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Coronavirus disease 2019 (COVID-19): A literature review

Harapan harapan.

a Medical Research Unit, School of Medicine, Universitas Syiah Kuala, Banda Aceh, Indonesia

b Tropical Disease Centre, School of Medicine, Universitas Syiah Kuala, Banda Aceh, Indonesia

c Department of Microbiology, School of Medicine, Universitas Syiah Kuala, Banda Aceh, Indonesia

d Division of Infectious Diseases, AichiCancer Center Hospital, Chikusa-ku Nagoya, Japan

Amanda Yufika

e Department of Family Medicine, School of Medicine, Universitas Syiah Kuala, Banda Aceh, Indonesia

Wira Winardi

f Department of Pulmonology and Respiratory Medicine, School of Medicine, Universitas Syiah Kuala, Banda Aceh, Indonesia

g School of Medicine, The University of Western Australia, Perth, Australia

Haypheng Te

h Siem Reap Provincial Health Department, Ministry of Health, Siem Reap, Cambodia

Dewi Megawati

i Department of Microbiology and Parasitology, Faculty of Medicine and Health Sciences, Warmadewa University, Denpasar, Indonesia

j Department of Medical Microbiology and Immunology, University of California, Davis, CA, USA

Zinatul Hayati

k Department of Clinical Microbiology, School of Medicine, Universitas Syiah Kuala, Banda Aceh, Indonesia

Abram L. Wagner

l Department of Epidemiology, University of Michigan, Ann Arbor, Michigan, MI 48109, USA

Mudatsir Mudatsir

In early December 2019, an outbreak of coronavirus disease 2019 (COVID-19), caused by a novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), occurred in Wuhan City, Hubei Province, China. On January 30, 2020 the World Health Organization declared the outbreak as a Public Health Emergency of International Concern. As of February 14, 2020, 49,053 laboratory-confirmed and 1,381 deaths have been reported globally. Perceived risk of acquiring disease has led many governments to institute a variety of control measures. We conducted a literature review of publicly available information to summarize knowledge about the pathogen and the current epidemic. In this literature review, the causative agent, pathogenesis and immune responses, epidemiology, diagnosis, treatment and management of the disease, control and preventions strategies are all reviewed.

On December 31, 2019, the China Health Authority alerted the World Health Organization (WHO) to several cases of pneumonia of unknown aetiology in Wuhan City in Hubei Province in central China. The cases had been reported since December 8, 2019, and many patients worked at or lived around the local Huanan Seafood Wholesale Market although other early cases had no exposure to this market [1] . On January 7, a novel coronavirus, originally abbreviated as 2019-nCoV by WHO, was identified from the throat swab sample of a patient [2] . This pathogen was later renamed as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) by the Coronavirus Study Group [3] and the disease was named coronavirus disease 2019 (COVID-19) by the WHO. As of January 30, 7736 confirmed and 12,167 suspected cases had been reported in China and 82 confirmed cases had been detected in 18 other countries [4] . In the same day, WHO declared the SARS-CoV-2 outbreak as a Public Health Emergency of International Concern (PHEIC) [4] .

According to the National Health Commission of China, the mortality rate among confirmed cased in China was 2.1% as of February 4 [5] and the mortality rate was 0.2% among cases outside China [6] . Among patients admitted to hospitals, the mortality rate ranged between 11% and 15% [7] , [8] . COVID-19 is moderately infectious with a relatively high mortality rate, but the information available in public reports and published literature is rapidly increasing. The aim of this review is to summarize the current understanding of COVID-19 including causative agent, pathogenesis of the disease, diagnosis and treatment of the cases, as well as control and prevention strategies.

The virus: classification and origin

SARS-CoV-2 is a member of the family Coronaviridae and order Nidovirales. The family consists of two subfamilies, Coronavirinae and Torovirinae and members of the subfamily Coronavirinae are subdivided into four genera: (a) Alphacoronavirus contains the human coronavirus (HCoV)-229E and HCoV-NL63; (b) Betacoronavirus includes HCoV-OC43, Severe Acute Respiratory Syndrome human coronavirus (SARS-HCoV), HCoV-HKU1, and Middle Eastern respiratory syndrome coronavirus (MERS-CoV); (c) Gammacoronavirus includes viruses of whales and birds and; (d) Deltacoronavirus includes viruses isolated from pigs and birds [9] . SARS-CoV-2 belongs to Betacoronavirus together with two highly pathogenic viruses, SARS-CoV and MERS-CoV. SARS-CoV-2 is an enveloped and positive-sense single-stranded RNA (+ssRNA) virus [16] .

SARS-CoV-2 is considered a novel human-infecting Betacoronavirus [10] . Phylogenetic analysis of the SARS-CoV-2 genome indicates that the virus is closely related (with 88% identity) to two bat-derived SARS-like coronaviruses collected in 2018 in eastern China (bat-SL-CoVZC45 and bat-SL-CoVZXC21) and genetically distinct from SARS-CoV (with about 79% similarity) and MERS-CoV [10] . Using the genome sequences of SARS-CoV-2, RaTG13, and SARS-CoV [11] , a further study found that the virus is more related to BatCoV RaTG13, a bat coronavirus that was previously detected in Rhinolophus affinis from Yunnan Province, with 96.2% overall genome sequence identity [11] . A study found that no evidence of recombination events detected in the genome of SARS-CoV-2 from other viruses originating from bats such as BatCoV RaTG13, SARS-CoV and SARSr-CoVs [11] . Altogether, these findings suggest that bats might be the original host of this virus [10] , [11] .

However, a study is needed to elucidate whether any intermediate hosts have facilitated the transmission of the virus to humans. Bats are unlikely to be the animal that is directly responsible for transmission of the virus to humans for several reasons [10] : (1) there were various non-aquatic animals (including mammals) available for purchase in Huanan Seafood Wholesale Market but no bats were sold or found; (2) SARS-CoV-2 and its close relatives, bat-SL-CoVZC45 and bat-SL-CoVZXC21, have a relatively long branch (sequence identity of less than 90%), suggesting those viruses are not direct ancestors of SARS-CoV-2; and (3) in other coronaviruses where bat is the natural reservoir such as SARS-CoV and MERS-CoV, other animals have acted as the intermediate host (civets and possibly camels, respectively). Nevertheless, bats do not always need an intermediary host to transmit viruses to humans. For example, Nipah virus in Bangladesh is transmitted through bats shedding into raw date palm sap [12] .

Transmission

The role of the Huanan Seafood Wholesale Market in propagating disease is unclear. Many initial COVID-19 cases were linked to this market suggesting that SARS-CoV-2 was transmitted from animals to humans [13] . However, a genomic study has provided evidence that the virus was introduced from another, yet unknown location, into the market where it spread more rapidly, although human-to-human transmission may have occurred earlier [14] . Clusters of infected family members and medical workers have confirmed the presence of person-to-person transmission [15] . After January 1, less than 10% of patients had market exposure and more than 70% patients had no exposure to the market [13] . Person-to-person transmission is thought to occur among close contacts mainly via respiratory droplets produced when an infected person coughs or sneezes. Fomites may be a large source of transmission, as SARS-CoV has been found to persist on surfaces up to 96 h [16] and other coronaviruses for up to 9 days [17] .

Whether or not there is asymptomatic transmission of disease is controversial. One initial study published on January 30 reported asymptomatic transmission [18] , but later it was found that the researchers had not directly interviewed the patient, who did in fact have symptoms prior to transmitting disease [19] . A more recent study published on February 21 also purported asymptomatic transmission [20] , but any such study could be limited by errors in self-reported symptoms or contact with other cases and fomites.

Findings about disease characteristics are rapidly changing and subject to selection bias. A study indicated the mean incubation period was 5.2 days (95% confidence interval [95%CI]: 4.1–7.0) [13] . The incubation period has been found to be as long as 19 or 24 days [21] , [22] , although case definitions typically rely on a 14 day window [23] .

The basic reproductive number ( R 0 ) has been estimated with varying results and interpretations. R 0 measures the average number of infections that could result from one infected individual in a fully susceptible population [24] . Studies from previous outbreaks found R 0 to be 2.7 for SARS [25] and 2.4 for 2009 pandemic H1N1 influenza [26] . One study estimated that that basic reproductive number ( R 0 ) was 2.2 (95% CI: 1.4–3.9) [13] . However, later in a further analysis of 12 available studies found that R 0 was 3.28 [27] . Because R 0 represents an average value it is also important to consider the role of super spreaders, who may be hugely responsible for outbreaks within large clusters but who would not largely influence the value of R 0 [28] . During the acute phase of an outbreak or prepandemic, R 0 may be unstable [24] .

In pregnancy, a study of nine pregnancy women who developed COVID-19 in late pregnancy suggested COVID-19 did not lead to substantially worse symptoms than in nonpregnant persons and there is no evidence for intrauterine infection caused by vertical transmission [29] .

In hospital setting, a study involving 138 COVID-19 suggested that hospital-associated transmission of SARS-CoV-2 occurred in 41% of patients [30] . Moreover, another study on 425 patients found that the proportion of cases in health care workers gradually increased by time [13] . These cases likely reflect exposure to a higher concentration of virus from sustained contact in close quarters.

Outside China, as of February 12, 2020, there were 441 confirmed COVID-19 cases reported in 24 countries [6] of which the first imported case was reported in Thailand on January 13, 2020 [6] , [31] . Among those countries, 11 countries have reported local transmission with the highest number of cases reported in Singapore with 47 confirmed cases [6] .

Risk factors

The incidence of SARS-CoV-2 infection is seen most often in adult male patients with the median age of the patients was between 34 and 59 years [20] , [30] , [7] , [32] . SARS-CoV-2 is also more likely to infect people with chronic comorbidities such as cardiovascular and cerebrovascular diseases and diabetes [8] . The highest proportion of severe cases occurs in adults ≥60 years of age, and in those with certain underlying conditions, such as cardiovascular and cerebrovascular diseases and diabetes [20] , [30] . Severe manifestations maybe also associated with coinfections of bacteria and fungi [8] .

Fewer COVID-19 cases have been reported in children less than 15 years [20] , [30] , [7] , [32] . In a study of 425 COVID-19 patients in Wuhan, published on January 29, there were no cases in children under 15 years of age [13] , [33] . Nevertheless, 28 paediatric patients have been reported by January 2020 [34] . The clinical features of infected paediatric patients vary, but most have had mild symptoms with no fever or pneumonia, and have a good prognosis [34] . Another study found that although a child had radiological ground-glass lung opacities, the patient was asymptomatic [35] . In summary, children might be less likely to be infected or, if infected, present milder manifestations than adults; therefore, it is possible that their parents will not seek out treatment leading to underestimates of COVID-19 incidence in this age group.

Pathogenesis and immune response

Like most other members of the coronavirus family, Betacoronavirus exhibit high species specificity, but subtle genetic changes can significantly alter their tissue tropism, host range, and pathogenicity. A striking example of the adaptability of these viruses is the emergence of deadly zoonotic diseases in human history caused by SARS-CoV [36] and MERS-CoV [37] . In both viruses, bats served as the natural reservoir and humans were the terminal host, with the palm civet and dromedary camel the intermediary host for SARS-CoV and MERS-CoV, respectively [38] , [39] . Intermediate hosts clearly play a critical role in cross species transmission as they can facilitate increased contact between a virus and a new host and enable further adaptation necessary for an effective replication in the new host [40] . Because of the pandemic potential of SARS-CoV-2, careful surveillance is immensely important to monitor its future host adaptation, viral evolution, infectivity, transmissibility, and pathogenicity.

The host range of a virus is governed by multiple molecular interactions, including receptor interaction. The envelope spike (S) protein receptor binding domain of SARS-CoV-2 was shown structurally similar to that of SARS-CoV, despite amino acid variation at some key residues [10] . Further extensive structural analysis strongly suggests that SARS-CoV-2 may use host receptor angiotensin-converting enzyme 2 (ACE2) to enter the cells [41] , the same receptor facilitating SARS-CoV to infect the airway epithelium and alveolar type 2 (AT2) pneumocytes, pulmonary cells that synthesize pulmonary surfactant [42] . In general, the spike protein of coronavirus is divided into the S1 and S2 domain, in which S1 is responsible for receptor binding and S2 domain is responsible for cell membrane fusion [10] . The S1 domain of SARS-CoV and SARS-CoV-2 share around 50 conserved amino acids, whereas most of the bat-derived viruses showed more variation [10] . In addition, identification of several key residues (Gln493 and Asn501) that govern the binding of SARS-CoV-2 receptor binding domain with ACE2 further support that SARS-CoV-2 has acquired capacity for person-to-person transmission [41] . Although, the spike protein sequence of receptor binding SARS-CoV-2 is more similar to that of SARS-CoV, at the whole genome level SARS-CoV-2 is more closely related to bat-SL-CoVZC45 and bat-SL-CoVZXC21 [10] .

However, receptor recognition is not the only determinant of species specificity. Immediately after binding to their receptive receptor, SARS-CoV-2 enters host cells where they encounter the innate immune response. In order to productively infect the new host, SARS-CoV-2 must be able to inhibit or evade host innate immune signalling. However, it is largely unknown how SARS-CoV-2 manages to evade immune response and drive pathogenesis. Given that COVID-19 and SARS have similar clinical features [7] , SARS-CoV-2 may have a similar pathogenesis mechanism as SARS-CoV. In response to SARS-CoV infections, the type I interferon (IFN) system induces the expression of IFN-stimulated genes (ISGs) to inhibit viral replication. To overcome this antiviral activity, SARS-CoV encodes at least 8 viral antagonists that modulate induction of IFN and cytokines and evade ISG effector function [43] .

The host immune system response to viral infection by mediating inflammation and cellular antiviral activity is critical to inhibit viral replication and dissemination. However, excessive immune responses together with lytic effects of the virus on host cells will result in pathogenesis. Studies have shown patients suffering from severe pneumonia, with fever and dry cough as common symptoms at onset of illness [7] , [8] . Some patients progressed rapidly with Acute Respiratory Stress Syndrome (ARDS) and septic shock, which was eventually followed by multiple organ failure and about 10% of patients have died [8] . ARDS progression and extensive lung damage in COVID-19 are further indications that ACE2 might be a route of entry for the SARS-CoV-2 as ACE2 is known abundantly present on ciliated cells of the airway epithelium and alveolar type II (cells (pulmonary cells that synthesize pulmonary surfactant) in humans [44] .

Patients with SARS and COVID-19 have similar patterns of inflammatory damage. In serum from patients diagnosed with SARS, there is increased levels of proinflammatory cytokines (e.g. interleukin (IL)-1, IL6, IL12, interferon gamma (IFNγ), IFN-γ-induced protein 10 (IP10), macrophage inflammatory proteins 1A (MIP1A) and monocyte chemoattractant protein-1 (MCP1)), which are associated with pulmonary inflammation and severe lung damage [45] . Likewise, patients infected with SARS-CoV-2 are reported to have higher plasma levels of proinflammatory cytokines including IL1β, IL-2, IL7, TNF-α, GSCF, MCP1 than healthy adults [7] . Importantly, patients in the intensive care unit (ICU) have a significantly higher level of GSCF, IP10, MCP1, and TNF-α than those non-ICU patients, suggesting that a cytokine storm might be an underlying cause of disease severity [7] . Unexpectedly, anti-inflammatory cytokines such as IL10 and IL4 were also increased in those patients [7] , which was uncommon phenomenon for an acute phase viral infection. Another interesting finding, as explained before, was that SARS-CoV-2 has shown to preferentially infect older adult males with rare cases reported in children [7] , [8] . The same trend was observed in primate models of SARS-CoV where the virus was found more likely to infect aged Cynomolgus macaque than young adults [46] . Further studies are necessary to identify the virulence factors and the host genes of SARS-CoV-2 that allows the virus to cross the species-specific barrier and cause lethal disease in humans.

