the National Institutes of Health (NIH) are based on scientific data and well-established discussions highlighting the risks and benefits of each treatment in patients. Changes in protocols reflect the evolving knowledge about the virus, its pathophysiology, and response among several different strains [69]. The decision to hospitalize a COVID-19 patient depends on the physician’s judgment based on the severity of the patient’s condition as well as the prioritization of the resources according to the number of cases and hospital beds available. Several triage protocols have been established to provide fairness and also to improve the quality of care while improving the response of hospital systems [68, 69]. Many mild cases of COVID-19, i.e. without pneumonia or hypoxia, may not need hospitalization. However, their situation should be properly monitored, and the final choice to pursue outpatient or inpatient care should be on a case-by-case basis [70, 71].

Severe cases of COVID-19 usually require hospitalization. They need supportive care for their symptoms and proper management to prevent complications. Their pneumonia, hypoxaemic condition, any sepsis or shock, as well as any organ damage should be addressed promptly. More than 75% of hospitalized COVID-19 patients required supplemental oxygen, and those who do not improve with conventional oxygen therapy are usually given heated high-flow nasal cannula oxygen. Additional techniques to improve their oxygenation such as prone positioning or the use of cisatracurium can also be adopted as needed [72, 73]. Their bleeding profile and other laboratory findings should be carefully monitored because COVID-19 positive patients are also at risk of multiple complications such as thromboembolism [71]. Imaging of the chest should be evaluated for findings such as ground glass appearance, and their progress should be tracked as per protocol [74]. Dexamethasone can be used with severe cases of COVID-19 who are also on ventilator support or require additional oxygen. Ahmed et al. reported that low doses can be useful in severe cases but do not show any positive impact on mortality for mild cases [75]. Tomazini et al. concluded that the use of intravenous dexamethasone along with standard care helped increase the number of ventilator-free days [76]. Data showed that the use of dexamethasone is more beneficial than other glucocorticoids at equivalent doses. The side effects of the drug should be carefully monitored. In a meta-analysis conducted by the WHO Rapid Evidence Appraisal for COVID-19 Therapies (REACT) Working Group, it was found that there is a lower 28-day all-cause mortality in patients using systemic corticosteroids compared to usual care or placebo [12, 77].

In the early months of the pandemic, the drugs chloroquine (CQ) and hydroxychloroquine (HCQ) were among the treatment options for COVID-19. However, in June 2020, the US FDA re-evaluated the use of these drugs and revoked their emergency use authorization. Both drugs are weak bases that interfere with the multiplication of a virus by affecting its entry through endosomes. Yao et al. also reported that hydroxychloroquine showed higher potency against the virus than chloroquine [78]. However, several articles and analyses eventually found that the use of the drug did not confer any improvement among several patient groups in terms of clinical status or mortality [71, 79, 80].

Remdesivir has previously shown a wide spectrum of antiviral properties. When used with MERS-CoV, the drug helped improve disease outcomes and pulmonary function [81]. Monotherapy of remdesivir for severe COVID-19 helps shorten recovery. It has also been useful in reducing mortality in severe COVID-19 cases that are using low-flow supplementary oxygen. The drug has also been approved by the FDA in the US to be used for children of at least 12 years of age and adults [12, 81–83].

Convalescent plasma from patients who have been COVID-19 positive and recovered at least 2 weeks prior is another therapy being used during the pandemic [71]. These patients have high levels of neutralizing antibodies, and their plasma can be used through the emergency use authorization issued in the United States. Its benefits for severe cases of COVID-19 are, however, still not fully understood [84, 85]. The plasma provides neutralizing antibodies that target the virus and prevent its entry into cells and enhance its clearance. Once administered, there is an initial wait of 2 to 3 weeks before a proper response is provided by the recipient [12, 71].

Because the pathophysiology of COVID-19 involves several cytokines including IL-6, various drugs that work against IL-6 have been tested as a possible therapy. Tocilizumab and sarilumab are receptor blockers, and siltuximab is a direct inhibitor. However, their use is not standard and should be evaluated on a case-by-case basis [1, 12]. Baricitinib is another drug that provides protection against viral entry [86]. It is a Janus kinase inhibitor that has previously been administered to rheumatoid arthritis patients. Its use along with remdesivir for COVID-19 has been approved in the United States. Modest improvement in recovery time was reported in patients using this drug combination as compared to glucocorticoids [87, 88]. Several other drug therapies such as ivermectin are also being studied [12, 71, 89].

Vaccination: past, present, and future

While no vaccine was released for SARS-CoV and MERS, the start of the vaccine study in those 2 viruses helped improve the speed of vaccine development for SARS-CoV-2. Studies targeting various molecular platforms were launched early on to find an effective vaccine against the virus. RNA vaccine studies focused on having a messenger RNA (mRNA) that can cause the build-up of foreign particles and lead to an adaptive immune response. Both the BNT162b2 vaccine (Pfizer-BioNTech COVID-19 vaccine) and mRNA 1273 vaccine (Moderna COVID-19 vaccine) are RNA vaccines. Pfizer–BioNTech COVID-19 vaccine reported a 95% efficacy as per data published on 10^th December 2020 [90]. The Moderna COVID-19 vaccine reported several positive results and had an efficacy of 94% [91].

