With close to 50% of the world’s population living in areas endemic to malaria and almost half a million malaria deaths per year, identifying asymptomatic carriers of this parasitic infection is a critical factor for lowering disease transmission rates. However, standard tests often miss identifying carriers, especially when parasitemias are low. Moreover, while DNA tests for identifying the malaria parasite usually show infection, the test is not very rapid and often difficult to utilize in many parts of the world due to impoverished conditions and lack of vital infrastructure.

Now, an international team of researchers is working toward a way to identify malaria patients, including infected individuals who show no malaria symptoms. The researchers wanted to see if they could identify changes in human odors associated with malaria infection that might be useful for diagnosing infected individuals. Findings from the new study were published recently in the Proceedings of the National Academy of Sciences (PNAS), in an article entitled “Volatile Biomarkers of Symptomatic and Asymptomatic Malaria Infection in Humans.”

“Our previous work in a mouse model found that malaria infection altered the odors of infected mice in ways that made them more attractive to mosquitoes, particularly at a stage of infection where the transmissible stage of the parasite was present at high levels,” explained lead study investigator Consuelo De Moraes, Ph.D., adjunct professor of biology at Penn State University, and professor of environmental systems science at ETH Zurich. “We also found long-term changes in the odor profiles of infected mice.”

In the current study, the researchers looked to expand upon what they had learned from their mouse models and test the accuracy of their hypothesis in humans. The research team was particularly interested in identifying those who were infected but had no symptoms. Initially, the investigators used microscopy and an SD Bioline Rapid Diagnostic Test to identify patients with malaria. Because these methods have limited sensitivity—particularly when parasite loads are low—infections were confirmed by DNA tests. They identified 333 people who unambiguously were either infected with malaria or were not infected with malaria.

Only if both microscopy and DNA studies were negative were subjects considered malaria-free. Infected patients for the initial studies were both microscopy and DNA positive for malaria. In some later analyses, the researchers included 77 people who were positive for malaria according to DNA but showed no parasites in the microscopic tests. Malaria infection does not create new volatile chemicals in the body but alters the amounts—up or down—of volatile chemicals that are already present in the odors of healthy people.

“It is interesting that the symptomatic and asymptomatic infections were different from each other as well as from healthy people,” noted senior study investigator Mark Mescher, Ph.D., adjunct professor of biology at Penn State and professor of environmental systems science at ETH Zurich.

The study authors added that “based on extensive collections of skin odors from human populations in Kenya, we report broad and consistent effects of malaria infection on human volatile emissions. Furthermore, we found that predictive models based on machine learning algorithms reliably determined infection status based on volatile biomarkers and, critically, identified asymptomatic infections with 100% sensitivity, even in the case of low-level infections not detectable by microscopy.”

This difference among infected, infected asymptomatic, and healthy individuals may eventually lead to tests capable of rapidly and accurately identifying infected people, even those without symptoms.

“But, we should emphasize that we are a long way away from developing a practical diagnostic assay based on odor cues,” Dr. De Moraes remarked.

For a test to succeed it would need to be rapidly and cheaply deployable under field conditions, but still detect infections with high sensitivity.

“In the near term, our goal is to refine the current findings to find the most reliable and effective biomarkers we can,” Dr. Mescher concluded. “This is really basic science to identify the biomarkers of malaria. There is still a lot more work to be done to develop a practical diagnostic assay.”

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