Clinical manifestations

Clinical manifestations of 2019-nCoV infection have similarities with SARS-CoV where the most common symptoms include fever, dry cough, dyspnoea, chest pain, fatigue and myalgia [7] , [30] , [47] . Less common symptoms include headache, dizziness, abdominal pain, diarrhoea, nausea, and vomiting [7] , [30] . Based on the report of the first 425 confirmed cases in Wuhan, the common symptoms include fever, dry cough, myalgia and fatigue with less common are sputum production, headache, haemoptysis, abdominal pain, and diarrhoea [13] . Approximately 75% patients had bilateral pneumonia [8] . Different from SARS-CoV and MERS-CoV infections, however, is that very few COVID-19 patients show prominent upper respiratory tract signs and symptoms such as rhinorrhoea, sneezing, or sore throat, suggesting that the virus might have greater preference for infecting the lower respiratory tract [7] . Pregnant and non-pregnant women have similar characteristics [48] . The common clinical presentation of 2019-nCoV infection are presented in Table 1 .

Clinical symptoms of patients with 2019-nCoV infection.

Severe complications such as hypoxaemia, acute ARDS, arrythmia, shock, acute cardiac injury, and acute kidney injury have been reported among COVID-19 patients [7] , [8] . A study among 99 patients found that approximately 17% patients developed ARDS and, among them, 11% died of multiple organ failure [8] . The median duration from first symptoms to ARDS was 8 days [30] .

Efforts to control spread of COVID-19, institute quarantine and isolation measures, and appropriately clinically manage patients all require useful screening and diagnostic tools. While SARS-CoV-2 is spreading, other respiratory infections may be more common in a local community. The WHO has released a guideline on case surveillance of COVID-19 on January 31, 2020 [23] . For a person who meets certain criteria, WHO recommends to first screen for more common causes of respiratory illness given the season and location. If a negative result is found, the sample should be sent to referral laboratory for SARS-CoV-2 detection.

Case definitions can vary by country and will evolve over time as the epidemiological circumstances change in a given location. In China, a confirmed case from January 15, 2020 required an epidemiological linkage to Wuhan within 2 weeks and clinical features such as fever, pneumonia, and low white blood cell count. On January 18, 2020 the epidemiological criterion was expanded to include contact with anyone who had been in Wuhan in the past 2 weeks [50] . Later, the case definitions removed the epidemiological linkage.

The WHO has put forward case definitions [23] . Suspected cases of COVID-19 are persons (a) with severe acute respiratory infections (history of fever and cough requiring admission to hospital) and with no other aetiology that fully explains the clinical presentation and a history of travel to or residence in China during the 14 days prior to symptom onset; or (b) a patient with any acute respiratory illness and at least one of the following during the 14 days prior to symptom onset: contact with a confirmed or probable case of SARS-CoV-2 infection or worked in or attended a health care facility where patients with confirmed or probable SARS-CoV-2 acute respiratory disease patients were being treated. Probable cases are those for whom testing for SARS-CoV-2 is inconclusive or who test positive using a pan-coronavirus assay and without laboratory evidence of other respiratory pathogens. A confirmed case is one with a laboratory confirmation of SARS-CoV-2 infection, irrespective of clinical signs and symptoms.

For patients who meet diagnostic criteria for SARS-CoV-2 testing, the CDC recommends collection of specimens from the upper respiratory tract (nasopharyngeal and oropharyngeal swab) and, if possible, the lower respiratory tract (sputum, tracheal aspirate, or bronchoalveolar lavage) [51] . In each country, the tests are performed by laboratories designated by the government.

Laboratory findings

Among COVID-19 patients, common laboratory abnormalities include lymphopenia [8] , [20] , [30] , prolonged prothrombin time, and elevated lactate dehydrogenase [30] . ICU-admitted patients had more laboratory abnormalities compared with non-ICU patients [30] , [7] . Some patients had elevated aspartate aminotransferase, creatine kinase, creatinine, and C-reactive protein [20] , [7] , [35] . Most patients have shown normal serum procalcitonin levels [20] , [30] , [7] .

COVID-19 patients have high level of IL1β, IFN-γ, IP10, and MCP1 [7] . ICU-admitted patients tend to have higher concentration of granulocyte-colony stimulating factor (GCSF), IP10, MCP1A, MIP1A, and TNF-α [7] .

Radiology findings

Radiology finding may vary with patients age, disease progression, immunity status, comorbidity, and initial medical intervention [52] . In a study describing 41 of the initial cases of 2019-nCoV infection, all 41 patients had pneumonia with abnormal findings on chest computed tomography (CT-scan) [7] . Abnormalities on chest CT-scan were also seen in another study of 6 cases, in which all of them showed multifocal patchy ground-glass opacities notably nearby the peripheral sections of the lungs [35] . Data from studies indicate that the typical of chest CT-scan findings are bilateral pulmonary parenchymal ground-glass and consolidative pulmonary opacities [7] , [8] , [20] , [30] , [32] , [53] . The consolidated lung lesions among patients five or more days from disease onset and those 50 years old or older compared to 4 or fewer days and those 50 years or younger, respectively [47] .

As the disease course continue, mild to moderate progression of disease were noted in some cases which manifested by extension and increasing density of lung opacities [49] . Bilateral multiple lobular and subsegmental areas of consolidation are typical findings on chest CT-scan of ICU-admitted patients [7] . A study among 99 patients, one patient had pneumothorax in an imaging examination [8] .

Similar to MERS-CoV and SARS-CoV, there is still no specific antiviral treatment for COVID-19 [54] . Isolation and supportive care including oxygen therapy, fluid management, and antibiotics treatment for secondary bacterial infections is recommended [55] . Some COVID-19 patients progressed rapidly to ARDS and septic shock, which was eventually followed by multiple organ failure [7] , [8] . Therefore, the effort on initial management of COVID-19 must be addressed to the early recognition of the suspect and contain the disease spread by immediate isolation and infection control measures [56] .

Currently, no vaccination is available, but even if one was available, uptake might be suboptimal. A study of intention to vaccinate during the H1N1 pandemic in the United States was around 50% at the start of the pandemic in May 2009 but had decreased to 16% by January 2010 [57] .

Neither is a treatment available. Therefore, the management of the disease has been mostly supportive referring to the disease severity which has been introduced by WHO. If sepsis is identified, empiric antibiotic should be administered based on clinical diagnosis and local epidemiology and susceptibility information. Routine glucocorticoids administration are not recommended to use unless there are another indication [58] . Clinical evidence also does not support corticosteroid treatment [59] . Use of intravenous immunoglobulin might help for severely ill patients [8] .

Drugs are being evaluated in line with past investigations into therapeutic treatments for SARS and MERS [60] . Overall, there is not robust evidence that these antivirals can significantly improve clinical outcomes A. Antiviral drugs such as oseltamivir combined with empirical antibiotic treatment have also been used to treat COVID-19 patients [7] . Remdesivir which was developed for Ebola virus, has been used to treat imported COVID-19 cases in US [61] . A brief report of treatment combination of Lopinavir/Ritonavir, Arbidol, and Shufeng Jiedu Capsule (SFJDC), a traditional Chinese medicine, showed a clinical benefit to three of four COVID-19 patients [62] . There is an ongoing clinical trial evaluating the safety and efficacy of lopinavir-ritonavir and interferon-α 2b in patients with COVID-19 [55] . Ramsedivir, a broad spectrum antivirus has demonstrated in vitro and in vivo efficacy against SARS-CoV-2 and has also initiated its clinical trial [63] , [64] . In addition, other potential drugs from existing antiviral agent have also been proposed [65] , [66] .

Control and prevention strategies

COVID-19 is clearly a serious disease of international concern. By some estimates it has a higher reproductive number than SARS [27] , and more people have been reported to have been infected or died from it than SARS [67] . Similar to SARS-CoV and MERS-CoV, disrupting the chain of transmission is considered key to stopping the spread of disease [68] . Different strategies should be implemented in health care settings and at the local and global levels.

Health care settings can unfortunately be an important source of viral transmission. As shown in the model for SARS, applying triage, following correct infection control measures, isolating the cases and contact tracing are key to limit the further spreading of the virus in clinics and hospitals [68] . Suspected cases presenting at healthcare facilities with symptoms of respiratory infections (e.g. runny nose, fever and cough) must wear a face mask to contain the virus and strictly adhere triage procedure. They should not be permitted to wait with other patients seeking medical care at the facilities. They should be placed in a separated, fully ventilated room and approximately 2 m away from other patients with convenient access to respiratory hygiene supplies [69] . In addition, if a confirmed COVID-19 case require hospitalization, they must be placed in a single patient room with negative air pressure – a minimum of six air changes per hour. Exhausted air has to be filtered through high efficiency particulate air (HEPA) and medical personnel entering the room should wear personal protective equipment (PPE) such as gloves, gown, disposable N95, and eye protection. Once the cases are recovered and discharged, the room should be decontaminated or disinfected and personnel entering the room need to wear PPE particularly facemask, gown, eye protection [69] .

In a community setting, isolating infected people are the primary measure to interrupt the transmission. For example, immediate actions taken by Chinese health authorities included isolating the infected people and quarantining of suspected people and their close contacts [70] . Also, as there are still conflicting assumptions regarding the animal origins of the virus (i.e. some studies linked the virus to bat [71] , [72] while others associated the virus with snake [73] ), contacts with these animal fluids or tissues or consumption of wild caught animal meet should be avoided. Moreover, educating the public to recognize unusual symptoms such as chronic cough or shortness of breath is essential therefore that they could seek medical care for early detection of the virus. If large-scale community transmission occurs, mitigating social gatherings, temporary school closure, home isolation, close monitoring of symptomatic individual, provision of life supports (e.g. oxygen supply, mechanical ventilator), personal hand hygiene, and wearing personal protective equipment such as facemask should also be enforced [74] .

In global setting, locking down Wuhan city was one of the immediate measure taken by Chinese authorities and hence had slowed the global spread of COVID-19 [74] . Air travel should be limited for the cases unless severe medical attentions are required. Setting up temperature check or scanning is mandatory at airport and border to identify the suspected cases. Continued research into the virus is critical to trace the source of the outbreak and provide evidence for future outbreak [74] .

Conclusions

The current COVID-19 pandemic is clearly an international public health problem. There have been rapid advances in what we know about the pathogen, how it infects cells and causes disease, and clinical characteristics of disease. Due to rapid transmission, countries around the world should increase attention into disease surveillance systems and scale up country readiness and response operations including establishing rapid response teams and improving the capacity of the national laboratory system.

Competing interests

The authors declare that they have no competing interests.

Ethical approval

Not required.

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• Review Article
• Published: 17 July 2020

A literature review of 2019 novel coronavirus (SARS-CoV2) infection in neonates and children

• Matteo Di Nardo 1 ,
• Grace van Leeuwen 2 ,
• Alessandra Loreti 3 ,
• Maria Antonietta Barbieri 4 ,
• Yit Guner 5 ,
• Franco Locatelli 6 &
• Vito Marco Ranieri 7  

Pediatric Research volume  89 ,  pages 1101–1108 ( 2021 ) Cite this article

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At the time of writing, there are already millions of documented infections worldwide by the novel coronavirus 2019 (2019-nCoV or severe acute respiratory syndrome coronavirus 2 (SARS-CoV2)), with hundreds of thousands of deaths. The great majority of fatal events have been recorded in adults older than 70 years; of them, a large proportion had comorbidities. Since data regarding the epidemiologic and clinical characteristics in neonates and children developing coronavirus disease 2019 (COVID-19) are scarce and originate mainly from one country (China), we reviewed all the current literature from 1 December 2019 to 7 May 2020 to provide useful information about SARS-CoV2 viral biology, epidemiology, diagnosis, clinical features, treatment, prevention, and hospital organization for clinicians dealing with this selected population.

Children usually develop a mild form of COVID-19, rarely requiring high-intensity medical treatment in pediatric intensive care unit.

Vertical transmission is unlikely, but not completely excluded.

Children with confirmed or suspected COVID-19 must be isolated and healthcare workers should wear appropriate protective equipment.

Some clinical features (higher incidence of fever, vomiting and diarrhea, and a longer incubation period) are more common in children than in adults, as well as some radiologic aspects (more patchy shadow opacities on CT scan images than ground-glass opacities).

Supportive and symptomatic treatments (oxygen therapy and antibiotics for preventing/treating bacterial coinfections) are recommended in these patients.

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Introduction.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) is the virus responsible for the coronavirus disease 2019 (COVID-19) pandemic. 1 Since its first outbreak in Wuhan, in the Hubei province of China in early December 2019, 2 SARS-CoV2 has spread all over the world infecting millions of people and causing hundreds of thousands o deaths [case fatality rate (CFR): 6.25%, John Hopkins Coronavirus Resource Center, accessed 7 May 2020]. 3

Respiratory viral infections, in general, are more frequent and severe in children than in adults. SARS-CoV2, instead, showed a different scenario. Infection rates appear to be similar between children and adults; however, children develop a milder illness with a low CFR (<0.1%). 3 , 4 , 5 , 6 , 7 The reasons for this milder severity in childhood are not yet understood, and the actual epidemiologic and clinical data of infected neonates and children are not sufficient to solve these gaps. Thus, due to the scarcity of data on SARS-CoV2 in children, we aimed at evaluating the current literature available to provide useful information for clinicians dealing with this particular population.

Search strategy

References for this review were identified through searches on PubMED, Ovid MEDLINE, and EMBASE from 1 December 2019 to 7 May 2020, by two highly experienced librarians at Children’s Hospital Bambino Gesù by using relevant terms related to 2019-nCoV, COVID-19, and SARS-CoV2 in neonates and children (Supplementary Material  1 ). Reference lists of the articles identified by this search strategy were also searched. Earlier reports were not excluded, especially if they were highly cited articles. Only articles published in English were included in this review. Three hundred and seventy-four papers were published in PubMed, 117 in Ovid MEDLINE, and 119 in EMBASE. Among them, 73 were deemed relevant to the purposes of this review (PRISMA flowchart Supplementary Material  2 ).

Biological mechanisms of viral infection and lung injury

Coronaviruses are single-strand, positive-sense RNA viruses with spike-like projections on their surface. 8 These viruses can infect both animals and humans. Among human-infecting coronaviruses, four types (HKU1, NL63, 229E, and OC43) are responsible for mild forms of respiratory disease. 9 , 10 SARS-CoV2, SARS-CoV, and the Middle East respiratory syndrome coronavirus (MERS-CoV) are zoonotic viruses and can infect humans, causing severe respiratory infections, only crossing from animals (Fig.  1 ).

Summary of coronavirus diseases (adapted from Zimmermann and Curtis 8 ).

