In May, musicians from dozens of countries descended on Rotterdam, the Netherlands, for the Eurovision Song Contest. Over the course of the competition, the performers — clad in sequined dresses, ornate crowns or, in one case, an enormous pair of angel wings — belted and battled it out for their chance at the title.
But before they were even allowed onstage, they had to pass another test: a breath test.
When they arrived at the venue, the musicians were asked to exhale into a water-bottle-sized device called the SpiroNose, which analyzed the chemical compounds in their breath to detect signatures of a coronavirus infection. If the results came back negative, the performers were cleared to compete.
The SpiroNose, made by the Dutch company Breathomix, is just one of many breath-based COVID-19 tests under development across the world. In May, Singapore’s health agency granted provisional authorization to two such tests, made by the domestic companies Breathonix and Silver Factory Technology. And researchers at Ohio State University say they have applied to the U.S. Food and Drug Administration for an emergency authorization of their COVID-19 breathalyzer.
“It’s clear now, I think, that you can detect this disease with a breath test,” said Paul Thomas, a chemist at Loughborough University in England. “This isn’t science fiction.”
Scientists have long been interested in creating portable devices that can quickly and painlessly screen a person for disease simply by taking a whiff of their breath. But delivering on this dream has proved to be a challenge. Different diseases may cause similar breath changes. Diet can affect the chemicals someone exhales, as can smoking and alcohol consumption, potentially complicating disease detection.
Still, scientists say, advances in sensor technology and machine learning, combined with new research and investment spurred by the pandemic, mean that the moment for disease-detecting breathalyzers may have finally arrived.
“I’ve been working in the area of breath research for almost 20 years now,” said Cristina Davis, an engineer at the University of California, Davis. “And during that time, we’ve seen it progress from a nascent stage to really being something that I think is close to being deployed.”
The biology of breath
Human breath is complex. Whenever we exhale, we release hundreds of gases known as volatile organic compounds, or VOCs — byproducts of respiration, digestion, cellular metabolism and other physiological processes. Disease can disrupt these processes, altering the mix of VOCs that the body emits.
People with diabetes, for instance, may have breath that smells fruity or sweet. The odor is caused by ketones, chemicals produced when the body begins to burn fat instead of glucose for energy, a metabolic state known as ketosis.
“The idea that exhaled breath could hold diagnostic potential has been around for some time,” Davis said. “There are reports in ancient Greek and also ancient Chinese medical training texts that reference a physician’s use of smell as a way to help guide their clinical practice.”
Modern technologies can detect more subtle chemical changes, and machine-learning algorithms can identify patterns in breath samples from people with certain diseases. In recent years, scientists have used these methods to identify unique “breathprints” for lung cancer, liver disease, tuberculosis, asthma, inflammatory bowel disease and other conditions. (Davis and her colleagues have even used VOC profiles to distinguish among cells that had been infected with different strains of flu.)
Before COVID hit, Breathomix had been developing an electronic nose to detect several other respiratory diseases.
“We train our system, ‘OK, this is how asthma smells, this how lung cancer smells,” said Rianne de Vries, the company’s chief technology and scientific officer. “So it’s building a big database and finding patterns in big data.”
Last year, the company — and many other researchers in the field — pivoted and began trying to identify a breathprint for COVID-19. During the virus’ initial surge in the spring of 2020, for instance, researchers in Britain and Germany collected breath samples from 98 people who showed up at hospitals with respiratory symptoms. (Participants were asked to exhale into a disposable tube; the researchers then used a syringe to extract a sample of their breath.)
Thirty-one of the patients turned out to have COVID, while the remainder had a variety of diagnoses, including asthma, bacterial pneumonia or heart failure, the researchers reported. The breath samples from people with COVID-19 had higher levels of aldehydes, compounds produced when cells or tissues are damaged by inflammation, and ketones, which fits with research suggesting that the virus may damage the pancreas and cause ketosis.
