As we understand more about the role that the immune system plays in COVID-19, we may learn why some patients have much worse outcomes. James Hamblin discusses his recent story with Katherine Wells on the podcast Social Distance.

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What follows is an edited and condensed transcript of their conversation.

Katherine Wells: We keep looking for patterns in who is most affected by this coronavirus and why. It seems like the reports are constantly changing: At first it was supposedly only older people who were severely affected, and then it was people with underlying conditions. Are there other diseases that have such a wide range of manifestations, from asymptomatic to deadly?

James Hamblin: There are other diseases that can manifest in a wide variety of ways, but this one is unique in its unpredictability. What was striking to me is this period of anywhere from a few days to two weeks where you feel pretty sick, but not in ways that are unfamiliar to you. And then there is this sudden crash: within a matter of hours, you can’t breathe, and you feel like you might die.

Wells: Can we identify who is going to crash and who’s not? Or what the risk factors are?

Hamblin: We’re looking at those patterns right now. And we have basic ideas of that. But we can’t tell anyone with 100 percent certainty that it’s not going to happen to them.

Wells: What do we know about what actually makes someone crash?

Hamblin: There’s a phenomenon called the “cytokine storm.”

Wells: You’ve told me about this. It’s where your immune system basically freaks out and goes into overdrive, and your immune system actually kills you, not the virus.

Hamblin: Right, specifically by releasing these molecules called cytokines, which are like a fire alarm and which are telling your whole immune system, Hey, bring out everything you’ve got.

With a virus, your body’s immune system is trying to kill the virally infected cells and not kill the uninfected cells, which requires some precision.

This coronavirus seems pretty stealthy. It can sneak around your body for quite a while without setting off these alarm bells. That’s when you’re feeling a low-grade illness, and your body knows something’s wrong, but is not quite sure what.

And then there’s a tipping point where the immune system realizes, We know how to identify these cells now. Oh no, these virally infected cells are everywhere.

It’s that recognition process that causes this sudden decline we see in some patients. If we could detect the beginning phases of that response, people could theoretically be helped.

Wells: How many people are dying because of this cytokine storm, this overreaction of the immune system?

Hamblin: That storm is part of something that causes acute respiratory failure. It’s inflammation throughout the body, centered in the lungs, but it can affect all kinds of different places. There have been reports of brain hemorrhages, heart conditions, liver failure, kidney failure. Those effects may be initiated by the virus being in those organs, but they are ultimately accomplished by the body attacking its own cells and not knowing which ones have the virus in them and which ones don’t.

The hopeful news is that this virus is new to us. We don’t know exactly how it works. But the immune system is not new. People have been studying the immune system for quite some time. There aren’t new cells; there aren’t new cytokines or new processes that we don’t know about that are happening here. What I’ve been told by immunologists is that we may be able to reverse-engineer this process and identify it earlier and address it with medications that we already have to help people get through it.

Wells: We might be able to treat the immune system rather than the virus?

Hamblin: That cytokine-storm process happens in a lot of infectious diseases, and we can tamp it down. While we’re trying to find a drug that kills the virus itself, which could take a very long time, doctors are finding promise in targeting those signaling molecules that send the body into crash mode, and shutting them down.

Wells: I understand that this disease gets so severe because of an immune overreaction. But what implications does that have for who gets sick and why and how we can help treat people?

Hamblin: Your immune system functions as a reflection of your overall health. And part of that you can’t change, like your age and maybe some genetic predispositions. But part of it you can change.

Your immune system is also shaped on a more granular level over the years by your lifestyle, by sleeping well and eating well and avoiding stress and exercising. These things all have small impacts on those cytokines and how hypersensitive that immune system is, how efficient it is at targeting what it needs to target and not targeting what it doesn’t.

But not everybody can do those things. This disease is killing people of low socioeconomic status and people in traditionally marginalized racial groups in ways that are not genetic. The disease is killing the same people who are more likely to die of any disease. They’re predictable lines that we draw that shape a person’s overall resilience.

If you get sick, and you are just getting over another cold, you are almost certainly going to have a worse experience than if you were top of your game.

Wells: Because your immune system is tuckered out from fighting. But if your immune system is tuckered out from fighting off discrimination or environmental hazards or other conditions that you might have, then you will also have a harder time beating this. Is that right?

Hamblin: Yes. It’s this groundwork that we lay throughout the course of our lives. But we still perpetuate it every day. You probably saw the photos of homeless people in Las Vegas sleeping in a parking lot where social-distancing lines had been drawn? When you’re experiencing homelessness, that increases your risk of everything. Your baseline immune functioning is going to take a hit. If and when you do get sick, you are going to have a worse course of the disease and higher rates of death even if you have access to care. We see these exact same causal relationships with other diseases, like cardiac disease and cancer. In Chicago, more than half the people who have died of COVID-19 are African American.

Why does one 35-year-old white person with no chronic conditions have a worse experience than another 35-year-old white person with no chronic conditions? That’s an interesting academic question, which we could potentially one day understand. But if we want to know how to prevent half of the severe disease cases from escalating or how to prevent many thousands of people from dying, we have answers to that.

Wells: Because we know so little about the disease and the virus, we didn’t know if it could be it interacting with something very random in the body, and that’s why some people are getting really sick. But now that we know that a lot of the most severe illness comes from immune responses malfunctioning, so we actually know whose immune system is vulnerable to this. We know who’s at risk, because we already know how the immune system interacts with data that we do have.

Hamblin: We have very good predictors. It’s not just age and chronic disease. Those read to me now as euphemisms. It effectively ages you to not have stable income, to not be able to sleep at night, to not feel safe at home, to not have reliable access to good food.

These are things we could be addressing right now. We’re not going to turn around overnight a lifetime of patterns that have prematurely aged a person and worn down their immune system. But we can give them a better shot.

Wells: I understand how we can use this insight to increase our urgency to build a better, more fair society in the future. But these problems are already endemic; we’re not going to fix these things in time to make people less vulnerable.

My question is, now that we know much more about how the immune system is interacting with this disease, does that offer any new ways to think about treatment?

Hamblin: What makes this disease so scary is [its] capacity to decompensate so quickly. And if we could identify that earlier, we would be able to treat it better.

You could treat it by saying, Okay, we’re starting to see markers of this diffuse, inflammatory process within your blood. You should come in right now. We’re going to start tamping down your immune system.

Even if we can’t totally prevent that crash, we could do a lot better. Half of the people who come into NewYork-Presbyterian with COVID-19 are staying in ICU for 20 days, which is unheard-of. If you could get that down to 10, that would be a major improvement.

That’s what I’m hopeful for right now. I think we’re starting to identify these things.

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