CHAPTER II

REVIEW OF RELATED LITERATURE

Covid-19 classification

According to [44], SARS-CoV-2 is a novel human-infecting

betacoronavirus. Based on a Phylogenetic analysis of the SARS-CoV-2 genome,

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 [44]. In a further study using the genome sequences of SARS-

CoV-2, RaTG13, and SARS-CoV, the researchers found out that the virus is

more related to BatCoV RaTG13. It is a bat coronavirus that was previously

detected in Rhinolophus affinis from Yunnan Province, with a 96.2% overall

genome sequence identity [45]. In the study of [45], they found out 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. Altogether [44][45], these findings suggest that bats might be the

original host of this virus.

Transmission

The possibility of propagation of the virus in the Huanan Seafood

Wholesale Market is unclear. Many COVID-19 cases were linked to this market,

suggesting that SARS-CoV-2 transmission is from animals to humans [46].

However, a genomic study has provided evidence that the virus came from

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another unknown location where human-to-human transmission may have

occurred earlier [47]. Many infected family members and medical frontlines have

confirmed that the virus can be transmitted person-to-person[48]. Likewise, less

than 10% of patients had market exposure, while more than 70% had no

exposure to the market [46]. Person-to-person transmission can occur among

close contacts mainly via respiratory droplets produced when an infected person

coughs or sneezes. Fomites may be a substantial source of transmission, as

SARS-CoV could persist on surfaces up to 4 days [49] and other coronaviruses

for up to 9 days [50].

Whether or not there is an asymptomatic transmission of the number of

cases is increasing. The first reported asymptomatic transmission was last

January 30, 2020 [51], but later it was found out that the researchers had not

interviewed the patient, who did have symptoms before transmitting disease

[53]. 

The findings of disease characteristics are rapidly changing and subject to

selection bias. A study indicated that the mean incubation period was 5.2 days

(95% confidence interval [95%CI]: 4.1–7.0) [46]. The incubation period is as long

as 19 or 24 days [53], [54], although case definitions typically rely on a 14-day

window [55].

The necessary reproductive number (R0) has varying results and

interpretations. R0 measures the average number of infections that could result

from one infected individual in a fully susceptible population [56]. Studies from

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previous outbreaks found R0 to be 2.7 for SARS [57] and 2.4 for the 2009

pandemic H1N1 influenza [58]. One study estimated that the primary

reproductive number (R0) was 2.2 (95% CI: 1.4–3.9) [46]. However, later in a

further analysis of 12 available studies found that R0 was 3.28 [59]. Because R0

represents an average value, it is also essential to consider the role of

international traveler carriers, who may be hugely responsible for outbreaks

within large clusters but who would not largely influence the value of R0 [60].

During the acute phase of the outbreak or pre-pandemic, R0 may be unstable

[56].

In pregnancy, a study of nine pregnant women who developed COVID-19

in their later days of pregnancy suggested COVID-19 did not lead to substantially

worse symptoms than in non-pregnant persons, and there is no evidence for

intrauterine infection caused by vertical transmission [61].

In a hospital setting, 41% of patients fall under hospital-associated

transmission [62]. Furthermore, another study on 425 patients found that the

proportion of cases in health care workers gradually increased by the time [46].

These cases likely reflect exposure to a higher concentration of virus from

sustained contact in close quarters.

Risk factors

According to [63, 62, 53, 64], SARS-CoV-2 infection incidence prominent

in male adult patients between 34 and 59 years old. People with chronic

comorbidities such as cardiovascular and cerebrovascular diseases and diabetes

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were also at risk [65]. In the research of [62] and [63] found out that adults ≥60

years of age have the highest proportion of severe cases and those with certain

underlying conditions, such as cardiovascular and cerebrovascular diseases and

diabetes. Severe manifestations may also be associated with coinfections of

bacteria and fungi [65].

