Coronavirus – is it just “a type of ‘flu”?

Ten years since the Swine Flu pandemic, the world is coming to terms with another rapidly spreading, potentially fatal respiratory viral infection. This time, the culprit is a coronavirus, but is it correct or helpful to think of the disease as “a type of ‘flu”?

Virology
Both influenza and coronaviruses have a single strand of RNA as their genome, but that is where the genomic similarity ends. The influenza virus genome comprises 7 or 8 segments, while the coronavirus has one long strand. Influenza virus RNA is what is known as ‘negative sense RNA’. This means that its sequence is the mirror image of the correct code for proteins and a complementary strand must be made from it before production of new viruses within a host cell can proceed. In contrast, the coronavirus genome is ‘positive sense’ which means it can act as messenger RNA and code for proteins. So from a virological point of view, coronavirus is definitely not a type of flu.

Coronaviruses
Thousands of coronaviruses have been identified to date. Most have been found in animals, including many species in bats. There are at least 7 coronavirus species known to infect humans. Two, namely Human Coronavirus 229E (HCoV-229E) Human Coronavirus OC43 ( HCoV-OC43), were identified in the 1960s and between them they are thought to account for 25% of all common colds. Subsequently, the use of more sensitive techniques, which detect the viral genome, has led to the identification of two more species. These are called HCoV-NL63 and HCoV-HKU1, reflecting the fact that they were first found in patient samples in the Netherlands and Hong Kong respectively. They are associated with occasional outbreaks of serious respiratory infection, particularly in young children, the elderly and immunocompromised, but only small numbers of cases each time^1.

In the 21^st century, three new coronaviruses associated with widespread transmission have emerged. Severe acute respiratory syndrome coronavirus (SARS-CoV) was first reported from China in late 2002. Then in 2012 a different epidemic virus, Middle Eastern respiratory syndrome coronavirus (MERS-CoV) was identified in Saudi Arabia. The most recent addition to the list has been named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) since its sequence shows that it is very closely related to the 2002 SARS virus. The disease it causes is to be called COVID-19 ( coronavirus identified in 2019)². 

Mutation in RNA viruses
All living organisms, including bacteria, use DNA as their genetic material. Therefore, they have sophisticated and reliable mechanisms to detect and correct any errors in DNA replication during their replication and cellular activity. They do not waste energy on mistakes in RNA, since a defective RNA strand will degrade and be replaced with a fresh one of the appropriate sequence. Viruses rely heavily on host cell metabolic processes to reproduce their genome and make the proteins required to make new virus particles. They are not complicated enough biologically to troubleshoot any mistakes. Thus, the replication of the genome of an RNA virus is particularly error prone and the production of progeny RNA viruses is a precarious enterprise. Most of the time, the mutation which arises in the viral genome causes a fatal error, so this new version of the virus cannot survive. However, occasionally the mutant proves to be a viable virus and thus a new strain or even species emerges.  

The mutation process accounts for the slight differences in strains of seasonal influenza each year as viruses circulate between humans and around the world on an annual basis. Pandemic influenzas occur when viruses from different animal hosts mix some of their segments and the outcome is a new species which can infect humans. This is why the associated infections have names like swine flu and avian flu. SARS-CoV, MERS-CoV and SARS-CoV-2 also have a zoonotic origin. Detailed analysis of the sequences has shown that in all three cases, it was a mutation in a bat coronavirus that gave rise to a novel species which could survive and indeed thrive. Interestingly, the jump to humans appears to involve an intermediate animal. For SARS-CoV it was probably the civet cat, for MERS-CoV it was camels and for SARS-CoV-2 it has yet to be determined. A number of animals have been suggested as the possible source, but the virological evidence is inconclusive so far. This will be one the many lines of scientific enquiry about this new virus to be pursued in future.    

