Coronavirus disease 2019 (COVID-19) is a newly emerged disease that has become a global public health concern as it rapidly spread around the world. This disease first appeared in Hubei province of China and it follows human-to-human transmission but the path this virus took to set up human infection remains a mystery. By 17 April 2020, there have been 2,074,529 confirmed cases with 139,378 deaths because of COVID-19. SARS-CoV-2 shows several similarities with SARS‐CoV and MERS‐CoV with its clinical presentations. This can vary from asymptomatic infection to severe disease and mortality. rRT-PCR screening is considered as the standard laboratory test for the diagnosis of COVID-19. There is no proven antiviral agent against SARS-CoV-2 so the treatment for COVID-19 is symptomatic, aiming for the management of the symptoms and prevention of the complications. The outbreak of COVID-19 has led to the implementation of extraordinary public health measures throughout the world. Numerous antiviral compounds used for treating other infections are being clinically researched in pursuit of possible treatment. Similarly, the traditional public health outbreak response strategy of isolation, quarantine, social distancing and community containment has been implemented in multiple countries and has played an important role in the prevention of new outbreaks. This review aims to enhance our understanding of COVID 19.
INTRODUCTION
In December 2019, a local outbreak of pneumonia of unknown etiology was detected in Wuhan City, Hubei Province of China. World Health Organization (WHO) declared the COVID-19 outbreak as a pandemic on 11 March 2020. By 17 April 2020, there have been 2,074,529 confirmed cases from over 200 countries and territories with 139,378 deaths.
Etiology
Coronavirus is the virus belonging to the subfamily family Coronaviridae which is an enveloped virus with a single strand, positive-sense RNA genome. The emergence of the SARS-CoV resulted in a global outbreak of pneumonia in 2003 which affected 8096 people in approximately 30 countries and resulted in about 774 deaths with a case-fatality rate of 9.6 percent. Ten years after the outbreak of SARS-CoV in 2012 another highly pathogenic coronavirus was discovered in Saudi Arabia; this was called Middle East Respiratory Syndrome Coronavirus (MERS-CoV) as it emerged in Middle Eastern countries. By the end of November 2019, there were 2494 confirmed cases of MERS-CoV accounting for 856 deaths demonstrating a case-fatality rate of 34.4 percent.
In December 2019, a local outbreak of pneumonia of unknown etiology was detected in Wuhan city of Hubei Province in China. The Chinese Center for Disease Control and Prevention (CCDC) dispatched a rapid response team to conduct an epidemiologic and etiologic investigation in Hubei on 31 December 2019. It was observed that the virus genome was 85% identical with bat SARS-like CoV and the isolated virus was named 2019 novel coronavirus (2019-nCoV).
Prior studies suggested that all human coronaviruses have animal origins and considered to have originated in bats while HCoV-OC43 and HKU1 likely originated from rodents. The International Committee on Taxonomy of Viruses (ICTV) announced that the name of 2019 novel coronavirus as SARS-CoV-2 and WHO announced the name of the disease caused by this novel virus (COVID-19) on 11 February 2020.
Epidemiology
In December 2019, a cluster of patients was admitted to the hospitals in Wuhan with unknown etiology of pneumonia. These patients were epidemiologically linked to the seafood and wet animal wholesale market of Wuhan. On 3 January 2020, the Chinese Government notified WHO about the epidemic which was later confirmed to be 2019-nCoV. The number of cases increased rapidly in China and outside and WHO declared the COVID-19 outbreak as a pandemic on 11 March 2020. By 17 April 2020, there have been 2,074,529 confirmed cases with 139,378 deaths (Table 1).
Table 1: Confirmed cases and deaths of COVID-19 in WHO Regions on April 17, 2020.
| Region | Confirmed Cases | Deaths |
| European Region | 1,050,871 | 93,480 |
| Region of the Americas | 743,607 | 33,028 |
| Western Pacific Region | 127,595 | 5558 |
| Eastern Mediterranean Region | 115,824 | 5662 |
| South-East Asia Region | 23,560 | 1051 |
| African Region | 12,360 | 586 |
| Globally | 2,074,529 | 139,378 |
Figure 1: Geographic distribution of COVID-19 cases worldwide as of April 17, 2020.
