Coronavirus and COVID-19 outbreak

Introduction 

Coronaviruses (CoV) are a large family of diverse group of RNA viruses belonging to the family of Coronaviridae and the order Nidovirales that can infect birds and mammals, including humans. They are divided in 4 genera: alpha, beta, gamma and delta that cause disease in human and animals (1).   Most human coronavirus infections that have been recognized in the last two decades have caused  illness ranging from the common cold to more severe pandemics such as Severe Acute Respiratory Syndrome (SARS-CoV), Middle-East Respiratory Syndrome (MERS-CoV) and a novel coronavirus disease (COVID-19) from a new strain of virus that had not been previously identified in humans. In addition, there are 4 more different serotypes such as OC43and HKU1 belonging to alphacoronavirus and 229E and NL63, belonging to betacoronavirusesresponsible for mild respiratory symptoms similar to common cold (1). These cold viruses have not jumped from animals to human beings, and they utilize humans as their primary hosts. It is worth noting that those coronaviruses which have jumped from animals to humans appear to cause more severe illness in human. Coronaviruses get transmitted between humans through respiratory droplets that are expelled when the infected person breathes, coughs or sneezes.

Structure

Coronaviruses are enveloped, non-segmented, particles. They are spherical and the core beneath the greasy surface contains matrix protein enclosed within which is a single strand of positive-sense RNA. The genetic material in the core can inject into vulnerable cells to infect them. There are spiky glycoprotein projections on the outer surfaces of the envelope, resembling the points of a crown or a halo. The viruses are named coronaviruses because of the crown-like (or ‘corona’ in Latin) appearance of their virus particles when seen under an electron microscope.  The spikes bind and fuse with host-cell receptors and facilitate the entry of the virus into the host cell. On entry into the cell it gets uncoated and the genome gets transcribed and then translated to the new host and begins to replicate. The genetic material of the virus becomes host cell’s internal machinery. The cells are converted into a factory. New virions bud from host cell membrane.

Transmission

Coronaviruses are zoonotic and are transmitted between animals and humans. They appear to jump easily between species.  Investigations have suggested that the virus has passed through an intermediate animal before infecting humans. SARS-CoV has jumped from bats to civet cats (small nocturnal mammal) on its way to humans and MERSCoV from Arabian (dromedary) camels to humans. There are still many coronaviruses circulating in animals which have not infected humans.

Coronaviruses cannot survive for more than a few hours on surfaces outside a human host. However, persons can pick up the virus from a contaminated surface for a short period of time.

Covid-19 Infection

World Health Organization (WHO) has declared International Health Emergency following reports of a number of cases Pneumonia from Wuhan, China and subsequently in other countries. The condition is due to an infection from a corona (crown-like or hollow shape) virus (2019-nCoV) (Fig.1).

Coronaviruses are a family of viruses that cause illness ranging from the common cold to more severe diseases such as severe respiratory distress syndrome (SARS) and Middle-East respiratory syndrome (MERS).

Aetiology

The causative agent is a virus that causes upper respiratory tract infection and pneumonia. It is an enveloped RNA virus found in birds, animals and human being.  Under electron microscope, the image of the virus is a reminiscent of a solar corona. Earlier the World had witnessed outbreaks of two serious corona virus (CoV) infections, namely Severe acute respiratory syndrome (SARSCoV) and Middle-East respiratory syndrome (MERS-CoV). The outbreak of SARS which made its appearance in Southern China in 2002 spread to 30 counties. It infected 8437 persons and killed 813 persons. MERS which appeared in Saudi Arabia in 2012 spread to 27 countries. There were 2492 confirmed cases of whom 858 died.  MERS has been considered more deadly as there were deaths in 30% of cases who were infected.  The current novel corona virus (nCOV) has emerged in Hubei province capital Wuhan (3) (Fig.2). The causative agent was identified on January 7, 2020 and was named as 2019-nCoV, a new strain that had not been previously identified in humans (4). The current epidemic of 2019-nCoV is more widespread compared to the epidemic of earlier corona viruses. Coronavirus outbreak has a larger negative effect on the global economy than the SARS outbreak in 2003.This deadly coronavirus was named by WHO following a scientific approach as COVID-19, name of the disease caused by the novel coronavirus. The ‘CO’ in COVID stands corona, while ‘VI ‘is for virus and‘D‘for disease.  The number 19 stands for year 2019, when the outbreak was first identified.

