Abstract
Coronavirus disease (COVID-19) is now dominating the lives of everyone, and its history is constantly being rewritten. This article gives a brief account of the story so far: where SARS-CoV-2 might have originated, how it compares with other viruses that cause major respiratory disease, and some of the treatments and vaccines currently being investigated to combat it.
On 31 December 2019, the World Health Organization (WHO) was formally notified about a cluster of cases of pneumonia in Wuhan City, home to 11 million people and the cultural and economic hub of central China. By 5 January, 59 cases were known and none had been fatalater, WHO was aware of 282 confirmed cases, of which four were in Japan, South Korea and Thailand.2 There had been six deaths in Wuhan, 51 people were severely ill and 12 were in a critical condition. The virus responsible was isolated on 7 January and its genome shared on 12 January.3 The cause of the severe acute respiratory syndrome that became known as COVID-19 was a novel coronavirus, SARS-CoV-2. The rest is history, albeit history that is constantly being rewritten: as of 12 May, 82,591 new cases of COVID-19 worldwide were being confirmed daily and the death rate was over 4200 per day.4
Coronaviruses in man
Phylogenetic analysis suggests that SARS-CoV-2 originated in animals, probably bats, and was transmitted to other animals before crossing into humans at the Huanan wet market in Wuhan City.5, 6 There is some evidence that the intermediate vector may have been pangolin, a type of nocturnal anteater imported illegally for its flesh. This animal carries a coronavirus that is very similar to SARS-CoV-2 but differs in a crucial region that determines viral infectivity and host range. It is therefore possible that the virus passed into humans and then, through adaptation as it infected more people, mutated to acquire the characteristics that made it spread so quickly.
SARS-CoV-2 is not the first coronavirus to cause outbreaks of respiratory infection in humans. Six others have been identified so far, all believed to have originated in animals.6, 7 The four coronaviruses that are now endemic in humans cause 10–15% of common colds, mostly peaking between December and April in temperate climates.8 NL63 and 229E probably came from bats; OC43 and HKU1 seem to have originated in rodents. Each of these causes mild symptoms, though OC43 has ancestry as a bovine coronavirus that may have caused a pandemic at the end of the 19th century.
Two non-endemic coronaviruses have caused serious disease. SARS-CoV was the first to be recognised, occurring first in November 2002 in China (though not known at the time) and coming to the attention of WHO early in 2003 in Viet Nam.9 The outbreak was largely over by July, and the last cases were reported in China in April 2004. This virus was responsible for Severe Acute Respiratory Syndrome (SARS), a flu-like illness, though diarrhoea was common. It could progress to pneumonia and respiratory failure in two weeks and 25% of people infected required intensive care. A total of 8098 cases and 774 deaths were notified.10 SARS-CoV appears to have originated in horseshoe bats and possibly transmitted to humans via palm civet cats, traded in China for their meat.
The second serious infection due to a coronavirus was Middle Eastern Respiratory Syndrome (MERS). The MERS-CoV virus was first identified as the cause of a fatal infection in Saudi Arabia in 2012.11 It spread to 27 countries. Unlike SARS, MERS is still prevalent and, as of November 2019, 2494 infections had been notified, of which 858 proved fatal.12 Like SARS, MERS causes a flu-like illness with symptoms ranging from mild (with about one-quarter of people also having diarrhoea) to severe pneumonia, acute respiratory distress syndrome, septic shock and multiorgan failure. MERS-CoV is believed to have reached humans via dromedary camels, which appear to be a reservoir in several Middle East states. The original source species is not known, but bats are the most likely.
SARS-CoV-2 more closely resembles the bat wild virus than it does either SARS-CoV or MERS-CoV, strongly suggesting that it is a novel coronavirus in humans.5 The coronavirus spike protein – the structure that binds the virus to the target receptor and mediates cell entry – requires six amino acids: SARS-CoV-2 shares only one of these with SARS-CoV. This spike protein confers high affinity for angiotensin-converting enzyme 2 (ACE2), the host receptor in humans (and many other species, including pigs, primates and cats).13 The second major structural difference from SARS-CoV is a unique subunit of the spike protein that determines viral infectivity and host range. It may have been a mutation of this feature during human infection that led to the rapid spread of COVID-19 in humans. There is currently no evidence that any of the mutations identified since SARS-CoV-2 virus emerged in humans have altered the key characteristics of COVID-19.8
How do major respiratory viral infections compare?
Outbreaks of MERS-CoV now occur mostly due to animal-to-human transmission (probably during the camel calving season).14 Person-to-person spread seems to depend on close contact, such as providing care to an infected person or within a hospital setting. In all, 40% of confirmed cases have been acquired nosocomially – on one day in May 2015, an individual with MERS visited several hospitals in Korea and infected 186 people.11
SARS-CoV is transmitted via droplets in respiratory aerosol, contact with surfaces and possibly via faecal-oral contact.10Within one month of 55 index cases being recognised in Hong Kong, Hanoi and Singapore, a total of 3000 cases had been confirmed globally with a peak reporting rate of 200 new cases per day.15 At the time, this was described as devastating. For comparison, one month after 5 January when the first 59 cases of COVID-19 were recognised, 24,554 cases had been confirmed globally.16
These figures are influenced by the restrictions on travel and lockdown measures recommended by WHO in liaison with governments to control the spread of infection. They are not, therefore, solely an indicator of the natural pathogenicity of the viruses.