An emergency use authorization for BNT162b2 vaccine (Pfizer-BioNTech COVID-19 vaccine) and mRNA 1273 vaccine (Moderna COVID-19 vaccine) was granted by the FDA in the United States for patients of ages 16 years and more and 18 years and more, respectively. Both vaccines are administered intramuscularly over 2 doses. For BNT162b2 (Pfizer-BioNTech COVID-19 vaccine) the second dose is given after 3 weeks, while the second dose of mRNA 1273 (Moderna COVID-19 vaccine) is given a month later. While it is highly advised to use the same vaccines for both doses, on January 21^st 2021, the CDC issued recommendations for exceptional situations where if the first-dose vaccine cannot be determined, then any available mRNA COVID-19 vaccine can be given with an interval of at least 28 days to provide the complete dose [92].

Several other vaccines are also currently being developed, and some have been approved for use in some countries. The Oxford–AstraZeneca COVID-19 vaccine is an adenovirus vector vaccine [93] that has an efficacy ranging from 62% to 90% [94]. Its use has been approved in several countries such as India, Pakistan, Nepal, Brazil, and Argentina amongst many [95]. The BBIBP-CorV (Sinopharm) and CoronaVac (Sinovac) vaccines are inactivated SARS-CoV-2 vaccines, which have shown 79% and 65–91% efficacy, respectively [96–100]. In an article published on 2^nd February 2021, Logunov et al. reported that the phase 3 trial of Gam-COVID-Vac, also known as Sputnik V, resulted in an overall efficacy of 91.6% efficacy [101]. Johnson & Johnson issued a statement on 29^th January 2021 that their Single-Shot Janssen COVID-19 Vaccine had an 85% efficacy in preventing severe outcome of COVID-19 and also 66% efficacy at preventing moderate to severe COVID-19. It also demonstrated “complete protection against COVID-19-related hospitalization and death as of day 28” [102]. The company further announced on 4^th February that they have applied for Emergency Use Authorization from the FDA for their vaccine. Its main advantages also include a longer storage at 36–46°F (2.2–7.8°C) for at least 3 months, and they can produce 100 million doses in the first 6 months of 2021 to meet the demands in the United States [103, 104].

Some common reactogenicity symptoms have been reported with the administration of these vaccines, and they are mostly mild such as fever, chills, headache, and myalgias [105]. The CDC also reported that as of 23 December 2020, 21 anaphylaxis reactions were confirmed among the 1,893,360 recipients of the Pfizer-BioNTech COVID-19 vaccine in the United States. Seventeen of those had a history of allergies or allergic reactions and 7 had an anaphylaxis in the past [106].

Lockdowns and mental health during the pandemic

In order to combat the spread of the virus, several countries issued strict lockdowns. Anyone violating the curfew would be arrested or charged [107]. However, some people believed that these rules were in violation of their freedom of choice, and several anti-lockdown as well as anti-mask movements and marches have been reported in various countries [108, 109]. Alison Thompson, who is a bioethics professor at the University of Toronto, suggested that “the opposition to masks speaks to an underlying mistrust of public health messaging and the science around coronavirus disease 2019 (COVID-19)” [110].

The lockdowns and changes in lifestyle have had a very heavy impact on the mental health of many individuals. Xiong et al. reported that higher rates of anxiety, depression, psychological distress, and stress as well as post-traumatic stress disorder were seen during the pandemic in the general population [111]. Health care workers have also been overburdened, and in some hospitals several coping mechanisms have been provided to help them [112, 113]. Sher hypothesized that the social isolation, uncertainty, and chronic stress of lockdowns and a pandemic can lead to an increased risk of suicidal thoughts, and they may peak later than the actual pandemic [114]. It has been strongly encouraged that people continue normal routine activities, exercise regularly, avoid alcoholic drinks and drugs, and keep a normal sleeping pattern during lockdowns. The general population has easy access to technology and can easily communicate and be in touch with each other while respecting social distancing protocols. Schools have used several media such as Skype and Zoom to teach their students while prioritizing their safety [115–119].

Major hurdles during the year and what to expect now

While the world was experiencing one of the worst pandemics in recent times, there were many factors that complicated the proper management of the spread of the virus. Several countries were at first hesitant to close their borders and issue lockdowns, and this led to a spike in the number of new cases as the virus spread in multiple crowded areas. Conspiracy theories about the virus as well as misinformation and downplaying the severity of the virus on social media worsened the efforts made to contain the spread [120–123]. The plan and action to protect and combat COVID-19 locally and internationally by the authorities in New Zealand and Australia were praiseworthy. They acted fast and issued border closures as well as major lockdowns to reduce the local spread [124]. The strict response from Taiwan resulted in only 909 cases and 8 deaths [125]. The island of Mauritius has also reported a very positive approach to the pandemic. They have shut down their international borders, and all passengers are required to undergo quarantine as well as multiple tests to rule out any trace of COVID-19. They also issued strict lock-downs, and it was illegal to spread any misinformation on social media regarding the pandemic [7].

There are many challenges ahead of us for 2021. With the introduction of several vaccines, proper education about their benefits as well as risks should be expanded to combat misinformation. The public should also be encouraged to use masks and respect the social distancing protocols set by several international bodies that can help prevent the spread of COVID-19. The idea of a “vaccine-passport” has also been mooted [126]. During this last year, several countries have recorded massive economic losses. Businesses have gone bankrupt with lockdowns, and there is a long road towards a “normalization” of life [127].

Conclusions

COVID-19 is an ongoing pandemic that has already crossed its 1-year anniversary, and the number of new cases and deaths is on the rise daily. However, with the approval of new vaccines, the world started the year 2021 with a more optimistic approach. The World Health Organization is investigating the sources and causes of the emergence of the virus, and strict measures should also be taken to prevent any possible SARS-CoV-3 or equivalent from surging in the next few years.

Conflict of interest

The authors declare no conflict of interest.