New Genomic Tests Aim to Diagnose Deadly Infections Faster

Ryan Springer’s mystery illness began last summer with a dull ache in his chest. Over the next few days, the symptoms grew more alarming: sharp pain with every breath, a rapid heartbeat and a spiking fever.

Emergency room doctors at Carle Foundation Hospital in Urbana, Ill., were stumped. They ordered up a lung biopsy and started Mr. Springer, 47, on a broad-spectrum antibiotic. But his condition worsened, and doctors feared he might not survive the five or more days it would take to get the lab results back.

There was one more option: a new genomic test that can offer much faster results by rapidly sorting through the DNA in a blood sample and picking out the pathogen most likely making a patient sick. It is part of a rapidly growing new generation of lab tests under development that could revolutionize the way doctors diagnose and treat infections.

The usual method, based on growing and analyzing germ cultures in a lab, has barely changed since the 1880s, when Julius Petri came up with a way to grow germs in a gelatinous bed of algae set between two nesting discs of glass.

The new genomic diagnostics work by matching the DNA or RNA of microbes in a patient’s bodily fluid against vast databases of all known bacteria, viruses or fungi that can sicken humans. Many of the tests produce results in hours, a marked contrast to traditional cultures, which can take days or even weeks to get results — when they work at all. The turnaround in getting test results has become even more urgent with the coronavirus epidemic in China that is spreading around the world.

“We’re still using 19th-century technology for most microbiology diagnostics and they just don’t work well for many patients,” said Kevin Outterson, a professor of health law at Boston University and the executive director of CARB-X, a nonprofit focused on combating antimicrobial resistance. “These new technologies advance what we do by more than a century.”

Dr. Amir Khan, an infectious disease specialist, sent Mr. Springer’s blood to Karius, a San Francisco-area company that is among a dozen American start-ups developing genomic diagnostic tests.

Less than 48 hours later, the results came back: Mr. Springer had tularemia, or rabbit fever, a rare bacterial infection transmitted by animals and ticks that sickens fewer than 200 Americans a year. It is tough to diagnose — and it can be fatal if untreated.

“The previous case I saw was three years earlier, and it was diagnosed after an autopsy,” Dr. Khan said.

The cure was simple: the antibiotic doxycycline. Mr. Springer took it and was discharged five days later.

The coronavirus outbreak has ratcheted up interest in rapid genomic tests. Developers of the some of the devices say that once the genetic sequence of a novel pathogen has been made publicly available, the information could be quickly uploaded and used to identify those infected.

“With a traditional reference lab, by the time a clinic takes a sample and ships it off, you’ve lost 12 to 24 hours,” said Dr. Jack Regan, the chief executive of LexaGene, a Massachusetts company that hopes to sell its coffee maker-size instrument to airports, schools and clinics. “We can get results in under an hour, which makes a huge difference during deadly outbreaks.”

A wider rollout of these tests faces a number of hurdles. Most of the tests identify a patient’s infection 80 to 90 percent of the time — regulators would like that figure to be closer to 100 percent — and many of them are still awaiting a green light from the F.D.A. But health experts say a larger impediment to their widespread use is economics: Most of the tests run $500 to $3,000 (the test used to diagnose Mr. Springer was $2,000) and because few private insurances companies cover them, the costs are largely borne by hospitals or patients.

“The technology is incredibly promising but the challenge right now is how to get insurers to pay for it,” said Prof. Outterson of Boston University. “We need a system in which hospitals can at least break even for doing the right thing.”

John A. Prendergass, associate director of digital health at Ben Franklin Technology Partners, who invests in medical device start-ups, said he was concerned by the high costs, false negatives and low sensitivity of the tests he had looked at.

“The entire diagnostic test space is trying to solve these issues,” he said. “That said, we know one day they are going to be a major component of health care not only in America, but all over the world.”

These diagnostics have little in common with those once promoted by Theranos, the blood-testing company that promised to rapidly diagnose a host of infections through a finger prick, but which turned out to be colossal fraud. Unlike Theranos, which was highly secretive about its technology, the mechanics of these new diagnostics are well understood, and many of the tests are already being road-tested by hospitals across the country as they wait final clearance from the F.D.A.

In addition to saving lives, the new tests could also ameliorate the growing crisis of drug-resistant infections, because pinpointing infections quickly would show doctors which antibiotic to use, rather than resorting to the shot-in-the dark dispensing of broad-spectrum antibiotics for patients with hard to diagnose infections.

Broad-spectrum antibiotics that act on a wide array of bacteria are commonly used in emergency rooms and intensive care units to combat bloodstream infections, or sepsis, which kill 270,000 Americans a year, accounting for a third of all hospital deaths. Septic shock is also quick to kill, with mortality increasing 8 percent each hour an infection goes untreated.

