How the coronavirus goes from mild to deadly in 7 steps

• Two new Chinese studies outline a step-by-step path for how the coronavirus kills patients.
• Both studies found that critical patients undergo an aggressive immune response that causes their bodies to deteriorate quickly.
• Most coronavirus deaths are due to respiratory failure, but many patients also experience failure in other organs, including the kidneys and heart.

Researchers have by now developed a good picture of the common symptoms of COVID-19, but explaining why some cases get so much more severe than others is still a challenge.

Since the coronavirus is a respiratory infection, the main cause of death is usually respiratory failure, meaning the lungs aren't supplying enough oxygen to the blood. But the virus can also damage the heart, kidneys, intestines, and liver.

An emerging body of research suggests that the very mechanism designed to protect our bodies from infection — our immune response — causes some cases to go from mild to critical. A new review from Chinese researchers at Zunyi Medical University found that an aggressive immune response called a "cytokine storm" may be a key factor in coronavirus deaths.

Another study out of Wuhan University (which is still awaiting peer review) found that coronavirus patients "undergo significant immune dysregulation" after they're infected, which can cause their bodies to deteriorate quickly. The study examined the decline of 18 coronavirus patients from the time they were admitted to the hospital to the day they died — an average period of around two weeks.

Both studies outlined a step-by-step path for how the coronavirus kills patients:

• Step One: The virus' spiky proteins latch onto cell receptors found throughout the body called ACE2. It starts by binding to ACE2 receptors in the lungs.
• Step Two: The immune system senses a threat and responds by activating white blood cells. Wuhan researchers found an "obvious increase" in two types of white blood cells — leukocytes and neutrophils — and a decrease in lymphocytes (another type of white blood cell) among critically ill patients. In an article that's still awaiting peer review, Beijing researchers found that this high neutrophil-to-lymphocyte ratio was an early predictor of severe illness.
• Step Three: White blood cells release too many cytokines: proteins that further activate the immune response and trigger inflammation in the body. Wuhan researchers found elevated levels of a key cytokine called interleukin-6 (IL-6) among severe and critically ill patients.
• Step Four: This "cytokine storm" prompts white blood cells to attack healthy lung tissue. The reaction can lead to severe symptoms including blood clots, excessive leaking in the blood vessels, fluid in the lungs, depleted oxygen in the blood, and low blood pressure. Wuhan researchers found extremely high levels of D-dimer, a protein fragment that signals the presence of blood clots, among severe and critically ill patients.
• Step Five: An aggressive immune response can damage the lungs, heart, kidneys, intestines, and liver. Wuhan researchers found elevated levels of two proteins that may signal a heart attack — highly sensitive troponin I and C-reactive proteins — among severe and critically ill patients. Those people also had decreased levels of albumin, a sign of kidney or liver problems.
• Step Six: Proteins and dead cells form a membrane around the alveoli (tiny air sacs in the lungs), making it difficult to absorb oxygen. This can lead to acute respiratory distress syndrome (ARDS), a life-threatening lung injury.
• Step Seven: Most coronavirus deaths are due to respiratory failure, but many patients also experience multiple organ failure. Out of 18 patients who died in the Wuhan study, 17 developed ARDS, 10 suffered from acute cardiac injury, and 7 suffered from acute kidney injury. All but one patient presented signs of a secondary bacterial infection on the day of death.

Both the Zunyi and Wuhan researchers stressed the importance of treating symptoms early.

Once a cytokine storm is set in motion, the chances of survival go down. The Chinese Academy of Medical Sciences recently determined that knowing precisely when to block that storm is critical to reducing the death rate among coronavirus patients.

The studies also point to how complicated treatment can be in the absence of antiviral drugs or a vaccine. The Zunyi researchers determined that preventing organ failure should be the cornerstone of any coronavirus treatment, while the Wuhan researchers suggested that doctors might also need to address bacterial infections.

The Wuhan scientists cautioned, however, that although their study "might provide clues" about how the disease progresses, a better understanding of critical cases is "essential to the control and treatment of this epidemic."