Sepsis: influenced by your genes

Sepsis is an immune overreaction to infection that ultimately culminates in the body effectively shooting itself in the foot and damaging its own tissues, sometimes fatally. This is what nearly happened to Suzanne, who spoke to Eva Higginbotham a bit earlier...

Eva - After the ventilator in Glasgow wasn’t enough, Suzanne ended up being transferred through the night by a team of off-duty doctors and nurses to a hospital in Aberdeen who could deliver specialist treatment, which she thankfully responded well to despite being in liver and kidney failure already. Once back in Glasgow and doing better, her sedation was lifted…

Suzanne - The sedation was lifted when I came off the ventilator and it was, you know, trying to understand what had happened. Two weeks of my life had kind of disappeared, and I couldn't understand why I'd been in Aberdeen and what was going on. And then it was just kind of trying to recover from that, and being in intensive care and just lying in a bed for two week you lose a lot of your muscle mass. So it was, you know, I thought I could just stand up and get out of bed, but it took three or four physios to get me standing for the first time. Full recovery to full fitness was probably about a year, but I did go back to work on a phased return after about four months. It's amazing what one small pathogen can do, what a few small pathogens... I think that's the thing with sepsis, that so much of it is misunderstood, or not misunderstood, it's just not understood, why sepsis happens with one person and not another person

And that’s the key question: how an infection that’s relatively trivial for one person can cause a lethal catastrophic reaction in another. Some of that might be down to differences in our DNA. Kenneth Ballie studies the role of genetics in sepsis at the University of Edinburgh and spoke with Eva Higginbotham...

Kenneth - Well, your genes provide the code from which the whole of your immune system is created. So everything in your immune system is potentially altered by your genes

Eva - And how much variation is there between people's immune systems due to DNA, because of course, people's immune systems change all the time just from being in different parts of the world, being exposed to different infections, et cetera.

Kenneth - Yes, and you'd think that if you get an infection that the reason that's happened is because you've been exposed to a bug and that's what's causing you to become sick. But in fact, the degree of sickness you get is very strongly influenced by your genes. So in the 1980s, a group of scientists looked at people who were adopted in Scandinavia and found that if your adoptive parent died young of an infection, remember that's the person who brought you up, who you called mum or dad, and who may even have coughed on you during their final illness, you're no more likely to die of an infection yourself if you're adoptive parent died of one. But if your biological parents, someone you might never have met in your entire life, died of an infection, then you're six times more likely to die of infection yourself.

Eva - And is that then, that amazing statistic, is that then because your DNA has the code for making your white blood cells and the other cells that play important roles in your immune system?

Kenneth - Yes. So the immune system is an incredibly complex system, probably second only to consciousness in the level of complexity in the body. And of course, consciousness hasn't had to change since it first evolved, whereas your immune system changes the threats that it has to fight with each new generation of organisms. So it's become an incredibly complicated system. The other thing that makes it complicated is that the organisms themselves, the bugs that infect us directly, interfere in the function of your immune system. So if there's a vulnerability in it, the bugs find it. So trying to understand that system has been a colossally difficult challenge.

Eva - And so you've been trying to understand the link between people's genetics and sepsis. What have you been doing and what have you found so far?

Kenneth - We've been trying to use genetics to understand that system, to really find a shortcut to find the components of the immune system that change. The outcome for the patient and the reason of course we want to find those is because we want to find parts of the system that we might be able to change with a drug treatment. To do that we need to compare DNA from the right people, patients who are unfortunate enough to become desperately sick with sepsis and need care and intensive care units, and compare them to the rest of the population to find out what specifically in their DNA, what in their genes is different about them that's led to them becoming so desperately sick.

Eva - And have you identified any differences in the genes so far?

Kenneth - We find many differences in genes relating to COVID, but not in sepsis yet. So sepsis is a very difficult challenge. I think, as Andy hinted at in his interview, the definition of sepsis is very, very broad. So it's really hundreds of different diseases. And so in order to tackle that problem, using genetics, we're going to need to recruit very, very large numbers of patients. In fact, we've recruited many more patients with COVID into our studies than we have so far managed to recruit with sepsis. And of course, the reason for that is that intensive care medicine all over the world for the last year and a half has been very dominated by huge numbers of patients with COVID.

Eva - So seeing as your genetics has such an influence on your immune system, does that mean then that if you develop certain illnesses like sepsis or COVID that you just have a sort of weaker genetically defined immune system?

Kenneth - Not always, there are immunodeficiency diseases that often present in childhood in which part of the immune system is broken if the patient is born with that problem. But what we're teasing apart in COVID and sepsis is more the genetic tweaking of the immune system to make it better at one thing and worse at another. So the mantra in evolutionary biology is that adaptation comes at a cost. It's likely that the patients that we're seeing who are genetically susceptible to COVID or sepsis are probably resistant to something else. And we do have examples of that. So for example, in HIV, there was a group of sex workers in Africa who were exposed to HIV and never got it. And many of them were found to have a specific genetic mutation that made it hard for the virus to get into their cells. And that exact mutation that made them resistant to HIV, were the same people susceptible to a different virus called West Nile Virus, and in fact, a couple of other viruses. So those sorts of patterns probably exist across the whole immune system.

Eva - So how could a better understanding of the genetics lead to better outcomes for patients? How might this work in practice?

Kenneth - The effect of a gene is sometimes a bit like the effect of a drug. So it changes the way a bit of your immune system behaves at a molecular level. And in some cases we understand those mechanisms a bit. So where we find those sorts of signals, where we find that gene that changes your chance of becoming desperately sick with COVID or sepsis, and we've got some understanding of the biology of the molecular interactions that gene has, we might be able to design treatments that will have the same effect, the effect of preventing or ameliorating critical illness. And we've come quite close to doing that in COVID. There are two treatments that were inspired, at least in part, by genetic evidence that we provided early in the outbreak from a large study in intensive care units in the UK that are now being tested in the Recovery Trial. We don't have answers yet, but there's evidence from other trials that they might be effective.