The magnitude of the risk posed by this novel coronavirus is assessed by three parameters such as transmission rate (Ro) giving average number of newly infected people from a single case  to a naïve population, case fatality rate (CFR) giving the percent of cases that result in death and to determine whether asymptomatic transmission is possible. On average every case of the nCoV is able to create 3 t0 4 new cases indicating the infection is likely to spread. Case fatality rate for nCoV has been estimated to be 2% (for comparison, the case fatality rate for SARS was 10%, and for MERS 34%).

Attempts were made quickly in Wuhan and surrounding region in China, to contain the spread of the infection by suspending live animal markets throughout the country, cancelling the trains and flights out of the city, banning the movement of private cars,  suspending the long-distance bus services, restriction of movement of people in the city, confining them in their houses, providing health care facilities by converting the exhibition grounds into make-shift hospitals, construction of hospitals to provide additional beds to take care of the patients.

Epidemiology

On December 31, 2019, China reported a cluster of Pneumonia cases of unknown aetiology, from Wuhan city (‘China’s thoroughfare, river city, The Chicago of China, Different everyday) in the Hubei Province. Within a week, it was found to be due to a novel Corona virus, labelled as 2019nCoV, belonging to genus Beta-coronavirus found in humans, bats, and wild animals.  The virus had 96% concordance with an already known batborne coronavirus. These viruses are zoonotic viruses and they are transmitted between animals to humans. SARS-CoV was transmitted from civet cats (small mammals) to humans and MERS-CoV from dromedary (Arabian)camels to humans. The natural animal host of nCoV-2019 is yet to be identified. The intermediate host responsible for its transmission to humans is not known. It most closely resembles coronaviruses from Chinese horseshoe bats. Environmental samples were positive for nCoV in human seafood Wholesale Market, where wild animals are traded in Wuhan city. It is noteworthy that some laboratory confirmed patients did not visit this market.  Wuhan city is the epicenter of the current outbreak. Cases were being reported from other provinces of China. Within a month, 14,562 persons were reported to be infected this virus.  31,535 cases were reported worldwide, most of which belonged to China. They have been confirmed by laboratory tests.  It included 17 healthcare workers. A total of 1,63,844 persons had been exposed to the infection in Hubei province. There were 636 deaths in Hubei province, including Li Wenliang (34), an Ophthalmologist, who tried to sound warning about the viral infection that ravaged China two decades ago. Philippines reported first death outside China, and Hong Kong reported one death. The victim had arrived from Wuhan.  The virus spread within a month to 28 countries including India, the US, the UK, Russia, Japan, Australia, Thailand, Republic of Korea, Germany, Vietnam, Bangladesh, Sri Lanka, and United Arab Emirates. India, the US, Sri Lanka, Bangladesh and many other countries evacuated their nationals from Wuhan. India airlifted 654 persons including 7 Maldivians to Delhi and they were kept in quarantine facility at Manesar, near Delhi, to monitor the signs of infection for 2 weeks. 3 cases were reported positive from Kerala and they had returned from China.

On 5rd March 2020, China reported 80,430 cases with 3913 deaths. Globally, there were 96,268 cases and 3,304 deaths. These confirmed cases had been reported from 81 countries and territories. South Korea (5,766), Iran (3,513) and Italy (3,089) were other countries which reported maximum number of cases outside China. Thus, the virus has exhibited pandemic potential. In South Korea more than 90 per cent of the new cases were in Daegu city and the neighboring North Kyongsang province according to the Korea Centers for Disease Control and Prevention. 29 cases were reported from India, of which there were 15 Italian tourists. The cases were reported from Delhi, Rajasthan, UP, Kerala and Telangana.

