A review of scientific advisor Dr. sc med Vladan Čokić from the Institute for Medical Research, University of Belgrade and a member of MASE on the COVID-19 virus pandemic

Coronavirus disease 2019 (Coronavirus disease 2019: COVID-19)

Vladan P. Čokić
Institute for Medical Research, University of Belgrade

Summary

At the end of 2019, the first cases of viral pneumonia of unknown origin appeared in China. On January 7, 2020, a new coronavirus was identified, which the World Health Organization named Coronavirus disease 2019 (COVID-19) and declared a pandemic on March 11, 2020. The first case of coronavirus was officially confirmed on March 6, 2020 in Serbia. It started on March 15 with public health measures for the prevention of the coronavirus: first, the closing of the state border and home self-isolation, then on March 17, the introduction of a night ban on movement and the all-day outing of pensioners, on March 21, the cancellation of public transport and the ban on gatherings, and on March 23, the opening of collective centers for patients with medical supervision. After a month, on April 6, the number of infected people in Serbia is 2,200 cases with 58 deaths. As of that date, the number of coronavirus detection tests per capita in Serbia is the lowest in the region. COVID-19 has paralyzed life in Serbia, and the goal of this paper is to bring the issues of the pandemic closer to the public in Serbia.

Key words: SARS-CoV-2, COVID-19, Angiotensin Converting Enzyme 2 (ASE2), Epidemic Prevention Measures

Introduction

In the last 20 years, there have been three global epidemics and the current pandemic [1, 2]:
1. Severe acute respiratory syndrome - severe acute respiratory syndrome coronavirus 1 (SARS-CoV-1) from November 2002 to August 2003. It spread to 32 countries, where 8422 people became ill with 916 deaths (10,87%).
2. H1N1 flu in 2009. 201,200 respiratory deaths and 83,300 cardiovascular deaths were estimated, of which 80% deaths were among those under 65 years of age. [3]
3. Middle East respiratory syndrome - Middle East respiratory syndrome coronavirus (MERS-CoV), was discovered in Saudi Arabia from April 2012 to December 2019. It spread to 27 countries, 2496 people became ill with 868 deaths (34,77%).
4. On December 12, 2019, patients with viral pneumonia of unknown origin were reported in Wuhan, China. The new pandemic called coronavirus disease 2019 (COVID-19) is a disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). It has spread to all countries of the world. Until 5/4/2020. it infected 1,268,851 people and led to the death of 69,330 patients (5,46%).

Etiology

Coronaviruses are the largest single-stranded RNA viruses, described for the first time in 1966. They got their name based on their spherical shape with an envelope and protrusions that resemble the Sun's corona (in Latin: corona = crown). [4] The subfamily Orthocoronavirinae has 4 genera [5]:
(a) alpha‐CoVs, cause stomach diseases in humans, dogs, pigs and cats.
(b) beta‐CoVs, attack mammals, and include SARS‐CoV, MERS‐CoV and SARS‐CoV‐2. [6, 7]
(c) gamma‐CoVs, attacks birds. [8]
(d) delta-CoV, attacks birds and mammals. [9]
Genetic analysis of SARS-CoV-2 showed 88% to be similar to 2 types of bat SARS coronavirus, but genetically distant from SARS-CoV (79%) and MERS-CoV (50%). [6] Additional genetic study showed 96% similarities to the third type of bat coronavirus. [10] Phylogenetic studies of SARS-CoV-2 have shown that the closest common ancestor is from 22-24. November 2019 [11]
Population genetic analyzes of the SARS-CoV-2 genome showed 2 types of these viruses [12]:
– L type (∼70%), more frequent, spreading faster and more aggressive, with more mutations,
– S type (∼30%), older and less aggressive.

