November 22, 2019
By Marilynn Larkin
NEW YORK (Reuters Health) - New strains of Plasmodium falciparum may not be detected by the only rapid diagnostic test (RDT) approved in the U.S., raising the potential for improper, missed or delayed malaria diagnoses, researchers say.
Many RDTs, including the only one approved by the U.S. Food and Drug Administration (BinaxNOW/Abbott), work by detecting a protein called histidine rich protein 2 (HRP2). "Recently, researchers have shown that some mutant malaria parasites...do not contain this protein, which means that the RDTs would show up as negative, even though the patient does have malaria," Dr. Brett Forshey of the Armed Forces Health Surveillance Branch in Silver Spring, Maryland explained in an email to Reuters Health.
"A false negative might mean that the patient does not get appropriate treatment, or that appropriate control measures are not put in place," he said.
Because the RDT currently in use by the US military might give the wrong answer in some instances, "Our recommendation is that when malaria is suspected in a U.S. service member, more advanced testing should be utilized," Dr. Forshey said. "If that testing is not available and malaria is suspected, then patients should be treated as if they have malaria, even if the RDT results are negative."
In their Military Medicine report, online October 28, Dr. Forshey and colleagues note that P. falciparum strains lacking the HRP2-encoding gene (pfhrp2) and/or a cross-reactive protein HRP3 (pfhrp3) were first identified in Peru, and subsequently have been detected in various countries around the world, particularly in the US Southern Command (SOUTHCOM) and Africa Command (AFRICOM).
Steps to address this emerging problem for the US military, they say, should include informing medical personnel of potential false-negative RDT results; establishing systematic and harmonized surveillance studies; and evaluating RDTs that do not rely solely on HRP2 for a malaria diagnosis.
"Development of a new RDT should be considered now because of the long development and regulatory approval process; although this timeline could be shortened by starting with an existing assay, FDA approval and fielding will still require years to accomplish," the authors state.
Dr. Forshey said, "Beyond the U.S. military, malaria-endemic countries around the world utilize RDTs that target the same protein for malaria treatment and control. The World Health Organization (WHO) and its partners are actively engaged in evaluating existing RDTs and exploring new RDTs that have higher sensitivity and do not rely on the same target protein for diagnosis."
"Any results from Department of Defense laboratory studies would have relevance for the U.S. military as well as public health practitioners in endemic countries," he noted.
Dr. Anna Bershteyn, Assistant Professor in the Department of Population Health at NYU Langone Health in New York City, commented by email, "Resistance to detection is one piece of a wider arc. Malaria is also developing growing resistance to antimalarial drugs, and malaria-carrying mosquitoes are developing resistance to insecticides."
"It's reasonable to expect that resistance to detection by the diagnostic will become more and more common as resistant strains become selected," she told Reuters Health. "If that happens, diagnostic failures will increasingly become an issue, not just for the U.S. military, but for front-line health workers in malaria-endemic places."
"Two things can be done," she said. "First, we need to keep innovating in the areas of diagnostics, drugs, and insecticides. Second, we can make it harder for resistance to develop by using combinations of multiple drugs, or insecticides, or diagnostic target molecules, instead of just one at a time."
"Treatment of malaria is very time-sensitive because a patient can go downhill fast. So, in many malaria-endemic settings, it's crucial to be able to diagnose malaria quickly without relying on a microscopist or a laboratory," she said.
"The WHO is grappling with this by recommending that some places with a higher prevalence of HRP2 deletion in local malaria strains switch to different RDTs, but these other tests tend to be less sensitive, especially for people with lower parasite counts in their blood," Dr. Bershteyn noted. "It's a tough trade-off until better tests become available. This is a case where military advances in technology could also have a tremendous global health benefit."
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