Causative agent

SARS-CoV and COVID-19 share structural similarity and binding to the same receptor on the cells. Bats are considered to be the original host of SARS-CoV.  COVID-19 appears to have jumped the species barrier possibly via close contact with infected animals, and may then be spread personto-person. Changes in the surface protein may facilitate the virus to attach itself to the new host cell either by mutation or recombination. Similar to SARS-CoV, the spike protein of COVID-19, that is responsible for the disease, binds to the cellular receptor (angiotensin-converting enzyme 2, ACE2), serving as the entry point into the cells of human body. It is worth noting that both SARS-CoV and COVID-19 bind to the same receptor (ACE2) allowing virus to get deep into human lungs. Unlike SARS-CoV, the spike protein of COVID-19 binds to the cell receptor with much higher (10to-20 fold) binding affinity. This characteristic is unique to COVID-19 and it explains high humanto-human transmissibility of the virus compared with SARS-CoV. COVID-19 might be spread even during the incubation period when the person is not exhibiting any symptoms.

Spread of infection

The role of environmental contamination in the transmission of COVID-19 is not yet clear. The infection spreads from person-to-person from close contact. The spread occurs via the respiratory tract through the droplets following cough or sneeze of the infected person. There is a suspicion that the infection can spread from fomites such as chair, door, utensils, door handle that have been touched by the infected persons. It must be noted that the spread can occur even when the person is asymptomatic. The residents of Wuhan city had been isolated and experienced frightening time. Most forms of traffic had been banned and 11 million people were shut up in their homes, to minimize the spread of the virus.

People of all ages are susceptible to COVID-19. Older persons and persons with pre-existing medical conditions such as heart disease, asthma, diabetes appear to be more vulnerable to becoming severely ill with the virus. According to China’s National Health Commission, about 80% of those who died were over the age of 60 and 75% of them had pre-existing health conditions. The virus is contagious even when the patient is not displaying any symptoms.

Pathology

COVID-19 infects human respiratory epithelial cells through an interaction between the viral S protein and the angiotensin-converting enzyme 2 receptor on human cells. The causative viruses possess spiky projections on their outer surfaces that have a resemblance to the points of a crown (5).  Beneath this exterior lie a greasy membrane and a round core. The core contains genetic material which the virus can inject into vulnerable cells to infect them. The spike proteins extend from within the core to the viral surface. When the spike engages its receptor on a host cell there is merger of the virus with the cell. This will facilitate the release of genetic material to take over the internal machinery of the cell and produce large number of viruses.

Post-mortem samples from a 50-year old male patient from Wuhan were taken from the lung, liver, and heart. Histological examination showed bilateral diffuse alveolar damage with cellular fibromyxoid exudates. The lung showed evidence of desquamation of pneumocytes and hyaline membrane formation, indicating acute respiratory distress syndrome (ARDS). Interstitial mononuclear inflammatory infiltrates, dominated by lymphocytes, were seen in both lungs. Multinucleated syncytial cells with atypical enlarged pneumocytes characterized by large nuclei, amphophilic granular cytoplasm, and prominent nucleoli were identified in the intra-alveolar spaces, showing viral cytopathiclike changes. No obvious intranuclear or intracytoplasmic viral inclusions were identified.

Clinical features

Huang and co-workers reported 41 cases of novel coronavirus infected pneumonia (NCIP) in which majority of patients gave a history of exposure to seafood wholesale market. There were 30 (73%) men and 13 (32%) had underlying diseases including diabetes, hypertension and cardiovascular disease. Median age was 49 years. They presented with fever, non-productive cough, dyspnoea, myalgia, and fatigue. They had lymphopaenia. All of them exhibited pneumonia and chest CT images showed bilateral ground-glass opacity.  Complications included acute respiratory distress syndrome, anaemia, acute cardiac injury and secondary infection.  There were six (15%) deaths. No antiviral treatment was found to be effective.⁶

After giving details of 99 patients of NCIP from the same hospital at Wuhan, Chen et al came to the conclusion that 2019-nCoV infection is clustered within groups of humans in close contact. It had affected older men with comorbidities.⁷ The condition could progress to adult respiratory distress syndrome (ARDS).

