14 April 2020
Whilst every person has a vital role to play in reducing the risk of infection and combating the current COVID-19 pandemic, should a person become infected, the individual risk of disease is highly variable. Most disease outbreaks affect groups of people to different extents, either because they are more or less likely to become infected in the first place, or more often because their responses to infection are different. Usually, those most at risk are the youngest, oldest, and those with pre-existing disease, but patterns can vary: the 2009 ‘swine flu’ pandemic proved unexpectedly dangerous for otherwise healthy pregnant women, whilst the notorious 1918 ‘Spanish flu’ pandemic was unusually devastating because it caused severe disease and deaths in young, healthy adults.
In the current outbreak, the UK government has designated certain groups of people as ‘extremely vulnerable’ to severe illness due to underlying health conditions, requiring the highest possible degree of protection (known as ‘shielding’) from infection with the SARS-CoV-2 virus that causes COVID-19. The relevant health conditions are those with significant impairment of immune system function, including from cancer treatment or organ transplant; serious lung disease; and pregnant women with heart disease. This all makes sense – they are unlikely to be able to mount an effective immune response (which is how the body responds to fight off infections), and/or are especially vulnerable to virus-induced respiratory distress.
The next group of people are those classed as ‘high risk’ who should be particularly stringent in efforts to avoid SARS-CoV-2 infection – those aged 70 or older, pregnant women, the very obese, and those with significant medical conditions such as diabetes, neurological disorders, or heart, lung, liver and kidney disease. Again, these individuals are either less likely to be able to resist initial infection – immune system function typically decreases with age, and during pregnancy – or to cope with the physiological effects of infection. Obesity can both weaken the immune system and worsen respiratory distress, which could explain why patients who develop severe disease are more likely to be overweight or obese.
People from these high-risk groups account for the majority of deaths from COVID-19, but less common cases catch our attention: younger, and apparently healthy, people who develop severe disease, and sometimes die. Why do these ‘low risk’ individuals suffer so badly with a viral infection that in others causes mild disease, or even no apparent disease at all?
Environmental (external) factors could account for some cases. Health professionals who treat COVID-19 patients are potentially exposed to much higher levels of virus, and this could be one reason why otherwise healthy adults such as the Wuhan doctor Li Wenliang (who tried to sound an early alarm about the new disease) become very ill and die. This underlines the importance of appropriate personal protective equipment (PPE) for front-line staff. Another potentially aggravating factor is that people who have been working very hard indeed under difficult conditions and with little time for healthy levels of rest may have temporarily weakened immune systems and be less able to fight off any form of infection.
However, in other cases there may be no clear reason at all why a healthy person should develop severe disease and die, and in this instance, it is very likely that human genomics plays a significant role. This is aside from any changes in the viral genome that affect risk; it was almost certainly a genetic change that enabled the virus to make the jump from infecting animals to human transmission, and viral genetic changes can also affect how infectious or dangerous they are. However, viral genome analysis has so far suggested relatively little variability between different strains of SARS-CoV-2.
Human genomic variation is rapidly coming under scrutiny. The newly formed COVID-19 Host Genetics Initiative brings together major genome sequencing groups from around the world, (including UK Biobank and Genomics England) in an effort to uncover genetic determinants of susceptibility, severity and outcomes. Until such collaborative research efforts are further advanced, we can’t know for sure what genomic features may contribute to the disease – but there are a number of possibilities.
In the first place, people with genomic variants that affect their immune response may be more susceptible to severe disease, either because they have slightly impaired general antiviral responses, or conversely because they have over-vigorous antiviral responses. Immune overreaction called a cytokine ‘explosion’ or ‘storm’ was what caused the unusual levels of mortality in healthy young adults infected with the H1N1 Spanish flu strain due to dangerous levels of lung inflammation. It has been suggested that some COVID-19 patients with severe respiratory distress may also be suffering from this type of cytokine storm, and propensity to cytokine storms is likely to be at least partly genetic.
Secondly, some individuals are probably more susceptible to respiratory symptoms, which are associated with severe disease and death. Resistance and susceptibility to viral infections is often associated with the surface proteins through which viruses gain entry to human cells; for example, people who have defective blood cell CCR5 receptors are highly resistant to HIV infection. One possibility that has been proposed for SARS-CoV-2 is that variants in the ACE2 gene for a lung cell receptor could make it easier or harder for the virus to infect these cells; variants that enable viral entry might lead to more extensive lung infection and more serious symptoms, especially since these are the cells that normally produce surfactant, a substance that helps lungs to work properly.
Right now we don’t know enough about the new virus and how and why it causes disease to different extents in different people. Scientists around the world are hard at work analysing not only viral genome sequences, but also human genome sequences, to start piecing together this puzzle. There is also increasing concern about the disproportionately high numbers of black, Asian and minority ethnic individuals among severely ill patients; there may be complex causes behind this, including higher levels of poverty and related diseases, but it seems likely that genetic factors are playing a part – one that needs to be understood, and quickly.
Ultimately, better understanding could enable precision medicine for coronavirus infections, refining what we already know about who is at greatest risk of serious disease, and which treatments may be more or less effective in individual patients with severe symptoms. This may not happen in time to have a major impact on the current wave of infections – even with current technology, sequencing and analysing huge human genomes takes quite a long time – but it is worth pursuing with all speed - the more we learn now, the better prepared we will be for the future. Undoubtedly, human genomics will provide some important answers.