SARS-CoV2 infects the host cells through an envelope spike (S) protein that mediates the binding and membrane fusion through the angiotensin-converting enzyme 2 (ACE-2) receptor (Fig.  2a, b ). The spike protein is functionally divided into an S1 domain, responsible for receptor binding, and an S2 domain, responsible for cell membrane fusion. 11 SARS-CoV2 employs the transmembrane serine protease 2 of the host cell to prime the S protein and bind the ACE-2 receptor. Other transmembrane pore-forming viral proteins (viroporins) can trigger the NLRP3 (NOD-like receptor 3 inflammasome)-inducing pyroptosis in the host cell. 12

a Renin–angiotensin system (RAS): normal physiology. Renin converts angiotensinogen in angiotensin 1 (ANG 1). Angiotensin-converting enzyme (ACE) converts ANG1 in angiotensin 2 (ANG2). Angiotensin-converting enzyme 2 (ACE-2), a homolog of ACE, is a monocarboxypeptidase that converts ANG2 into angiotensin 1–7 (ANG1–7), which, by virtue of its actions on the MasR (mitocondrial assembly receptor), opposes the molecular and cellular effects of ANG2. ANG2 promotes vasoconstriction, inflammation, and oxidative stress via the activation of AT1R (angiotensin 2 receptor 1). b  SARS-CoV2 host cell entry mechanism: Spike protein (S1) binds the ACE-2 receptor once primed by the transmembrane protease serine 2 inhibitor (TMPRSS2). This binding leads to viral entry and replication and induces mechanisms of lung injury. c  Potential therapeutic strategies against SARS-COV2. Spike protein-based vaccine; TMPRSS2 inhibitors to block the priming of the spike protein; surface ACE-2 receptor blocker; soluble form of ACE-2 receptor compete with the binding of SARS-CoV2 to the surface ACE-2 receptor.

ACE-2 receptors are expressed in many tissues; however, the majority are present on the alveolar epithelial type II cells. 13 In addition, gene ontology enrichment analysis showed that the ACE-2-expressing epithelial cells have high levels of multiple viral process-related genes, including regulatory genes for viral processes, life cycle, assembly, and genome replication. 13 All these features strongly support the hypothesis that the ACE-2 receptor mediates SARS-CoV2 replication in the lung. SARS-CoV2, through the binding to the ACE-2 receptor, downregulates the ACE-2 intracellular signaling (mitochondrial assembly receptor), causing inflammation, vasoconstriction, and fibrosis in the lung. 13

Epidemiology and pathogenesis in neonates and children

Published data and anecdotal reports support the notion that the number of children found to be infected by SARS-CoV2 is small and their clinical manifestations of COVID-19 are milder compared to adults. 4 , 5 , 6 , 14 , 15 , 16 , 17 , 18

The incidence of SARS-CoV2 confirmed that pediatric cases are low and variable among countries (China: 2–12.3%, 4 , 5 Italy: 1.2%, 19 Korea: 4.8%, 20 USA: 5% 21 ). Several reasons justify this variable incidence: testing availability, testing policy 22 , 23 (at the beginning of pandemics some countries tested only children with established contact with a person with COVID-19, then only hospitalized children with symptoms), and the fact that the infection in children is mild or without symptoms. 24 , 25 Available data also suggest that all ages (0–18) can be infected, but infants seem to be most vulnerable. 5 , 26

Human-to-human transmission (mainly family clustered) is the major transmission mode. 4 , 5 , 27 Children can be infected by inhalation of large droplets generated during coughing or sneezing or by contact with contaminated surface (fomite). 9 , 10 , 28 , 29 , 30 As the virus can be also released in the stool, the fecal–oral transmission cannot be ruled out. 31 , 32 , 33 , 34 Similar to SARS-CoV and MERS-CoV, nosocomial transmission of SARS-CoV2 is high, 9 , 10 , 35 , 36 although no cases of nosocomial infections have been described in children during hospital recovery.

Despite the absence of clinical features of infection or positive microbiological findings in neonates born from SARS-CoV2-positive mothers, 14 , 18 , 37 , 38 , 39 , 40 , 41 , 42 vertical maternal–fetal transmission cannot be ruled out completely. 43 , 44 Conversely, SARS-CoV2 has not been isolated from cord blood, amniotic fluid, and breast milk to date. However, it is crucial to screen pregnant women, implement strict infection control measures on those who tested positive, and monitor the neonates at risk. 44 , 45

Since the incubation period (median 5–7 days) in children and young adolescent varies from 2 to 14 days, but is generally longer than in adults, 10 , 46 , 47 , 48 dynamic observation is mandatory for suspected children. 49 , 50 The median period from symptom onset to hospital admission for patients who were hospitalized is 2 days (1.00–3.50). Recovery generally happens in 1–2 weeks after onset. 40 , 48 Both symptomatic patients and asymptomatic carriers can transmit SARS-CoV2. 49 , 51 , 52

The basic case reproduction (R0) of SARS-CoV2 is variable (2–3.5 in the early stage of the disease); 9 however, the R0 of SARS-CoV2 is higher than SARS-CoV and H1N1. 10 The CFR is ~6.25% (data from 7 May, John Hopkins Coronavirus Resource Center) 3 and varies among countries, 53 patients’ age, and is influenced by testing availability. 54 CFR of patients below 18 years is below <0.1% (adapted from John Hopkins Coronavirus Resource center at 7 May 2020). 3 , 7

This age specificity is still not completely understood. 24 , 55 It is speculated that children, as compared with adults, may have a higher expression of ACE-2 receptors in the type II lung pneumocytes, protecting them from the severe clinical manifestation of COVID-19 (low cytokine release, low pulmonary vascular permeability, etc.). 55 Other immunologic mechanisms (trained immunity, an early and high polyclonal B cell response to SARS-CoV2 with the production of substantial numbers of plasmablasts, and an high level natural killer cells) could also contribute to explain this age-specific characteristic. 55 , 56 A less intense mechanism of antibody-dependent enhancement, instead, could explain why COVID-19 clinical features are milder in children than in adults. 12

Since the World Health Organization (WHO) recently declared COVID-19 a pandemic on 11 March 2020, every patient presenting with evidence of fever, respiratory symptoms, gastrointestinal symptoms, or fatigue should be considered potentially infected (suspected case) with SARS-CoV-2.

Diagnosis of COVID-19 is made by using real-time polymerase chain reaction (RT-PCR) on samples from nasopharyngeal, oropharyngeal swabs, and lower respiratory tract samples whenever possible. 4 , 5 Negative nasopharyngeal swab is generally re-tested after 24 h due to the low negative predictive value of this testing. 57 SARS-CoV2 can be also detected on stools. 33 , 58 , 59 A “positive” RT-PCR result reflects only the detection of viral RNA and does not necessarily indicate the presence of a viable virus. 52

Confirmed cases are defined by positive molecular tests, while asymptomatic cases are defined by positive molecular tests without symptoms.

In children, more than in adults, COVID-19 poses important diagnostic challenges due to the longer incubation period that includes a prolonged interval (~5–6 days) of viral shedding prior to the onset of symptoms. 51 , 60 Moreover, the duration of asymptomatic shedding is not only variable, but also differs according to the anatomic level (upper versus lower airways) of the infection. 49 , 50

At present, among adult patients in affected areas, the most common cause of viral pneumonia with unclear etiology is SARS-CoV2; 2 conversely, in children several other pathogens (influenza, para-influenza, adenovirus, respiratory syncytial virus, metapneumovirus, or other human coronaviruses) can produce very similar clinical and radiologic findings and should be considered in the differential diagnosis. 6 , 8 , 26 , 61 Atypical microorganisms, such as chlamydia pneumoniae and mycoplasma, must be also excluded. 10

No laboratory investigations and radiological findings are diagnostic of SARS-CoV2. 4 , 5 , 6 , 10 , 47 , 62

Clinical features

Clinical manifestations of COVID-19 in neonates and children reported are generally mild and similar among countries. 4 , 5 , 6 , 14 , 16 , 22 , 23 , 37 , 38 , 46 , 63 , 64 , 65 Most commonly, at hospital admission, children presented with fever and respiratory symptoms with cough, sore throat, pharyngeal erythema, nasal congestion, tachypnea/dyspnea, and tachycardia. 22 , 23 , 65 Often, gastrointestinal symptoms, including abdominal pain, nausea, vomiting, and diarrhea, were the first manifestations. 4 , 5 , 15 , 46 , 64 , 66 Neurological manifestations such as seizures, dystonia, and altered mental status were rare. 66 Neonates, instead, showed tachypnea, cough, grunting, nasal flaring, vomiting, poor feeding, diarrhea, and lethargy. 45 , 61 , 67 , 68 , 69 Hospital admission was higher in Italy and Spain than in China and USA; 4 , 21 , 22 , 65 however, this was mainly due to local policies (testing availability and policy, need of patient isolation) rather than clinical condition. 22 , 65

In the largest retrospective cohort of COVID-19 pediatric patients reported so far [2134 patients including 731 (34.1%) laboratory-confirmed and 1412 (65.9%) suspected cases], Dong et al. 5 defined the severity of COVID-19 in asymptomatic infection, mild, moderate, severe, and critical cases, based on the clinical features, laboratory testing, and X-ray imaging (Table  1 ). In this cohort, 4.4% of infected children were asymptomatic, while the remaining children presented a mild (50.9%) or moderate disease (38.8%), respectively. Only 5.2% had severe disease, while 0.6% had critical disease. The proportion of severe and critical cases was 10.6%, 7.3%, 4.2%, 4.1%, and 3.0% for the age group of <1, 1–5, 6–10, 11–15, and >16 years, respectively.

Lu et al. 4 showed 15.8% of COVID-19 children included in their retrospective cohort (171 SARS-CoV2 confirmed cases) were completely asymptomatic and did not show any radiological findings of pneumonia.

Respiratory coinfections were present in almost half of the cases. 4 , 5 , 26 Comorbidities, as in adult patients, 70 may affect outcome 23 and the likelihood of Pediatric Intensive Care Unit (PICU) admission. 4 , 23

In adults, the incidence of ICU admission was high and variable among countries (5% in China and 9% in Italy); 70 , 71 in children, the incidence was lower (0.21–5.2% among Chinese PICUs, 4 , 5 , 15 0.04% in USA 23 ). Of note, several biases (retrospective nature of these studies, 5 , 61 the proportion of the detected cases, the use of different PICU admission criteria among centers, 5 the use of the same data source with overlapping data—Chinese Centers for Disease Control and Prevention database—and the high number of suspected cases 47 ) could have affected the interpretation of these results.

Most of the laboratory abnormalities in children with COVID-19 are nonspecific. Henry et al. 62 reviewed the data of 66 children from 12 different studies and found that 69.2% of children had normal leukocyte counts and that neutrophilia or neutropenia were rare (<5%). Platelet count was variable among studies (generally higher than the normal range), while C-reactive protein and procalcitonin were increased in 13.6% and 10.6% of the cases, respectively. 62

Children admitted to the PICU 15 showed normal or increased whole blood counts (7/8) and increased C-reactive protein, procalcitonin, and lactate dehydrogenase (6/8). High levels of pro-inflammatory and anti-inflammatory cytokines were also present similarly to the adult patients. 72 , 73

Although lymphocytopenia is very common in adults with severe COVID-19 and associated with worse outcomes, 47 it is less common in children (2–3.5%), likely due to the constitutional high percentage of lymphocytes typical of this age. 62 , 74 In adult patients, high ferritin, high d -dimers, and coagulopathy were associated with poor prognosis, 70 but these laboratory findings were rare in children; high d -dimers levels were found in one of the two patients who died from COVID-19. 4 , 15 However, during April 2020, a surge of anecdotal cases showing a hyper-inflammatory state (pediatric multisystem inflammatory syndrome temporally associated with COVID-19) and features similar to atypical Kawasaki disease or Kawasaki disease shock syndrome were reported in Europe (United Kingdom, Spain, Italy). 75 , 76 Many of these patients had positive SARS-CoV2 antibodies and presented an inflammatory state (elevated concentration of C-reactive protein, procalcitonin, ferritin triglycerides, and d -dimers) with cutaneous rash, peripheral edema, conjunctivitis, myocardial dysfunction (elevated cardiac enzymes), and coronary vessels inflammation.

Radiologic findings of SARS-CoV2 viral pneumonia were also variable among children (Fig.  3 ). 4 At hospital admission, many children presented a chest X-ray showing an interstitial pneumonia, 26 while chest computed tomography (CT) scan showed patchy shadows (unilateral and bilateral) with opacities of high density. The typical adult feature of ground-glass opacity was less frequent at hospital admission (32.7%); 4 instead, it was more common in patients admitted to the PICU for respiratory failure. 4 , 5 , 6 , 26 , 77 , 78 , 79 Bedside lung ultrasonography was also used as a diagnostic tool in the emergency departments in a minority of patients; 80 90% of these received a diagnosis of interstitial lung syndrome without further radiographic imaging. 65

a Chest X ray and b chest computed tomography. Vital signs: respiratory rate 22 breaths/min, SpO 2 : 97% in room air. The patient was supported with high-flow nasal cannula 25 L/min, FiO 2 : 30% in the pediatric ward.

Treatment of COVID-19 in neonates and children mainly relies on supportive care. 4 , 10

Home isolation is the first step to manage children with mild symptoms and no underlying chronic conditions. Hospitalization may be considered if rapid deterioration is anticipated or if the patient is not able to urgently return to hospital when signs and symptoms of complicated disease arise. Moderate cases should be managed in hospital, monitoring vital signs and oxygen saturation. Supportive care for these children includes temperature control with antipyretics, bed rest, hydration, and good nutrition. Routine antibiotics and antifungal drugs must be avoided and used only when coinfections are proven or strongly suspected. 10 , 15

In hypoxic patients, oxygen therapy should be immediately initiated. 81 Several devices [low flow nasal cannula, high-flow nasal cannula (HFNC), and noninvasive ventilation (NIV)] can be used according to the centers’ experience. Caution must be taken, since all noninvasive techniques bear the risk of aerosol contamination; strict personal protection equipment (PPE) must be used when caring for these patients.

