Why was a marathon runner in his 40s stricken with a case of COVID-19 so severe it landed him in the intensive care unit? Why did a healthy 12-year-old boy lose his life to a disease that mostly harms older people? One of the most terrifying aspects of the pandemic is that the severity of the disease seems so cruelly and arbitrarily variable.

Although the SARS-CoV-2 virus is most often fatal in patients who are elderly or have chronic medical conditions such as diabetes, heart disease or high blood pressure, exceptions that bring down apparently healthy young people are commonplace. Even patients who do not die of the infection show a huge spread in their symptoms: Some never get sick; some need to be hospitalized but recover; some have lingering disabilities that last for months.

So far, scientists have been largely at a loss to explain why COVID-19 hits patients as hard as it does, though reasons surely exist. Its not just bad luck, said Helen Su, an immunologist at the National Institute of Allergy and Infectious Diseases.

One possibility under investigation is that some people harbor genes that put them at greater or lesser risk from COVID-19. The COVID Human Genetic Effort, for example, is enrolling hundreds of patients from around the globe who wound up in intensive care after infection with the SARS-CoV-2 virus. Initially, the project only enrolled patients who were under age 50 and had no underlying health conditions, though it has more recently expanded eligibility.

My hope is to understand the genetic basis of severe COVID in patients of all ages and regardless of comorbidities, said Jean-Laurent Casanova, a researcher in pediatric medicine and immunology at the Rockefeller University who co-founded the project with Su and others. And from that, to understand the mechanism that makes them vulnerable to SARS-CoV-2.

Some genetic clues may already be coming to light. Last week, a team of researchers in the Netherlands published a preliminary communication online in JAMA about four young male patients from two families who all suffered severe COVID-19 respiratory illnesses. The men, who were between the ages of 21 and 32, had no history of chronic medical problems, but DNA sequencing revealed that each of them had a rare form of a gene on his X chromosome that was linked to a deficient immune response. Much more study will be needed to determine whether similar deficiencies, possibly involving other genes, are common among COVID-19s worst cases.But in a study appearing in Nature today, researchers at the Yale University School of Medicine who followed the progression of COVID-19 in 113 hospitalized patients for two months found that greater severity of the disease was associated with maladaptive immune responses. (The causes for those immunological misfires was not determined.)

The significance of these discoveries may not be limited to COVID-19. Casanova is a champion for an idea that has been slowly gaining credence among medical researchers for many years: that genetics is always a factor in infectious diseases. Many if not all people may have very specific genetic vulnerabilities, such as weaknesses in their immune system, that go unnoticed until one particular pathogen crosses their path. That genetic trait is their Achilles heel, and that pathogen is the one thing that can take advantage of it.

The theory has emerged out of both clinical practice and scientists growing appreciation of the interconnection between genes and infectious diseases. Casanova has spent the past 25 years scanning the genomes of young people who were inexplicably debilitated by commonplace pathogens like the herpes simplex and varicella zoster viruses (which cause cold sores and chickenpox, respectively). In these children, who showed no outward symptoms of compromised immunity, he has found defects in genes that make them susceptible to severe infection with a single pathogen. In most cases, there were no clinical signs of a genetic problem until they were infected.

For many of these immune deficiencies where children or adults have very severe infections there is a genetic basis, said Trine Mogensen, a physician at Aarhus University and a member of the COVID Human Genetic Effort steering committee.

If the COVID project succeeds in finding genes relevant to the course of the infection, it could fuel interest in widening that search for other conditions. Further work on the interplay of infections, immunity and genomes could change how future gene-based medicine routinely diagnoses and treats diseases.

Infectious disease has always been one of greatest threats to humanity. Before the invention of antibiotics, infections killed half of all children by age 15. Yet as terrible as their collective toll has been, even the worst infectious diseases kill relatively few of those they infect. Tuberculosis has been a scourge, but fewer than 10% of people infected with it even get sick. Even the terrible Spanish flu pandemic that started in 1918 had a mortality rate often estimated at around 2.5%.

Variability in disease severity is usually chalked up to circumstantial factors: the virulence of different pathogen strains, the amount of pathogen exposure, the nutrition or general health of a patient. Researchers have suspected, however, that something more is lurking in the genes of the hardest-hit patients.

The idea of a genetic component to infection dates back to 1905, when an English scientist named Rowland Biffen discovered a gene responsible for a devastating fungal disease called yellow rust that was killing wheat and diminishing crop yields across England. He found that resistance to the fungus was present in some of the plants as a recessive trait passed down from parent to offspring without affecting other characteristics of the plant. The discovery was celebrated, and his method of breeding for resistant plants is still widely used today.

These types of genes were later found in other plants and animals. But genetic immunodeficiencies in humans didnt start to attract attention until the 1950s, when an immune disorder was identified in an 8-year-old boy being treated at Walter Reed Army Medical Center for recurrent blood infections. The disorder, known as X-linked agammaglobulinemia, inhibits the bodys ability to make the antibodies called gamma globulins, resulting in severe infections even from fairly innocuous pathogens.

The boy had suffered 19 bouts of pneumococcal meningitis, which were repeatedly treated with antibiotics. His condition improved more lastingly only after his physician, Ogden Bruton, discovered that the boy had almost no gamma globulins in his blood. Bruton promptly began treating him with monthly injections of gamma globulins, and the boy survived to adulthood. The discovery, which was described in Pediatrics in 1952, was later recognized as a milestone, highlighting the role of defects of the immune system in inhibiting the fight against infection. These defects were later termed inborn errors of immunity.

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Our Genes May Explain Severity of COVID-19 and Other Infections - Quanta Magazine