Epidemiology

SARS, MERS and endemic human coronaviruses can survive on metal, glass or plastic surfaces for up to 9 days. However, they are successfully inactivated by disinfectants such as 70% ethanol, 0.5% hydrogen peroxide or 0.1% sodium hypochlorite in 1 minute. [13] SARS-CoV-2 is more persistent on plastic (7 hours) and stainless steel (6 hours) than on copper and cardboard. SARS-CoV-2 can no longer be found on copper after 4 hours. On cardboard, SARS-CoV-2 does not survive for more than 24 hours. The half-lives of SARS-CoV-2 and SARS-CoV-1 are similar in air, with a median of approximately 1.2 hours [14]. For COVID‐19, the average incubation period is 5.2 to 6.4 days (with a range of 1 to 14 days), while the median incubation period is 3 to 5 days. [15,16] For SARS-CoV, the incubation time is longer than for influenza (up to 5 days compared to only 2 days).[17] There is no noticeable difference between the incubation times for SARS-CoV-2, SARS-CoV (4 days) and MERS-CoV (4.5-5.2 days). [18] A higher viral load of SARS-CoV-2 is present immediately after the onset of symptoms in patients, with a higher viral load in the nose than in the throat. The viral load detected in an asymptomatic patient is similar to that in a symptomatic patient.[19]
In the COVID‐19 pandemic, the most important is the "basic reproductive number" that measures the potential of this disease and represents the average number of people to whom the disease will be transmitted from one infected person in a population that has never been infected before. The base reproduction number for SARS‐CoV‐2 is between 2.24 and 3.58, which is consistent with estimates for SARS‐CoV (from 2 to 5) and MERS‐CoV (from 2.7 to 3.9). The basic reproduction number for seasonal flu usually ranges from 1.2 to 1.4, but it still infects many more people than SARS‐CoV. For smallpox, the basic reproduction number is 12 to 18, and in 2009, for H1N1 flu, it was 1.2-1.6. [5, 16, 20] The basic reproductive number is affected by the duration of infectiousness, the transmissibility of pathogens and the number of susceptible contacts.
There are three main routes of transmission of COVID‐19: droplet, contact and airborne. Droplet transmission occurs when respiratory droplets (created when an infected person coughs or sneezes) are swallowed or inhaled by people in close proximity. Contact transmission occurs when a subject touches a surface or object contaminated with the virus and then touches their mouth, nose, or eyes. Airborne transmission occurs when respiratory droplets mix in the air, forming aerosols, and can cause infection when high doses of aerosols are inhaled into the lungs in a relatively closed environment. [21]

Risk of infection with COVID‐19 [22]:

 - Negligible risk: a person who had a short (<15 minutes) contact with a confirmed case in public areas, such as public transport, restaurants and shops; healthcare personnel who treated a confirmed case while wearing appropriate protective equipment.
- Low risk: a person who has had close (within 1 meter) but brief (<15 minutes) contact with a confirmed case, or distant (> 1 meter) but prolonged contact in public events, or any contact in private events that do not match the criteria of moderate / high exposure risk.
– Moderate / high risk: a person who had prolonged (> 15 minutes) direct contact closer than 1 meter (face-to-face) with a confirmed case, shared the same hospital room, lived in the same household or shared any leisure or professional activity in the immediate vicinity proximity to a confirmed case, traveled together with a confirmed case without appropriate personal protective equipment. Healthcare personnel who treated a confirmed case without wearing appropriate protective equipment.
Adults represent the population with the highest infection rate; however, infants, children and elderly patients can also be infected with SARS‐CoV‐2. In addition, nasopharyngeal infection of hospitalized patients and healthcare workers is also possible in transmission of the virus from asymptomatic patients with COVID‐19 [16].

Pathophysiology

Entry of coronaviruses into host cells is mediated by a transmembrane protrusion, called Ѕ glycoprotein, that forms homotrimers that protrude from the surface of the virus. As a result, entry of coronaviruses into susceptible host cells is a complex process that requires concerted receptor binding and proteolytic processing of Ѕ glycoproteins for virus-host cell fusion to occur. [23] SARS‐CoV‐2 uses the surface receptor angiotensin‐converting enzyme 2 (ASE2) to enter cells, and has a higher affinity for ASE2 receptors than SARS‐CoV, which is consistent with the more efficient spread of SARS‐CoV‐2 between humans. . [6, 23-27] The primary physiological role of ASE2 is in the production of angiotensin, a peptide hormone that controls vasoconstriction, i.e. blood pressure. [25] The entry of SARS-CoV-2 into the cell, dependent on the ASE2 receptor, can be blocked by an inhibitor of a certain cellular protease (TMPRSS2) necessary for interaction with the Ѕ glycoprotein of SARS-CoV-2. [28]
ASE2 expression is significantly increased in patients with type 1 or type 2 diabetes treated with ASE inhibitors and angiotensin II type I receptor blockers, as well as in patients with hypertension. Such therapy, in a feedback loop, leads to increased generation of ASE2 receptors on the surface of cells. Patients with heart disease, hypertension or diabetes, who are treated with drugs that increase ASE2, have a higher risk of severe infection with COVID-19. The ACE2 receptor is highly expressed in the lower respiratory tract, as well as in absorptive enterocytes from the ileum and colon, which coincides with abdominal discomfort and diarrhea in COVID-19. [21, 26]

