What explains Covid-19’s lethality for the elderly? Scientists look to ‘twilight’ of the immune system

Researchers on Monday announced the most comprehensive estimates to date of elderly people’s elevated risk of serious illness and death from the new coronavirus: Covid-19 kills an estimated 13.4% of patients 80 and older, compared to 1.25% of those in their 50s and 0.3% of those in their 40s.

The sharpest divide came at age 70. Although 4% of patients in their 60s died, more than twice that, or 8.6%, of those in their 70s did, Neil Ferguson of Imperial College London and his colleagues estimated in their paper, published in Lancet Infectious Diseases.

The new estimates come as scientists have been scrambling to figure out the underlying reasons for older people’s greater susceptibility to the virus — and, in particular, why some mount a stronger immune response than others.

It starts with preexisting conditions: Data from China show that such comorbidities dramatically raise the risk of dying from Covid-19. But chronic illnesses may be not only a contributor to Covid-19 deaths but also a mark of biological aging and declining immunity.

“It is not chronological age alone that determines how one does in the face of a life-threatening infection such as Covid-19,” cautioned geriatrician and gerontologist George Kuchel of the University of Connecticut. “Having multiple chronic diseases and frailty is in many ways as or more important than chronological age. An 80-year-old who is otherwise healthy and not frail might be more resilient in fighting off infection than a 60-year-old with many chronic conditions.” Reason: She may have a younger immune system.

The new calculations, based on 70,117 laboratory-confirmed and clinically-diagnosed cases in mainland China and 689 cases among people evacuated from Wuhan on repatriation flights, allowed the Imperial College researchers to estimate the overall death rate from the disease. In the outbreak’s early weeks that was thought to be as high as 3% to 8%. Instead, the fatality rate among people with confirmed disease is 1.38%, they concluded.

That supports an estimate by researchers at the Harvard T.H. Chan School of Public Health earlier this month of a 1.4% fatality rate in confirmed cases.

The British group said the fatality rate among all of those infected with the new coronavirus — including those who don’t have symptoms — is 0.66%. By comparison, that is more than 30 times greater than the death rate for the H1N1 influenza, the cause of a 2009 pandemic, which was 0.02%.

The chance that a Covid-19 patient would develop symptoms severe enough to require hospitalization, especially for respiratory support, also rose sharply with age, Ferguson and his colleagues reported. In patients 80 and older, 18.4% did. While 12% of people in their 60s required hospitalization, 3.4% of 30-somethings and 1.1% of 20-somethings did. The sharpest difference came in late middle age: 4.3% of people 40 to 49 with Covid-19 required hospitalization, while 8.2% of 50-somethings did.

That is partly why the situation in Italy is so disastrous, with many hospitals overwhelmed by Covid-19 cases: The country’s median age (47) is the highest in Europe, and 23% of its people are 65 or older. Last week, doctors in Italy reported in the Journal of the American Medical Association that as of mid-March, 7.2% of Covid-19 patients had died. That might be partly explained by the high rates of infection among the elderly: 38% of Italy’s Covid-19 cases are in people 70 and older, compared to 12% in China.

The explanation for the generally heightened risk to the elderly, but also for the fact that Covid-19 kills many younger people even as some seniors survive, lies in a growing understanding of “immunosenescence.” Immunologists have identified some of the specific ways the immune system changes with age, allowing them to go beyond the simple assertion that it weakens.

“Older people are not as good at reacting to microorganisms they haven’t encountered before,” said physician and immunobiologist Janko Nikolich-Zugich of the University of Arizona College of Medicine. He calls it “the twilight of immunity.”

Our immune systems have two sets of defenses against viruses and other pathogens: a first-line army of cells, called leukocytes, that attack invading microbes within minutes to hours, and a second-line force of precisely targeted antibodies and T cells that surge to the battle front as late as several days after.

With advancing age, the body has fewer T cells, which produce virus-fighting chemicals. By puberty, the thymus is producing tenfold fewer T cells than it did in childhood, Nikolich-Zugich said; by age 40 or 50, there is another tenfold drop.

That leaves the body depleted of T cells that have not yet been programmed to defend against a specific microbe. Fewer such “naïve T cells” means fewer able to be deployed against a never-before-seen microbe.

“We just have fewer soldiers dealing with attackers we’ve never experienced before, like the new coronavirus,” Nikolich-Zugich said. (The body does retain the “memory T cells” that learned to fight attackers in youth, which is why immunization against smallpox and many other viral disease lasts decades.)

Another age-related change keeps T cells away from battle. Even before T cells enter the fray, other cells recognize invaders and dispatch natural killer cells and other soldiers to destroy as many as possible in the first few hours after infection. Then these same front-line cells literally show the virus to T cells, saying in essence, this is the enemy; produce virus-killing compounds.

“But this communication doesn’t work as well as we get older,” Nikolich-Zugich said. The instructor cells grow scarce and start to do the biological equivalent of mumbling. T cells therefore respond too late and too little.

Antibodies are made by B cells, and their decline is less precipitous than the fall-off in T cells. But old B cells, like old factories, can’t produce as much of their product — antibodies — as when they were new. Specifically, they have lower levels of the molecule that rearranges their genome so as to produce never-before-seen antibodies to a never-before-seen virus.

As if old age weren’t cruel enough, it brings one more change to the immune system: It slows down how quickly natural killer cells and other first responders hand off the defense to activated T cells and B cells. “This initial response remains in overdrive,” Nikolich-Zugich said. The core of that response is a fusillade of inflammatory molecules called cytokines.

That fusillade attacks the lungs and causes acute respiratory distress syndrome (ARDS), a common cause of Covid-19 deaths.

The cytokine barrage varies somewhat by sex, however. In a study published last month, Kuchel and colleagues showed that older men had, on average, more cytokine-producing cells than older women, who had more and better B cells and T cells.

That might explain the apparent, but still tentative, sex-based differences in the Covid-19 epidemic, with elderly men generally faring worse than elderly women. Hobbled B and T cells leave the body with fewer anti-coronavirus defenses.

Immunosenescence spells bad news if the new coronavirus continues to circulate, even at sub-pandemic rates, because it suggests that older people who have survived Covid-19 may not have robust immunity should they be exposed to the virus again.

With the flu, younger people have a stronger “immune memory” than older people — their T cells and B cells primed to attack if a flu virus they contracted decades ago returns. If immune memory for coronavirus resembles that for flu, Kuchel said, then “young people will be much more protected when it comes back.”