It's the ultimate noninvasive medical test: A growing number of health problems can be diagnosed by analyzing a patient's breath alone.

The concept goes back to Hippocrates, who wrote a treatise on breath aroma and disease around 400 B.C. For centuries afterward, doctors noticed that patients with liver and kidney disorders had distinctive smells to their breath.

Now, scientists are identifying thousands of chemical compounds that create those telltale odors. Tools called mass spectrometers can detect them in quantities as minute as parts per trillion, the equivalent of finding a single ping-pong ball in a thousand baseball fields filled with ping-pong balls.

And researchers are developing tests that can diagnose and monitor not just liver and kidney disorders, but also asthma, diabetes, tuberculosis, gastrointestinal infections—even the rejection of transplanted organs—by analyzing biomarkers in exhaled breath.

"Anything you can have a blood test for, there is potentially a breath test for, as long as there is a volatile component," says Raed A. Dweik, director of the pulmonary vascular program at the Cleveland Clinic's Lerner Research Institute.
 

Breath tests are also painless, faster to return results and potentially less expensive than blood tests—and easy to repeat as often as needed, even while patients are sleeping or exercising.

And some go well beyond what blood tests can do. In a study in the Journal of Thoracic Oncology this month, researchers from Israel and Colorado reported that breath analysis could distinguish between benign and malignant pulmonary nodules in a group of 72 patients with 88% accuracy; the test could also assess the specific type and stage of the lung cancers.

"The Holy Grail is the Star Trek Tricorder concept, where you would breathe into a device and a sign would pop up saying what health problems you have," says Cristina Davis, a professor of mechanical and aerospace engineering at the University of California, Davis, who is co-chairing an international conference on breath analysis later this month.

Dr. Davis is also developing a portable pediatric asthma monitor. The cellphone-like device would have a tube that children could breathe into during the day; it would analyze the level of nitric oxide in their breath, an indicator of inflammation, and transmit the data to their doctors to aid in fine tuning their medication. (This is different than the simple peak-flow meters that most asthmatics use to measure how quickly air can be blown from their lungs.)

Many of these breath tests are still in the research stage and need to be standardized and validated in large clinical trials before they will be ready for use in doctors' offices. Meanwhile, scientists are still cataloging the thousands of different molecules in exhaled breath and determining what concentrations are normal and what indicate health problems.

Every individual has a unique breath signature—like a fingerprint—that contains not only oxygen, nitrogen and carbon dioxide but also volatile organic compounds. Those are chemicals from inside and outside the body that evaporate at room temperature and are the source of most breath odors. Exhaled breath also contains nonvolatile compounds—microscopic droplets of proteins, antibodies, peptides and DNA that contain a wealth of additional health information.

Exhaled breath also contains a host of "confounders" inhaled from the ambient air—including molecules of pollution, paint, furniture, even carpet fibers—that can interfere with breath sampling. In fact, what people eat, what medications they take and how often they brush their teeth can all affect their breath signature.

So can patients' heart rates, ages and other health conditions, making it difficult for researchers to get consistent results in clinical trials. "For doctors and the FDA to buy into this concept," says Dr. Dweik, "we have to tell them what we are smelling and why and how that compound is related to the disease process."

Some forms of breath analysis require a tagging material. Patients tested for Helicobacter pylori, the gut bacteria behind peptic ulcers, swallow a capsule containing urea, made from a carbon isotope. If H. pylori is present, it breaks up the urea into carbon dioxide, which travels through the blood to the lungs. The isotope can then be detected in the patient's exhaled breath.


Other breath tests use various forms of mass spectrometry, that can identify and measure specific volatile organic compounds. Scientists say mass spectrometry is a billion times more sensitive than the breath analyzers used by police to detect blood-alcohol levels, but it is also expensive and cumbersome.

That is why many experts believe that the future of breath testing lies in the use of sensor arrays (or "electronic noses") that can recognize patterns in exhaled breath the way people and animals can identify familiar smells without knowing the chemical compounds that create them. Sensor arrays are smaller and less expensive than mass spectrometers and portable enough to be administered at a patient's bedside with the results given in real time. But like humans and animals, they need to be trained, or programmed, to know what patterns to look for.

At the Cleveland Clinic's Respiratory Institute, Peter Mazzone, director of the lung cancer program, is testing a sensor array that changes color when a patient's breath passes over it, made by Metabolomx, a Mountain View, Calif.-based diagnostic company. In a study of 229 patients reported in the Journal of Thoracic Oncology in December, the test was able to distinguish those with lung cancer with 80% accuracy. A larger trial with a far more sensitive version of the test is under way.

At the same time, Dr. Mazzone and his colleagues are collecting breath samples from as many patients as possible, with and without lung cancer, in order to develop still more specific patterns for breath tests to look for in the future. "My vision is being able to say, 'This is a 60-year old with emphysema who smoked for 30 years—what's the chance of there being cancer there?' But we have to teach the device what it looks like first."

He and other experts hope that breath tests can be used in conjunction with CT scans to cut down on the number of unnecessary biopsies. "If you do a CT scan of the lungs and find a nodule, but the breath test was negative, you could say, 'I don't need a biopsy now. I'll follow it up in six months'," Dr. Mazzone says.

Researchers at the Cleveland Clinic and elsewhere are also studying breath tests for breast and colon cancer, which send similar telltale compounds through the blood stream and out in exhaled breath.

Many hurdles remain in getting such tests standardized and validated, but research is moving rapidly. Says Dr. Davis: "The field is at the point where we'll start to see some exciting developments in the next one to four years."