Clinical picture

The main clinical manifestations of SARS-CoV-2 infection are elevated body temperature (fever - 91.7%), cough (67-75.0%), sore throat (13.9%), shortness of breath (18.6-30%), general weakness (38- 75.0%), diarrhea (3.8%), headache (13.6%), pneumonia. [1,21,29-31] The most common finding on chest imaging in patients with pneumonia is bilateral ground-glass-like opacity (56,4%) or patchy shadowing (51,8%). [16, 30] Computed tomography (CT) scans of the chest usually show abnormal results even in those without symptoms or mild disease. COVID-19 is a mild illness in most people, while in some (usually the elderly and those with comorbidities) it can progress to pneumonia, acute respiratory distress syndrome, and multi-organ dysfunction. The mortality rate is estimated to be 1.4 to 3%. There is a higher prevalence of men with COVID-19 compared to women, however, there are studies with an equal number of female and male patients. [16, 32, 33] Significantly elevated mortality rates included the following patient characteristics: male gender, age over 60 years, primary diagnosis of severe pneumonia, and late diagnosis. [16]
Common laboratory findings for COVID-19 include a normal or low white blood cell count with elevated S-reactive protein (CRP). Lymphopenia (75.4%) and eosinopenia (52.9%) were observed in most patients. [32] Hypertension (17-30.0%) and diabetes mellitus (8-12.1%) are the most common comorbidities, followed by cardiovascular (5%) and respiratory (2%) diseases. [32, 33] Cancer patients have been shown to have a worse outcome if they contract COVID-19. [34]
COVID-19 has not led to the death of pregnant women and there have been no confirmed cases of intrauterine transmission of SARS-CoV-2 from mothers to their fetuses. [35] The most common symptoms of COVID-19 in pregnant women are fever and cough, and the laboratory finding is lymphocytopenia. Pregnancy and childbirth did not worsen the course of symptoms or ST features of COVID-19-induced pneumonia. [36] The median age of infected children was 6.7 years. Fever was present in 41.5% children. Other common symptoms include cough and pharyngeal erythema. Unlike infected adults, most infected children have a milder clinical course. [37]

Therapy

Chloroquine, an old and inexpensive malaria drug, has been shown to have apparent efficacy and acceptable safety in the treatment of pneumonia caused by COVID-19 in clinical trials conducted in China. [7, 38] Chloroquine is known to block virus infection by increasing the endosomal rN required for virus-cell fusion, as well as affecting glycosylation of the SARS‐CoV receptor. In addition to antiviral activity, chloroquine also has immune-modulating activity, which can synergistically enhance its antiviral effect. [39] Chloroquine phosphate has been shown to inhibit the worsening of pneumonia, improve lung imaging findings, support viral clearance, and shorten the course of the disease. [38] Treatment with lopinavir/ritonavir did not significantly accelerate clinical improvement, reduce mortality and the presence of RNA virus in the throat in severely ill patients with COVID-19. [40] Patients in Serbia receive lopinavir/ritonavir and chloroquine for the treatment of COVID-19 in mild and severe respiratory problems.
The case fatality ratio of cases of COVID-19 in China is 1.38% (1.23–1.53), with a significantly higher percentage in those over 60 years old where it is 6.4% (5.7–7.2), and over 80 years old where it is 13.4% (11.2– 15.9). [41] It is also evident that the outcome of SARS‐CoV‐2 pneumonia is highly destructive, despite a mortality rate lower than 3% compared to SARS‐CoV (9.6% mortality rate) and MERS‐CoV (34% mortality rate). [18]

Public health measures to prevent the coronavirus

The primary goal is to prevent the spread of disease between people and to separate people to stop transmission. The measures we have are isolation, quarantine, social distancing and community restriction [42]:

• Isolation is the separation of infected from non-infected persons, in order to protect them, and usually takes place in hospital conditions.
  Quarantine means restricting the movement of persons who are presumed to have been exposed to an infectious disease but are not sick, either because they have not been infected, or because they are still in the incubation period.
• Quarantine can be applied to individuals or a group and usually includes a restriction on leaving the house or a certain facility. Quarantine can be voluntary or mandatory.
• Social distancing is meant to reduce interactions between people in the wider community, where individuals may be contagious but not yet identified and isolated. As diseases transmitted by respiratory droplets require a certain proximity to people, social distancing of people reduces transmission. Social distancing is particularly useful in settings where community transmission is believed to have occurred, but where the links between cases are unclear and where restrictions placed only on exposed individuals are considered insufficient to prevent further transmission. Examples of social distancing include closing schools and business buildings, suspending public markets and canceling gatherings. [43]
• Community-wide containment is an intervention that applies to an entire community, city, or region, and is designed to reduce personal interactions, except for minimal interactions to ensure vital supplies.
  The value of wearing a face mask is controversial to say the least. Surgical masks do not fully protect against airborne viruses because they do not fully cover the nose and mouth. Thus, small droplets, which can travel further than large droplets, and in more unpredictable ways, can be inhaled around the sides of the masks. Since the virus is enveloped, washing your hands with soap and water for at least 30 seconds is helpful in killing SARS-CoV-2. Hand sanitizers can be used if soap and water are not readily available, while touching the eyes, nose, and mouth should be avoided. [5]

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