Sniffing Out the Deadliest Disease on Earth

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Anopheles mosquito taking a blood meal.

by Richard Conniff/Scientific American

One of the more disturbing things about parasites is their ability to manipulate the behavior of a host, sometimes to suicidal extremes.  The classic example is the liver fluke. It infects a ant as an intermediate host, then manipulates the ant to climb onto a blade of grass, where it is likelier to get eaten by the parasite’s definitive host, a cow or other grazing ruminant.

Over the past few years, scientists have come to recognize that something similar happens to humans under the influence of one of the deadliest pathogens in our history as a species:  The human Plasmodium parasite not only causes malaria, but also makes victims more attractive to mosquitoes, which then transmit the parasite to other victims with every bite. New research suggests, however, that this manipulative behavior couldmake it easier to identify and treat carriers who now elude medical detection.  That could spell the potential demise of the parasite, which has killed hundreds of millions of people over the millennia, including 445,000 in 2016.

The research, published Monday in Proceedings of the National Academy of Sciences, characterizes the distinctive profile of the volatile organic compounds (VOCs)—chemicals often perceived as smells–produced by people infected with the Plasmodium parasite. That is, the researchers identify the odor of malaria—the stuff the mosquitoes are smelling–and propose developing new odor-based technology to detect malaria with far greater accuracy than any method currently available, even in patients who show no symptoms.

A research team led by Mark C. Mescher, a behavioral ecologist at ETH Zurich (the Swiss Federal Institute of Technology), tested the approach on 400 children at 41 schools in malarial areas near Lake Victoria in western Kenya.  The scientists used a portable, briefcase-size device that pulls air from the surface of the skin and collects VOCs in a filter, for later laboratory analysis by gas chromatography/mass spectrometry.  At the same time, they took blood samples for testing by two conventional but quicker methods–examination under a microscope, or screening for antigens with a rapid diagnostic test. The researchers provided treatment for children who tested positive.

But both of those methods, and even molecular analysis, fail to diagnose many cases where people infected with the Plasmodium parasite are partially immune or otherwise show no symptoms of disease. These undetected carriers still have the odor profile of malaria, meaning they are more likely to attract mosquitoes and pass the disease along to their neighbors. And this “hidden reservoir” of infection may account for “up to 90 percent of onward transmission” by mosquitoes, according to the new study.  That’s a major reason malaria continues to kill so many people, especially children in sub-Saharan Africa. Using the odor profile, on the other hand, “identified asymptomatic infections with 100 percent sensitivity,” the study says, suggesting “significant potential for the development of a robust noninvasive method for detecting malaria infections under field conditions.”

If other studies replicate these findings, malaria would join a growing list of diseases with known odor profiles, including asthma, tuberculosis, diabetes, and numerous cancers, as well as diseases of the teeth, gut, heart, liver, and kidneys.  Moreover, the new research comes at a time of increasing commercial and medical interest in developing practical tools for detecting and diagnosing these odor profiles in a timely way.

“I’m not sure it’s a huge leap to make this practical in the field,” says co-author Andrew F. Read, an evolutionary biologist at Pennsylvania State University, adding that a breathalyzer-style device might speed detection of hidden carriers and thus hasten elimination of malaria from areas where it is now endemic. The Gates Foundation, which funded the new research, has made not just local elimination but worldwide eradication of malaria one of its stated goals.

Read cautions that the new study is based on only a single population. “The question is how variable this is around the world. Is it the same profile for people with different diets, different lifestyles? We don’t know if we need to fine-tune the profile for different countries.” But he adds that mosquitoes everywhere seem to cue into something about malaria, “and that suggests it’s the same signal all around the world.”

“It’s really, really interesting” work, says James A. Covington, who works on odor-based medical detection devices at the University of Warwick, and who wasn’t involved in the new research. But he suggests a larger caveat: “The range of chemicals” identified in the new study “are ones that I have seen before for other diseases.” So they might just be the body’s way of saying “I am ill, I am under stress,” rather than, “I have malaria.” The study would have been more persuasive, he says, if it had compared malaria victims with people suffering from another illness, rather than using healthy children as a control group.

But Sabine Dittrich, a public health microbiologist at the Geneva-based Foundation for Innovative New Diagnostics, who also was not involved in the research, calls it an impressive start. “If they have data from 400 children in Kenya, that’s obviously very exciting, 400 is a significant number,” she says. The possibility of a noninvasive device to test for malaria “would obviously make it easier to reach more people,” she says, and that is “extremely important” for finding and treating people who are acting as reservoirs of the parasite.

Eric Halsey, a tropical disease physician with the Centers for Disease Control and Prevention’s Malaria Branch, who also was not part of the new study, adds one final caveat:  Current malaria programs often fail to reach even the obvious symptomatic cases.  Having just returned last week from southern Africa, Halsey says the existing diagnosis and treatment technologies are perennially in short supply in the “poorest of poor” areas, and training programs for health care centers and for community volunteers is inadequate.  The World Health Organization reports that the $2.7 billion 2016 global investment in the fight against malaria was less than half the $6.5 billion needed to reach targets for malaria control.  “Promising research and new tools are always welcome in the malaria field,” says Halsey.  But the important thing is to put the tools we already have at hand to work.

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Richard Conniff is the author of “The Species Seekers: Heroes, Fools, and the Mad Pursuit of Life on Earth,” and other books.