University of South Florida

Biomarker can help predict children’s risk for potentially fatal malaria

A USF-Health led study analyzing plasma cell-free DNA indicates host inflammation is as important as damage inflicted by the parasite in cerebral malaria

A mother and her comatose child with cerebral malaria on the Malaria Research Ward at Queen Elizabeth Central Hospital, Blantyre, Malawi. [Photo by Jim Peck, Blantyre Malaria Project/Michigan State University]

TAMPA, Fla. (Oct. 16, 2020) — Cerebral malaria is a devastating form of the parasitic disease mainly affecting children under age 5 in sub-Saharan Africa. The mosquito-borne P. falciparum parasites that cause malaria accumulate in brain blood vessels, which commonly leads to increased brain pressure from swelling and coma.

Even with good antimalarial treatment, about one in five children diagnosed with cerebral malaria (CM) dies — and those who survive often have long-lasting neuropsychiatric complications such as learning disabilities, hyperactivity and behavioral problems.

It remains challenging for doctors to predict which particular pediatric patients are at highest risk for potentially fatal CM; the vast majority of children contract uncomplicated malaria with flu-like symptoms that typically resolve.  Current tools to help identify and triage those with the severest forms of malaria — including a specialized ophthalmic examination to pinpoint abnormalities in retinal blood vessels, brain imaging, blood work requiring a phlebotomist, and immunology laboratory testing — are cost-prohibitive in developing countries where malaria is most common.

A retrospective study led by researchers at the University of South Florida Health (USF Health) Morsani College of Medicine suggests that measuring cell-free DNA in plasma (cfDNA) offers a simple, rapid way to identify severe and potentially deadly cases of malaria.  The team’s findings were published recently in in JCI Insight, a journal of the American Society for Clinical Investigation.

Kami Kim, MD

Kami Kim, MD, (above) and Iset Vera, PhD (below), of the USF Health Division of Infectious Disease and International Medicine, led this study. They conduct malaria research with the Blantyre Malaria Project in Malawi, Africa, and other collaborators.

DNA is normally contained inside cells. Cell-free DNA circulates freely in plasma or other bodily fluids and often indicates the destruction of cells, including immune cells (neutrophils) that play a role in clearing malaria parasites.

A simple biological molecule (biomarker) like cfDNA that correlates with disease severity and risk of death can help guide clinical decisions, such as whether to admit a child with malaria into the intensive care unit, or start adjuvant treatments (in addition to antimalarial drugs) to decrease brain swelling or control platelet counts, said the paper’s senior author Kami Kim, MD, professor and director of the USF Health Morsani College of Medicine’s Division of Infectious Disease & International Medicine.  While uncomplicated malaria can be treated with oral antiparasitic drugs, treating severe malaria requires IV medications in a hospital setting.

“Plasma cell-free DNA offers a clinical tool to help (health providers) target specific treatments and more effectively use medical resources, especially in rural settings where specialized equipment and therapies are limited or unavailable,” Dr. Kim said. “That can end up benefiting more patients.”

The USF Health study compared the plasma of Malawian children with cerebral malaria, uncomplicated malaria (symptomatic but no severe illness) and no malaria (healthy controls).

Blood smear from a patient with cerebral malaria depicts red blood cells infected by the malaria parasite Plasmodium falciparum. At the center of the image is a DNA neutrophil extracellular trap, or NET, near the infected cells.

The researchers measured levels of total cfDNA in the children’s plasma by streamlining a test employing an easy-to-use, portable device to detect cellular genetic material with fluorescent molecules. They used laboratory-based polymerase chain reaction (PCR) technology to specifically measure each of the two types of cfDNA that make up total cfDNA — the host (patient) cfDNA and the parasite cfDNA.  The bedside test required just a finger prick of blood to provide results in about 5 minutes, versus the 5-hour turnaround time of the more technologically-advanced PCR test. Both tests performed comparably in detecting total cfDNA levels, Dr. Kim said.

Other research groups previously linked the concentration of parasite cfDNA in human plasma to malaria severity in children and adults.  But this new study was the first to show that total plasma cfDNA is predominantly made up of host cfDNA, rather than cfDNA derived from the malaria parasite.

The higher that levels of total cfDNA (and major contributor host cfDNA) rise, the sicker children with malaria get, said first author Iset M. Vera, PhD, a research instructor in the USF Health Department of Internal Medicine. Both were better indicators of disease severity than parasite cfDNA alone, Dr. Vera added.

“Host inflammation promoted by the immune response of white blood cells (neutrophils) contributed to disease progression, and therefore the total cfDNA in plasma correlated with severity of malaria infection, including deaths from cerebral malaria,” Dr. Kim said.  “The cfDNA marker gave us insight into what may be causing inflammation in the super sick kids. The study  substantiated our hypothesis that host inflammation is as much a critical part of cerebral malaria as the damage done by the parasite.”

Dr. Karl Seydel (MSU and Blantyre Malaria Project) about to examine a young patient recovering from cerebral malaria on the Malaria Research Ward at Queen Elizabeth Central Hospital, Blantyre, Malawi. [Photo by Jim Peck, BMP/MSU]

While more research is needed, quantifying cfDNA can help determine which children with CM are at risk for fatal outcomes — and offers promise as a point-of-care test suitable for use outside the hospital, the researchers concluded.

That’s important because malaria exacts disproportionate human and economic costs on the world’s poorer countries, Dr. Vera said.  “Malaria burdens the mothers who travel to urban hospitals and spend days there so their sick children can get the advanced care unavailable in their communities. And, it burdens developing countries when children die from malaria or develop long-term complications so they cannot grow up to be productive adults.”

The study was supported in part by grants from the National Institutes of Health’s Center for Advancing Translational Science, the Burroughs Welcome Fund, and the National Health and Medical Research Council of Australia.

The female Anopheles mosquito transmits the malaria parasite to humans through its bite. P. falciparum malaria—the most deadly type—is most common in sub-Saharan Africa, where it causes more than 400 000 deaths a year, mostly in young children.

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