REVIEW

Epidemiology

As of March 3, 2020, the WHO has confirmed 87,317 cases worldwide [4]. Of these confirmed cases, 2,977 (3.42%) patients have succumbed to the virus [4]. The majority of cases and deaths have been reported in China. Of the total number of cases, 79,968 (92%) patients have been identified in China [4]. Likewise, the majority of fatalities (2,873 [96.5%]) have also been reported in China [4]. It is important to note that confirmed cases are clinically diagnosed and laboratory-confirmed. Outside China, a total of 7,169 cases have emerged in 59 countries. Due to the ongoing nature of the pandemic, the number of cases and involved countries are expected to vary. Table 1 provides a comparison of the epidemiological characteristics of SARS-CoV, MERS-CoV and SARS-CoV-2.

SARS-CoV-2, severe acute respiratory syndrome corona virus 2; SARS-CoV, severe acute respiratory syndrome corona virus; MERS-CoV, Middle East respiratory syndrome corona virus; R0, reproduction number.

Etiology

Corona virus (COV) is a single strand RNA virus with a diameter of 80-120 nm. It is divided into four types: a-corona virus (a-COV), 􀀦-corona virus (􀀦-COV), o-corona virus (o-COV) and y-corona virus (y-COV) [5]. Six corona viruses were previously known to cause disease in humans; SARS-CoV-2 is the seventh member of the corona virus family that infects human beings after SARS-CoV and MERS-CoV [6]. SAR -C V-2, like SARS-CoV and MERS-CoV, belongs to corona virus. The genome sequence homology of SARS-Co V-2 and SARS is about 79%, the 2019-nCoV is closer to the SARS-like bat Co Vs (MG772933) than the SARS-CoV [7], which is descended from SARS-like bat Co Vs. Interestingly, for high similarity of receptor-binding omain (RBD) in Spike-protein, several analyses reveal that SARS-Co V-2 uses angi tension-converting enzyme 2 (ACE2) as receptor, just like as SARS-CoV [8]. Corona virus mainly recognizes the corresponding receptor on the target cell through the S protein on its surface and enters into the cell, then causing the occurrence of infection. A structure model analysis shows that SARS-Co V-2 binds ACE2 with above 10 folds higher affinity than SARS-Co V, but higher than the threshold required for virus infection [9]. The detailed mechanism about whether the SARS-Co V-2 would infect humans via binding of S-protein to ACE2, how strong the interaction is for risk of human transmission, and how SARS-Co V-2 causes pathological mechanisms of organs damage remains unknown, which need more studies to elaborate. These results further explain the more rapid transmission capability of the SARS-CoV-2 in humans than SARS-CoV and the number of confirmed COVID-19 much higher than people with SARS-Co V infection. Considering the higher affinity of SARS-Co V-2 binds ACE2, soluble ACE2 might be a potential candidate for COVID-19 treatment.

CoVs are a large family of RNA viruses that are found diversely in animal species. They are known to cause diseases of the respiratory, hepatic, nervous system, and gastrointestinal systems in humans [3]. Under the electron microscope, they impart a crown-like appearance due to the presence of envelope spike glycoproteins [4]. CoVs belong to the Roniviridae, Arteriviridae, and Corona viridae families [3]. The Corona viridae family can be classified into four genera of alpha-COV, beta-COV, delta-COV, and gamma-COV [4]. Furthermore, beta-COV can be sub-divided into 5 lineages [5]. Gene characterization has helped identify that bats and rodents are the gene source of alpha-COV and beta-COV [4]. On the other hand, avian species are deemed as genetic sources of delta-COV and gamma-COV [4].

CoVs are responsible for 5-10% of acute respiratory infections [3]. It has been estimated that 2% of the population are deemed healthy carriers of these viruses [3]. Some common human CoVs include HCoV-OC43, HCoV-HKU1, HCoV-229E, and HCoV-NL63 [4]. In the immune competent, these CoVs clinically present with self-limiting respiratory infections and common colds [4]. In the elderly and immune compromised, they can involve the lower respiratory tracts [4]. Other human CoVs such as MERS-CoV, SARS-CoV, and SARS-CoV-2 present with pulmonary and extra-pulmonary features [4].

