Why do some people get extremely sick with COVID-19 while others have benign symptoms? Three key molecules appear to play a crucial role, new research revealed this week.
These key indicators, which are all found in the bloodstream of critically ill patients, can be characterized as specific cytokines or hormone-like molecules that are produced by the immune cells in the body and can regulate the immune response. When overproduced, cytokines accelerate inflammation and can have serious consequences.
Their scientific names won’t mean much to the average reader – EN-RAGE, TNFSF14, and Oncostatin-M – but researchers at Stanford University School of Medicine along with others in Atlanta and Hong Kong believe these specific molecules could help shed light on exactly what̵
“One of the big puzzles with COVID-19 infection has been that some people develop serious illnesses while others appear to recover quickly,” said Bali Pulendran, lead author on the study and Stanford Professor of Pathology, Microbiology and Immunology. “Now we have some insight into why this is happening.”
The researchers found higher concentrations of these molecules in the blood of very sick patients. Scientists are now working to block the activity of these molecules as a potential therapy for the disease, hoping to help very sick patients whose immune systems are overreacting to the virus.
The study, published Tuesday in the journal Science, looked at the immune system responses of 76 COVID-19 patients and 69 uninfected people from Hong Kong University’s Princess Margaret Hospital and Emory University’s Hope Clinic in Atlanta.
When an infection like COVID-19 occurs, the body’s immune system produces cytokines that help the body fight the virus. When too many cytokines are produced, it leads to an immune system malfunction and an attack on the body. This can lead to life threatening symptoms.
The three specific molecules found in high concentrations in the most seriously ill patients had not previously been identified in COVID-19 patients, the Stanford study shows. Researchers are now testing therapeutic drugs that target these molecules as possible treatments. A drug that inhibits the activity of the TNFSF14 molecule, also called LIGHT, is expected to reduce inflammation. It is similar to the anti-inflammatory steroid dexamethasone, which is hailed for improving outcomes in extremely sick coronavirus patients, but is more targeted and could be more effective against one of the most commonly produced molecules in these patients.
Pulendran and other Stanford researchers are conducting a study in September testing the drug on hamsters. If they’re successful, they’ll test it on non-human primates, then humans.
The study also found high levels of bacterial debris in the blood of extremely sick COVID-19 patients. The study’s authors believe these entered the bloodstream from the lungs or intestines, demonstrating the far-reaching effects of the infection. The scientists suspect that debris contributes to the overproduction of the molecules in very sick patients. They hope another study will reveal more about the progression of the disease.
The study’s authors found something else surprising: although extremely ill patients had widespread inflammation in the lungs, the innate immune system in their blood was suppressed. The researchers want to investigate what this means for recovered COVID-19 patients, such as whether they are susceptible to blood-borne infections.
While researchers now know more about what happens in the body’s immune system when someone becomes seriously ill with COVID-19, it is not yet clear what causes this reaction. People with health problems like diabetes are more prone to worse results, but how these risk factors affect a person’s immune system hasn’t been thoroughly scientifically studied, Pulendran said. That study didn’t have enough samples to assess the effects, he added.
Working with Emory researchers, Pulendran and colleagues are now enrolling hundreds of non-COVID-19 healthcare workers in a baseline study to collect blood samples every two weeks. If participants become infected, the researchers will look to see if those patients’ immune systems have anything else that may have made them susceptible to developing a more severe disease.
The study helps shed light on the sometimes confusing experiences of tens of thousands in the Bay Area infected with the virus. This includes a Sunnyvale family who have all received COVID-19 with a variety of symptoms.
Connie Lares Ruspini, a medical interpreter at Lucile Packard Stanford Children’s Hospital, spent her April 7th birthday checking her family’s temperatures and oxygen levels and listening to their lungs. Her daughter Natalia, 16, felt tired, her body ached and she had difficulty breathing. Her husband Diego coughed, had a fever and vomited. Ruspini himself had joint pain, a slight fever and lost appetite. The couple both had diarrhea. Her 12-year-old son Santiago had no symptoms – other than eating three times as much as he normally would.
The family’s nanny, who was already suffering from diseases like obesity, high blood pressure and diabetes, dropped to dangerously low levels of oxygen and was treated in the intensive care unit for about 10 days. Diego, who has asthma, also spent a week in the hospital on oxygen.
The whole family tested negative in the first week of May. The nanny was given oxygen at home for six weeks after her hospital stay and continues to have difficulty breathing, Ruspini said. Sometimes Diego is still tired and his chest feels tight. In contrast, Ruspini, fully recovered, climbed Mount Whitney on August 3rd.
“There was a tremendous fear in this family,” said Ruspini. “I would hope people take this seriously … because it can be devastating. We are lucky that everyone made it, even though they have a suitcase and are sick. “
Mallory Moench is a contributor to the San Francisco Chronicle. Email: [email protected] Twitter: @mallorymoench