Invasive mechanical ventilation is indicated if: SpO 2 /FiO 2  < 221 or if there is no improvement in oxygenation (target SpO 2 92–97% with FiO 2  < 0.4) within 30–60 min of HFNC or if there is no improvement in oxygenation (target SpO 2 92–97% and FiO 2  < 0.6) within 60–90 min of CPAP/NIV. 81 Escalating therapies are recommended in case of refractory hypoxia (surfactant therapy in neonates, inhaled nitric oxide, high frequency oscillatory ventilation, and extracorporeal membrane oxygenation). 81 , 82 , 83

A small portion of children with COVID-19 developed septic shock; 5 , 15 , 84 thus, this condition must be always suspected and managed according to the current pediatric guidelines since specific issues for COVID-19 have not been reported so far. 85 Corticosteroids should not be used in pediatric patients, 86 except when required for other indications, such as asthma exacerbations, refractory shock, or evidence of cytokine storm. 16

Several treatment options (intravenous immunoglobulin, interleukin-1 (IL-1) blockade, IL-6 receptor blockade, azythromycin-chloroquine, plasma exchange, infusion of plasma from convalescent subjects, cytokine adsorption filters) have been used in critically ill adult patients; however, data on their efficacy and safety have not been reported yet, thus caution should be used also in children. 87

Antiviral drugs should be used with caution after weighing advantages and disadvantages. For those with mild symptoms, low dosage of interferon-α nebulization has been used 16 in combination with oral ribavirin. Lopinavir/litonavir 15 and remdesivir 88 , 89 have been used in more severe cases; however, their efficacy and safety in children remain to be determined. 90 Remdesivir should be preferred in children because of its positive effects in a recent adult trial; 88 , 89 however, when not available, or when patients are not good candidate to remdesivir, hydroxychloroquine could be considered. 88 The combination of three or more antiviral drugs is generally not recommended. 90

Potential therapeutic strategies for SARS-COV2 are the spike protein-based vaccine, the inhibitors of transmembrane protease serine 2 activity, and the delivery of excessive soluble form of ACE-2 or antibody against the surface of ACE-2 receptors (Fig.  2c ). 13

Prevention and healthcare organization

COVID-19 has no approved treatment in neonates and children and a large-scale vaccine is still under development; thus, prevention is crucial. 10 , 91

SARS-CoV-2 has unique characteristics that makes its prevention complex. SARS-CoV-2 can cause an asymptomatic infection, can be transmitted during the incubation period and after clinical recovery, 13 has a very high affinity to ACE-2 receptors, which are expressed on many mucosal surfaces, resulting in high transmissibility, and can be spread also by fomite. 10

The high transmissibility and low CFR, combined with the discouraging projections of the spread of the virus among adults, 70 fostered many governments, at the beginning of March 2020, to adopt stringent containment and self-isolation measures to reduce the spread of the virus. An intense public health response was started by many countries after the pandemic declaration and involved many strategies: lockdown of the cities and mass quarantine, social distancing mandates, schools closure, cancellation of public gatherings, reduction of domestic and international flights, development of environmental measures and personal protection procedures, and strict contacts tracings by the medical and public health professionals. These measures aim to delay major surges of patients and to lower the demand for hospital extra beds, while protecting the most vulnerable subjects from infection, especially the elderly and those with comorbidities. 92

Data showed that pediatric cases requiring high-intensity medical assistance are uncommon; 5 , 15 however, isolation of all suspected and confirmed patients remains mandatory to avoid the spread of SARS-CoV2 among caregivers and healthcare workers. Therefore, many pediatric hospitals have developed local guidelines and logistic plans (simulations and training courses, reduction of elective surgeries and visits to outpatient clinics, etc.) to identify in advance potential surge capacity in the form of dedicated environment with extra beds for isolation, quarantine, and dedicated staff. As stocks of PPE might run low during a period of pandemic, strict hospital policies should also be adopted according to the WHO guidelines. 93 Furthermore, considering the high number of adult ICU admissions and the difficulties associated to create extra beds in a short period of time, 70 pediatric intensivists and nurses should be ready and prepared to offer help by managing adult patients in PICU 94 or to help in adult ICUs.

Differently from adults, home isolation is not easily performed in children, because they often require the presence of the parents, limiting the use of protective distances (>1.5 m). In those cases, all people sharing a common environment with a SARS-CoV2-positive child should consider the use of gloves and face masks, if available. Hand hygiene practices are extremely important to prevent the spread of the COVID-19 virus at home and in public environments. The WHO recommends washing hands, especially after coughing or sneezing (including sneeze/cough into elbow or tissue), before eating and after using the toilet or sharing common spaces. 95 Hand washing also interrupts transmission of other viruses and bacteria causing common colds, flu, and pneumonia, thus reducing the general burden of disease. Relatives at risk (e.g., people over the age of 65 years, pregnant women, people who are immunocompromised or who have chronic heart, lung, or kidney conditions) 96 should be isolated in protected environment, avoiding exposures to infected children. Because infants cannot wear masks, parents must wear masks, wash hands before close contacts, and sterilize the toys and tablet regularly. 97

All suspected children requiring hospital assistance must be isolated in single rooms (whenever possible, or in dedicated environments, maintaining adequate distances between beds) until the results of the test are available; confirmed patients must be placed in dedicated area for quarantine. A dedicated algorithm must be adopted for the use of the operating theaters in suspected or confirmed COVID-19 cases, according to the urgency of the operation, anticipated viral burden at the surgical site, and the risk that a procedure could spread the virus by aereosol. 98 , 99 Negative pressure rooms are of help, but not mandatory to manage these patients. 10 All rooms and transition environments must be decontaminated after the patient discharge (Fig.  3 ).

Since a high number of health care workers has been infected by SARS-CoV2, all suspected patients, until proven negative, must be assisted by health care providers using PPE 93 and all aerosol generating procedures (intubation, bronchoscopy, tube/tracheostomy suctioning, etc.) must be also performed using airborne transmission precautions. 93

Enhanced traffic control bundling strategies must be adopted by all emergency departments, 100 including a triage zone, transition zones conduction to a quarantine ward or to an isolation ward (Fig.  4 ). A dedicated pathway for children non-SARS-CoV2 suspected (e.g., trauma, poisoning, etc.) must also be created in parallel to avoid contact. Telemedicine should be implemented to help reduce hospital and clinic visits, 101 , 102 by triaging low-acuity patients while delivering high-quality care. 103

Enhanced traffic control system used in Children’s Hospital Bambino Gesù, Rome, Italy.

The scarcity of pediatric cases and the current literature on the topic, as well as the absence of high-quality evidence-based guidelines, has led pediatricians to share experiences and personal communication via online meetings and open access medical education channels. The use of webinars and communication about newly released papers on social media channels such as Twitter, Telegram and WhatsApp, greatly improved the dissemination of knowledge among health care providers.

At the time of this review (7 May 2020), SARS-CoV2 has infected millions of people in the world and caused hundreds of thousands confirmed deaths, but data regarding the epidemiologic and clinical characteristics in neonates and children are still scarce. The purpose of this review was to evaluate the current literature that includes neonates and children to date, providing useful information for clinicians dealing with this selected population. The earliest epidemiologic data show that SARS-CoV2 has a dominant family-cluster transmission and that children present a mild form of COVID-19 (CFR: <0.1%), rarely requiring high-intensity medical treatment in PICU. Vertical transmission is unlikely, but not completely excluded. Diagnosis is performed primarily via molecular nucleic acid amplification testing. Patients with confirmed or suspected COVID-19 should be isolated and healthcare workers should wear appropriate protective equipment. Some clinical features (higher incidence of fever, vomiting and diarrhea, and a longer incubation period) are more common in children than in adults, as well as some radiologic aspects, including the presence of patchy shadow opacities on CT scan images. Treatment options are extrapolated from adult data. Thus, supportive and symptomatic treatments (oxygen therapy and antibiotics for bacterial coinfections) are recommended in these patients. More studies on neonates and children are needed to address these gaps and to provide more robust recommendations to manage COVID-19.

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• Matteo Di Nardo

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Emergency Department, Bambino Gesù Children Hospital, Palidoro, Rome, Italy

Maria Antonietta Barbieri

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Each author made a substantial contribution to this review and met the Pediatric Research authorship requirements. M.D.N., G.V.L., and A.L. contributed to the review design, data acquisition, and screening. M.D.N., M.A.B., and Y.G. contributed to the interpretation of the data and article drafting. M.D.N., F.L., and V.M.R. contributed to the article drafting and revisions. All authors have approved the final manuscript.

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Di Nardo, M., van Leeuwen, G., Loreti, A. et al. A literature review of 2019 novel coronavirus (SARS-CoV2) infection in neonates and children. Pediatr Res 89 , 1101–1108 (2021). https://doi.org/10.1038/s41390-020-1065-5

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• http://orcid.org/0000-0003-1512-4471 Emily Long 1 ,
• Susan Patterson 1 ,
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• Carolyn Blake 1 ,
• http://orcid.org/0000-0001-7342-4566 Raquel Bosó Pérez 1 ,
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• http://orcid.org/0000-0002-4409-6601 Kirstin R Mitchell 2
• 1 MRC/CSO Social and Public Health Sciences Unit , University of Glasgow , Glasgow , UK
• 2 MRC/CSO Social and Public Health Sciences Unit, Institute of Health & Wellbeing , University of Glasgow , Glasgow , UK
• Correspondence to Dr Emily Long, MRC/CSO Social and Public Health Sciences Unit, University of Glasgow, Glasgow G3 7HR, UK; emily.long{at}glasgow.ac.uk

This essay examines key aspects of social relationships that were disrupted by the COVID-19 pandemic. It focuses explicitly on relational mechanisms of health and brings together theory and emerging evidence on the effects of the COVID-19 pandemic to make recommendations for future public health policy and recovery. We first provide an overview of the pandemic in the UK context, outlining the nature of the public health response. We then introduce four distinct domains of social relationships: social networks, social support, social interaction and intimacy, highlighting the mechanisms through which the pandemic and associated public health response drastically altered social interactions in each domain. Throughout the essay, the lens of health inequalities, and perspective of relationships as interconnecting elements in a broader system, is used to explore the varying impact of these disruptions. The essay concludes by providing recommendations for longer term recovery ensuring that the social relational cost of COVID-19 is adequately considered in efforts to rebuild.

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https://doi.org/10.1136/jech-2021-216690

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Introduction

Infectious disease pandemics, including SARS and COVID-19, demand intrapersonal behaviour change and present highly complex challenges for public health. 1 A pandemic of an airborne infection, spread easily through social contact, assails human relationships by drastically altering the ways through which humans interact. In this essay, we draw on theories of social relationships to examine specific ways in which relational mechanisms key to health and well-being were disrupted by the COVID-19 pandemic. Relational mechanisms refer to the processes between people that lead to change in health outcomes.

At the time of writing, the future surrounding COVID-19 was uncertain. Vaccine programmes were being rolled out in countries that could afford them, but new and more contagious variants of the virus were also being discovered. The recovery journey looked long, with continued disruption to social relationships. The social cost of COVID-19 was only just beginning to emerge, but the mental health impact was already considerable, 2 3 and the inequality of the health burden stark. 4 Knowledge of the epidemiology of COVID-19 accrued rapidly, but evidence of the most effective policy responses remained uncertain.

The initial response to COVID-19 in the UK was reactive and aimed at reducing mortality, with little time to consider the social implications, including for interpersonal and community relationships. The terminology of ‘social distancing’ quickly became entrenched both in public and policy discourse. This equation of physical distance with social distance was regrettable, since only physical proximity causes viral transmission, whereas many forms of social proximity (eg, conversations while walking outdoors) are minimal risk, and are crucial to maintaining relationships supportive of health and well-being.

The aim of this essay is to explore four key relational mechanisms that were impacted by the pandemic and associated restrictions: social networks, social support, social interaction and intimacy. We use relational theories and emerging research on the effects of the COVID-19 pandemic response to make three key recommendations: one regarding public health responses; and two regarding social recovery. Our understanding of these mechanisms stems from a ‘systems’ perspective which casts social relationships as interdependent elements within a connected whole. 5

Social networks

Social networks characterise the individuals and social connections that compose a system (such as a workplace, community or society). Social relationships range from spouses and partners, to coworkers, friends and acquaintances. They vary across many dimensions, including, for example, frequency of contact and emotional closeness. Social networks can be understood both in terms of the individuals and relationships that compose the network, as well as the overall network structure (eg, how many of your friends know each other).

Social networks show a tendency towards homophily, or a phenomenon of associating with individuals who are similar to self. 6 This is particularly true for ‘core’ network ties (eg, close friends), while more distant, sometimes called ‘weak’ ties tend to show more diversity. During the height of COVID-19 restrictions, face-to-face interactions were often reduced to core network members, such as partners, family members or, potentially, live-in roommates; some ‘weak’ ties were lost, and interactions became more limited to those closest. Given that peripheral, weaker social ties provide a diversity of resources, opinions and support, 7 COVID-19 likely resulted in networks that were smaller and more homogenous.

Such changes were not inevitable nor necessarily enduring, since social networks are also adaptive and responsive to change, in that a disruption to usual ways of interacting can be replaced by new ways of engaging (eg, Zoom). Yet, important inequalities exist, wherein networks and individual relationships within networks are not equally able to adapt to such changes. For example, individuals with a large number of newly established relationships (eg, university students) may have struggled to transfer these relationships online, resulting in lost contacts and a heightened risk of social isolation. This is consistent with research suggesting that young adults were the most likely to report a worsening of relationships during COVID-19, whereas older adults were the least likely to report a change. 8

Lastly, social connections give rise to emergent properties of social systems, 9 where a community-level phenomenon develops that cannot be attributed to any one member or portion of the network. For example, local area-based networks emerged due to geographic restrictions (eg, stay-at-home orders), resulting in increases in neighbourly support and local volunteering. 10 In fact, research suggests that relationships with neighbours displayed the largest net gain in ratings of relationship quality compared with a range of relationship types (eg, partner, colleague, friend). 8 Much of this was built from spontaneous individual interactions within local communities, which together contributed to the ‘community spirit’ that many experienced. 11 COVID-19 restrictions thus impacted the personal social networks and the structure of the larger networks within the society.

Social support

Social support, referring to the psychological and material resources provided through social interaction, is a critical mechanism through which social relationships benefit health. In fact, social support has been shown to be one of the most important resilience factors in the aftermath of stressful events. 12 In the context of COVID-19, the usual ways in which individuals interact and obtain social support have been severely disrupted.

One such disruption has been to opportunities for spontaneous social interactions. For example, conversations with colleagues in a break room offer an opportunity for socialising beyond one’s core social network, and these peripheral conversations can provide a form of social support. 13 14 A chance conversation may lead to advice helpful to coping with situations or seeking formal help. Thus, the absence of these spontaneous interactions may mean the reduction of indirect support-seeking opportunities. While direct support-seeking behaviour is more effective at eliciting support, it also requires significantly more effort and may be perceived as forceful and burdensome. 15 The shift to homeworking and closure of community venues reduced the number of opportunities for these spontaneous interactions to occur, and has, second, focused them locally. Consequently, individuals whose core networks are located elsewhere, or who live in communities where spontaneous interaction is less likely, have less opportunity to benefit from spontaneous in-person supportive interactions.

However, alongside this disruption, new opportunities to interact and obtain social support have arisen. The surge in community social support during the initial lockdown mirrored that often seen in response to adverse events (eg, natural disasters 16 ). COVID-19 restrictions that confined individuals to their local area also compelled them to focus their in-person efforts locally. Commentators on the initial lockdown in the UK remarked on extraordinary acts of generosity between individuals who belonged to the same community but were unknown to each other. However, research on adverse events also tells us that such community support is not necessarily maintained in the longer term. 16

Meanwhile, online forms of social support are not bound by geography, thus enabling interactions and social support to be received from a wider network of people. Formal online social support spaces (eg, support groups) existed well before COVID-19, but have vastly increased since. While online interactions can increase perceived social support, it is unclear whether remote communication technologies provide an effective substitute from in-person interaction during periods of social distancing. 17 18 It makes intuitive sense that the usefulness of online social support will vary by the type of support offered, degree of social interaction and ‘online communication skills’ of those taking part. Youth workers, for instance, have struggled to keep vulnerable youth engaged in online youth clubs, 19 despite others finding a positive association between amount of digital technology used by individuals during lockdown and perceived social support. 20 Other research has found that more frequent face-to-face contact and phone/video contact both related to lower levels of depression during the time period of March to August 2020, but the negative effect of a lack of contact was greater for those with higher levels of usual sociability. 21 Relatedly, important inequalities in social support exist, such that individuals who occupy more socially disadvantaged positions in society (eg, low socioeconomic status, older people) tend to have less access to social support, 22 potentially exacerbated by COVID-19.

