Dr. Megan Ranney has learned a lot about Covid-19 since she began treating patients with the disease in the emergency department in February.
But there’s one question she still can’t answer: What makes some patients so much sicker than others?
Advancing age and underlying medical problems explain only part of the phenomenon, said Ranney, who has seen patients of similar age, background and health status follow wildly different trajectories.
“Why does one 40-year-old get really sick and another one not even need to be admitted?” asked Ranney, an associate professor of emergency medicine at Brown University.
In some cases, provocative new research shows, some people — men in particular — succumb because their immune systems are hit by friendly fire. Researchers hope the finding will help them develop targeted therapies for those patients.
In an international study in Science, 10 percent of nearly 1,000 Covid-19 patients who developed life-threatening pneumonia had antibodies that disable key immune system proteins called interferons. These antibodies — known as autoantibodies, because they attack the body itself — weren’t found at all in 663 people with mild or asymptomatic Covid-19 infections. Only four of 1,227 healthy patients had the autoantibodies. The study was led by the Covid Human Genetic Effort, which includes 200 research centers in 40 countries.
“This is one of the most important things we’ve learned about the immune system since the start of the pandemic,” said Dr. Eric Topol, executive vice president for research at Scripps Research in San Diego, who wasn’t involved in the new study. “This is a breakthrough finding.”
In a second Science study by the same team, the authors found that an additional 3.5 percent of critically ill patients had mutations in genes that control the interferons involved in fighting viruses. Given that the body has 500 to 600 of those genes, it’s possible that researchers will find more mutations, said Qian Zhang, lead author of the second study.
Interferons serve as the body’s first line of defense against infection, sounding the alarm and activating an army of virus-fighting genes, said virologist Angela Rasmussen, an associate research scientist at the Center for Infection and Immunity at Columbia University’s Mailman School of Public Health.
“Interferons are like a fire alarm and a sprinkler system all in one,” said Rasmussen, who wasn’t involved in the new studies.
Lab studies show that interferons are suppressed in some people with Covid-19, perhaps by the virus itself.
Interferons are particularly important for protecting the body against new viruses, such as the coronavirus, which the body has never encountered, said Zhang, a researcher at Rockefeller University’s St. Giles Laboratory of Human Genetics of Infectious Diseases.
When infected with the novel coronavirus, “your body should have alarms ringing everywhere,” Zhang said. “If you don’t get the alarm out, you could have viruses everywhere in large numbers.”
Significantly, patients didn’t make autoantibodies in response to the virus. Instead, they appeared to have had them before the pandemic even began, said Paul Bastard, the antibody study’s lead author, who is also a researcher at Rockefeller University.
For reasons that researchers don’t understand, the autoantibodies never caused a problem until patients were infected with Covid-19, Bastard said. Somehow, the coronavirus, or the immune response it triggered, appears to have set them in motion.
“Before Covid, their condition was silent,” Bastard said. “Most of them hadn’t gotten sick before.”
Bastard said he now wonders whether autoantibodies against interferon also increase the risk from other viruses, such as influenza. Among patients in his study, “some of them had gotten flu in the past, and we’re looking to see if the autoantibodies could have had an effect on flu.”
Scientists have long known that viruses and the immune system compete in a sort of arms race, with viruses evolving ways to evade the immune system and even suppress its response, said Sabra Klein, a professor of molecular microbiology and immunology at the Johns Hopkins Bloomberg School of Public Health.
Antibodies are usually the heroes of the immune system, defending the body against viruses and other threats. But sometimes, in a phenomenon known as autoimmune disease, the immune system appears confused and creates autoantibodies. This occurs in diseases such as rheumatoid arthritis, when antibodies attack the joints, and Type 1 diabetes, in which the immune system attacks insulin-producing cells in the pancreas.
Although doctors don’t know the exact causes of autoimmune disease, they’ve observed that the conditions often occur after viral infections. Autoimmune diseases are more common as people age.
In yet another unexpected finding, 94 percent of patients in the study with the autoantibodies were men. About 12.5 percent of men with life-threatening Covid-19 pneumonia had autoantibodies against interferon, compared with 2.6 percent of women.
That was unexpected, given that autoimmune disease is far more common in women, Klein said.