SARS-CoV-2, which is responsible for the COVID-19 pandemic, is a type of beta-COV. Genomic characterization studies of the new strain have indicated an 89% nucleotide match with bat SARS-like CoVZXC21 [3,6]. There is also an 82% nucleotide match with the human SARS virus [6]. Therefore, these findings form the basis for the new strain to be called SARS-CoV-2. It has a full genomic length of 29,891 to 29,903 nucleotides. The virus is sensitive to ultraviolet light and heat [4]. SARS-CoV-2 bind to their target cells through angiotensin-converting enzyme 2 (ACE2), which is expressed in the lungs. Furthermore, these viruses can be functionally inactivated with the use of ethanol (60%), ether (75%), and chlorine-containing disinfectants.

Transmission

The initial cases were presumably linked to direct exposure to infected animals (animal-to-human transmission) at a seafood market in Wuhan, China. However, clinical cases with diversity in exposure history have emerged. This helps further elaborate that human-to-human transmission of the virus is also possible. Therefore, human-to-human transmission is now considered the main form of transmission. Individuals who remain asymptomatic could also transmit the virus [4]. However, the most common source of infection is symptomatic people. Transmission occurs from the spread of respiratory droplets through coughing or sneezing [4]. Data also suggest that close contact between individuals can also result in transmission [7]. This also indicates possible transmission in closed spaces due to elevated aerosol concentrations [4].

SARS-CoV-2 has a basic reproduction number of 2.2 [4]. This suggests that a patient can transmit the infection to two other individuals. Current data suggest that the virus has an incubation period of three to seven days [8]. These findings are based on initial cases. Therefore, further studies are needed to address transmission dynamics and incubation times. 

CLINICAL FEATURES

COVID-19 manifests with a wide clinical spectrum ranging from asymptomatic patients to septic shock and multiorgan dysfunction [4]. COVID-19 is classified based on the severity of the presentation [4]. The disease may be classified into mild, moderate, severe, and critical [9]. The most common symptoms of patients include fever (98.6%), fatigue (69.6%), dry cough, altered sense of smell/taste, anorexia and diarrhoea [9].

Mild disease

Patients with mild illness may present with symptoms of an upper respiratory tract viral infection [4]. These include dry cough, mild fever, nasal congestion, sore throat, headache, muscle pain and malaise [4]. It is also characterized by the absence of serious symptoms such as dyspnea. The majority (81%) of COVID-19 cases are mild in severity [9]. Furthermore, radiograph features are also absent in such cases [9]. Patients with mild disease can quickly deteriorate into severe or critical cases.

Moderate disease

These patients present with respiratory symptoms of cough, shortness of breath, and tachypnea [4]. However, no signs and symptoms of severe disease are present.

Severe disease

Patients with severe disease present with severe pneumonia. acute respiratory distress syndrome (ARDS), sepsis, or septic shock [4]. Diagnosis is clinical and complications can be excluded with the help of radiographic studies. Clinical presentations include the presence of severe dyspnea, tachypnea (respiratory rate > 30/min), respiratory distress, SpO2 ≤ 93%, PaO2/FiO2 < 300, and/or greater than 50% lung infiltrates within 24 to 48 h [4]. Even in severe forms of the disease, fever can be absent or moderate [4].

In addition, 5% of patients can develop a critical disease with features of respiratory failure, RNAaemia, cardiac injury, septic shock, or multiple organ dysfunction [4,9]. Data from the Chinese Centres for Disease Control and Prevention (CDC) suggest that the case fatality rate for critical patients is 49% [4]. Patients with pre-existing comorbidities have a higher case fatality rate. These comorbidities include diabetes (7.3%), respiratory disease (6.5%), cardiovascular disease (10.5%), hypertension (6%) and oncological complications (5.6%) [9]. Patients without comorbidities have a lower-case fatality rate (0.9%) [9].