For children less than 15 years, [63], [62], [53], [64] reported that there

are few COVID-19 cases. In a study of [46], [33] on 425 COVID-19 patients in

Wuhan, which were published on January 29, they found that there were no

cases in children under 15 years of age. Nevertheless, 28 pediatric patients have

been reported by January 2020 [66]. The clinical features of infected pediatric

patients vary, but most have had mild symptoms with good prognosis and no

fever or pneumonia[66]. There was also a study in which the researcher found

that despite the child had radiological ground-glass lung opacities, the child was

asymptomatic [67]. Thus, 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 treatment, leading to underestimating COVID-19

incidence in this age group.

Control measure

Quarantine and isolation measures, as well as useful screening and the

diagnostic tool, was institutionalized to control the spread of COVID-19. Likewise,

the WHO released a guideline on case surveillance of COVID-19 to differentiate

other respiratory infections that may be more common in a local community[55].

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For a person who meets specific criteria, WHO recommends the first screening

for more common causes of respiratory illness, given the season in the country

and location. If the result is negative, the sample is sent to a referral laboratory

for SARS-CoV-2 detection.

Case definitions can vary by country and evolving 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 symptoms such as fever, pneumonia, and low white blood cell count.

After three days, the epidemiological criterion includes contact with anyone who

had a travel history in Wuhan in the past 2 weeks [68]. Later, the case definitions

removed the epidemiological linkage.

The WHO has put forward case definitions [55]. Suspected cases of

COVID-19 are persons with (a) severe acute respiratory infections (history of

fever and cough) and with no other etiology that thoroughly describe the clinical

manifestations, and a history of travel to or residence of China during the 14 days

before symptom onset; or (b) a patient with an acute respiratory illness and at

least one of the following during the 14 days before symptom onset: contact with

a confirmed or probable case of SARS-CoV-2 infection or visited a hospital with

confirmed or probable SARS-CoV-2 acute respiratory disease patients were

being treated. For those for whom testing for SARS-CoV-2 is inconclusive or test

positive, probable cases are tested using a pan-coronavirus assay and without

laboratory evidence of other respiratory pathogens. A confirmed case is one with

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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 a collection of the nasopharyngeal and oropharyngeal swab

and, if possible, the lower respiratory tract (sputum, tracheal aspirate, or Broncho

alveolar lavage) [69]. In other countries, the tests were performed by laboratories

designated by the government.

Treatments

Same with MERS-CoV and SARS-CoV, there is still no specific antiviral

treatment for COVID-19 [70]. Isolation and supportive care, including oxygen

therapy, fluid management, and antibiotics treatment for secondary bacterial

infections, are recommended [71]. Some COVID-19 patients progressed rapidly

to ARDS and septic shock, which was eventually followed by multiple organ

failure [53], [65]. 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 [72].

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 [73].

Neither is a treatment available. Therefore, the management of the

disease has been mostly supportive, referring to the disease severity, which has

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been introduced by the WHO. The empiric antibiotic should be administered

based on clinical diagnosis and local epidemiology and susceptibility information

if there is an identified sepsis. Routine glucocorticoid administration should not

be used unless there is another indication [74]. Clinical evidence also does not

support corticosteroid treatment [75]. The use of intravenous immunoglobulin

might help for severely ill patients [65].

Evaluation of drugs is in line with past investigations into treatments for

SARS and MERS [76]. Overall, there is no robust evidence that these antivirals

can significantly improve clinical outcomes A. Antiviral drugs such as oseltamivir

combined with empirical antibiotic treatment was also used to treat COVID-19

patients [77]. The developed Remdesivir, which is for the Ebola virus, has been

used to treat imported COVID-19 cases in the US [77]. A brief 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 [78]. There is an ongoing clinical trial evaluating the

safety and efficacy of lopinavir-ritonavir and interferon-α 2b in patients with

COVID-19 [71]. Ramsedivir, a broad spectrum antivirus, has demonstrated in

vitro and in vivo efficacy against SARS-CoV-2 and has also initiated its clinical

trial [79], [80]. Other potential drugs from existing antiviral agents have also been

proposed [81], [82].

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