The COVID patients also had lower levels of methanol, which could be a sign that the virus had inflamed the gastrointestinal system or killed the methanol-producing bacteria that live there. Those breath changes combined “give us a COVID-19 signal,” said Thomas, a co-author of the study.
Waiting to exhale
Several other studies have also detected unique chemical patterns in the breath of patients with COVID-19, and some devices claim impressive results. In one study of the SpiroNose, which included 4,510 participants, a team of Dutch researchers reported that the device correctly identified at least 98% of people who were infected with the virus, even in a group of asymptomatic participants. (The study, which included researchers from Breathomix, has not yet been peer-reviewed.)
But the SpiroNose had a relatively high rate of false positives, the study found. Because of this problem, the device does not provide consumers with a definitive diagnosis; the results either come back negative or inconclusive, in which case a standard polymerase chain reaction test is administered.
Dozens of testing sites in the Netherlands are now using the machine, de Vries said, but there have been some hiccups. In May, Science reported that Amsterdam’s public health authorities suspended use of the SpiroNose after 25 false negatives. Officials later determined that user error was largely responsible, and SpiroNose screening has resumed, de Vries said.
Other groups are working on their own breathalyzers. Researchers at the Children’s Hospital of Philadelphia, who have identified a breathprint of COVID in children, are now trying to identify breath markers of a rare but dangerous complication of the disease, known as multisystem inflammatory syndrome in children (MIS-C).
“The clinicians on the front line, they’re really struggling with which children we need to worry most about,” said Dr. Audrey Odom John, an infectious disease specialist at Children’s Hospital of Philadelphia, who is leading the research.
In addition to studying the VOCs emitted by COVID patients, Davis and her colleagues are analyzing what is known as exhaled breath condensate, a concentrated solution of the tiny droplets of fluid, or aerosols, that are present in breath. These aerosols contain all sorts of complex biological molecules, including proteins, peptides, antibodies and inflammatory markers.
They hope to find biomarkers to help doctors predict which COVID-19 patients are most likely to become severely ill.
“I think that that will be a part of a clinical arsenal, where clinicians cannot only do rapid diagnostics, but then they could try to understand what’s the trajectory for that particular patient,” she said.
Other teams are working to create breath tests that look for the virus itself. Researchers at Washington University in St. Louis, for instance, are developing a biosensor that is coated in tiny antibody fragments, or nanobodies, that bind to SARS-CoV-2. If someone is exhaling viral particles, they should attach to the nanobodies, activating the sensor.
Passing the smell test
Interest in the technology is fierce. Perena Gouma, a materials scientist at Ohio State who has applied for FDA authorization for her COVID-19 breathalyzer, said she has already heard from colleges, theaters, sports leagues, travel authorities and others who want to get their hands on the device.
“I don’t think that there has been anyone who has been affected by this pandemic that hasn’t been excited about the prospect of having a breath test,” she said.
But the approach still needs to be validated in larger studies, and basic scientific questions remain unanswered.
“If we take a blood test for example, it’s well established that there is a normal range for, let’s say, hemoglobin levels or white blood cell count,” said Oliver Gould, an analytical chemist at the University of the West of England. “So, of course, then it’s very easy to see when something is abnormal.”
Those reference ranges do not yet exist for breath, he noted.
Researchers said that they do not expect breath-based tests to completely replace other diagnostic tests.
“Do I think that a breathalyzer is going to be used in your pediatrician’s office? Probably not,” John said. “Where I really see breath testing being useful is where you need to screen a whole bunch of people quickly. Could you screen every child in a school on a Monday? Could you do it before people enter a mall or a bounce house?”
And once the technology has been developed and validated, it could theoretically be used to screen for a wide variety of different diseases.
“The thing about a breath test is, if you have the technology in place, you can learn the signal for a new disease very fast,” Thomas said.
So the research being done now could pay long-term dividends.
“We’re developing the tools necessary to hopefully help us in the fight for the next disease,” said Edward DeMauro, an engineer at Rutgers University who is working on a COVID breathalyzer. “There is a very big value in, even if the pandemic’s over, not sitting back. That’s not the time to catch our breath.”