“I’ve been studying sex differences in viral infections for 22 years, and I don’t think anybody who studies autoantibodies thought this would be a risk factor for Covid-19,” Klein said.
The study might help explain why men are more likely than women to become critically ill with Covid-19 and die, Klein said.
“You see significantly more men dying in their 30s, not just in their 80s,” she said.
Akiko Iwasaki, a professor of immunobiology at the Yale School of Medicine, noted that several genes involved in the immune system’s response to viruses are on the X chromosome.
Women have two copies of this chromosome — along with two copies of each gene. That gives women a backup in case one copy of a gene becomes defective, Iwasaki said.
Men, however, have only one copy of the X chromosome. So if there is a defect or a harmful gene on the X chromosome, they have no other copy of the gene to correct the problem, Iwasaki said.
Bastard noted that one woman in the study who developed autoantibodies has a rare genetic condition in which she has only one X chromosome.
Women more likely to be ‘long-haulers’
Scientists have struggled to explain why men have a higher risk of hospitalization and death from Covid-19. When the disease first appeared in China, experts speculated that men suffered more from the virus because they are much more likely to smoke than Chinese women.
Researchers quickly noticed that men in Spain were also more likely to die of Covid-19, however, even though men and women there smoke at about the same rate, Klein said.
Experts have hypothesized that men might be put at higher risk by being less likely to wear masks in public than women and more likely to delay seeking medical care, Klein said.
But behavioral differences between men and women provide only part of the answer. Scientists say it’s possible that the hormone estrogen may somehow protect women, while testosterone may put men at greater risk. Interestingly, recent studies have found that obesity poses a much greater risk to men with Covid-19 than to women, Klein said.
Yet women have their own form of suffering from Covid-19.
Studies show that women are four times more likely to experience long-term Covid-19 symptoms, lasting weeks or months, including fatigue, weakness and a kind of mental confusion known as “brain fog,” Klein said.
As women, “maybe we survive it and are less likely to die, but then we have all these long-term complications,” she said.
After reading the studies, Klein said she would like to learn whether patients who become severely ill from other viruses, such as influenza, also harbor genes or antibodies that disable interferon.
“There’s no evidence for this in flu,” Klein said. “But we haven’t looked. Through Covid-19, we may have uncovered a very novel mechanism of disease, which we could find is present in a number of diseases.”
To be sure, scientists say the new study solves only part of the mystery of why patient outcomes can vary so greatly.
Researchers say it’s possible that some patients are protected by previous exposure to other coronaviruses. Patients who get very sick also may have inhaled higher doses of the virus, such as from repeated exposure to infected co-workers.
Screening patients for autoantibodies against interferons could help predict which patients are more likely to become very sick, said Bastard, who is also affiliated with the Necker Hospital for Sick Children in Paris. Testing takes about two days. Hospitals in Paris can now screen patients on request from a doctor, he said.
Although only 10 percent of patients with life-threatening Covid-19 have autoantibodies, “I think we should give the test to everyone who is admitted,” Bastard said. Otherwise, “we wouldn’t know who is at risk for a severe form of the disease.”
Bastard said he hopes his findings will lead to new therapies that save lives. He noted that the body manufactures many types of interferons. Giving patients a different type of interferon — one not disabled by their genes or autoantibodies — might help them fight off the virus.
In fact, a pilot study of 98 patients published Thursday in the Lancet Respiratory Medicine journal found benefits from an inhaled form of interferon. In the industry-funded British study, hospitalized Covid-19 patients randomly assigned to receive interferon beta-1a were more than twice as likely as others to recover enough to resume their regular activities.
Researchers need to confirm the findings in a much larger study, said Dr. Nathan Peiffer-Smadja, a researcher at Imperial College London who wasn’t involved in the study but wrote an accompanying editorial. Future studies should test patients’ blood for genetic mutations and autoantibodies against interferon to see whether they respond differently from others.
Peiffer-Smadja said inhaled interferon may work better than an injected form of the drug because it’s delivered directly to the lungs. While injected versions of interferon have been used for years to treat other diseases, the inhaled version is still experimental and not commercially available.
