Scientists develop COVID test that’s as easy as breathing


In May, musicians from dozens of countries traveled to Rotterdam, the Netherlands, for the Eurovision Song Contest. During the competition, the performers – dressed in sequined dresses, ornate crowns or, in one case, a huge pair of angel wings – belted and fought to try to win the title.

But before they were even allowed to go on stage, they had to pass another test: a breathalyzer.

Upon arriving at the scene, the musicians were asked to breathe out into a water bottle-sized device called SpiroNose, which analyzed chemicals in their breath for signatures of a coronavirus infection. If the results were negative, the artists were allowed to compete.

The SpiroNose, made by Dutch company Breathomix, is just one of several breath-based COVID-19 tests being developed around the world. In May, the Singapore health agency granted provisional approval for two such tests, carried out by national companies Breathonix and Silver Factory Technology. And researchers at Ohio State University said they’ve asked the U.S. Food and Drug Administration for emergency clearance 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. “It’s not science fiction.”

Scientists have long been interested in creating portable devices that can quickly and painlessly detect sick people simply by breathing their breath. But realizing this dream turned out to be a challenge. Different diseases can cause similar respiratory changes. Diet can affect the chemicals a person exhales, as can smoking and alcohol consumption, potentially making it difficult to detect disease.

Yet, scientists say advancements in sensor technology and machine learning, combined with new research and investment spurred by the pandemic, mean the time for disease-testing breathalysers may finally be over. come.

“I have been working in 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 go from a nascent stage to really something that I think is about to be rolled out.”

The biology of breath

Human breathing is complex. Every time we breathe out, we release hundreds of gases known as volatile organic compounds, or VOCs, byproducts of respiration, digestion, cell metabolism, and other physiological processes. The disease can disrupt these processes, altering the mix of VOCs emitted by the body.

People with diabetes, for example, may have fruity or sweet breath. The smell 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 might contain diagnostic potential has been around for some time,” Davis said. “There are reports in ancient Greek and ancient Chinese medical education texts that refer to a physician’s use of smell as a means to help guide 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 “airways” for lung cancer, liver disease, tuberculosis, asthma, inflammatory bowel disease, and other conditions. (Davis and his colleagues used VOC profiles to distinguish cells that had been infected with different strains of influenza.)

Before COVID hit, Breathomix was developing an electronic nose to detect several other respiratory illnesses.

“We train our system, ‘OK, this is how asthma smells, how lung cancer smells,” said Rianne de Vries, chief technology and science officer for the company. “So it’s about 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 respiratory footprint for COVID-19. In the initial outbreak of the virus in spring 2020, for example, British and German researchers collected breath samples from 98 people who presented to hospitals with respiratory symptoms. (Participants were asked to breathe out into a disposable tube; the researchers then used a syringe to extract a sample from their breath.)

Thirty-one of the patients were found to have COVID, while the rest had various diagnoses, including asthma, bacterial pneumonia or heart failure, the researchers reported. Breath samples from people with COVID-19 showed higher levels of aldehydes, compounds produced when cells or tissues are damaged by inflammation, and ketones, consistent with research suggesting the virus can damage the pancreas and cause ketosis.

COVID patients also had lower methanol levels, which could be a sign that the virus had inflamed the gastrointestinal system or killed the methanol-producing bacteria that live there. These combined respiratory changes “give us a COVID-19 signal,” said Thomas, co-author of the study.

Waiting to expire

Several other studies have also detected unique chemical patterns in the breath of patients with COVID-19, and some devices claim impressive results. In a study of SpiroNose, which included 4,510 participants, a team of Dutch researchers reported that the device correctly identified at least 98% of people infected with the virus, even in a group of asymptomatic participants. (The study, which included Breathomix researchers, has not yet been peer reviewed.)

But the SpiroNose had a relatively high rate of false positives, according to the study. Due to this problem, the device does not provide consumers with a definitive diagnosis; the results are either negative or inconclusive, in which case a standard polymerase chain reaction test is administered.

Dozens of test sites in the Netherlands are now using the machine, de Vries said, but there have been some issues. In May, Science reported that public health authorities in Amsterdam had suspended the use of SpiroNose after 25 false negatives. Officials later determined that user error was largely to blame, and SpiroNose screening resumed, de Vries said.

Other groups are working on their own breathalysers. Researchers at the Children’s Hospital of Philadelphia, who have identified a respiratory imprint of COVID in children, are now trying to identify respiratory markers of a rare but dangerous complication of the disease, known as multisystem inflammatory syndrome in children (MIS-C).

“Frontline clinicians, they really struggle with the kids we need to worry about the most,” said Dr. Audrey Odom John, 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 his colleagues analyze what is known as exhaled breath condensate, a concentrated solution of the tiny droplets of liquid, or aerosols, present in the breath. These aerosols contain all kinds 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 seriously ill.

“I think this will be part of a clinical arsenal, where clinicians can not only make quick diagnoses, but they could then try to figure out what the trajectory of that particular patient is,” she said.

Other teams are working to create breath tests that look for the virus itself. Researchers at Washington University in St. Louis, for example, are developing a biosensor coated with tiny fragments of antibodies, or nanobodies, that bind to SARS-CoV-2. If someone exhales virus particles, they should attach to the nanobodies, activating the sensor.

Pass the smell test

Interest in technology is fierce. Perena Gouma, a materials scientist at Ohio State who sought FDA clearance for her COVID-19 breathalyzer, said she has heard from colleges, theaters, sports leagues, travel authorities before and others who wanted to get their hands on the device.

“I don’t think there has been anyone who has been affected by this pandemic who has not been excited about the prospect of having a breathalyzer test,” she said.

But the approach has yet to be validated in larger studies, and fundamental scientific questions remain unanswered.

“If we take a blood test for example, it is well established that there is a normal range for, say, hemoglobin levels or white blood cell count,” said Oliver Gould, analytical chemist at the University of West of England. “So, of course, then it’s very easy to see when something is wrong.”

These reference ranges do not yet exist for the breath, he noted.

The researchers said they didn’t expect breath tests to completely replace other diagnostic tests.

“Do I think a breathalyzer is going to be used in your pediatrician’s office? Probably not,” John said. “Where I really see breath testing is helpful is where you have to quickly screen a whole bunch of people. Could you screen all the kids in a school on a Monday? that people don’t walk into a mall or a bounce house? “

And once the technology is developed and validated, it could theoretically be used to screen for a wide variety of different diseases.

“The problem with a breathalyzer is that if you have the technology in place, you can learn the signal for a new disease very quickly,” Thomas said.

So current research could pay dividends in the long run.

“We are developing the tools necessary to hopefully help us in the fight against the next disease,” said Edward DeMauro, an engineer at Rutgers University who is working on a COVID breathalyzer. “There is tremendous value in not sitting still, even though the pandemic is over. Now is no time to catch our breath.”

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