Seasonal coronavirus versus seasonal influenza
During the winter, several strains of seasonal influenza virus are usually circulating, along with a wide array of respiratory viruses including the HCoV species. The symptoms of influenza infection are sudden onset of extreme tiredness, headache, aching and a temperature.  Most people get themselves to bed and then find that they are unable to move much further than the nearest bathroom for at least a week. There are several species of virus associated with the common cold, which mainly comprises a sore throat and sneezing. A very bad cold with a temperature, cough, headache and aching ( - ie. ‘flu-like symptoms, but without the total inability to get out of bed) could be caused by a coronavirus. An interesting feature of coronaviruses is that they are shed in faeces, so if someone says that they have ‘gastric flu’ it is probably actually a coronavirus infection. While the number of ordinary colds is not recorded, it has been estimated that around 400,000 people die annually from the complications of a seasonal influenza infection³

Pandemics : COVID-19 versus Swine flu
In 2009, a new influenza virus, Influenza A H1N1 was recognized in Mexico. It had genetic traits which showed it was a combination of influenzas from pigs and birds as well as humans. It took the world by surprise, not least because virologists and epidemiologists were expecting an imminent outbreak of avian influenza originating in the Far East. Travellers spread the virus around the world rapidly and it became a pandemic. Initially, healthcare services in most countries offered virology tests to everyone showing symptoms. This was mainly because ‘flu-like symptoms are rather non-specific and could be caused by other types of infection, including seasonal influenza.

There was a reasonably effective anti-viral treatment available and they wanted to ensure that people with H1N1 influenza received it. As the number of cases grew rapidly, testing stopped and people were diagnosed clinically and usually given the anti-viral drug on that basis. Therefore the final figures for the number of people infected by the 2009 H1N1 Influenza A during the pandemic is an estimate. It is considered that up to 20% of the global population was infected with the virus. The number of deaths from complications of the infection was somewhere  between 100,000 and 500,000⁴. The proportion of people who died out of all who were infected ( the ‘case fatality rate’) is hard to calculate without exact figures. However it is thought to be less than 1%.

SARS-CoV infected just over 8,000 people between 2002 and 2004 and killed 774 (case fatality rate of 9.6%). Since 2012, there have been at least 2,500 cases of MERS-CoV and 866 deaths which gives a case fatality rate of 34.4% SARS-CoV-2 has spread rapidly through China since the end of 2019 and then across the world. As for the 2009 H1N1 influenza pandemic, the world was unprepared to deal with this new virus. By the Spring of 2020, it had reached all continents of the world ( except Antarctica)  and COVID-19  was declared as a pandemic disease by the World Health Organisation on 11th March 2020⁵. 

Only three months after the virus was first identified by virologists in China⁶, the absolute number of people recorded as infected with SARS-CoV-2 and those who had died from COVID-19 had exceeded the figures for the other epidemic coronaviruses . It is becoming clear that not every ‘case’ is being identified. Not everyone has defining symptoms and in most countries, not everyone suspected of having COVID-19 is being tested. Therefore it is difficult to determine an accurate case fatality rate, but it seems to be between 1% and 5%.  Therefore, the chances of someone dying from a SARS-CoV-2 infection seems to be lower than for SARS-CoV but greater than for the 2009 H1N1Influenza A. 

‘Flu-like symptoms
The clinical symptoms during the initial stages of COVID-19 are similar to those experienced by people with influenza. The key features are a fever (over 37.8°C) and a persistent dry cough. Patients also report lethargy, aching, sore throat, headache and diarrhoea. Most people with either influenza or COVID-19 will have some or all of these symptoms. In both infections, the majority of people will feel really ill for 1 to 2 weeks and then start to get better. Due to the effects of the virus on the body, feeling tired for a few more weeks and with a low mood (‘ post viral syndrome’) is quite common. This does not last in the majority of cases and a full recovery would be expected. As mentioned above, people are more likely to be incapacitated for a while during an uncomplicated influenza infection than COVID-19. Indeed, it is becoming clear that a significant proportion of people infected with SARS-CoV-2 experience either the mild symptoms of bad cold or nothing at all.  

The most dangerous complication of influenza is a secondary bacterial infection. This occurs because the lungs are made vulnerable by the effects of the virus within the body. In COVID-19 the host’s immune system seems to overreact to the presence of the virus itself, causing damage to the lungs, which results in shortness of breath and severe respiratory distress. In both situations, the patient may become ill enough to require hospital treatment and may die.

Control
The seasonal influenza vaccine affords some protection against pandemic type of influenza A, so it has implemented as part of the control programme against the 2009-10 H1N1 virus. Anti-viral drugs, including Tamiflu, were already in use as treatment for influenza in very severe cases and so they could be made available to anyone who met the criteria for treatment. These two measures helped to protect individuals against the complications for the infection and also to reduce the length of time that a person was shedding active virus, which slowed the transmission rate.

