Sepsis: From Infection To AI

One of the most eagerly awaited dates on the scientific calendar has just arrived with the announcement of the winners of this year's ignobel prizes. Every year, some of the most unusual scientific studies - that famously make people laugh, but then stop and think - win this great honour. Chris Smith spoke with Marc Abrahams who founded the Ig Nobel Prizes and oversees the ceremony to talk through this year’s crop of the cream of scientific endeavour...

Marc - These are prizes for something unusual. So they may strike you as being important or completely worthless or whatever, but there's more to them than you expect. We've been doing this, as you point out, for 31 years now

Chris - When you set them up, did you think you'd be having a conversation with me 31 years later, or at least anyone, about this initiative?

Marc - I believe I did not have that very specific wish, but generally we hope that it will continue for a long time. We've been very happy to see that it has been, and we hope will be, continuing for quite a while

Chris - You came to Cambridge once and did a presentation during the Cambridge Science Festival on this and made everyone roar with laughter, but when you normally run them you normally do this on stage and people come to visit you for them. Obviously that hasn't happened because of the pandemic, has it?

Marc - Normally this happens at Harvard University here in the US inside the biggest theatre there, so there are 1100 people jammed into the audience and winners come - 10 winners a year - from around the World. We have a bunch of Nobel Prize winners there to shake their hands, and everybody's throwing paper aeroplanes at each other for an hour and a half. But yes, we couldn't do that because of the pandemic. So last year, and again this year, we've done the whole thing online, which is much more complicated, at least in a different way

Chris - What sorts of entries have you considered though? Because obviously that hasn't changed - people are still doing fantastic science around the World, despite the best efforts of coronavirus to thwart science

Marc - Yeah, we still get many thousands of new nominations every year. Let me just dive into a few of this year's. One of them was the Biology Prize, which went to a team in Sweden - Susanne Schötz and her colleagues. They analysed variations in purring, chirping, chattering, trilling, tweedling, murmuring, meowing, moaning, squeaking, hissing, yowling, growling and other modes of cat-human communication

Chris - I think we've actually got a clip of that one. Let's have a listen to her. This is her actually doing the cat noises...

<CAT NOISES>

Chris - I bet she's great fun at dinner parties

Marc - Yes, I bet you're right about that

Chris - The other one that caught my eye this year, as a microbiologist with an interest in all things microbes, was this paper on people looking at what's living in chewing gum. I love that

Marc - Yeah, this is a team in Valencia, Spain, that analysed chewing gum that they took off pavements in many different countries and they analysed what kinds of bacteria are living in those wads of chewing gum

Chris - And what did they conclude?

Marc - It's different. And also that if the gum has been there on the sidewalk for quite a while, if somebody goes and very carefully analyses that hunk of chewed chewing gum, you can get a sort of history of what was happening there on the bacterial level, because it changes from the surface down into the interior, about how things progressed during the long period that the gum was living on the sidewalk

Chris - Any other prizes that particularly stand out?

Marc - The explosion of press coverage initially seems to centre on the Transportation Prize we gave to a large international team for some work that they did in Namibia. They did some experiments to try to see whether it's safer to transport an airborne rhinoceros upside down. They were trying to move some of the rhinoceroses who are growing scarce from areas where they live now, which are becoming extremely dangerous, to areas quite a distance away that would probably be much safer places for them to live, but it's not such a simple thing to transport a rhinoceros. It was too far to do it easily and well by truck. So they were using helicopters. And the question came, how do you do this in a way that's safest for the rhinoceroses? They did some tests and discovered that health-wise, it seems to be notably better for the rhinoceroses to be dangled upside down by their legs. Before they did this with the rhinoceroses, they ran a bunch of tests on human beings - on themselves - dangling each other upside down

Chris - I've been on a few flights where it's been uncomfortable and leg room has been an issue. I hope this doesn't give our low-cost airlines any ideas

Marc - Possibly you haven't thought this through

Chris - Go on

Marc - Possibly this is a good idea

Chris - But did they actually do the experiment? Have they actually done the experiment with real rhinos, Marc?

Marc - Yeah, this has been going on for quite a while, and this has become now the standard method for transporting rhinos. And they're also starting to use this as a fairly standard method for transporting other very large animals - elephants and others. They have experiments planned for possibly giraffes and some additional kinds of animals

Chris - So this must be one wonderful example of how an Ig Nobel Prize winning paper was serious science that has not just made people laugh and think, but also translated into real positive action

Marc - Yeah, it's a good reminder that almost all science, when it's in its very first stage, involves just a small number of people doing something that might look kind of crazy to everybody except themselves

Chris - I'm going to keep my thinking cap on. We did make a chocolate teapot once. Maybe I'll send you our manuscript on the making of a chocolate teapot to test whether it really does actually hold water

Marc - That would be so kind of you, thank you

Sepsis has been known by a lot of different names in the past, from blood poisoning and septicaemia to ‘blood rot’ back in the 11th Century. But these terms all refer to the same dangerous condition, where the body’s exaggerated reaction to an infection causes severe collateral damage to its own organs and tissues. It’s a medical emergency, and the WHO estimates that it kills around 11 million people each year. Thankfully, prompt diagnosis and treatment can turn the tables on the condition. Eva Higginbotham spoke to Suzanne, a sepsis survivor, to hear her story...

