Europe is in the grip of yet another deadly heatwave. Over 10,000 excess deaths were recorded during late-June 2026 alone – and the toll keeps climbing.
With the acceleration of the climate crisis, heatstroke is predicted to become more prevalent. Understanding why it is so often fatal is now an urgent question.
Heatstroke happens when the body’s core temperature climbs above 40°C. This can cause the brain to malfunction, resulting in confusion and seizures. It can also cause muscles to break down and flood the bloodstream with damaging cellular waste.
All of this is dangerous on its own. But direct heat damage doesn’t fully explain why patients can die hours or days after their temperature has returned to normal. The answer lies in the immune system’s response.
Heatstroke tricks the body into launching the kind of all-out inflammatory attack it normally saves for life-threatening infections. Except there is no infection: the immune response is activated with no clear target, and it stays hyperactive long after the body has cooled. This hyperactive inflammatory response can overwhelm and shut down vital organ functions.
Starts in the gut
The exact sequence of events is still debated, but the trouble is thought to start in the gut. When your body overheats, it pulls blood away from the organs and pushes it toward the skin, trying to dump heat. The gut is suddenly starved of blood flow.
The intestines are lined with a barrier that keeps trillions of bacteria safely contained. When that barrier loses its blood supply, it is thought to become destabilised. Microbial components leak into the bloodstream and promptly activate the immune system.
At the same time, heat-damaged cells throughout the body release their own distress signals. The immune system is receiving activating signals from two sides at once. The result is a runaway chain reaction of inflammation, strikingly similar to what happens in sepsis or severe COVID.
My research focuses on white blood cells called neutrophils. They are the immune system’s first responders: fast, aggressive, armed with chemicals intended to destroy bacteria. They are usually part of the protective inflammatory response – an evolutionarily ancient mechanism that fights infection and allows wounds to heal.
In heatstroke, body-wide “systemic” inflammation causes neutrophils to go into overdrive, much like they do in sepsis. They release enzymes (specialised proteins that break down other molecules) that destabilise blood vessel walls and damage organs. Recent research suggests they stay in this hyperactive state for days, even after the person’s temperature has returned to normal.
Neutrophils can also inappropriately activate the blood clotting system. The enzymes they release during heatstroke can trigger the formation of tiny clots in capillaries (tiny blood vessels) throughout the body. This chokes off blood supply to the kidneys, liver and brain.
In animal studies, preventing inflammation-induced blood clots improved survival. That’s a clue that targeting what neutrophils do, not just cooling the patient, could be the key to better treatment.
Cruel paradox
Here is the cruel paradox. By the time someone reaches a hospital and is immersed in cold water, the immune cascade is already running on its own momentum. Cooling removes the trigger, but it doesn’t stop the reaction. This is why survivors sometimes develop kidney failure or brain damage in the days that follow.
Some people are far more vulnerable than others. Older adults and babies struggle to regulate body temperature. So do people with heart disease, diabetes or obesity, and those on common medications like diuretics, antidepressants and blood pressure drugs. Alcohol, dehydration and social isolation also increase the risk.
Athletes and outdoor workers face a different problem: pushing their bodies past what their cooling systems can handle.
Right now, the only real treatment is to cool the person down as fast as possible. That saves lives, but it’s not enough. The next step is finding ways to calm the immune response itself – to rein in the neutrophils, break up the dangerous clots, and protect the gut barrier before it fails.
Borko Amulic receives funding from UKRI Medical Research Council.