Potential risk factors that have been identified to date include:

·         Age

·         Race/ethnicity

·         Gender

·         Some medical conditions

·         Use of certain medications

·         Poverty and crowding

·         Certain occupations

·         Pregnancy

Acute Respiratory Distress Syndrome

The development of ARDS indicates new-onset or worsening respiratory failure. It occurs as a complication within one week of known clinical insult. The values of PaO2/FiO2 are used to distinguish ARDS based on varying degrees of hypoxia. PaO2/FiO2 ≤ 100 mm Hg is indicative of severe ARDS [4]. PaO2/FiO2 values between 100 mm Hg and 200 mm Hg are diagnostic for moderate ARDS [4]. PaO2/FiO2 values between 200 mmHg and 300 mmHg support the diagnosis of mild ARDS [4]. Levels of AST (aspartate transaminase) and ALT (alanine transaminase) at the time of admission correlate with clinical deterioration to ARDS. Therefore, higher levels at admission result in rapid clinical deterioration to ARDS.

In addition to the clinical and ventilatory criteria, chest imaging modalities such as chest X-ray, computed tomography (CT) scan, and lung ultrasound can be used to support the diagnosis. The most frequent finding on CT scan includes ground-glass opacity (86%), consolidation (29%), crazy paving (19%), bilateral disease distribution (76%), and peripheral disease distribution (33%) [10]. It is important to note that a chest X-ray has a lower sensitivity (59%) to detect subtle opacities. A CT scan can further detect mediastinal lymphadenopathy, nodules, cystic changes, and pleural effusion. The aforementioned abnormalities might be detectable before the onset of symptoms.

Sepsis and septic shock

Patients with COVID-19 and sepsis are deemed the most critical of them all. The accompanying multiorgan dysfunction results as a consequence of dysregulated host response to infection. Signs of organ dysfunction include severe dyspnea, low oxygen saturation, reduced urine output, tachycardia, hypotension, cold extremities, skin mottling, and altered mentation [4]. Laboratory evidence of other homeostatic dysregulation includes acidosis, high lactate, hyperbilirubinemia, thrombocytopenia, and evidence of coagulopathy [4].

Patients with septic shock are persistently hypotensive despite volume resuscitation. They may also have an accompanying serum lactate level of >2 mmol/L.

LABORATORY FEATURES

Laboratory findings specific to COVID-19 include elevated prothrombin time, LDH (lactate dehydrogenase), D-dimer, ALT, C-reactive protein (CRP), and creatine kinase [9]. In the early stages of the disease, a marked reduction in CD4 and CD8 lymphocytes can also be noted [9]. Patients in the intensive care unit have shown higher levels of interleukin (IL) 2, IL-7, IL-10, GCSF (granulocyte colony-stimulating factor), IP10 (interferon gamma-induced protein 10), MCP1 (monocyte chemotactic protein 1), MIP1A (macrophage inflammatory protein alpha), and TNF-α (tumor necrosis factor-α) [11]. They also displayed other abnormal findings indicative of coagulation activation, cellular immune deficiency, myocardial injury, renal injury, and hepatic injury [9]. In critical patients, amylase and D-dimer levels are significantly elevated [4,11]. However, blood lymphocyte counts progressively decreased [4,11]. Common to non-survivors are the elevations in ferritin, neutrophil count, D-dimer, blood urea, and creatinine levels [12]. Elevations in procalcitonin levels are not a feature of COVID-19. Therefore, an elevated level of procalcitonin may suggest an alternative diagnosis such as bacterial pneumonia. Levels of CRP correlate directly with disease severity and progression.

DIAGNOSIS

The U.S. CDC has developed criteria for persons under investigation (PUI) [4]. If a person is deemed a PUI, immediate prevention and infection control measures are undertaken. Epidemiological factors are used to assess the requirement of testing. These include close contact with a laboratory-confirmed patient within 14 days of symptoms or travel history to an infected area within 14 days of symptom onset [4].