And doctors should be cautious about interferon for now, because a study led by the World Health Organization found no benefit to an injected form of the drug in Covid-19 patients, Peiffer-Smadja said. In fact, there was a trend toward higher mortality rates in patients given interferon, although the finding could have been due to chance. Giving interferon later in the course of disease could encourage a destructive immune overreaction called a cytokine storm, in which the immune system does more damage than the virus.
Around the world, scientists have launched more than 100 clinical trials of interferons, according to clinicaltrials.gov, a database of research studies from the National Institutes of Health.
Until larger studies are completed, doctors say, Bastard’s findings are unlikely to change how they treat Covid-19.
Dr. Lewis Kaplan, president of the Society of Critical Care Medicine, said he treats patients according to their symptoms, not their risk factors.
“If you are a little sick, you get treated with a little bit of care,” Kaplan said. “You are really sick, you get a lot of care. But if a Covid patient comes in with hypertension, diabetes and obesity, we don’t say: ‘They have risk factors. Let’s put them in the ICU.'”
The past few months have taught us that mink are particularly susceptible to the coronavirus. In what’s believed to be the first documented case of animal-to-human transmission, Dutch officials announced in May that a worker at a fur farm in the Netherlands seems to have gotten COVID-19 from a mink. In June, the country decided to shut down its mink fur farming industry—the fourth largest in the world—likely by the end of the year. The virus has since been found at mink farms in Spain and Denmark.
And now, the U.S.
On Monday, the U.S. Department of Agriculture announced two mink farms in Utah reported “deaths in numbers they’d never seen before,” a USDA spokesperson told Science, in addition to several staff coming down with COVID-19. Nat Geo’s Dina Fine Maron tells me there’s no information yet on whether the virus spread from mink to humans or vice versa (that’ll require genetic testing, which is currently underway), and the USDA hasn’t shared whether it’s testing for the virus at any of the nation’s other 275 mink farms. (U.S. mink farms produce about three million mink pelts a year.)
Hundreds of thousands of mink have already been culled in Europe (above, in the Netherlands) to help control spread of the virus, but there are no plans yet to cull the animals on U.S. farms. Maron discusses the situation further on this tweet thread.
That said, there’s still no evidence that animals—including mink—play a significant role in the spread of the virus. We do know that humans have occasionally spread the virus to animals, such as their pet dogs and tigers and lions at the zoo, but those cases too are extremely rare. Scientists are still trying to learn in which species the virus can not only take hold but also replicate.
What’s clear at this point? We need a lot more research.
Coronavirus continues to spread at high rates across the US South, Midwest and West, even as the total number of new Covid-19 cases has declined since a summer surge.
Nationally, over the last seven days, the US is averaging just under 53,000 new cases of Covid-19 per day, down 11% from the week prior.
As a result of all those cases, deaths from the virus have remained high. The seven-day average of daily coronavirus deaths was just over 1,000 on Tuesday, the 16th consecutive day the US averaged over 1,000 deaths per day.
Adjusting for population, states in the Southeast are seeing the most new cases. Georgia and Florida — states led by Republican governors who have not issued face mask requirements — have the highest per capita new cases over the last seven days, followed by Alabama and Mississippi.
On Wednesday, Florida reported more than 8,000 new cases and 212 new deaths, according to data released by the Florida Department of Health.
Covid-19 causes worse outcomes for older people, but young people are not immune. In Florida, people under 44 make up about 57% of the state’s 545,000 cases, 20% of the state’s 31,900 hospitalizations, and 3% of the state’s 8,765 deaths, according to state data.
Robert Ruiz, 31 and the father of a 3-year-old, was one of the 265 people under 44 who died from coronavirus in Florida.
His sister, Chenique Mills, told CNN he was overweight and had seasonal asthma but otherwise did not smoke or drink and had no underlying health conditions.
“This is all really sudden, unexpected,” she said. “I (saw) him on Friday. I (saw) him on Saturday. He was fine, to say that he was up, and he was walking and he was eating. He was functioning. So for him to be gone on Sunday? It’s just a lot to take in.
“This virus is so serious. It really really is. And I think people (won’t) understand until it hits home, because I would be one to say that I took it really lightly until it hit home.”
The virus’s ongoing spread around the country has frustrated plans to safely reopen schools, forced college football conferences to postpone the lucrative fall season, and caused vast medical and economic pain.