The COVID-19 is transmitted only through human-to-human. The main route of transmission is respiratory droplet and close contact. Droplet transmission may occur through close contact, tears as well as from the fomites in immediate surroundings of the infected person. The average incubation period is estimated to be five days with a range from 1 to 14 days. The symptoms can be experienced within 11 to 12 days of contact with SARS-CoV-2 in 95% of the patients. However, in case of the asymptomatic carrier of COVID-19 it has been noted that there can be 19 days of incubation period.
Clinical Features
The COVID-19 showed several similarities with the SARS‐CoV, and MERS‐CoV, in regards to the clinical presentations, which can vary from asymptomatic infection to severe disease. SARS-CoV-2 affects people in different ways as it has a wide range of signs and symptoms that infected persons might experience. The most common symptoms of the COVID-19 include fever, dry cough, lethargy and fatigue, muscle pains, and productive cough which are similar to that of SARS-CoV and MERS-CoV infection. Some patients might also experience symptoms like aches and pains, nasal congestion, runny nose, sore throat or diarrhea. These symptoms are usually mild and begin gradually. Some of the people might not develop any symptoms and be may remain well. Most of the infected people (nearly 80%) might not need any special treatment while around one out of every six people might become seriously ill and develops difficulty in breathing. Elder people, with underlying medical problems like high blood pressure, heart problems or diabetes, chronic obstructive pulmonary disease (COPD) and immunodeficiency are more likely to develop serious illnesses. The people with fever, cough and difficulty breathing should seek early medical attention.
Diagnosis
Diagnosis of COVID-19 is ultimately confirmed by real-time reverse transcription-polymerase chain reaction (rRT-PCR) on respiratory samples. As there is primary involvement of the respiratory system in COVID-19, a chest computed tomography (CT) is strongly recommended in suspected cases, for both initial evaluation and follow-up. rRT-PCR screening is considered as the standard laboratory test for diagnosis of COVID-19, but it may yield a false-negative result in some cases. In the early stage of the disease, several cases with false-negative RT-PCR results were reported probably because of inadequate viral loads in the sample/technical issues during nucleic acid extraction. In such cases with typical clinical manifestations, chest CT may prove to be an invaluable asset because it may show characteristic features of the disease even when the RT-PCR screening test is negative. The viral RNA was detected at a different rate when rRT-PCR were performed in 1070 specimens (Table 2).
Table 2: Detection result of clinical specimens by rRT-PCR by Wang et al.
| Specimens | Positive result No. (%) | Cycle threshold, mean (SD) | Range | 95% CI |
| Bronchoalveolar lavage fluid (n=15) | 14 (93) | 31.1 (3.0) | 26.4-36.2 | 28.9-33.2 |
| Fibrobronchoscope brush biopsy (n-13) | 6 (46) | 33.8 (3.9) | 26.9-36.8 | 29.8-37.9 |
| Sputum (n=104) | 75 (72) | 31.1 (5.2) | 18.4-38.8 | 29.3-33.0 |
| Nasal swabs (n=8) | 5 (63) | 24.3 (8.6) | 16.9-38.4 | 13.7-35.0 |
| Pharyngeal swans (n=398) | 126 (32) | 32.1 (4.2) | 20.8-38.6 | 31.2-33.1 |
| Feces (n=153) | 44 (29) | 31.4 (5.1) | 22.3-38.4 | 29.4-33.5 |
| Blood (n=307) | 3 (1) | 34.6 (0.7) | 34.1-35.4 | 0.0-36.4 |
| Urine (n=72) | 0 | No data |
Drugs and Vaccines under Trials
The WHO stated that as of April 18, 2020, there are no known vaccines and anti-viral treatments that can be used in the prevention and treatment of COVID- 19. Possible vaccines and some specific drugs are under investigation, and may take a minimum of 12 to 18 months may require to develop the vaccines. Several antiviral compounds used in treating other infections are being clinically researched in pursuit of any possible treatment for COVID-19. WHO has initiated a large global trial “Solidarity trial” in collaboration with more than dozens of countries to compare the safety and effectiveness of four different drugs or drugs combination against COVID-19. Studies suggested that lopinavir/ritonavir can be used for the treatment of COVID-19. Two tablets of lopinavir 200 mg/ritonavir 50 mg was provided to the patients for eight days in South Korea. It was observed that from the next day of lopinavir/ritonavir administration, β-coronavirus viral load started to decrease and no detectable/little coronavirus titers were observed after administration of the drug. Though there was a reduction in viral load, the researchers were not certain if it was due to the administration of lopinavir/ritonavir or due to the natural course of the healing process, or both. Studies suggest that chloroquine (anti-malarial drug) seems to have potential broad-spectrum antiviral activities as it increases endosomal pH required for virus/cell fusion, as well as interferes with the glycosylation of cellular receptors of SARS-CoV so, it is suggested that chloroquine may have potential for treating COVID-19 pneumonia because of its anti-viral and anti-inflammatory properties.