The COVID-19 pandemic has often been compared with global influenza outbreaks in an attempt to put this new threat in an historical context. According to WHO data, seasonal flu causes three to five million cases of severe illness and 290,000–650,000 deaths from respiratory disease each year.17 H1N1, the virus that caused the swine flu pandemic of 2009/10, infected 11–21% of the global population (750 million – 1.4 billion people) and caused around 280,000 deaths from respiratory disease and cardiovascular disorders; about two thirds of those deaths occurred in people aged 18–64 years.18,19 As of 12 May, the number of deaths attributed to COVID-19 worldwide has already surpassed 280,000.4
COVID-19 infection
Like SARS-CoV, the SARS-CoV-2 virus responsible for COVID-19 can survive in aerosols for hours and on surfaces including stainless steel, plastic and cardboard for days,20 although washing with soap or detergent will destroy the virus. It can be transmitted during the asymptomatic incubation phase (this is estimated to occur in 50–60% of cases) and for up to two weeks after the onset of symptoms.21 Each person infected passes the virus on to an average of three others.8 The incubation period is about 5–6 days (range 1–14 days). Clinical presentation varies from asymptomatic, subclinical infection and mild illness to severe or fatal illness; deterioration can occur rapidly, often during the second week of illness.8 Viral load is up to 60 times greater in people with severe symptoms compared with mild cases. Death is due to pneumonia and possibly hyperinflammation associated with cytokine storm syndrome.22 Hospitalisation rates and crude mortality rates in Europe up to 22 April, showing the influence of increasing age, are shown in Figures 1 and 2.

Figure 1
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Figure 2
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As reported on 21 April, the most common symptoms of COVID-19 reported in Europe are fever/chills (49%), dry or productive cough (24%), sore throat (12%), general weakness (8%), pain (7%), rhinorrhoea (4%) and diarrhoea (2%).8 These data are largely from Germany and may not be representative of all COVID-19 cases. Complications include cardiomyopathy, thrombosis, acute kidney injury and encephalitis.
Probable risk factors for severe disease and death include increasing age, being of minority ethnic background, immunosuppression, hypertension, diabetes, cardiovascular disease, chronic respiratory disease, obesity, smoking and cancer. Men in these groups appear to be at higher risk. Chronic obstructive pulmonary disease (COPD), cardiovascular disease and hypertension are strong predictors of admission to intensive care.23, 24
Some risk factors may be explained by the virus's affinity for ACE2, which is expressed by the epithelial cells of the lung, intestine, kidney and vasculature.25 ACE2 expression is upregulated in older people, tobacco smokers, and people with diabetes or hypertension, many of whom are treated with ACE inhibitors, and by the glitazones and ibuprofen. However, two recent studies from Italy and the USA26, 27 have shown that treatment with an ACE inhibitor or angiotensin II-receptor blocker (or indeed any other single antihypertensive agent) is not associated with an increased risk of contracting COVID-19, severe symptoms or a fatal outcome. The link therefore appears to be simply due to the higher risk associated with cardiovascular disease.
The latest advice (14 April) from the Commission on Human Medicines (CHM) is that there is insufficient evidence to establish a link between NSAIDs/ibuprofen and susceptibility to COVID-19 or worsening of symptoms, and it says patients can take either paracetamol or ibuprofen when self-medicating for symptoms of COVID-19. However, additional risks are plausible, and a rapid evidence summary from NICE rounds up all the evidence on this topic to date (ES23).28
Treatments under evaluation for COVID-19
Management of the complications of COVID-19 relies on supportive care and oxygen supplementation via non-invasive or mechanical ventilation. Patients who are critically ill may require vasopressor support and antibiotics for secondary bacterial infections.8
The search for drugs and vaccines to treat or prevent COVID-19 began quickly but, with many studies carried out independently in small numbers of people, there is a risk that the trials will lack statistical rigour. WHO has launched a non-blinded clinical trial (SOLIDARITY) to evaluate four candidate treatments (remdesivir, lopinavir/ritonavir, lopinavir/ritonavir/interferon beta-1a, and chloroquine or hydroxychloroquine) versusstandard of care in 18 countries worldwide. France is co-ordinating the Discovery trial to compare the same drugs with standard care in 3200 patients in Belgium, France, Germany, Luxembourg, the Netherlands, Spain, Sweden and the UK. This will be randomised but non-blinded and will assess outcomes at 15 days.29, 30
Some of the drugs currently reported as under investigation specifically for treating COVID-19; others that have shown potential for the treatment of SARS and MERS are also being evaluated on the basis that the viruses share structural similarities with SARS-CoV-2. These include novel agents in development and antivirals currently in use for other indications, and several studies have also evaluated potential treatments in vitro.Treatments appear to have been introduced in China but are not well reported in English language scientific literature. China, as the country with the longest experience of managing COVID-19, is likely to have valuable expertise to share with other states. To date (early May), no drug treatment has been proven to be effective.