Why the most unusual COVID cases matter

Like many people around the world and in Brazil where she lives, Parouhi Darakjian Kouyoumdjian became infected with the coronavirus last year; she had mild symptoms and recovered. But her case is remarkable: Kouyoumdjian is a centenarian.

Still, while the elderly are more likely to suffer severe and fatal cases of COVID-19, Kouyoumdjian is not alone. She is part of a study led by Mayana Zatz, director of the Human Genome Research Center at the University of São Paulo, to understand how very old people who became infected with SARS-CoV-2 can emerge unscathed.

The scientists are looking at genes from 15 centenarians — including those of a 114-year-old woman who also recovered from COVID-19 — to see whether there are any mutations that provided protection against the coronavirus.

"To survive until 114 years old is not easy, and to survive after having had COVID-19 is even more difficult," Zatz said. "I want to understand what makes someone survive."

Throughout the pandemic, there have been various kinds of medical anomalies. There are people who test positive for months and others who never get infected despite living in close quarters with COVID sufferers. Such surprising cases are often declared "outliers" and shrugged off (and, indeed, should be downplayed when designing public health policies for the general population), but unusual examples of any disease can offer important insights for scientists, and most critically, lead to new medicines for that illness and others.

The sheer, devastating scale of the coronavirus spread has also meant that there is a unique opportunity for researchers to advance knowledge of the immune system.

One famous example of a treatment arising from someone who is seemingly impervious to a disease: Stephen Crohn, whose partner became ill in 1978 with the disease later known as AIDS, became a beacon of hope for a new medication. Crohn's partner died, and so did many of his friends in the gay community, as HIV spread during the 1980s. But Crohn did not fall ill.

That's not the only time that unique genetic traits have inspired a new medicine. Almost two decades ago, scientists uncovered an intriguing link between mutations in a particular gene to sky-high cholesterol levels. They identified the mutated gene in a handful of families where many members had a condition called hypercholesterolemia, a risk factor for heart disease.

Ultimately, drug companies took notice and developed new drugs that targeted the same pathway as this gene that can be used to lower cholesterol even in people without the mutations. The first such medication received approval in 2015.

Outliers can appear as solitary cases, but in this pandemic they are often bellwethers. In February 2020, just as the pandemic began to accelerate, a 71-year-old woman who was immunocompromised by a kind of cancer that limited her ability to produce antibodies became infected with the coronavirus at a Washington nursing home. When scientists reported that she had tested positive for the coronavirus for at least 105 days and was infectious for at least 70 days, it seemed like an extraordinary case. But since then, there have been numerous cases of immunocompromised people who harbor the virus for months.

This, say the authors of one study (which has not yet been peer-reviewed) of another immunocompromised man who tested positive for more than 300 days until treated with antibody drugs, provides evidence that the branch of the immune system that makes antibodies is critical in fighting COVID-19.

Scientists have also learned that the long-lasting infections seen in some patients with weakened immune systems provide opportunities for the virus to evolve, likely contributing to the rise of new variants.

The insights about immunity gleaned from COVID-19 outliers could also help scientists developing treatments and vaccines for other diseases. For example, a lack of protection from vaccination is not a problem only for COVID-19.

Brianne Barker, a professor at Drew University in New Jersey who teaches virology and immunology, says that some people who receive the hepatitis B vaccine, for example, don't seem to produce antibodies from it. "If we could understand why they aren't responding, that could really help us understand the factors that allow for immune memory and vaccine protection," Barker said. Learning what elements in the body tend to weaken immune responses could also help scientists design treatments for autoimmune disorders.

The immune system is intricate, with myriad different kinds of cells and molecules. "The complexity of the immune system cannot be overstated," said Kaitlyn Sadtler, an immunologist at the U.S. National Institute of Biomedical Imaging and Bioengineering who has studied COVID-19. "It makes it amazingly effective but amazingly difficult to understand."

But studies are starting to provide clues, including one published last July that found genetic abnormalities in two pairs of young brothers, aged 21 to 32, who had severe COVID-19. The genetic changes are known to impair the role of an important immune system molecule called interferon. A few months later, in September, another paper in the journal Science identified gene mutations affecting the interferon response in people who developed severe COVID-19, including young adults, suggesting that giving these interferons to people who lack them might work as a therapy.

While identifying the biological vulnerabilities that make some people more prone to COVID-19's wrath is useful, it's equally important to spot what immune system traits might make a person stronger against the virus.