Eva - Suzanne was a healthy 40 year old woman who, like many of us, seemed to catch a bit of a cold in the stressful run-up to Christmas three years ago.

Suzanne - I just started to get worse and worse, and I thought I was developing the flu. It came round to Christmas day and I was feeling really, really unwell but I managed to get to my family and my parents' house to spend an hour with them, when I was meant to be spending the whole day. I had to go home, just feeling really unwell. I was feeling terrible. Couldn't sleep. At four o'clock in the morning I was Googling symptoms about flu and for some reason thought maybe it's not flu, maybe I've got pneumonia. Quite quickly realised that my symptoms were much more like pneumonia rather than influenza. The advice was you must go and see your GP as soon as possible.

Eva - By this point she was so weak her husband had to drive her the hundred meters to her GPS office for her appointment the next morning

Suzanne - She did look a bit concerned, I think, when she saw me, but she put their sensor on my finger that measures your blood oxygen. It was in the 80 something percent, which is not good at all. I very clearly remember her saying, "I don't mean to alarm you, but I will be calling an ambulance and we'll be taking you to the Queen Elizabeth. You're not very well. You need to get to hospital as soon as possible."

Eva - Although Suzanne remembers the GP appointment, her memory pretty much goes blank for the next two weeks. She's had to rely on friends and family's descriptions of what happened next. She was rushed to hospital and put in intensive care before being put on a ventilator with her family waiting outside.

Suzanne - The consultant came back and said that things had spiralled out of control. I guess at some point in all of that, that's when it became apparent that I had sepsis. I don't really know at what point it was first diagnosed. I was on the ventilator, but my body had just kind of gone out of control and the oxygen that I was receiving through the ventilator wasn't enough to sustain me, to keep me going...

So, let’s explore what sepsis actually is, and how doctors treat it. Chris Smith spoke to Colin Begg from the Paediatric Intensive Care Unit in Glasgow...

Colin - The straight medical definition is essentially where your body gets an infection and then your immune system's reaction to that infection causes damage to your organs.

Chris - And how would a person who's going down that path know it's happening to them?

Colin - That's the million dollar question Chris. Really the initial signs of sepsis can be quite nonspecific. What we as medical professionals try to do is separate those people who have sepsis from those people who perhaps just have a bad infection. All sepsis starts with an infection and it's trying to identify those people who are going to progress on to sepsis. That is probably the hardest part of our job at times.

Chris - How quickly is it clear that someone is on that slippery slope from just what could be a trivial infection for most people to life-threatening overwhelming sepsis in that person?

Colin - It can be very fast. Sepsis is one of the few conditions in the modern world that can kill a healthy adult in a matter of hours. Globally it's still the number one cause of preventable death. Often we can get an idea within minutes by looking at somebody's vital signs and certain other simple tests that they are progressing to a more severe case of sepsis.

Chris - When we make the diagnosis, do we actually know, right this person's definitely got sepsis? Is that more a judgment call on the part of a doctor like you, who's putting together various measures and thinking, this person's not going in the right direction, they're heading towards this situation? Or are there some clear indicators this person has got sepsis?

Colin - There are clear indicators, but those can be quite non-specific. What I teach my registrars is, can they say for certain that this is not sepsis? Because the treatment is really broadly simple measures. By initiating those measures you can stop the cascade of sepsis very early and prevent people progressing to multiorgan failure, which is what you want to do. Really it's almost a 'shoot first ask questions later' approach a lot of the time in terms of the simple things we deliver like -  oxygen, antibiotics, intravenous fluids. Then it's a question of going back and constantly reassessing the patient. It's one of those situations where expertise can be key, bringing a senior person in to see the patient can often make a difference.

Chris - Are there certain groups of patients that are particularly vulnerable to this happening that we need to watch out for?

Colin - Yeah. Like many diseases. Sepsis affects disproportionately the very young and the very old, particularly the preschool toddler/infant group and also the elderly, people over the age of 70, and people that have got any sort of immune problems. Patients who are immunosuppressed because of cancer, HIV, rheumatological disease, they're all more vulnerable to sepsis than the general.

Chris - Are there any particular diseases that we associate with sepsis happening more frequently? If one person is diagnosed with them we know to watch out?

Colin - Particularly simple things like pneumonia, a chest infection, or certain types of skin infection like cellulitis, certain urine infections. All of those can progress towards sepsis fairly easily depending on the bug that is involved.

Chris - How long does it take for a person to turn the corner and then recover after a bout of sepsis?

Colin - Again, that varies. It very much depends on the person's premorbid state. If they were healthy beforehand then generally they will recover quicker but that is not always the case. Sepsis can take a terrible toll, particularly the multiorgan failure aspect of it. If you spend a fortnight in ICU on support, that takes a toll on your muscle strength, on your physical ability to do simple things like move and breathe. It can take a long process of rehabilitation before you get back to your normal self and some people say they never fully recover.

Chris - What fraction of people don't make it?

Colin - Globally, the fatality from sepsis varies. In the UK it's probably in the order of 15 to 25% mortality, which is high. That's in adults. In my own field in paediatrics our baseline mortality is in the order of 3%. For every hundred people who come into children's intensive care; sadly three of them will not make it through. For sepsis the fatality rate, the mortality is much higher than that, probably in the order of about 10 to 15%.

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.