But at least half of all antibiotics are wrongly prescribed, researchers have found, and some studies suggest that a third of antibiotics prescribed by doctors are unnecessary, many of them dispensed without having a diagnosed infection. Such overuse is one of the major causes of mounting antibiotic resistance as germs mutate to survive.

“We believe patients should be treated based on what they’re infected with, not what doctors think they might have,” said Tom Lowery, the chief scientific officer of T2 Biosystems, a Boston company whose bacteria panel test has been the first to pass muster with the Food and Drug Administration and the Centers for Medicare & Medicaid Services.

As they navigate the regulatory process and work to raise funds, the companies have been putting their tests through clinical studies and trying them out in hospitals and labs across the country.

Dr. Stephen Zekan, a West Virginia surgeon, recently used a test by the company Aperiomics to diagnose what was sickening a 67-year-old woman he initially thought had a tick-borne infection.

“It was frustrating as hell,” he said of the months he spent trying to determine what was causing the woman’s arthritic pain and fatigue. The new test quickly determined that she had tuberculosis.

“I’ve been practicing medicine for 40 years and it’s mind-boggling to think that a supercomputer can go through billions of nucleotides and spit out a result in a few hours,” Dr. Zekan said.

In addition to solving medical mysteries, doctors say the tests could be especially useful to those who are immune-compromised, like cancer patients on chemotherapy or organ transplant recipients, because they often contract dangerous and tough to identify infections.

The array of new products is striking. Arc Bio in Cambridge, Mass., is developing a diagnostics platform that focuses solely on the 400 viruses that make people sick. Day Zero Diagnostics in Boston is field-testing a sequencing and analysis service that allows hospitals to quickly detect infectious disease outbreaks. And then there is the hand-held gadget made by medical device company BD that allows doctors to rapidly determine whether a patient with a high fever needs an antibiotic for strep throat or simply bed rest for what is most likely a viral respiratory bug.

Another Boston company, Selux Diagnostics, started five years ago in a makeshift lab in the attic of its founder, Dr. Eric Stern, has developed a dishwasher-size machine that can test pathogens against a panel of 60 antibiotics and determine which ones are most likely to work. Unlike standard antibiotic susceptibility tests that take three or more days, Selux’s powerful algorithm can yield results within hours of a pathogen being identified from a patient sample.

Dr. William J. Muller, a pediatric infectious disease specialist at Ann & Robert H. Lurie Children’s Hospital in Chicago, has used the test created by Karius more than 200 times over the past three years, and said he was impressed by its ability to diagnose lung infections. The test results, he said, have the potential to spare patients lung biopsies, which involve some risk and often yield inconclusive results.

“Anything that reduces the need for painful, invasive procedures should be welcome by hospitals,” said Dr. Muller, who has collaborated with Karius in the past and recently published the results of his findings in the journal Open Forum Infectious Diseases.

In a separate study published in December in JAMA Oncology, doctors at St. Jude Children’s Research Hospital in Memphis found that the test was able to predict the onset of life-threatening infections in pediatric leukemia patients three days before the onset of symptoms.

Dr. Amy P. Abernethy, principal deputy commissioner at the F.D.A., who oversees the regulation of new medical devices, said speed remained a concern, given that many of the companies seeking the agency’s approval operate proprietary labs, meaning that doctors must send off a blood, urine or fecal sample by overnight mail. That can add a day or more to the sequencing and diagnosis process, a lag that can be fatal for sepsis patients.

“We have a fair amount of excitement over next-generation sequencing, but we do acknowledge a few practical hurdles we need to get over,” she said in an interview.

The excitement is also tempered by a hard-nose reality: although administrators of Medicaid and Medicare recently agreed to cover 65 percent of the cost for the T2 Biosystems test for the first two or three years, most insurance companies will not pay for genomic diagnostics without federal approval and peer-reviewed clinical studies that can definitively establish their efficacy, a process that can take years.

Dr. Charles Chiu, a professor of laboratory medicine at University of California, San Francisco, and the director of a lab that is developing its own genomic sequencing platform, said many insurers remained unconvinced that the new tests were cost effective, despite scores of cases that led to reduced health care costs, shortened hospital stays and saved lives.

He listed a number of mysteries solved by his lab’s sequencing tests, and documented last year in The New England Journal of Medicine. They included a Los Angeles woman with liver failure who was scheduled for a liver transplant — at the cost of $1 million — but who it turned out had a rare, treatable form of hepatitis. Then there was the 14-year-old boy desperately ill with meningitis who had to be put in a medically induced coma because doctors could not figure out what was causing his brain to swell.

After months of inconclusive cultures, genomic testing pointed to leptospirosis, an extremely rare bacterial infection that is easily treated with old-school penicillin.

“Insurance companies won’t think twice about covering a $4,000 cancer gene panel,” Dr. Chiu said, “so why not cover an infectious disease test that can save a child’s life?”

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