Though several drugs are under clinical trials, it should be considered either the drug does more harm to the patient than benefiting them. In the context of SARS-CoV-2, majority of the patients who died were elderly and people with comorbidities such as cardiovascular disease, chronic obstructive pulmonary disease, diabetes and other comorbidities. In these cases, use of chloroquine/hydroxychloroquine, lopinavir-ritonavir and azithromycin could increase the risk of cardiac death. At the time of SARS-CoV and MERS-CoV, it was observed that the use of intravenous steroids as anti-inflammatory therapy was associated with delayed clearance of coronavirus from blood and lungs as well as the steroids were associated with increased risk of secondary infection of influenza and mortality. Studies suggest that the rapid and simultaneous combination of supportive care and randomized controlled trials (RCTs) are the only way to find effective and safe treatments for COVID-19 and any other future outbreak. As Bacille Calmette-Guerin (BCG) vaccine against tuberculosis is known to produce a series of beneficial immune responses, some countries have undertaken BCG vaccine trials to see if it can help reduce the prevalence and severity of COVID-19 symptoms. A subgroup of patients with severe COVID-19 might have a cytokine storm syndrome and use of steroids and anti–IL-6 inhibitors for prevention of cytokine storm may be beneficial but clinical trial results are awaited.
Management
As there are no recommended medicines for COVID-19, the treatment is symptomatic for the management of the symptoms and prevention of the complications. Oxygen therapy is represented as a major treatment intervention for patients with severe infection. Mechanical ventilation may be necessary in cases of respiratory failure refractory to high flow oxygen therapy, whereas hemodynamic support is essential for managing septic shock. Some evidence suggests that intravenous high-dose vitamin C treatment can benefit the treatment of sepsis and septic pneumonia which seems to be a lung injury caused by hyper-activation of immune effector cells. Similarly, the convalescent plasma therapy is also under trial that could be effective against COVID-19 as it was used for the SARS, influenza A (H1N1), avian influenza A (H5N1) and other viral infections. Plasma was transfused to five critically ill patients and the viral loads were found to have decreased and become negative within 12 days after the transfusion, while SARS-CoV-2–specific ELISA and neutralizing antibody titers increased after the transfusion.
Preventive Measures
People who are in closed contact with the COVID-19 patients are at a high risk of the infection. WHO has suggested some of the actions which are believed to be the most effective preventive measures in the community. These actions include frequent hand hygiene with an alcohol-based hand rub if your hands are not visibly dirty or with soap and water if hands are dirty; avoiding touching your eyes, nose, and mouth; practicing respiratory hygiene by coughing or sneezing into a bent elbow/tissue and then immediately disposing of the tissue; wearing a medical mask if you have respiratory symptoms and performing hand hygiene after disposing of the mask and maintaining social distance (minimum one meter). Hand washing and maintaining personal hygiene and the use of N95 masks were found to be effective to protect it.