The WHO recommends collecting samples from both the upper and lower respiratory tracts. This can be achieved through expectorated sputum, bronchoalveolar lavage, or endotracheal aspirate [4]. These samples are then assessed for viral RNA using polymerase chain reaction (PCR). If a positive test result is achieved, it is recommended to repeat the test for re-verification purposes. A negative test with a strong clinical suspicion also warrants repeat testing. Furthermore, Zhang F of MIT developed ate t paper for rapid detection of SARS-Co V-2 in one hour by SHERLOCK technology. Although the clinical verification has not been carried out yet, this technology, once proved, might be conducive to rapid diagnosis of the disease [12]. A research group f Peking University claimed to have developed a new method for rapid construction of transcriptome sequencing library of SHERRY, which is helpful for rapid sequencing ofSARS-CoV-2 [13].

MANAGEMENT

Isolation remains the most effective measure for containment of COVID-19. No specific anti-viral medication or vaccine is currently available [4]. Therefore, the treatment of COVID-19 includes symptomatic care and oxygen therapy. Patients with mild infections require early supportive management. This can be achieved with the use of acetaminophen, external cooling, oxygen therapy, nutritional supplements and anti-bacterial therapy [9]. Critically ill patients require high flow oxygen, extracorporeal membrane oxygenation (ECMO), glucocorticoid therapy, and convalescent plasma [9]. The administration of systemic corticosteroids is not recommended to treat ARDS [4]. Moreover, unnecessary administration of antibiotics should also be avoided. ECMO should be considered in patients with refractory hypoxemia despite undergoing protective ventilation [4]. Patients with respiratory failure may require intubation, mechanical ventilation, high-flow nasal oxygen, or non-invasive ventilation [4]. Treatment of septic shock requires hemodynamic support with the administration of vasopressors. Organ function support is necessary for patients with multiple organ dysfunction [4].

Therapeutically, aerosol administration of alpha-interferon (5 million units twice daily), chloroquine phosphate, and lopinavir/ritonavir have been suggested [4]. Other suggested anti-virals include ribavirin and abidor [9]. The use of three or more anti-viral drugs simultaneously is not recommended. Ongoing clinical studies suggest that remdesivir (GS5734) can be used for prophylaxis and therapy [4]. Furthermore, a fusion inhibitor targeting the HR1 domain of spike protein is reported to have the potential to treat COVID-19.

Synthetic recombinant interferon a has proven to be effective in treatment of SARS patients in clinic trials [15]. Pulmonary X-ray abnormal remission time was reduced by 50% in the interferon-treated group compared with the glucocorticoid-treated group alone. Interferon was also found to be an effective inhibit r ofMERS-Co V replication [16]. Those findings suggested that interferon could be ed in the treatment of COVID-19. Intravenous immunoglobulin might be the safest immunomodulator for long-term use in all ages, and could help to inhibit the production of pro inflammatory cytokines and increase the production of anti-inflammatory mediators [17]. Moreover, Thymosin alpha-1 (Tal) can be an immune booster for SARS patients, effectively controlling the spread of disease [18]. Intravenous immunoglobulin and Tal may also be considered as therapeutics for COVID-19.