The description of COVID-19 as ‘a type of flu’ raised expectations among non-scientists that a similar approach could be used to control SARS-CoV-2.There is no vaccine against any coronavirus. Funding of work to produce a vaccine against SARS-CoV for precisely the situation that we are facing now has been reduced. It was proving a difficult task and since the virus had disappeared, it was hard to justify the expense.  Experiments with potential anti-viral drugs to work against SARS-CoV and MERS-CoV have continued, but again they are making slow progress.

Testing
Chinese virologists published the sequence of SARS-C0V-2 in December 2019. Thus it was possible for specialists in reference centres across Europe to collaborate and develop a reliable reverse transcriptase polymerase chain reaction (PCR) assay and protocol⁷ 

This is a specialised method requiring specific equipment and reagents and, importantly, qualified biomedical scientists to carry it out. These limitations on capacity mean that in most countries only certain people are being tested. Patients with severe symptoms require a test to diagnose COVID-19 as the cause of their current illness, to ensure they receive correct treatment and management.  Samples from frontline healthcare workers are also being tested after they have been ill and are ready to return to work, to ensure that they are no longer carrying SARS-CoV-2.

The test can also be useful to determine whether someone who is ‘self isolating’ due to known contact with someone who has COVID-19 does in fact have the virus themselves or could safely be at work. Scientists in industry and universities have been contributing their knowledge and expertise to the international health crisis, by for example by providing reagents, lending PCR machines, evaluating commercially available testing kits and designing and manufacturing ventilators. It is very important to maintain high standards of quality management and oversight by qualified and registered hospital laboratory professionals in any test protocols implemented. Any response to the pressure to “do more testing” should not lead to a compromise in the quality of the results.  

Kits intended to detect the antibody response to SARS-CoV-2 are also becoming available. While this could be a useful addition to the diagnostic laboratory service, there are two points to note. The first is that they have been developed very quickly and must be fully evaluated for parameters of quality (reliability, reproducibility, sensitivity and specificity) before being brought into routine use. Some of those on the market use the Point of Care lateral flow format, which often have a less than optimal sensitivity. The other point is that immunity to coronaviruses is not well defined and studies of patients post infection with the 2002 SARS-CoV have shown that a significant proportion of them lost detectable serum antibody within 12 months⁸. 

Conclusion
COVID-19 is not a type of flu and describing it as such may not have been very helpful during the early stages of the spread of the infection. It is seems that the emergence of novel coronaviruses, capable of wide spread human-to-human transmission, is to be a feature of 21^st century life. Scientists around the world have about 8 years to cooperate, develop reliable laboratory tests, effective vaccines and useful treatments and a strong control strategy in time for the next one. It is also important to keep an eye on the bats!

References

1. Malik Peiris JS and Poon LLM (2009). Coronaviruses and Toroviruses , chapter 21 In: Zuckerman AJ et al. Principles and Practice of Clinical Virology: Chichester:Wiley Blackwell
2. Gorbalenya AE et al . (2020). The species Severe acute respiratory syndrome-related coronavirus: classifying 2019-nCoV and naming it SARS-CoV-2. Nature Microbiology, doi: 10.1038/s41564-020-0695-z
3. Paget J et al. (2019) Global mortality associated with seasonal influenza epidemics: new burden estimates and predictors of the GLaMOR project. Journal of Global Health, 9(2): 020421.
4. Dawood FS et al (2012). Estimated global mortality associated with the first 12 months of 2009 pandemic influenza H1N1. Lancet infectious diseases, 12(9): 687-695.
5. World Health Organisation: who.int/ Coronavirus disease (COVID-19) Pandemic.
6. Zhu N et al. (2020). A novel coronavirus from patients with pneumonia in China, 2019. New England Journal of Medicine, 382: 727-733
7. Corman VM et al. (2020). Detection of 2019 novel coronavirus (2019-nCoV) by real time RT-PCR. Eurosurveillance , 25 (3): pii=2000045
8. Chen J and Subbarao K (2007). The Immunobiology of SARS . Annual Review of Immunology, 25: 443-472

Author
Sarah J Pitt PhD CSci FIBMS is principal Lecturer at University of Brighton and the Chief Virology Examiner, Institute of Biomedical Science