And it will continue to rattle American society until people more seriously adopt recommended public health measures: social distancing, avoiding large indoor gatherings, hand-washing, mask-wearing, rapid testing and quarantining the sick.
“We have to figure out how to deal with this as a whole country because as long as there are cases happening in any part, we still have transit, especially now we have students going back to college,” said Dr. Michael Mina, assistant professor of epidemiology at Harvard T.H. Chan School of Public Health. “Any cases anywhere really keep risk pretty high all across the entirety of the United States.”
Airborne virus plays a significant role in community transmission, many experts believe. A new study fills in the missing piece: Floating virus can infect cells.
Skeptics of the notion that the coronavirus spreads through the air — including many expert advisers to the World Health Organization — have held out for one missing piece of evidence: proof that floating respiratory droplets called aerosols contain live virus, and not just fragments of genetic material.
Now a team of virologists and aerosol scientists has produced exactly that: confirmation of infectious virus in the air.
“This is what people have been clamoring for,” said Linsey Marr, an expert in airborne spread of viruses who was not involved in the work. “It’s unambiguous evidence that there is infectious virus in aerosols.”
A research team at the University of Florida succeeded in isolating live virus from aerosols collected at a distance of seven to 16 feet from patients hospitalized with Covid-19 — farther than the six feet recommended in social distancing guidelines.
The findings, posted online last week, have not yet been vetted by peer review, but have already caused something of a stir among scientists. “If this isn’t a smoking gun, then I don’t know what is,” Dr. Marr tweeted last week.
But some experts said it still was not clear that the amount of virus recovered was sufficient to cause infection.
The research was exacting. Aerosols are minute by definition, measuring only up to five micrometers across; evaporation can make them even smaller. Attempts to capture these delicate droplets usually damage the virus they contain.
“It’s very hard to sample biological material from the air and have it be viable,” said Shelly Miller, an environmental engineer at the University of Colorado Boulder who studies air quality and airborne diseases.
“We have to be clever about sampling biological material so that it is more similar to how you might inhale it.”
Previous attempts were stymied at one step or another in the process. For example, one team tried using a rotating drum to suspend aerosols, and showed that the virus remained infectious for up to three hours. But critics argued that those conditions were experimental and unrealistic.
Other scientists used gelatin filters or plastic or glass tubes to collect aerosols over time. But the force of the air shrank the aerosols and sheared the virus. Another group succeeded in isolating live virus, but did not show that the isolated virus could infect cells.
In the new study, researchers devised a sampler that uses pure water vapor to enlarge the aerosols enough that they can be collected easily from the air. Rather than leave these aerosols sitting, the equipment immediately transfers them into a liquid rich with salts, sugar and protein, which preserves the pathogen.
“I’m impressed,” said Robyn Schofield, an atmospheric chemist at Melbourne University in Australia, who measures aerosols over the ocean. “It’s a very clever measurement technique.”
As editor of the journal Atmospheric Measurement Techniques, Dr. Schofield is familiar with the options available, but said she had not seen any that could match the new one.
The researchers had previously used this method to sample air from hospital rooms. But in those attempts, other floating respiratory viruses grew faster, making it difficult to isolate the coronavirus.
This time, the team collected air samples from a room in a ward dedicated to Covid-19 patients at the University of Florida Health Shands Hospital. Neither patient in the room was subject to medical procedures known to generate aerosols, which the W.H.O. and others have contended are the primary source of airborne virus in a hospital setting.
The team used two samplers, one about seven feet from the patients and the other about 16 feet from them. The scientists were able to collect virus at both distances and then to show that the virus they had plucked from the air could infect cells in a lab dish.
The genome sequence of the isolated virus was identical to that from a swab of a newly admitted symptomatic patient in the room.
The room had six air changes per hour and was fitted with efficient filters, ultraviolet irradiation and other safety measures to inactivate the virus before the air was reintroduced into the room.
That may explain why the researchers found only 74 virus particles per liter of air, said John Lednicky, the team’s lead virologist at the University of Florida. Indoor spaces without good ventilation — such as schools — might accumulate much more airborne virus, he said.
But other experts said it was difficult to extrapolate from the findings to estimate an individual’s infection risk.
“I’m just not sure that these numbers are high enough to cause an infection in somebody,” said Angela Rasmussen, a virologist at Columbia University in New York.