Convalescent plasma therapy

When there are no sufficient vaccines and specific drugs, convalescent plasma therapy could be an effective way to alleviate the course of disease for severely infected patients [19]. In a retrospective analysis, convalescent plasma therapy is more effective than severe doses of hormonal shock in patients with severe SARS, reducing mortality and shortening hospital stays [20]. A prospective cohort study by Hung and colleagues showed that for patients with pandemic HlNl influenza virus infection in 2009, the relative risk of death was significantly lower in patients treated with convalescent plasma [21]. Moreover, from the perspective of immunology, most of the patients recovered from COVID-19 would produce specific antibodies against the SARS-Co V-2, and their serum could be used to prevent reinfection. At the same time, antibodies can limit the virus reproduction in the acute phase of infection and help clear the virus, which is conducive to the rapid recovery of the disease [22]. Theoretically, viremia peaks during the first week of most viral infections, and it should be more effective to give recovery plasma early in the disease [23]. Therefore, the plasma of some patients recovered from COVID-19 could be collected to prepare plasma globulin specific to SARS-Co V-2. However, the safety f plasma globulin products specific to SARS-Co V-2 deserves further consideration. Auxiliai1·blood purification treatment. At present, extracorporeal blood purification technology in the treatment of severe NCP patients. According to the latest studies [24], ACE2, the key receptor ofSARS-CoV-2, is highly expressed in human kidney (nearly 100 times higher than that in lung). Kidney might be main target of attack for novel corona virus. Early continuous blood purification treatment could reduce renal workload and help to promote the recovery of renal function [25]. Most of the severe patients with novel corona virus might suffer from cytokine storm. The imbalance of pro-inflammatory factors and anti-inflammatory factors might cause immune damage. Therefore, blood purification technology could be used to remove inflammatory factors, eliminate cytokine storm, correct electrolyte imbalance, and maintain acid-base balance, to control patient's capacity load in an effective manner [26]. In this logic, the patient's symptoms could be improved and the blood oxygen saturation could be increased.

In summary, the drug treatment for COVID-19 mainly comprised four ways, i.e., antiviral Western medicine, Chinese medicine, immune enhancement therapy, and viral specific plasma globulin. Machines could be used as auxiliary therapy. Howe r, randomized double-blind large sample clinical trial should be served as the standard to determine whether the antiviral drugs could be used in clinical practice.

PREVENTION

Preventive measures must focus on optimizing infection control protocols, self-isolation, and patient isolation during the provision of clinical care. The WHO has advised against close contact with patients, farm animals, and wild animals [4]. Dr. Tedros, director-general of WHO, said th t novel corona virus vaccine was expected to be ready in 18 months. In addition, SARS-Co V-2 is an RNA virus. RNA virus related vaccines, including measles, polio, encephalitis B virus and influenza virus, could be the most promising alternatives. And interpersonal transmission of the virus could be prevented by immunizing health care workers and non-infected population [66]. Patients and the general public must cover coughs and sneezes to help prevent aerosol transmission. Frequent hand washing with soap and water is also required. As an alternative measure, hand sanitizers can also be used. Immunocompromised individuals are advised to avoid public gatherings. Emergency medicine departments must apply strict hygiene measures for the control of infections. Healthcare personnel must use personal protective equipment such as N95 masks, FFP3 masks, gowns, eye protection, gloves, and gowns.

CONCLUSION

The COVID-19 pandemic is spreading across the globe at an alarming rate. It has caused more infections and deaths as compared with SARS or MERS. Based on R0 values, it is deemed that SARS-CoV-2 is more infectious than SARS or MERS. Elderly and immune compromised patients are at the greatest risk of fatality. The rapid spread of disease warrants intense surveillance and isolation protocols to prevent further transmission. No confirmed medication or vaccine has been developed. The most likely source of SARS-Co V-2 is bats. This virus is highly infectious and can be transmitted through droplets and close contact. Some patients are life-threatening and such disease has posed a great threat to global health and safety, so to control the spread of the epidemic and reduce the mortality as soon as possible is our burning issue. But by far, the specific mechanism of the virus remains unknown, and no specific drugs for the virus have been developed. At present, it is important to control the source of infection, cut off the transmission route, and use the existing drugs and means to control the progress of the disease proactively. We should also strive to develop specific drugs, promo the research and development of vaccines, and reduce morbidity and mortality f the disease, so as to better protect the safety of people's lives. Current treatment strategies are aimed at symptomatic care and oxygen therapy. Prophylactic vaccination is required for the future prevention of COV-related epidemic or pandemic.