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Genetic and immune basis of severe COVID-19 cases revealed

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Two new research papers published in Science have uncovered the biological basis for over 10% of severe COVID-19 cases, revealing the critical importance of interferon in effective anti-viral responses.

Variation in COVID-19 severity

Infection with SARS-CoV-2 produces a wide range of responses in different individuals, ranging from completely asymptomatic infection through to overwhelming disease. Patients with severe disease need hospitalisation, and in many cases intensive care, for a chance of survival. However even with improvements in ventilation and other supportive care over the last six months, a significant proportion do not survive.

As the pandemic progresses, some of the risk factors for developing these most severe reactions have become apparent, with men more at risk than women, people of certain ethnicities more than Caucasians, and also older people and those with pre-existing conditions such as cardiovascular disease and diabetes. Even so, apparently low-risk healthy people can sometimes be badly affected and even die.

It is clear that at least some of the variation in disease severity between individuals must arise from innate factors, such as genomics, which has driven extraordinary efforts in research – alongside healthcare and health protection efforts to care for patients and protect the public – to try to understand this. Greater understanding can inform how best to care for those affected and also, potentially, to identify those at greatest risk.

New evidence on the impact of interferon

The new research identifies that 14% of patients with serious COVID-19 have significantly impaired or absent interferon responses; in particular, a lack of type 1 interferon. Interferon is an important mediator of the body’s normal immune responses to viral infection; release of different interferon proteins by infected cells stimulate immune cells to gear up for anti-viral action.

There were two different reasons for this lack of type 1 interferon response in the patient cohort; a minority of patients with severe COVID-19 pneumonia in a study by Zhang et al. were found to have a genetic mutation that blocked production of functional type 1 interferon proteins, which is just the sort of genetic risk factor that major research collaborations such as the COVID Human Genetic Effort have set out to identify.

However, a second paper by Bastard et al. reports that over 10% of patients with severe COVID-19 had antibodies against type-1 interferon, i.e. an auto-immune response that effectively disabled their interferon. Significantly, they did not find any patients with asymptomatic or mild SARS-CoV-2 infection with these auto-antibodies, and only a tiny proportion of uninfected people had them.

The auto-immunity phenomenon, which appears to be observed across different ethnicities - making it relevant world-wide – was observed mostly, though not exclusively (94%), in male COVID-19 patients.. This is despite the fact that autoimmunity in general is more common among women than men, which could go a long way towards explaining the previously observed higher risks of severe disease in men compared with women.

Implications for COVID-19 management

Each of these studies examined around 1,000 patients with severe disease, a very respectable sample size. It remains to be seen whether the same effect size will be seen in larger samples, but it seems likely that these findings are valid, and could represent an important step forward in the fight against COVID-19.

It appears that patients found to have mutations or auto-antibodies preventing type-1 interferon responses did not have previous history of severe reactions to viral infection, so the type-1 interferon response may be particularly important in the body’s response to SARS-CoV-2 compared with other viruses.

Patients with genetic mutations that prevent production could benefit from treatment with synthetic type-1 interferons, and others might benefit from efforts to boost existing type-1 interferon responses. Testing for auto-antibodies against type-1 interferon antibodies could also inform treatment choices for severely ill patients – and potentially, be used to reveal which people in the wider population are at high risk for severe disease and who would need additional protection from infection.

We can expect to see the emergence of more information about both the pathology of severe COVID-19 and the genomic and other biological risk factors that increase risk in the coming weeks and months, as researchers around the world continue incredible efforts to yield answers. These latest results may, however, be part of the bigger picture that leads us towards a proper understanding and effective management of the virus.

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