In a retrospective study of 139 consecutive hospitalized patients with confirmed Novel Corona-virus infected pneumonia at Zhongnan Hospital of Wuhan University in Wuhan in the initial four weeks of January 2020 followed up to Feb 3, 2020 by Wang and co-workers, it was found the median age of the patients was 56 years(range 22-92 years) and 75 (54.3%) were men. Hospital-associated transmission was thought in 40 (29%) affected health professions and 17 (12.3%) hospitalized patients.⁸

They presented with fever (98.6%), fatigue (96.69%), dry cough (59.4%) and dyspnoea as the common features. Laboratory investigations showed lymphopaenia, prolonged prothrombin time and elevated lactate dehydrogenase (LDH).  Chest computed tomographic scans showed bilateral patchy shadows or ground glass opacity in the lungs of all patients. The cases were confirmed by the study of throat swabs with real time reverse transcription polymerase chain reaction (RT-PCR).

The patients received antiviral (oseltamivir) or antibacterial therapy and glucocorticoid therapy. Due to complications such as acute respiratory distress syndrome (ARDS) (61%), arrhythmia, (44.4%) and shock (30.6%) the patients had to be shifted to intensive care unit (36 patients). These patients belonged to older age group (66 years) and had underlying comorbidities. There was 4.3%) mortality.

The patients exposed to the corona virus infection may remain asymptomatic or seriously ill requiring treatment is intensive care unit (ICU). After an incubation period varying from 2 to 14 days, the condition presents with symptoms similar to any other upper respiratory tract infection such as running nose, sneezing, sore throat, cough, shortness of breath and sometimes fever. Many of these symptoms simulate flu or a common cold. Due to similarities of the symptoms from different viruses, it becomes difficult to identify the disease based on symptoms alone. The laboratory help is needed to confirm COVID infection.  The infection can cause pneumonia, severe acute respiratory distress, impaired liver and kidney functions, and even death.

In a subset of individuals, including those with cardiopulmonary disease or a weakened immune system, the viral infection can progress to a more severe lower-respiratory infection.  The novel coronavirus causes symptoms similar to those of other coronaviruses, triggering fever, cough and difficult breathing in most patients. Rarer symptoms include dizziness, nausea, vomiting and a runny nose.

Case definition⁹

The Clinical management guidelines of COVID is based on case definition.

Suspect case

a. Patient with severe acute respiratory infection such as fever, cough, and requiring admission to the hospital, and with no other aetiology that fully explains the clinical presentation, and history of travel to or residence in China during the 14 days prior to symptom onset, or

b. Patient with acute respiratory illness and at least one of the following during the 14 days prior to symptom onset;

i. Close contact with a confirmed or probable case of 2019-nCoV infection or ii. Worked in or attended a health care facility where patients with confirmed or probable 2019-nCoV acute respiratory disease patients were being treated.

Probable case

A suspect case for whom testing for 2019 nCoV is inconclusive or  is tested positive using a pan-coronavirus assay  and without laboratory evidence of other respiratory pathogens.

Confirmed case

A person with laboratory confirmation of 2019 nCoV infection irrespective of clinical signs and symptoms.

Close contact 

1.  Health care associate exposure, including providing direct care for nCoV patients, working with health care workers infected with nCoV, visiting patients or staying in the same close environment of an nCoV patient.

2. Working together in close proximity or sharing the same classroom environment with a nCoV patient.

3. Traveling together with nCoV patient in any kind of conveyance.

4. Living in the same household as a NCoV patient.

The samples are to obtained from the lower respiratory tract, including sputum, bronchoalveolar lavage (BAL) and tracheal aspirate. In situations where the sample can’t be obtained from the lower respiratory tract, samples from the upper respiratory tract (nasopharyngeal swab and oropharyngeal swab) can used. The swabs should be kept and transported in the tube with viral transport medium. Samples should be kept refrigerated at 4-8⁰C and sent to the laboratory with molecular diagnostic facility. Real-time reverse transcriptase–polymerase chain reaction (RT-PCR) tests for COVID-19 nucleic acid is used to determine positivity of the sample and those positive are to be notified immediately (10).

In a retrospective analysis of serial chest CT scans of 81 patients with COVID-19 pneumonia in Wuhan hospital, the predominant pattern of abnormality observed was bilateral (79%), peripheral (54%), ill-defined (81%) and ground-glass opacification (65%) (11). It was concluded that chest imaging abnormalities are recognizable even in asymptomatic patients which get rapidly evolved from focal unilateral to diffuse bilateral groundglass opacities within 1-3 weeks. The radiological evolution of COVID-19 pneumonia was consistent with the clinical course of the disease (Fig. 3).