“The only conclusion I can take from this paper is you can culture viable virus out of the air,” she said. “But that’s not a small thing.”
Several experts noted that the distance at which the team found virus is much farther than the six feet recommended for physical distancing.
“We know that indoors, those distance rules don’t matter anymore,” Dr. Schofield said. It takes about five minutes for small aerosols to traverse the room even in still air, she added.
The six-foot minimum is “misleading, because people think they are protected indoors and they’re really not,” she said.
That recommendation was based on the notion that “large ballistic cannonball-type droplets” were the only vehicles for the virus, Dr. Marr said. The more distance people can maintain, the better, she added.
The findings should also push people to heed precautions for airborne transmission like improved ventilation, said Seema Lakdawala, a respiratory virus expert at the University of Pittsburgh.
“We all know that this virus can transmit by all these modes, but we’re only focusing on a small subset,” Dr. Lakdawala said.
She and other experts noted one strange aspect of the new study. The team reported finding just as much viral RNA as they did infectious virus, but other methods generally found about 100-fold more genetic matter.
“When you do nasal swabs or clinical samples, there is a lot more RNA than infectious virus,” Dr. Lakdawala said.
Dr. Lednicky has received emails and phone calls from researchers worldwide asking about that finding. He said he would check his numbers again to be sure.
But ultimately, he added, the exact figures may not matter. “We can grow the virus from air — I think that should be the important take-home lesson,” he said.
A growing body of research has made it clear that airborne transmission of the coronavirus is possible.
Why it matters: That fact means indoor spaces can become hot spots. Those spaces also happen to be where most business and schooling takes place, so any hope for a return to normality will require better ways of filtering indoor air.
- That marked a shift from initial assumptions that the virus was mostly transmitted via contaminated surfaces and respiratory droplets emitted at close range, like an infected person coughing near someone susceptible.
- More evidence was added to the airborne hypothesis last week, when researchers at the University of Nebraska Medical Center reported in a paper published in Nature that they had found coronavirus-filled aerosols — small airborne particles of fluid — in the air of COVID-19 patients’ hospital rooms.
- It’s still not clear just how much or how often the airborne transmission happens, a question Anthony Fauci has said the White House coronavirus task force will examine.
Context: If coronavirus-contaminated aerosols can indeed hang in the air, perhaps for hours, then “mitigating airborne transmission should be at the front of our disease-control strategies for COVID-19,” Joseph Allen of Harvard’s Healthy Building program wrote in the Washington Post.
- Schools in particular “definitely present a challenge,” says Barry Po, president of connected solutions for mCloud Technologies, a provider of cloud-based remote HVAC management. Many school buildings in the U.S. are old and poorly ventilated, which makes them prime locations for indoor transmission.
The good news is there are existing technologies that can filter out or destroy coronavirus trapped in indoor air.
- The easiest way is simply opening windows whenever possible, which dilutes the amount of virus in the air. In Japan windows are kept open in subway trains, which has helped prevent outbreaks in the country’s crowded transit system.
- Portable HEPA filters, which can cost as little as a few hundred dollars, are capable of capturing particles as small as the novel coronavirus and could be used to clean individual classrooms.
- Commercial HVAC systems can be adjusted to increase the number of times they exchange air per hour, analysts from McKinsey said in a report last month.
The catch: Increasing ventilation decreases energy efficiency, and Po estimates that net energy costs for buildings could increase by at least 10% in the COVID-19 era.
A more high-tech solution involves the use of specialized UV light to deactivate coronavirus in the air or on surfaces.
- Fred Maxik, the founder of Healthe Lighting, developed Far UVC 222, a short-wave UV light spectrum that the company reports can neutralize 99.9% of coronavirus in a space. The UV light breaks the chemical bonds in the virus, Maxik says, making it incapable of replicating.
- Unlike the UVB rays in sunlight that can damage DNA and cause skin cancer, Far UVC 222 doesn’t penetrate the human body.
- The Healthe system has been installed in Seattle’s reopening Space Needle, as well as the practice facilities of the Miami Dolphins. “This is one of the only methodologies where we can continually clean a space in real time,” says Maxik.
The bottom line: Despite the runs early in the pandemic on Clorox wipes, it may be the air we breathe more than the surfaces we touch that need to be kept clean.