The medical professionals caring for patients with COVID-19 are at high risk of acquiring the infection. The high risk of transmission of acute respiratory infections is due to aerosol-generating procedures, such as non-invasive ventilation (NIV), a high-flow nasal cannula (HFNC), bag-mask ventilation, and intubation. So, the medical personnel who are involved in the management of COVID-19 patients or suspected cases must follow airborne precautions, hand hygiene and use of personal protective equipment (PPE). Ensuring the safety of the health-care providers is essential to take some aggressive measures such as the use of N95 masks, goggles, face visor and protective gowns during the outbreak. Some of the protective masks designed to achieve a very close facial fit and extremely efficient filtration of airborne particles (up to 0.3 μm) that can be inhaled through the nose/mouth are N95, filtering facepiece (FFP2), or FFP3 respirator. It is suggested that using a protective mask alone is inadequate to eliminate the risk of transmission of the virus among the hospital workers. The inconsistent use of PPE increases the risk of transmission. The WHO has suggested guidelines for the rational use of PPE for COVID-19 in health care and community settings. Due to the rapid spread of COVID-19, there has been an acute shortage of PPE, especially in the regions that are hit hard by the disease. Similarly, there is also a shortage of ICU beds, ventilators, other medical supplies.
Response to the Pandemic
It has been suggested that in the absence of any pharmaceutical intervention, the strategy against COVID-19 is to lessen the mixing of susceptible/infectious people through early identification of cases or limiting their contact. The outbreak of COVID-19 has led to the implementation of extraordinary public health measures throughout the world. After the epidemic of COVID-19 in Hubei; China focused on traditional strategies of quarantine, isolation, community containment and social distancing. They took some extensive measures including the closing of schools, roads and transit systems, workplaces, control of public gatherings, and compulsory quarantine of uninfected general public without known exposure to SARS-CoV-2, along with large-scale electronic surveillance to ensure compliance. An estimated 40 to 60 million populations of Wuhan City and 15 other closed cities were put into community containment measures. South Korea also took extensive measures to screen the population for the virus, and isolate any infected people. They also used extensive contact tracing and used quarantine measures with electronic tracking on those who have contact with infected people. Learning from the SARS epidemic of 2003, the rapid and extensive measures taken by South Korea has been taken as a successful measure to limit the outbreak. Likewise, Taiwan, Hong Kong, and Singapore proactively implemented travel restrictions on passengers coming from the mainland even while the WHO stated at that time that travel bans were not necessary. Taiwan had established a central command center for epidemic after the 2003 SARS epidemic, the center quickly took actions such as border controls, the closing of schools and workplaces, public communication plans and resource assessments of hospitals which helped to limit the spread of COVID 19. These measures have played an important role to prevent the outbreaks.
Similarly, various strategies were adopted by these countries to tackle the COVID 19 crisis. South Korea tested hundreds of thousands of people for infection and tracked the potential carriers while Italy started out testing widely, then narrowed the focus. Both of these countries saw their first cases of infection in late January and by 17 April 2020, Italy had 168,941 confirmed cases with 22,172 deaths while South Korea limited COVID-19 infection to total 10,635 confirmed cases and 230 deaths. Epidemiologists advise the direct comparison of numbers is not possible as many other contributing factors should be analyzed but the visible difference in numbers of cases points out that the extensive and sustained testing is a potent tool to combat the virus.
The COVID-19 outbreak is a global health emergency with an increasing number of cases and deaths globally. Though there have been on-going research and clinical trials for the prevention and treatment of COVID-19, there is no effective medicine or vaccine currently available for it. In absence of any medical treatment for the control of viral infection, measures such as social-distancing and community containment which could help to reduce the mixing of susceptible and infectious people with healthy communities have been a major strategy to prevent the outbreaks. In the meantime, the suspected persons should be kept in quarantine and patients should be kept in isolation provided with proper symptomatic treatment and supportive care for the prevention of further complications and mortality.