Most patients in the study cohort by Shi et al showed bilateral lung involvement, with lesions mainly located peripherally and sub-plurally with diffuse distribution.⁹ The predominant pattern was ground-glass opacity, with ill-defined margins, air bronchograms, smooth or irregular interlobular or septal thickening, and thickening of the adjacent pleura. Some patients presented with pleural effusion, lymphadenopathy, and round cystic changes on CT

Analysing the CT abnormalities in COVID-19 lower respiratory tract infection, Kanne and colleagues have stated that the most common CT findings are bilateral, basal and peripheral predominant ground glass opacity, consolidation or both implying the presence of lung injury. These changes peak around 9-13 days and then slowly resolve.¹²

Virus isolation is to be conducted with various cell lines, such as human airway epithelial cells, Vero E6, and Huh-7. Cytopathic effects (CPE) are observed within 96 hours after inoculation. Typical crown-like particles are observed under transmission electron microscope (TEM) with negative staining. The cellular infectivity of the isolated viruses could be completely neutralized by the sera collected from convalescent patients.

Real-time PCR (RT-PCR) assays on these samples are positive for pan-Betacoronavirus. Using Illumina and nanopore sequencing, the whole genome sequences of the virus can be acquired. Bioinformatic analyses indicated that the virus had features typical of the coronavirus family and belonged to the Betacoronavirus 2B lineage.

Mortality

CoVID-19 is more contagious than the related viruses such as SARS-CoV and MERS CoV.

Covid-19 appears to be not as fatal on a case-bycase basis, its greater spread has already led to an increased number of deaths than its related coronaviruses. Old age, male sex, and presence of comorbidities and progressive radiographic deterioration on follow-up CT might be risk factors for poor prognosis in patients with COVID-19 pneumonia.

Chinese Center for Disease Control and Prevention (CDC) has stated that of the 44,672 confirmed cases, there were 1,023 deaths, with a crude mortality rate of 2.3%. By comparison, SARS had a mortality rate of 9,6% during the 2003 outbreak, while MERS showed a case fatality of 35%.¹³ The highly contagious seasonal influenza which affects a large number of people has a mortality rate of around 0.1%.

Many of the deaths seen during the current outbreak of COVID-19 in China is among elderly persons and those with pre-existing conditions that make them more susceptible to serious illness from the viral attack. According to Chinese CDC the crude fatality rate is 14.8% among patients aged 80 and above. The fatality rate was 10.5% among those with pre-existing illness especially cardiovascular disease.

In retrospective, observational study of 52 critically ill patients with SARS-CoV-2 pneumonia, in Jin Yin-tan Hospital, Wuhan over a period of 28 days  during January 2020,it was found they were of 59.7 years, 35 (67%) were men, and 21(40%) had chronic illness, 32(61.5%) had died at 28 days (14). Most patients had organ function damage, including 35(67%) with ARDS, 15(29%) with acute kidney injury, 12(23%) with cardiac injury, 15(29%) with liver dysfunction, and one (2%) with pneumothorax.  The study concluded that older patients (>65 years) with comorbidities and ARDS are at increased risk of death. FFeebruary2020DOI:https://doi.org/10.1016/ S2213-2600(20)30079-5

Treatment

There is no specific antiviral treatment available for any human coronavirus infection. The individuals who are affected by a coronavirus usually recover on their own. The suspected casesare to be kept isolated at designated medical institutions and treated.  The treatment is essentially symptomatic and supportive. They are advised staying at home to rest. The approach to contain this disease is to control the source of infection, use of personal protection to reduce the risk of transmission, and early diagnosis, isolation and supportive treatment for affected patients. Paracetamol and acetaminophen are given for the treatment of pain and fever. The patients are advised to drink plenty of fluids. Though antiviral agents, antibacterial agents and methylprednisolone have been given to these patients, no effective outcomes have been noted.⁷

Convalescent plasma has been used as a therapeutic method. People who have recovered from COVID-19 disease would demonstrate the presence of antibodies against the virus. Infusing the antibodies to critically ill patients is expected to improve the chance of survival. The plasma that is transfused contains the antibodies. Patients who received plasma therapy showed an improvement in the clinical symptoms, 12-24 hours after administration of the therapy. Antibodies in the plasma bind to the virus and prevent them from entering the cells. But by the time it is given, many cells would have been infected. Hence, convalescent plasma therapy appears to be not very effective.