Social and interactional norms

Interactional norms are key relational mechanisms which build trust, belonging and identity within and across groups in a system. Individuals in groups and societies apply meaning by ‘approving, arranging and redefining’ symbols of interaction. 23 A handshake, for instance, is a powerful symbol of trust and equality. Depending on context, not shaking hands may symbolise a failure to extend friendship, or a failure to reach agreement. The norms governing these symbols represent shared values and identity; and mutual understanding of these symbols enables individuals to achieve orderly interactions, establish supportive relationship accountability and connect socially. 24 25

Physical distancing measures to contain the spread of COVID-19 radically altered these norms of interaction, particularly those used to convey trust, affinity, empathy and respect (eg, hugging, physical comforting). 26 As epidemic waves rose and fell, the work to negotiate these norms required intense cognitive effort; previously taken-for-granted interactions were re-examined, factoring in current restriction levels, own and (assumed) others’ vulnerability and tolerance of risk. This created awkwardness, and uncertainty, for example, around how to bring closure to an in-person interaction or convey warmth. The instability in scripted ways of interacting created particular strain for individuals who already struggled to encode and decode interactions with others (eg, those who are deaf or have autism spectrum disorder); difficulties often intensified by mask wearing. 27

Large social gatherings—for example, weddings, school assemblies, sporting events—also present key opportunities for affirming and assimilating interactional norms, building cohesion and shared identity and facilitating cooperation across social groups. 28 Online ‘equivalents’ do not easily support ‘social-bonding’ activities such as singing and dancing, and rarely enable chance/spontaneous one-on-one conversations with peripheral/weaker network ties (see the Social networks section) which can help strengthen bonds across a larger network. The loss of large gatherings to celebrate rites of passage (eg, bar mitzvah, weddings) has additional relational costs since these events are performed by and for communities to reinforce belonging, and to assist in transitioning to new phases of life. 29 The loss of interaction with diverse others via community and large group gatherings also reduces intergroup contact, which may then tend towards more prejudiced outgroup attitudes. While online interaction can go some way to mimicking these interaction norms, there are key differences. A sense of anonymity, and lack of in-person emotional cues, tends to support norms of polarisation and aggression in expressing differences of opinion online. And while online platforms have potential to provide intergroup contact, the tendency of much social media to form homogeneous ‘echo chambers’ can serve to further reduce intergroup contact. 30 31

Intimacy relates to the feeling of emotional connection and closeness with other human beings. Emotional connection, through romantic, friendship or familial relationships, fulfils a basic human need 32 and strongly benefits health, including reduced stress levels, improved mental health, lowered blood pressure and reduced risk of heart disease. 32 33 Intimacy can be fostered through familiarity, feeling understood and feeling accepted by close others. 34

Intimacy via companionship and closeness is fundamental to mental well-being. Positively, the COVID-19 pandemic has offered opportunities for individuals to (re)connect and (re)strengthen close relationships within their household via quality time together, following closure of many usual external social activities. Research suggests that the first full UK lockdown period led to a net gain in the quality of steady relationships at a population level, 35 but amplified existing inequalities in relationship quality. 35 36 For some in single-person households, the absence of a companion became more conspicuous, leading to feelings of loneliness and lower mental well-being. 37 38 Additional pandemic-related relational strain 39 40 resulted, for some, in the initiation or intensification of domestic abuse. 41 42

Physical touch is another key aspect of intimacy, a fundamental human need crucial in maintaining and developing intimacy within close relationships. 34 Restrictions on social interactions severely restricted the number and range of people with whom physical affection was possible. The reduction in opportunity to give and receive affectionate physical touch was not experienced equally. Many of those living alone found themselves completely without physical contact for extended periods. The deprivation of physical touch is evidenced to take a heavy emotional toll. 43 Even in future, once physical expressions of affection can resume, new levels of anxiety over germs may introduce hesitancy into previously fluent blending of physical and verbal intimate social connections. 44

The pandemic also led to shifts in practices and norms around sexual relationship building and maintenance, as individuals adapted and sought alternative ways of enacting sexual intimacy. This too is important, given that intimate sexual activity has known benefits for health. 45 46 Given that social restrictions hinged on reducing household mixing, possibilities for partnered sexual activity were primarily guided by living arrangements. While those in cohabiting relationships could potentially continue as before, those who were single or in non-cohabiting relationships generally had restricted opportunities to maintain their sexual relationships. Pornography consumption and digital partners were reported to increase since lockdown. 47 However, online interactions are qualitatively different from in-person interactions and do not provide the same opportunities for physical intimacy.

Recommendations and conclusions

In the sections above we have outlined the ways in which COVID-19 has impacted social relationships, showing how relational mechanisms key to health have been undermined. While some of the damage might well self-repair after the pandemic, there are opportunities inherent in deliberative efforts to build back in ways that facilitate greater resilience in social and community relationships. We conclude by making three recommendations: one regarding public health responses to the pandemic; and two regarding social recovery.

Recommendation 1: explicitly count the relational cost of public health policies to control the pandemic

Effective handling of a pandemic recognises that social, economic and health concerns are intricately interwoven. It is clear that future research and policy attention must focus on the social consequences. As described above, policies which restrict physical mixing across households carry heavy and unequal relational costs. These include for individuals (eg, loss of intimate touch), dyads (eg, loss of warmth, comfort), networks (eg, restricted access to support) and communities (eg, loss of cohesion and identity). Such costs—and their unequal impact—should not be ignored in short-term efforts to control an epidemic. Some public health responses—restrictions on international holiday travel and highly efficient test and trace systems—have relatively small relational costs and should be prioritised. At a national level, an earlier move to proportionate restrictions, and investment in effective test and trace systems, may help prevent escalation of spread to the point where a national lockdown or tight restrictions became an inevitability. Where policies with relational costs are unavoidable, close attention should be paid to the unequal relational impact for those whose personal circumstances differ from normative assumptions of two adult families. This includes consideration of whether expectations are fair (eg, for those who live alone), whether restrictions on social events are equitable across age group, religious/ethnic groupings and social class, and also to ensure that the language promoted by such policies (eg, households; families) is not exclusionary. 48 49 Forethought to unequal impacts on social relationships should thus be integral to the work of epidemic preparedness teams.

Recommendation 2: intelligently balance online and offline ways of relating

A key ingredient for well-being is ‘getting together’ in a physical sense. This is fundamental to a human need for intimate touch, physical comfort, reinforcing interactional norms and providing practical support. Emerging evidence suggests that online ways of relating cannot simply replace physical interactions. But online interaction has many benefits and for some it offers connections that did not exist previously. In particular, online platforms provide new forms of support for those unable to access offline services because of mobility issues (eg, older people) or because they are geographically isolated from their support community (eg, lesbian, gay, bisexual, transgender and queer (LGBTQ) youth). Ultimately, multiple forms of online and offline social interactions are required to meet the needs of varying groups of people (eg, LGBTQ, older people). Future research and practice should aim to establish ways of using offline and online support in complementary and even synergistic ways, rather than veering between them as social restrictions expand and contract. Intelligent balancing of online and offline ways of relating also pertains to future policies on home and flexible working. A decision to switch to wholesale or obligatory homeworking should consider the risk to relational ‘group properties’ of the workplace community and their impact on employees’ well-being, focusing in particular on unequal impacts (eg, new vs established employees). Intelligent blending of online and in-person working is required to achieve flexibility while also nurturing supportive networks at work. Intelligent balance also implies strategies to build digital literacy and minimise digital exclusion, as well as coproducing solutions with intended beneficiaries.

Recommendation 3: build stronger and sustainable localised communities

In balancing offline and online ways of interacting, there is opportunity to capitalise on the potential for more localised, coherent communities due to scaled-down travel, homeworking and local focus that will ideally continue after restrictions end. There are potential economic benefits after the pandemic, such as increased trade as home workers use local resources (eg, coffee shops), but also relational benefits from stronger relationships around the orbit of the home and neighbourhood. Experience from previous crises shows that community volunteer efforts generated early on will wane over time in the absence of deliberate work to maintain them. Adequately funded partnerships between local government, third sector and community groups are required to sustain community assets that began as a direct response to the pandemic. Such partnerships could work to secure green spaces and indoor (non-commercial) meeting spaces that promote community interaction. Green spaces in particular provide a triple benefit in encouraging physical activity and mental health, as well as facilitating social bonding. 50 In building local communities, small community networks—that allow for diversity and break down ingroup/outgroup views—may be more helpful than the concept of ‘support bubbles’, which are exclusionary and less sustainable in the longer term. Rigorously designed intervention and evaluation—taking a systems approach—will be crucial in ensuring scale-up and sustainability.

The dramatic change to social interaction necessitated by efforts to control the spread of COVID-19 created stark challenges but also opportunities. Our essay highlights opportunities for learning, both to ensure the equity and humanity of physical restrictions, and to sustain the salutogenic effects of social relationships going forward. The starting point for capitalising on this learning is recognition of the disruption to relational mechanisms as a key part of the socioeconomic and health impact of the pandemic. In recovery planning, a general rule is that what is good for decreasing health inequalities (such as expanding social protection and public services and pursuing green inclusive growth strategies) 4 will also benefit relationships and safeguard relational mechanisms for future generations. Putting this into action will require political will.

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Twitter @karenmaxSPHSU, @Mark_McCann, @Rwilsonlowe, @KMitchinGlasgow

Contributors EL and KM led on the manuscript conceptualisation, review and editing. SP, KM, CB, RBP, RL, MM, JR, KS and RW-L contributed to drafting and revising the article. All authors assisted in revising the final draft.

Funding The research reported in this publication was supported by the Medical Research Council (MC_UU_00022/1, MC_UU_00022/3) and the Chief Scientist Office (SPHSU11, SPHSU14). EL is also supported by MRC Skills Development Fellowship Award (MR/S015078/1). KS and MM are also supported by a Medical Research Council Strategic Award (MC_PC_13027).

Competing interests None declared.

Provenance and peer review Not commissioned; externally peer reviewed.

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• Published: 29 July 2020

SARS-CoV-2: characteristics and current advances in research

• Yicheng Yang 1 , 2 ,
• Zhiqiang Xiao 3 ,
• Kaiyan Ye 4 ,
• Xiaoen He 2 ,
• Zhiran Qin 2 ,
• Jianghai Yu 2 ,
• Jinxiu Yao 5 ,
• Qinghua Wu 2 ,
• Zhang Bao 2 &
• Wei Zhao 2  

Virology Journal volume  17 , Article number:  117 ( 2020 ) Cite this article

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Coronavirus disease 2019 (COVID-19) caused by SARS-CoV-2 infection has spread rapidly across the world and become an international public health emergency. Both SARS-CoV-2 and SARS-CoV belong to subfamily Coronavirinae in the family Coronaviridae of the order Nidovirales and they are classified as the SARS-like species while belong to different cluster. Besides, viral structure, epidemiology characteristics and pathological characteristics are also different. We present a comprehensive survey of the latest coronavirus—SARS-CoV-2—from investigating its origin and evolution alongside SARS-CoV. Meanwhile, pathogenesis, cardiovascular disease in COVID-19 patients, myocardial injury and venous thromboembolism induced by SARS-CoV-2 as well as the treatment methods are summarized in this review.

The COVID-19 pandemic has resulted in more than 6.6 million confirmed cases worldwide. Previous studies showed that both SARS-CoV-2 and SARS-CoV belong to the subfamily Coronavirinae of the Nidovirales coronaviridae , and are classified as SARS-like species, but belong to different clusters. To further explore the characteristics of SARS-CoV-2, we compared different aspects of the virus with those of SARS-CoV; the clinical manifestations and treatment methods are also summarized.

Introduction

Coronaviruses belong to the subfamily Coronavirinae in the family Coronaviridae of the order Nidovirales and can cause respiratory, digestive, and nervous system diseases in humans and many other animals. Coronavirus particles are spherical with a diameter of approximately 80 to 160 mm. The envelope surface is covered with spike (S) protein, and the membrane (M) proteins and envelope (E) proteins are located among the S proteins. The genomic RNA and phosphorylated nucleocapsid (N) protein form a spiral nucleocapsid, which is located within the envelope [ 1 , 2 ]. The coronavirus genome is comprised of a single-stranded positive-strand RNA ranging from 26 Kb to 32 Kb in length, constituting the longest known genome among RNA viruses [ 3 ]. This genome has a 5′ cap structure, a 3′ polyadenylate tail structure, and six open reading frames (ORFs), of which the first (ORF1) near the 5′ terminus encodes 16 non-structural proteins (nsp1–16) involved in viral replication and transcription; other ORFs encode the four major structural proteins (S, M, N, and P) and eight accessory proteins (3a, 3b, p6, 7a, 7b, 8b, 9b, and ORF14), playing an important role in the assembly of viral particles.

According to genetic and antigenic characteristics, coronaviruses can be divided into four genera: α, β, γ, and δ. Among them, α and β coronaviruses only infect mammals, while γ and δ mainly infect birds, although some can also infect mammals [ 4 , 5 ]. Except for SARS-CoV and Middle East Respiratory Syndrome Coronavirus (MERS-CoV), most coronaviruses do not cause severe diseases in humans. It has been confirmed that the recent outbreak and epidemic of coronavirus disease 2019 (COVID-19) was caused by a new coronavirus that has been named SARS-CoV-2. Different from SARS-CoV and MERS-CoV in genetics and epidemiology, SARS-CoV-2 is a novel β-coronavirus [ 6 , 7 ]. As of now, three types of highly pathogenic coronaviruses have been confirmed, namely SARS-CoV, MERS-CoV, and SARS-CoV-2 [ 8 ].

In our review, we explore the differences in the origin and evolution, amino acid composition and protein structure, epidemiological and pathological characteristics between SARS-CoV-2 and SARS-CoV. In addition, the pathogenesis of SARS-CoV-2 has been summarized. Based on our expertise, comorbidity of cardiovascular diseases (CVD) in COVID-19 patients and SARS-CoV-2-induced myocardial injury and venous thromboembolism (VTE) are fully discussed, and medicines with recent clinical trial outcomes are also introduced.

Differences between SARS-CoV-2 and SARS-CoV

Classification.

According to the principle of international commission on virus classification, the coronavirus identification mainly depends on the similarity of the amino acid sequences of the seven domains encoded by ORF1ab, including ADRP, nsp5, and nsp12–16. Due to the extremely similar (more than 90%) amino acid sequences in the seven domains, both SARS-CoV-2 and SARS-CoV belong to the subfamily Coronavirinae in the family Coronaviridae of the order Nidovirales and are classified as SARS-like species, although they are classified into different clusters. The former belongs to the bat-like coronavirus cluster and the latter to the SARS cluster. Phylogenetic analysis showed that SARS-CoV-2 has a longer branch length compared to its closest relatives, including bat-SL-CoVZC45 and bat-SL-CoVZXC21; furthermore, it is genetically different from SARS-CoV. SARS-CoV-2 has only 79.5 and 40% homology with SARS-CoV and MERS-CoV, respectively, indicating a large genetic distance. At the same time, the S-protein homology between SARS-CoV and SARS-CoV-2 is also relatively low at 76.5% [ 9 , 10 , 11 , 12 ].

Amino acid composition and protein structure

While SARS-CoV-2 is very similar to SARS-CoV in amino acid composition and protein structure, with both having an Orf1ab encoding 16 predicted Nsps as well as the 4 typical coronavirus structural proteins, they also show some differences, mainly in the S, ORF8, ORF3b, and ORF10 proteins, with limited detectable homology between them.

