Catching your breath

The amounts of certain molecules in exhaled breath could be markers for disease.

Scientists would like to take your breath away. Literally.

A person’s breath is more than 99 percent water — and then a cocktail of many other molecules. Scientists are working to understand how the amounts of various molecules can serve as markers for some diseases, such as lung cancer.
BREATH AS EVIDENCE A person’s breath is more than 99 percent water — and then a cocktail of many other molecules. Scientists are working to understand how the amounts of various molecules can serve as markers for some diseases, such as lung cancer. Photo: Rosen Dukov, Design: J. Korenblat

Exhaled vapor holds clues to your health, revealing much more than just what you ate for lunch. In recent years, researchers have been scrutinizing the misty mixture of molecules with fervor, seeking evidence of conditions ranging from sleep apnea to cancer.

Breath can also reveal exposure to pollutants such as benzene and chloroform, providing a measure of internal dose that is missed by sampling polluted air.

“The lung is a soggy mess of tubes and sacs whose job is to exchange gases from blood into breath,” says Joachim D. Pleil, an analytical chemist and environmental health scientist with the U.S. Environmental Protection Agency. “The breath is a window into the blood.”

Collecting and analyzing breath is emerging as a kinder, gentler means for surveying the body, a complement to old standbys such as blood and urine tests, or invasive techniques that irritate the lungs, says Pleil, who reviews the role of exhaled breath analysis in an upcoming issue of the Journal of Toxicology and Environmental Health, Part B.

“You might have a 90-year-old man on a respirator, and it’s hard to tap a vein,” he says. “Or an 800-gram infant who doesn’t make enough urine in a week to analyze. That infant is always breathing.”

Even the ancients knew that there’s more to breath than meets the eye. Doctors have been sniffing breath for indications of disease since Hippocrates’ day. The sweet smell of acetone is a flag for diabetes, and advanced liver disease is said to make the breath reek of fish. Breath is 99 percent water, but roughly 3,000 other compounds have been detected in human breath—the average sample contains at least 200. There are also bits of DNA, proteins, and fats floating in the mist.

While research is being published at a rapid rate (more than 50 breath-related papers so far in 2008), scientists are still figuring out which breath-bound molecules are most meaningful and what collection methods work best.

“It’s unclear what we should be looking for in there—there’s stuff from A to Z,” says Rohit Katial, director of the allergy and immunology program at the National Jewish Medical and Research Center in Denver. Breath is “an intriguing source of a bodily sample,” he says. “But it is still in its infancy—the detection techniques just aren’t there yet.”

Although the results are still hazy in some areas of research, breath analysis is a reliable non-invasive means of detecting certain ills, such as lung inflammation, says John Hunt, a respiratory medicine specialist at the University of Virginia Children’s Hospital in Charlottesville. Breath from a normal airway is mildly alkaline, about pH 8, but someone with acute respiratory disease might have a breath pH of 3. “Kind of like putting lemonade in your eye,” says Hunt.

An airway making this much acid can be an early sign of pulmonary disease or lung transplant rejection, says Hunt, who cofounded a company that makes equipment for collecting breath condensate. And severe asthma—a suite of symptoms, not a disease—may be triggered by a number of cellular irritants, from viral infections to exposure to diesel emissions. Analyzing breath condensate can help discern whether acid reflux is causing irritation or contributing to it, helping doctors target drugs more effectively, says Hunt.

There is also a common breath test for Helicobacter pylori, the stomach-infecting bacterium that causes some ulcers. H. pylori has an enzyme—which humans lack—that breaks down urea. The patient drinks a cocktail laced with urea made with a heavy carbon isotope. If the bacterium has taken up residence, it breaks down the urea, and the heavy carbon isotope is detectable in the breath.

Scientists are also investigating volatile compounds in breath to see if there is a predictable compound or pattern in people with certain cancers. Cancerous cells burp different compounds than healthy cells—researchers have identified more than 20 of these volatiles. In papers published in Cancer Biomarkers last fall and in Clinica Chimica Acta in March, researchers present two analyses comparing the compounds in the breath of 193 lung cancer patients to 211 controls. Both models correctly identified the lung cancer patients about 84 percent of the time.

The target molecules will dictate the method of collection, says Michael C. Madden, a toxicologist with the EPA. Madden, Pleil and other colleagues recently published a new collection method in the Journal of Breath Research. The technique uses readily available equipment—a 75-milliliter glass bulb and a small tube—that allows many samples to be simultaneously prepared and stored, says Pleil.

Generally, collecting a sample involves breathing into the collection tube with the strength used to play a trumpet or clarinet. About five minutes of breathing yields one milliliter of breath condensate. Samples can then be capped, frozen if necessary and then brought to a lab for analysis.

The analysis side of things is where more work is needed, says Hunt. “That’s the downside,” he says. “Many of the assays are difficult to do. It’s easy for the patient, but tough for the lab.”

An expanding area of research involves looking for proteins made by distressed cells, says Madden. Lung cells that have been attacked by a pollutant often make interleukin 8, a protein that recruits immune system cells from the blood. If hundreds of school children were exposed to diesel exhaust, for example, breath analysis could reveal interleukins or cytokines, giving a quick take on how the kids’ lungs are dealing with the assault.

Eventually, says Madden, suites of proteins might be identified that indicate specific exposures. “If you look at 100 proteins, do 10 stick out as unique to smokestack emissions or 10 for ozone exposure?” Better collaboration between physicians on the clinical side and scientists on the environmental side would help move that prospect along, he says.
“It’s a fun and expanding field—an up-and-coming research tool that people are really trying hard to translate into the clinical world,” says Hunt. “I think a lot will happen in the next few years. Eventually, we’ll be able to smell how people are doing.”

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