Chloroquine phosphate, an old remedy for malaria, has shown to have apparent efficacy and acceptable safety against COVID-19 associated pneumonia in multi-centre clinical trials conducted in China (15). The drug is recommended to be included in the Guidelines for the Prevention, Diagnosis, and Treatment of Pneumonia Caused by COVID-19 issued by the National Health Commission of the People’s Republic of China for treatment of COVID-19 infection in larger populations in the future.

1. Upper respiratory tract infection without lung

   infiltrates, positive PCR

   Chloroquine phosphate 500 mg orally twice a day for 5 days.

   Oseltamivir 150 mg orally twice a day for 5 days.

2. Treatment of COVID-19 pneumonia

   Chloroquine phosphate 500 mg orally twice a day for 10 days.

Prevention of spread

No vaccine is available for preventive use.  In an attempt to prevent the spread of the infection, Chinese authorities effectively sealed off Wuhan, and placed restrictions on travel to and from several other cities.  The move was to ‘resolutely contain the momentum of the epidemic spreading’ and protect lives. WHO Director General Tedros Adhanom Ghebreyesus has said that, “Every country must be ready for its first case, its first cluster, the first evidence of community transmission, and for dealing with sustained community transmission,” Further he said, “ We are not defenseless,” he has urged that “every country and every person” to help ensure cases are detected early and that authorities are able to trace contacts, provide care and prevent widespread community transmissions.

Discharge

The patients are discharged or quarantine discontinued if they fulfil the following criteria¹⁶

• normal temperature lasting longer than 3 days,
• resolved respiratory symptoms,
• substantially improved acute exudative lesions on chest computed tomography (CT) images, and 2 consecutively negative RT-PCR test results separated by at least 1 day.

WHO’s strategic objectives¹⁷

• Interrupt human-to-human transmission including reducing secondary infections among close contacts and health care workers, preventing transmission amplification events, and preventing further international spread;
• Identify, isolate and care for patients early, including providing optimized care for infected patients;
• Identify and reduce transmission from the animal source;
• Address crucial unknowns regarding clinical severity, extent of transmission and infection, treatment options, and accelerate the development of diagnostics, therapeutics and vaccines;
• Communicate critical risk and event information to all communities and counter misinformation;
• Minimize social and economic impact through multisectoral partnerships.

Reduction of risk

WHO has suggested thatpeople can help to reduce their risk of getting respiratory illnesses by following simplemeasures.

• Wash your hands often with soap and water for at least 20 seconds, and help young children do the same. If soap and water are not available, use an alcohol-based hand sanitizer.
• Cover your nose and mouth with a tissue when you cough or sneeze, then throw the tissue in the trash.
• Avoid touching your eyes, nose, and mouth with unwashed hands.
• Avoid personal contact, such as kissing, or sharing cups or eating utensils, with sick people.
• Clean and disinfect frequently touched surfaces and objects, such as doorknobs       

Scrupulous personal hygiene has to be maintained. The dirty hands must be washed with soap and water. It is advisable to keep the hands clean with alcohol-based hand rubs. Close contact should be avoided with person showing symptoms of respiratory illness such as coughing or sneezing. Persons having flu-like symptoms with fever, cough, running nose, sneezing or sore throat must seek medical help. The face especially nose and mouth are to be covered while sneezing and coughing. It is necessary to maintain social distancing. It is advised to maintain at least 1meter (3 feet) distance between persons especially with those who are coughing, sneezing and have a fever.  This will prevent breathing in the virus. Wearing a triple-layer surgical mask can help limit the spread of infection to some extent. There is need to avoid touching eyes, nose and mouth with contaminated hands as it can transfer the virus from the surface to the individual. It is necessary to avoid raw and uncooked animal products. One should avoid travel when he/she is feeling unwell.

It is also necessary to avoid travelling to areas with outbreaks of infection. Recent travel history should be made available to the health care provider. It is necessary to keep track of all contacts of an infected person and keep them under surveillance. Since health care providers are under high risk, they have to take all personal protective measure.