Like SARS-CoV, the entry of SARS-CoV-2 is mediated by the recognition of the receptor binding domain (RBD) in the S protein and the angiotensin converting enzyme 2 (ACE2) receptor on the surface of the host cell, and the activation of S protein is related to TMPRSS2, whose inhibitors can prevent virus invasion [ 13 ]. Most of the SARS-CoV-induced polyclonal antibodies can prevent the S-mediated entry of the virus, which further illustrates the similarity between these two coronaviruses. However, according to previous researches, the outer subdomain of the receptor-binding domain in the S protein of SARS-CoV-2 has only 40% amino acid homology with other SARS-associated coronaviruses [ 3 ]. A recent research found that Furin protease cleavage site exists at the boundary between the S1 subunit and S2 subunit in the S protein of SARS-CoV-2, and it is processed during the biosynthesis [ 14 ]. This is similar to several highly pathogenic avian influenza viruses [ 15 ] and pathogenic Newcastle disease virus [ 16 ], but distinguishes SARS-CoV-2 from SARS-CoV. The existence of the cleavage site of the Furin protease enhances the tissue and cell tropism and transmissibility of SARS-CoV-2, and alters its pathogenicity. Wrapp et al. [ 17 ] obtained the trimeric structure of the S protein by 3D reconstruction technology based on the genomic sequence of SARS-CoV-2, and found that it is structurally different from that of SARS-CoV. In addition, the affinity of S protein of SARS-CoV-2 to ACE2 increased by 10–20 times compared with that of SARS-CoV. Blocking the process of viral entry is an important way to prevent and control viral infections; identifying and understanding the protein molecules on the surface of the new coronavirus, related receptors of target cell, as well as their interaction mechanisms can provide a basis for effectively preventing viruses from invading host cells. RBD is recognized primarily via polar residues by the extracellular peptidase domain of ACE2. Yan et al. [ 18 ] analyzed the electron microscope structure of the complex of S protein and ACE2, and found that in the procedure of the virus-target cell binding, the loop region on RBD crossed the α1 helix of ACE2, and the loop regions of β3, β4 and α2 helix are also involved in the combination of RBD and ACE2. Superimposing of the structures of SARS-COV-RBD and SARS-COV-2-RBD suggests a very high degree of similarity between the two, but there are still differences. The R426, Y484, T487, V404, and L472 residues in SARS-COV-RBD were replaced by N439, Q498, N501, K417, and F486 in the SARS-COV-2-RBD respectively. The replacement of L472 by F486 will enhance the van der Waals effect, and that of R426 by N439 will eliminate the salt bridge effect of D329 in ACE2, which, however, would be strengthened when V404 is replaced by K417. The existence of these mutations may be a significant reason SARS-COV-specific RBD antibody drugs fail to work on SARS-COV-2.

The motif VLVVL (amino acids 75–79) was reported in SARS-CoV ORF8b, which can trigger the intracellular stress pathway and activate the NLRP3 endosome, while no functional domains containing this motif has been found in SARS-CoV-2. ORF8 is related to the evolution of SARS-associated coronaviruses, and plays a significant role in virus replication, transmission, and adaptation to its hosts. In SARS-CoV-2, ORF8 consists of 121 amino acids, while it exists as ORF8a (39 amino acids) and ORF8b (84 amino acids) in SARS-CoV. The ORF3b protein contains 154 amino acids in SARS-CoV, but only 67 amino acids in SARS-CoV-2. In addition, the ORF3b protein of SARS-CoV-2 contains four new helical structures, and shows no homology to that of SARS-CoV. Although ORF3b protein is not necessary for virus replication, it may be related to its pathogenicity and its importance in SARS-CoV-2 requires further study [ 19 ].

Recently, a study carried out by multiple teams in the United States, France, and the UK cloned, tagged and expressed 26 of the 29 SARS-CoV-2 proteins in human cells, and suggested that ORF10 of SARS-CoV-2 shows limited homology with that of SARS-CoV. The study found that ORF10 of SARS-CoV-2 is small in size (38 amino acids), but contains an alpha helical region, which can be linked to a Cullin 2 (CUL2) RING E3 ligase complex, especially the CUL2ZYG11B complex, and hijack it for ubiquitination and restriction factor degradation. Alternatively, ZYG11B may bind to the N-terminal glycine in Orf10 to target it for degradation, which is closely related to virus replication [ 20 ].

Currently, it is believed that the SARS-CoV-2 genome is more stable than SARS-CoV, but it is still necessary to strengthen the monitoring of viral genome mutations as the epidemic progresses. Some large-scale viral genome studies suggest that 149 mutation sites have appeared in SARS-CoV-2. Due to the sequence difference in site 28,144 in the viral RNA genome, SARS-CoV-2 is divided into two subtypes: L and S. The L type spreads more widely, and has more mutations and a stronger ability to spread. Compared with other coronavirus, the gene sequence of S protein in SARS-CoV-2 changes greatly, suggesting that this segment may show a higher mutation rate [ 21 ]. Su et al. used a second-generation sequencing platform to analyze the nasal swab samples of patients diagnosed with COVID-19 and found that the 3′-end of the SARS-CoV-2 genome has a fragment with 382 nt missing, resulting in the destruction of the function of the ORF8 region, which may relate to how SARS-CoV-2 adapts to human survival [ 22 ]. Distinctions in the structure between SARS-CoV and SARS-CoV-2 are shown in Fig.  1 .

Distinctions of amino acid composition and protein structure. Differences between SARS-CoV and SARS-CoV-2 are mainly in S protein, ORF8 protein and ORF3b protien. a The external subdomain of the receptor binding domain of the spike protein in SARS-CoV-2 shares only 40% amino acid identity with other SARS-related coronaviruses; b ORF8 in SARS-CoV-2 does not contain a known functional domain or motif while in SARS-CoV ORF8b the presence of the aggregation motif VLVVL has been found; c The ORF8a protein is absent in SARS-CoV-2; There are 121 amino acids that encode the 8b protein in SARS-CoV-2, while only 84 are involved in SARS-CoV. d ORF3b of SARS-CoV-2 has a novel protein with four helices and 67 amino acids that encode the 3b protein in SARS-CoV-2 while 154 amino acids are involved in SARS-CoV

Epidemiological characteristics

Studies indicate that SARS-CoV has an incubation period of 2 to 10 days and a median incubation period of 4 to 7 days, while the incubation period of SARS-CoV-2 is mostly within 14 days, and the median is 3–4 days.

Sources of infection

The SARS epidemic in 2003 first occurred in Guangdong Province. Sources of SARS-CoV infection include infected animals and humans. At present, it is generally believed that the virus originates from bats, and civet is a possible intermediate host, and humans are the final hosts [ 23 ].

At the end of 2019, the first outbreak of pneumonia caused by SARS-CoV-2 occurred in Wuhan, Hubei [ 24 ]. Besides infected animals and COVID-19 patients, asymptomatic infectors are the most important source of infection for SARS-CoV-2 [ 25 ]. Studies have demonstrated that SARS-CoV-2 is of bat origin [ 12 , 26 ], with pangolin or civet as one of the possible intermediate hosts, and humans are the ultimate hosts [ 27 ]. It is worth noting that a recent study isolated one coronavirus from a Malayan pangolin showing 100, 98.6, 97.8, and 90.7% amino acid identity with SARS-CoV-2 in the E, M, N and S genes, respectively, and the receptor-binding domain within the S protein of the Pangolin-CoV is virtually identical to that of SARS-CoV-2, with only one noncritical amino acid difference. This suggests that SARS-CoV-2 might have originated from the recombination of a Pangolin-CoV-like virus with a Bat-CoV-RaTG13-like virus [ 28 ]. However, more research is required to confirm this.

Routes of transmission

SARS-CoV is transmitted through close-up droplets and contact, while SARS-CoV-2 has a wider range of transmission routes. In addition to short-distance droplet transmission and contact transmission, SARS-CoV-2 can also be transmitted through aerosols in the enclosed space and urine, and mother-to-child transmission may also exist [ 29 , 30 , 31 ]. The Chinese Center for Disease Control and Prevention isolated the SARS-CoV-2 strain from a feces sample of a confirmed patient in Heilongjiang Province, indicating that SARS-CoV-2 can survive in the stool; it has been demonstrated that after intragastric administration of SARS-CoV-2, transgenic mice that express human ACE2 can get the infection and show related pathological changes [ 32 ]. This suggests that fecal-oral transmission may also be one of its transmission modes [ 29 , 33 ].

Susceptible population

The population is generally susceptible to SARS-CoV, mostly young adults; and people are also generally susceptible to SARS-CoV-2. Epidemiological analysis shows that 77.8% of patients with COVID-19 are between 30 and 69 years of age, with the highest proportion in the 50 to 60 years age group, while the infection rate of children is relatively low [ 8 , 34 ].

It is generally believed that SARS-CoV-2 has a stronger propagation capability than SARS-CoV. A previous study showeed basic reproduction number (R 0 ) was 2.9 [ 35 , 36 ]. Based on the epidemiological data of 425 patients, another study showed the basic reproduction number R0 of this new coronary pneumonia to be 2.20 [ 37 , 38 ]. Moreover, there is a study that predicts the R0 value of SARS-CoV-2 to be 3.28 [ 39 ]. Yang et al. [ 40 ] predicted the R 0 to be 3.77—higher than SARS-CoV—but because of the uncertainty, the accuracy of the estimate is limited. The latest research shows that the R 0 of SARS-CoV-2 is about 2.68, which is roughly similar to the R0 reported by World Health Organization (WHO) and the Chinese Center for Disease Control and Prevention [ 41 , 42 ]. SARS-CoV-2 is highly contagious and up to June 17, 2020, SARS-CoV-2 infection had occurred in as many as 216 countries and the cumulative number of COVID-19 patients globally had reached 8,061,550, according to the data from WHO.

SARS-CoV-2 spreads easily but it is less lethal. The mortality rate of SARS-CoV-2 was lower than that of SARS-CoV. Studies have shown that approximately 23 to 32% of patients with SARS will develop severe disease and are prone to death [ 43 ]. A report by WHO shows that 774 of 8098 SARS patients died, with a case fatality rate of 9.6%. In elderly patients, case fatality rate was up to 50% [ 36 ]. SARS-CoV-2 has a wider range of transmission than SARS-CoV or MERS-CoV, and infects a larger number of patients, but the ratio of critically ill COVID-19 patients is relatively lower. Epidemiological characteristics of more than 70,000 cases described that 80.9% COVID-19 patients presented mild/moderate illness. Meanwhile, the crude death rate of COVID-19 was 2.3% and the death rate was 0.015/10 person-days [ 34 ], much lower than the mortality rates of SARS [ 44 ]. Severe illness and death are more common in older patients with underlying conditions. Meanwhile, SARS-CoV-2 not only affects the lungs, but also the heart and kidneys, causing multiple organ failure. Consequently, therapy for severe COVID patients is more difficult than that for SARS.

Origin and evolution

During the widespread epidemic of SARS-CoV-2 in the world, analysis of the SARS-CoV-2 genomic system evolution network revealed three variants, which the researchers tentatively named A, B, and C. Among them, A is an ancestor type; B is derived from A through two mutations of the synonymous mutation T8782C and the non-synonymous mutation C28144T, which is derived from A. The difference between type C and its parent type B is the non-synonymous mutation G26144T, and this mutation converts glycine to valine. Notably, the different types have different geographical distributions in the world. A and C mainly exist in Europe and the United States, while B mainly exists in East Asia, suggesting that Wuhan, the first outbreak spot of type B SARS-CoV-2 may not be the origin of SARS-CoV-2. This provides a new idea for the origin and evolution of SARS-CoV-2 [ 45 ].

Pathological characteristics

Autopsy results in SARS patients suggest that SARS-CoV infection causes severe pulmonary edema, pulmonary congestion, hilar lymphadenopathy, and spleen shrinkage in general [ 46 , 47 ]. Histological features of patients with SARS include bronchial epithelial exfoliation, loss of cilia and squamous metaplasia, diffuse alveolar damage, formation of hyaline membranes, and severe fibrosis of the lung tissue. SARS-CoV can be detected in lymphocytes, monocytes, lymphoid tissues, and respiratory tract as well as in intestinal mucosa, renal tubular epithelial cells, and neurons [ 48 , 49 ].

Certain pathological characteristics of COVID-19 patients have been identified. Pulmonary pathological results attained by Tian et al. [ 50 ] suggested that the early pathological changes induced by SARS-CoV-2 pneumonia include pathological interstitial pneumonia and prominent pulmonary edema, with protein exudation and minor inflammatory cell infiltration. Xu et al. [ 51 ] performed a case dissection on a patient and the results showed that bilateral diffuse alveolar damage with cellular fibromyxoid exudates and hyaline membrane formation corresponded to acute respiratory distress symptoms (ARDS); moreover, the overall pathological characteristics of the lung were similar in SARS and MERS. Inflammatory infiltration of lymphocyte-dominated mononuclear cells and other viral cytopathic-like changes were seen in the lung, but no intranuclear or intracytoplasmic viral inclusions were found. Minor inflammatory infiltration of mononuclear cells was present in the myocardial interstitium and the existence of viral myocarditis could not be ruled out, but no obvious damage to the myocardium was found. Based on the pathology report of one particular patient, the impact of SARS-CoV-2 on the cardiovascular system cannot be determined; hence, additional sample research and analysis are necessary. Another autopsy of a COVID-19 patient in China found that mucus exudation was more obvious than that in SARS patients and lung damage involving diffuse alveolar damage and pulmonary hyaline membrane formation was serious. Histopathologic changes seen on postmortem transthoracic needle biopsies from a COVID-19 patient with hypertension and diabetes showed diffuse alveolar damage. Virus was more highly detected in alveolar epithelial cells, while viral protein expression was low in blood vessels or in the interstitial areas [ 52 ]. A recent pathological study of African American patients found that in addition to diffuse alveolar injury, inflammatory cell infiltration, and hyaline membrane formation, COVID-19 patients also have thrombi in peripheral small vessels with obvious bleeding in the lungs, while no obvious thrombus was found in other organs, including kidney, spleen, pancreas, and liver. At the same time, it was reported that there are a large number of CD61 + megakaryocytes in the alveolar capillaries, and a large number of platelets are actively produced. The large aggregation of platelets and fibrin deposition may jointly promote the production of thrombi within peripheral small vessels in lungs [ 53 ]. However, evidence of damage to other organs and/or systems requires more substantial autopsy results.

The differences between SARS-CoV and SARS-CoV-2 are shown in Table  1 .

Pathogenic mechanisms of SARS-CoV-2

As in SARS-CoV, the S protein of SARS-CoV-2 aids in cell invasion by binding to ACE2 receptors on the host cell surface, causing a series of lung injury responses [ 54 ].

SARS-CoV-2-induced direct damage

When SARS-CoV-2 invades the human body, the RBD on the S1 subunit of the S protein binds to ACE2 expressed on the host cell surface. Subsequently the conformation of the S protein undergoes a significant structural rearrangement, resulting in shedding of the S1 subunit and transition of the S2 subunit to a highly stable post-fusion conformation, which in turn mediates the fusion of the virus with the host cell membrane and cell entry [ 2 ]. After entering the cell, SARS-CoV-2 multiplies and eventually lyses the host cell, causing extensive alveolar damage and ARDS in infected patients.

Down-regulation of ACE2

In addition to mediating the entry of SARS-CoV and SARS-CoV-2 into host cells, ACE2 is also an important mediator of inflammation in the human body. It is mainly expressed in the small intestine, testis, adipose tissue, kidney, heart and thyroid, and lung tissue in the human body, and is also expressed in relatively low amounts in the colon, liver, bladder and adrenal glands, blood, spleen, bone marrow, brain, blood vessels, and muscles [ 55 ]. ACE2 is an enzyme that converts angiotensin (Ang) I to Ang 1–9, Ang II to Ang 1–7, and the latter can interact with MAS receptors, thereby inhibiting the harmful vasodilation and pro-fibrosis mediated by the AT1 receptor and mediating a variety of beneficial negative feedback regulation [ 56 ]. A lack of ACE2 will increase the levels of the two Ang peptides, thereby activating the Ang AT 1 and AT 2 receptors expressed on the surface of alveolar epithelium, vascular endothelium, intestinal epithelium, and kidney cells. During the fusion of the viral envelope with the host cell membrane and cell entry, ACE2 is internalized accordingly due to its binding to the virus, thereby down regulating ACE2 on the cell surface [ 56 ]. The dysregulation of the ACE2-Ang II-AT1 receptor axis and the ACE2-Ang1–7-Mas receptor axis is an important cause of endothelial cell damage, inflammation, and thrombosis [ 55 ].

Immune dysfunction

The disturbance of the immune system is also one of the factors that contributes to tissue and cell damage in patients with COVID-19. In both COVID-19 patients and animal models of SARS-CoV-2 infection, significant inflammatory cell infiltration, increased inflammatory mediators, thickened alveolar septa, and significant vascular system damage have been observed [ 32 ]. At present, pathological reports indicate that severe immune injury is an important pathogenic mechanism of SARS-CoV-2.

• Cytokine storm

A large number of studies have shown that the progression of severe COVID-19 patients is closely related to the massive production and activation of cytokines and inflammatory mediators. The inflammatory response is strong during SARS-CoV-2 infection, and the uncontrolled inflammation of the lungs caused by it may be the main cause of death in some cases. Intensive care unit (ICU) patients have higher levels of interleukin (IL)-1β, IL-1Ra, IL-7, IL-8, IL-9, IL-10, basic FGF, GCSF, GM-CSF, IFN-γ, CXCL10, CCL2, CCL3, CCL4, PDGF, TNF-α, and VEGF in the plasma than healthy controls, and higher levels of IL-2, IL-7, IL-10, GCSF, CXCL10, CCL2, CCL3, and TNF than non-ICU patients [ 57 ]. In addition, neutrophils, elevated D-dimers, and blood urea nitrogen were found in deceased patients infected with COVID-19, suggesting that death may be the result of cytokine storms, inflammatory responses, and acute kidney injury [ 58 ]. Nlrp3γ inflammasome, as a powerful pro-inflammatory system in the body, is also an important cause of cytokine storm. Nlrp3γ is expressed in many cells, including immune, endothelial, hematopoietic, lung epithelial, kidney, and heart cells. High levels of Ang II may over-activate Nlrp3γ in these cells and trigger an immune response through intracellular caspase-1, thereby releasing a large number of inflammatory factors, such as IL-1β and IL-18, and creating gasdermin D pore channels in cell membranes to mediate the release of several biologically active danger-associated molecular pattern molecules, finally mediating cell apoptosis and lysis [ 56 ].

Activation of complement system

The complement system is also involved in immune injury in COVID-19 patients. In the peripheral blood mononuclear cells of COVID-19 patients, the genes related to complement activation are enriched, and the serum complement levels in patients with severe COVID-19 are higher than those in mild cases and healthy controls, indicating that complement-mediated immune injury may be one of the causes of cell damage and aggravation of the disease in patients with COVID-19 [ 59 , 60 ]. Mannose-binding lectin (MBL), a pattern recognition protein present in serum can be combined with MBL-associated serine protease 2 (MASP-2) to initiate the complement-activated lectin pathway by binding to sugar molecules on the surface of pathogens. The SARS-CoV-2 N protein can interact with MASP-2, inducing MASP-2 to automatically activate and cleave complement protein C4 [ 59 ]. Massive deposition of MBL, MASP-2, and C3 and C4 lysates (C4a, C4d) in lung tissue and the membrane attack complex formed with C5b-9 can cause damage and lysis of alveolar cells.

Lymphocyte dysfunction

Lymphopenia, a common feature in patients with COVID-19, was identified in a patient by flow cytometry while lymphocytes were found to be over-activated. This potentially constitutes a key factor related to disease severity and mortality. The number of CD4 + and CD8 + T cells in the peripheral blood of patients was greatly reduced, while a higher number of double positive HLA-DR and CD38 suggested the activation of T cells. In addition, the number of CCR4 + CCR6 + Th17 cells with a high pro-inflammatory effect was increased and CD8 + T cells had a high concentration of cytotoxic granules including perforin and granulysin. Over-activation of T cells characterized by an increase in Th17 and high cytotoxicity of CD8 + T cells could partially explain the severe immune damage in SARS-CoV-2-infected patients. Viral infection rarely caused a Th17 response, but over-activation of Th17/CD8 was detected in patients with COVID-19 requiring medical attention.

However, the latest research indicates that patients with severe COVID-19 also have impaired cytotoxic lymphocyte killing function [ 61 ]. All subtypes of lymphocytes in patients with COVID-19 are reduced, including T cells, B cells, and NK cells. In quantitative analysis of CD4 + and CD8 + T cells at different stages of maturity [ 61 ], it was found that compared with healthy subjects, the frequency of TEMRA (CD45RA + CCR7 − ) and senescent CD8 + T cells (CD57 + ) in COVID-19 patients was significantly higher. However, Tem (CD45RA7 − CCR77 − ) and HLA-DR + CD8 + T cells did not show related changes compared with healthy subjects, exhibiting a skewing of CD8 + T cells towards a terminally differentiated/senescent phenotype; similar findings were also observed for CD4 + T cells. Research on NK cells showed that, in addition to a reduced number of the cells in patients with COVID-19, their ability to produce IFN-α, perforin, and granzymes was also reduced, leading to an impaired virus clearance function. IL-6 may play a major role in the process of the dysfunction of NK cell [ 61 , 62 ]. In patients with severe COVID-19, the decrease in NK cells and their dysfunction are significantly inversely proportional to the level of IL-6 in the serum, while anti-IL-6 receptor monoclonal antibody tocilizumab treatment is able to reverse this process, suggesting that high levels of IL-6 exposure can down-regulate the expression of perforin and granzyme in NK cell. In conclusion, the senescence of CD4 + and CD8 + T cells as well as the impaired function of NK cells can lead to the evasion of SARS-CoV-2 from the immune attack and clearance in patients with severe COVID-19.

Clinical manifestations

Basic clinical characteristics of covid-19.

SARS-CoV-2 infection causes systemic and respiratory symptoms such as fever, muscle soreness, cough, and dyspnea. Guan et al. [ 30 ] collected data of 1099 confirmed COVID-19 patients from 552 hospitals in 30 provinces, autonomous regions, and municipalities in China and demonstrated that cough (67.8%) is the most common symptom among patients, while only 43.8% of patients were diagnosed with fever. ARDS, respiratory failure, multiple organ dysfunction syndrome, as well as septic shock, metabolic acidosis, and coagulation dysfunction were found to manifest in severe cases. Meanwhile, nausea, vomiting, diarrhea, and other gastrointestinal symptoms as well as chest pain, heart palpitations, and other cardiovascular symptoms can also be the first symptoms in patients with COVID-19. Laboratory tests show normal or decreased peripheral blood leukocytes, reduced lymphocyte counts, and abnormalities in liver enzymes, myocardial enzymes, and C-reactive protein. In severe cases, increases in D-dimer and inflammatory factors are detected. Computerized tomography showed that ground-glass opacity is the most common radiologic characteristic and “paving stone sign” may appear in the advanced stage [ 63 , 64 ]. At present, the diagnosis is primarily based on the pathogenic examination of nucleic acid detection. However, nucleic acid detection is subject to factors such as material selection, which may cause a certain false negative rate. Therefore, patients presenting epidemiological characteristics, clinical manifestations, and typical imaging characteristics with negative nucleic acid detection are classified as clinically confirmed cases that must be treated in isolation in the clinic.

COVID-19 and CVD

Many studies report that patients with COVID-19 often have comorbidities—commonly CVD. Based on the published data in China, the prevalence of CVD in COVID-19 patients varied from 1% [ 65 ] to 39% [ 66 ]. CDC COVID-19 Response Team analyzed the data from 50 U.S. states, four U.S. territories, and affiliated islands and showed that 9.0% of patients were suffering from CVD [ 67 ]. Buckner et al. [ 68 ], however, demonstrated that the ratio reached to 38% in Washington State. Mehra et al. [ 69 ] enrolled 8910 patients with COVID-19 from 169 hospitals in Asia, Europe, and North America and showed that 10.2% of the patients had coronary artery disease. Meta-analysis confirmed considerable prevalence of CVD among COVID-19 patients. Li et al. [ 70 ] reported that the prevalence of cardia-cerebrovascular diseases in COVID-19 patients was 16.4% and another study [ 71 ] showed 11.9% of patients with COVID-19 also had CVD. Various proportions of COVID-19 patients with CVD have been singled out due to selection bias and different data samples. It is also worth noting that various definitions of CVD were used in the different studies. For example, some studies recognized coronary heart disease and heart failure as CVD, while some also included cerebrovascular disease and hypertension. Therefore, these results should be cautiously interpreted [ 72 ]. Broader data analysis with uniform definition for CVD remains necessary to determine the proportion of COVID-19 patients with CVD.

CVD is regarded as a risk factor of COVID-19 progression and is associated with higher risk of mortality of patients with COVID-19. A previous cross-sectional study reported that COVID-19 patients with CVD and hypertension were more likely to be transferred to the ICU [ 58 ]. Furthermore, the co-incidence of COVID-19 with coronary heart disease (5.8% vs. 1.8%) was higher in patients with severe COVID-19 than in non-severe patients [ 30 ]. Studies [ 73 , 74 ] found that CVD was associated with disease severity(OR = 3.14; 95% CI 2.32–4.24; OR = 2.74; 95% CI 1.50–5.00) and also the higher prevalence of CVD in critical/mortal COVID-19 patients compared to the non-critical group was shown(OR = 4.78, 95% CI = 2.71–8.42) in another latest study [ 75 ]. The Chinese Center for Disease Control and Prevention announced that the crude mortality of COVID-19 was approximately 0.9%, while in patients with CVD, it rose to 10.5%. Zhang et al. [ 74 ] enrolled 541 patients with COVID-19 and showed the mortality of patients with CVD reached to 22.2%. Presence of CVD was associated with higher mortality (OR = 4.85, 95% CI 3.07–7.70). These studies suggest that more intensive medical care should be provided to patients with COVID-19 having CVD to prevent disease progression and poor prognosis [ 76 ].

COVID-19 and myocardial injury

Myocardial injury is one of the most common complications in patients with COVID-19, especially those in severe condition, with rates reported variously and often indicating a poor prognosis. The prevalence of patients with myocardial injury complication varies from 7.2% [ 58 ] to 27.8% [ 77 ]. In our upcoming meta-analysis, 7 studies were included and the analysis indicated that the pooled prevalence of myocardial injury complication in COVID-19 patients is 17.0%. In addition, myocardial injury is more commonly seen in severe cases. Huang et al. [ 57 ] and Wang et al. [ 58 ] demonstrated that the incidence of myocardial injury was 30.7 and 22.2%, respectively. Li et al. [ 78 ] showed that the ratio was 34.9% in severe patients. Moreover, it has been proved that myocardial injury is associated with higher risk of in-hospital mortality. The mortality was 51.2% in myocardial injury group, while that in patients without myocardial injury was 4.5% (P < 0.001) [ 79 ]. Similar results were also demonstrated in other studies [ 80 , 81 , 82 ]. Although the specific mechanisms by which SARS-CoV-2 causes myocardial injury remain unclear, they may be related to the following:

Direct damage Due to the wide expression of ACE2 receptors in cardiomyocytes, a large number of SARS-CoV-2 may directly invade cardiomyocytes through binding to the receptor, which may cause the cardiac damage. Besides, replication and reproduction of SARS-CoV-2 rely on substrates in cardiomyocytes, which may lead to abnormal metabolism of cardiomyocytes and consequent damage.

Down-regulation of ACE2 Levels of Ang II, an inflammatory factor regulatory protein, are elevated by SARS-CoV-2 infection, leading to the production of reactive oxygen species and oxidative stress injury of myocardial cells [ 83 , 84 ]. After Ang II recognizes the AT 1 receptor, several kinases, including extracellular regulated protein kinases 1/2, c-Jun N-terminal kinase/signal transducer and activator of transcription, calcium kinase II and protein kinase C, are also activated. In addition, the down-regulation of ACE2 caused by SARS-CoV-2 activates the ADAM-17/TACE pathway, which leads to increased release of TNF-α and subsequent myocardial inflammatory damage [ 85 , 86 ]. However, changes in the content of Ang II and ACE2, the initiating factors, and the specific molecular mechanisms that damage the body, require further study.

Immune damage and cytokine storm Similar to SARS-CoV and MERS-CoV, SARS-CoV-2 induces the release of a large number of cytokines, causing a cytokine storm that damages myocardial cells [ 87 ]. TNF-α, produced by activated macrophages, may be a main chemokine in patients with COVID-19, causing the release of a series of pro-inflammatory factors that also plays an essential role in myocardial damage [ 88 ]. The specific molecular mechanisms involving immune damage and cytokine storms with myocardial damage must be studied further.

Oxygen supply-demand imbalance. Pulmonary pathology suggests that SARS-CoV-2 infection is mainly due to exudative changes, leading to hypoxemia or respiratory failure. In addition, patients with COVID-19 have systemic symptoms such as fever, leading to increased oxygen demand, which further exacerbates the imbalance between oxygen supply and demand. Mitochondrial damage and oxidative stress induced by the imbalance between oxygen supply and demand are important pathophysiological mechanisms of cardiac damage caused by viral infection [ 89 , 90 ]. It is speculated that myocardial damage induced by SARS-CoV-2 may also be related to oxidative stress. Mitochondrial structure and function are dysfunctional under hypoxic conditions, the production of antioxidant substances is reduced, and the level of reactive oxygen species is increased, which induces myocardial damage. In addition, endoplasmic reticulum stress induced by hypoxia promotes increase of pro-apoptotic factors and expression of apoptosis gene through activation of PERK-ATF4-CHOP (protein kinase R-like endoplasmic reticulum kinase-transcription activator 4-C/EBP homologous protein) pathway, thereby inducing cardiomyocyte apoptosis and myocardial injury [ 91 ]. The different mechanisms of myocardial injury induced by SARS-CoV-2 are shown in Fig.  2 .

Potential mechanisms of myocardial injury induced by SARS-CoV-2. a SARS-CoV-2 damages cardiomyocytes directly; b SARS-CoV-2 infection reduces ACE2 thus AngII is up-regulated. Kinases in cardiomyocytes are activated to induce an inflammation effect causing myocardial injury; c Inflammatory cytokines release; d Oxygen supply-demand imbalance

COVID-19 and VTE

SARS-CoV-2-induced hypercoagulability and VTE have received great attention recently [ 92 , 93 ]. Middeldorp et al. [ 94 ] showed that 19.6% pf patients with COVID-19 show VTE complication. Llitjos et al. [ 95 ], Klok et al. [ 96 ], and Cui SP et al. [ 97 ] demonstrated that the prevalence of VTE was up to 69.2, 27, and 24.7%, respectively, in ICU-COVID-19 patients. It has been shown that the level of D-dimer is higher in COVID-19 patients [ 98 ]. Compared with the non-severe patients of COVID-19, a higher proportion of elevated D-dimer was observed among severe cases [ 99 , 100 ] and higher level of D-dimer is one of the risk factors for disease progression [ 101 , 102 , 103 ]. Besides, higher concentrations of D-dimer (aHR = 1.10 [1.01–1.19] per decile increase) were independently associated with in-hospital mortality [ 104 ]. A retrospective cohort study also demonstrated that D-dimer > 1 μg/mL on admission was associated with higher risk of death (OR = 18.4, 95% CI: 2.6–128.6, p = 0.003) [ 105 ]. SARS-CoV-2 induces endothelial injury and cytokine storm may explain the appearance of VTE and elevated D-dimer in COVID-19 patients [ 106 , 107 ] while the exact molecular mechanisms still need to be elucidated. In clinics, VTE and dynamic changes in D-dimer levels should be considered to prevent the clinical deterioration of patients with COVID-19.

COVID-19 therapy

Treatment of COVID-19 patients is fully discussed nowadays and with worldwide researchers’ efforts, effective therapy strategies are shared to improve the prognosis of patients with COVID-19. Therapies including medicine, specific immunotherapy and cell therapy are expected to play an effective role in treating COVID-19 patients. Here, based on recent research and/or Chinese experience, we comprehensively introduce some effective treatments of patients with COVID-19.

Medicine therapy

Traditional chinese medicine (tcm).

TCM shows encouraging results in improving symptoms and decreasing the deterioration, mortality, and recurrence rates of COVID-19. In China, 91.5% of patients with COVID-19 have used TCM and efficiency exceeded 90%. Chinese scholars have proposed that TCM can modulate the dysfunction of ACE2 caused by viral infection in multiple pathways. Moreover, it can inhibit ribosomal proteins to obstruct viral replication, conferring a protective effect in humans. Additionally, TCM inhibits the excessive production of activated cytokines and eliminates the inflammatory response by regulating Th17 and cytokine-related pathways, which may provide protective effects in COVID-19 patients. A recent study showed that 8 core herbal combinations and 10 new formulae were regarded as potentially useful candidates for COVID-19 treatment [ 108 ]. Lianhuaqingwen capsule, which is a repurposed marketed Chinese herb product has been confirmed for influenza treatment. A prospective multicenter open-label randomized controlled trial [ 109 ] proved that it could also be considered to ameliorate clinical symptoms of COVID-19 after 14 days of use. However, further assessment through double blind and longer follow-up duration trials is necessary.

Chloroquine and Hydroxychloroquine

Chloroquine and hydroxychloroquine are used for treating malaria and whether they can be a potential drug for COVID-19 treatment is currently controversial. A previous study showed that the use of chloroquine in 100 COVID-19 patients was potentially able to inhibit the virus and it was suggested to be used in clinical treatment in Chinese guideline. Hydroxychloroquine, as an analog of chloroquine, was shown to have a stronger inhibitory effect on SARS-CoV-2 than chloroquine in vitro experiments with a higher safety. In addition, low-dose hydroxychloroquine may also play an immunoregulatory role in severely infected patients who cannot use glucocorticoids and immunosuppressants, and relieve the cytokine storm [ 110 ]. Conversely, a recent study demonstrated that there was no evidence for the efficacy of chloroquine or hydroxychloroquine against COVID-19. Furthermore, it increased the risk of serious cardiac complications and mortality of patients. However, because of the high dose of chloroquine or hydroxychloroquine used in this study as well as suspicion on data sources and data consistency, these results cannot be used to reach consensus. Notably, the article was retracted by Lancet [ 111 ]. Thus, the clinical value of repurposing these drugs for COVID-19 therapy still requires further investigation and high-quality research.

Remdesivir, an adenosine nucleotide analogue prodrug having broad-spectrum antiviral activity, is expected to become a potent drug for COVID-19 [ 112 ]. However, two recent randomized controlled trials showed contradictory results. A Chinese study [ 113 ] enrolled 237 severe COVID-19 patients and demonstrated that compared with the placebo group, no improvement in mortality was found after taking remdesivir for 28 days (13.9% versus 12.8%). This study failed to complete full enrollment due to the end of the disease outbreak and 2:1 randomization in trial, leading to lower inspection efficiency, both of which may decrease credibility of the conclusion. A larger American study [ 114 ], which included 1063 patients with COVID-19, demonstrated that remdesivir was effective for treatment. It showed that median recovery time in remdesivir group was 11 days compared to 15 days in the placebo group (P < 0.001), and 14-day mortality was 7.1 and 11.9% in remdesivir group and placebo group, respectively. Researchers are optimistic regarding the use of remdesivir for COVID-19 treatment, although more clinical trials are required to provide strong evidence.

Lopinavir/ritonavir

Lopinavir/Ritonavir, a kind of viral replication inhibitor, was used for SARS patients [ 115 ] and it may be effective for SARS-CoV-2 infection. A recent randomized, controlled, open-label trial [ 116 ] included 199 patients with COVID-19 and showed that the time to clinical improvement between lopinavir-ritonavir group and standard-care group was not different (HR = 1.31, 95% CI: 0.95 to 1.80). Besides, 28-day mortality was similar in the two groups, while gastrointestinal adverse events were more common in COVID-19 patients treated with lopinavir/ritonavir at 400/100 mg twice daily. The trial showed disappointing results with lopinavir/ritonavir. However, patients in this study were at the late stage in infection and tissue damage had already appeared, while viral replication inhibitor is more effective in early infection, which may explain inefficacy of the treatment. In addition, Baden et al. [ 117 ] also pointed out that the concentration of the drug used in patients failed to inhibit viral replication and both groups were heterogeneous, which may lead to inaccurate conclusion. Therefore, future high-quality blind randomized clinical trials should be carried out to examine the efficacy of lopinavir/ritonavir against COVID-19.

Immunomodulatory therapy

There is much attention recently on the use of dexamethasone, tocilizumab and anakinra for COVID-19. In a large RECOVERY trial [ 118 ], 2100 COVID-19 patients were enrolled for evaluating the efficacy of dexamethasone for treatment. Surprisingly, it showed that dexamethasone was able to reduce mortality by up to one third in hospitalised patients with severe complication. Dexamethasone, a cheap and widely available steroid, has such a large effect on reducing mortality of COVID-19 patients and it is expected to be an effective and affordable drug for treatment. Tocilizumab, the first IL-6 receptor inhibitor has a significant effect on the treatment of COVID-19 patients. A study [ 119 ] demonstrated that tocilizumab improved the clinical outcome in severe and critical patients and it has been recommended to use in severe COVID-19 patients in China. Recently, some randomized controlled trials are being launched, which will provide a more comprehensive knowledge on the use of tocilizumab in COVID-19 patients. A retrospective study [ 120 ] with 29 COVID-19 patients found that respiratory function was improved among 72% COVID-19 patients after using high-dose anakinra. Another study [ 121 ] which enrolled 8 severe COVID-19 patients with secondary hemophagocytic lymphohistiocytosis also showed the benefits of respiratory function after taking anakinra. However, lager randomized controlled trials are needed to verify the efficacy and safety of anakinra on COVID-19 patients treatment.

Specific immunotherapy

Vaccination.

COVID-19 vaccine including nucleic acid vaccine (including mRNA vaccine, DNA vaccine), recombinant genetic engineering (protein recombinant) vaccine, inactivated vaccine, attenuated influenza virus vector vaccine, and adenovirus vector vaccine are yet to be explored [ 122 , 123 ]. Faced with SARS-CoV-2 infection, global scientific researchers are stepping up the development of vaccines. Coronavirus glycoproteins are potential vaccine targets for SARS-CoV and MERS-CoV. Due to the lack of immunological research on SARS-CoV-2 and its similarity with SARS-CoV, most studies use SARS-CoV immune information to assist the development of a SARS-CoV-2 vaccine. Cytotoxic T-lymphocyte cell epitopes and B cell epitopes on the surface of SARS-CoV-2 are potential targets for the SARS-CoV-2 vaccine [ 124 ]. Some researchers think that the entire S protein or the S1 protein containing the RBD is an antigen that can be used for vaccine development [ 125 ]; however, some studies have pointed out that vaccines targeting antibodies against S2 linear epitopes may be more effective, because of less genetic mismatches rendering SARS-CoV-derived antibodies ineffective compared with S1 subunit [ 126 ].

After the outbreak of SAR-CoV-2, at least 37 biopharmaceutical companies or academic institutions have used multiple platforms including mRNA, DNA, adenoviral vectors, and recombinant proteins to develop preventive vaccines [ 125 ]. In China, 5 vaccines (1 for adenovirus vector vaccine, 4 for inactivated vaccines) are under phase II clinical trials. Recently, Zhu et al. [ 127 ] published the first inspiring clinical result of vaccine in human. In this dose-escalation, single-center, open-label, non-randomized, phase 1 trial of an Ad5 vectored COVID-19 vaccine, all 108 participants showed immune response after vaccination. From day 14 post-vaccination, rapid specific T-cell responses were found and peak of humoral immunity against SARS-CoV-2 appeared on day 28 post-vaccination. It suggested that the Ad5 vectored COVID-19 vaccine was worth further exploration. Besides, nucleic acid-based vaccines constitute the most advanced strategy in the development of new pathogen vaccines. With the recent improvements in the stability and efficiency of protein translation and the optimization of delivery systems such as lipid nanoparticles (LNPs), nucleic acid vaccines (including DNA and RNA vaccines) are a promising approach that needs further investigation [ 128 , 129 ]. However, vaccine-mediated harmful immune responses, the time and cost of research and development, the availability of large-scale production, and the ownership and management of vaccines will all be huge challenges that need to be overcome, and strengthening international cooperation is essential for accelerating research to develop new coronavirus vaccines.

Passive immunity

Injection of monoclonal antibodies is important for the short-term prevention of viral infections and it is used as an effective treatment upon viral infection. The SARS monoclonal antibody targets the S protein RBD on the SARS-CoV envelope. The RBDs in SARS-CoV-2 and SARS-CoV exhibit homology, prompting speculation that SARS monoclonal antibody is effective against COVID-19. A previous study determined that SARS monoclonal antibody CR3022 bound to the SARS-CoV-2 RBD and the epitope of CR3022 in SARS-CoV-2 RBD did not overlap with the ACE2 binding site. It was believed that CR3022—either alone or in combination with other neutralizing antibodies—might act as a therapeutic candidate for the prevention and treatment of SARS-CoV-2 infection. However, some of the strongest SARS-CoV-specific neutralizing antibodies (such as M396 and CR3014) failed to bind to the SARS-CoV-2 spike protein, establishing that differences in the RBD influenced the cross-reactivity of neutralizing antibodies [ 130 ]. It is vital to develop a new monoclonal antibody that can specifically bind to the SARS-CoV-2 RBD.

For patients with rapid disease progression, passive plasma therapy is an effective treatment. WHO recommends the use of convalescent plasma or serum to treat COVID-19 when vaccines or effective antiviral drugs are not available. In China, immune plasma therapy has been clinically effective for patients with severe COVID [ 131 ]. However, a randomized clinical trial [ 132 ] enrolled 103 patients with severe or life-threatening COVID-19 and showed that compared with the standard treatment group, there was no advancement in time to clinical improvement within 28 days after convalescent plasma therapy. This study was terminated early and was an open-label study, which may be underpowered to explore the differences in result. Further research is expected to provide a more accurate evaluation.

Antibody-dependent enhancement is common in various viruses [ 133 ] and it is a focus for vaccine design and passive immunization. Both SARS-CoV and MERS-CoV RBD-specific neutralizing antibodies can mediate antibody-dependent enhancement effects [ 134 ]. Whether SARS-CoV-2 exhibits an antibody-dependent enhancement effect remains to be investigated.

Cell therapy

Cell therapy is expected to emerge as a new way to fight SARS-CoV-2; indeed, projects on stem cell therapy for COVID-19 have been established in China (ChiCTR2000030020). Mesenchymal stem cells have immunomodulatory effects based on their location at the site of inflammation, regulating inflammation-related cytokines and reducing inflammation [ 135 ]. Via paracrine cytokines, they are expected to inhibit the cytokine storm and the overwhelming immune response caused by SARS-CoV-2. Consequently, alveolar epithelial cells and vascular endothelial cells are protected. NK cells can also improve human immunity and exert effective antiviral effects. Recently, Food and Drug Administration approved the use of mesenchymal stem cells to treat severe COVID-19 patients and clinical trial of mesenchymal stem cells in the treatment of COVID-19 has also launched in the UK. However, mesenchymal stem cells and NK cells still have a long way to go before their routine use in clinics.

The outbreak of COVID-19 induced by SARS-CoV-2 has gained much attention worldwide. By June 17, 2020, SARS-CoV-2 infection cases have occurred in as many as 216 countries, areas or territories, and a total of 8,061,550 cases have been confirmed; the scientists are now concentrated on researching the virus for a comprehensive understanding and for the development of preventive and management measures. Here, we summarized the differences between SARS-CoV-2 and SARS-CoV with regards to classification, amino acid composition and protein structure, and epidemiological and pathological characteristics. The pathogenic mechanisms of SARS-CoV-2 have been also discussed. Based on our expertise, we have focused on CVD in patients with COVID-19 and myocardial injury and VTE induced by SARS-CoV-2. Meanwhile, the information of potential medicines and therapies including TCM, chloroquine and hydroxychloroquine, remdesivir, lopinavir/ritonavir and immunomodulatory therapy, and specific immunotherapies and cell therapy have been summarized.

Availability of data and materials

Not applicable.

Abbreviations

Coronavirus disease 2019

Open reading frames

Non-structural proteins

Receptor binding domain

Angiotensin converting enzyme2

World Health Organization

Basic reproduction number

Acute respiratory distress syndrome

Interleukin

• Cardiovascular disease
• Venous thromboembolism

Traditional Chinese medicine

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Acknowledgements

This research was funded by the [National Key R&D Program of China] under Grant [number 2018YFC1602206]; [Yangjiang Science and Technology Program key projects] under Grant [number 2019010]; [Guangzhou Science and Technology Program key projects] under Grant [number 201803040006] and [Guangdong Science and Technology Program key projects] under Grant [number 2018B020207006].

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State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100037, China

Yicheng Yang & Bo Sun

Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, Guangzhou, 510515, China

Yicheng Yang, Xiaoen He, Zhiran Qin, Jianghai Yu, Qinghua Wu, Zhang Bao & Wei Zhao

Department of clinical medicine, Zhengzhou university, 100 Science Avenue, Zhengzhou, 450001, China

Zhiqiang Xiao

Second Clinical Medical College, Southern Medical University, Guangzhou, 510515, China

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Conceptualization, Yicheng Yang, Wei Zhao and Zhiqiang Xiao; validation, Xiaoen He, Zhiran Qin, Jianghai Yu and Qing Hua Wu; writing—original draft preparation, Yicheng Yang, Zhiqiang Xiao and Bo Sun; writing—review and editing, Jingxiu Yao, Wei Zhao and Bao Zhang; funding acquisition, Wei Zhao and Bao Zhang. The authors read and approved the final manuscript.

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Yang, Y., Xiao, Z., Ye, K. et al. SARS-CoV-2: characteristics and current advances in research. Virol J 17 , 117 (2020). https://doi.org/10.1186/s12985-020-01369-z

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DOI : https://doi.org/10.1186/s12985-020-01369-z

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