Asymptomatic Leishmaniasis Infected Nearly 20% of Soldiers in Iraq
U.S. Army Soldiers attached to the 4th Battalion, 31st Infantry Regiment search for three missing Soldiers in Yusifiyah, Iraq, May 14, 2007. (U.S. Air Force photo by Staff Sgt. Dennis J. Henry Jr.)
BETHESDA, MD—New research has identified three chemokines as potential biomarkers for asymptomatic visceral leishmaniasis (VL), a chronic infection caused by Leishmania (L.) donovani or L. infantum. While VL is one of the major parasitic diseases with significant outbreak and mortality potential, most infected individuals never develop clinical disease and are able to control the parasite and remain asymptomatic. Some, however, progress to the more severe VL form, which is potentially fatal if not promptly treated.
An estimated 50,000 to 90,000 new cases of VL occur annually worldwide, but research suggests there are far more cases of asymptomatic infection. One study found that 19.5% of military personnel who had served in Iraq—which translates to more than 300,000 people—seemed to have evidence of asymptomatic infection, said Naomi Aronson, MD, director of Infectious Diseases Division at the Uniformed Services University of the Health Sciences and one of the researchers conducting that study.1
That time-intensive study was conducted on blood samples from 200 soldiers using enzyme-linked immunosorbent assay (ELISA), rk39 test strips, quantitative polymerase chain reaction (PCR), and interferon gamma release (IGRA) assays available at only two centers nationwide.
Because of the prevalence of asymptomatic infection and time required for testing—the labs could process only 10 samples a day, Aronson said—the researchers began to look for something that could be used as a biomarker for asymptomatic infection.
“The way that we chose to study biomarkers in this particular study is we used cytokine and chemokine profiling, which is essentially taking advantage of the fact that it’s the immune response to the parasite that is so critical for allowing it to grow or keeping it under control,” she said.
The researchers used a commercially available 25-test profile using banked supernatants from stimulated cells they collected from 200 former or current military members for the previous study—all of whom had gone to Iraq during the summer months when the sand fly that transmits the infection would be most active—as well as 50 controls who had never traveled to a country with Leishmania. The researchers put a soluble Leishmania antigen (SLA) into the blood samples and then compared the responses to unstimulated responses in the same person’s blood.2
Their findings: Three chemokines—Monocyte Chemoattractant Protein-1 (MCP-1), Monokine Induced by Gamma (MIG) Interferon and Interleukin-8 (IL-8)—were detected at high levels in asymptomatic VL_ SLA-stimulated cultures from Iraq deployers compared to uninfected controls.
Aronson said the findings suggest that the three chemokines could be potential biomarkers for asymptomatic infection. If eventually validated as biomarkers, they could perhaps allow scientists to look at large populations quickly.
“You could use it now for surveillance if you had a lot of people who went to endemic countries, and you wanted to do surveillance of a population. You could use the biomarker and look at many more samples than we could clinically,” she said.
A biomarker used in a clinical setting, however, would have to go through extensive testing before the FDA would clear it. “If you used it in an individual person you would have to validate it, which at this point we’ll leave that to someone else if they’re interested,” she said.
Why Does It Matter?
Aronson said what surprised her most about the research was that 1 in 5 servicemembers appeared to be infected with Leishmania. “I was really surprised at the magnitude of that and the lack of interest the community seems to have,” she said. The issue, she said, is while the current treatments for VL are highly effective, they are administered intravenously and require a long course of treatment. “It’s hard to make a case when you have no symptoms? Why should we care?”
She offered three reasons why being able to screen for—and perhaps treat—asymptomatic VT is important. First is that even in asymptomatic people who went to Iraq, 1% had the parasite in their blood, so transmission is possible through transplants or blood transfusions. “[The parasite] lives in white blood cells,” Aronson explained. “We transfuse packed red blood cells—of course some white blood cells are not totally separated out in the preparation of PBRC—but in addition in US hospitals about 70% of infusions are given with blood fillers”. Also, she said, there is a permission sand fly vector, Lutzomyia shannoni, found widely in the U.S. and, if this sand fly bites an infected person and establishes infection inside the sand fly it could then bite and transmit VL to another American.
Second, because it is believed to be a lifelong infection, a young person who has no problem with it could later could have a reactivation of infection and become very ill if they were to require immunosuppressive treatment for cancer or some other condition. “If it activates 30 years after you were in Iraq, no one would ever associate it with it that,” says Aronson. And because there are only a couple of places in the U.S. where testing can be done, she fears the infection could go unidentified and untreated. “It is treatable if identified, but I worry about what the implications will be for that individual,” she said.
Finally, she is concerned about the effects of ongoing infection on the body. “If you have a parasite in your white blood cells constantly stimulating cytokines and chemokines to be made for decades, are you going to wear out your cells? Are you going to see immunoaging like we see with HIV infection where you have heart disease, dementia and kidney disease at much earlier ages?” she asks. “It is theoretic, but we just showed with our biomarkers that these cells are still very immunoactive, so those are my concerns and why I think this matters.”
Next Steps
The eventual hope is that VL will be like tuberculosis—another disease that remains dormant in the body and can be activated—in that there will be treatments to prevent that activation.
“We don’t have enough science to know what the right treatment would be for asymptomatic Leishmania, and we don’t have a pill like you can take for TB to make it go away.”
“This is a neglected tropical disease. There’s very little funding for it,” she said. “But we should think about what’s going to happen to this population over the next 30 or 40 years, and do we have anything we could study that would change the course of the infection?”
In the meantime, Aronson encouraged clinicians who see a patient with symptoms of active VL—including fever, enlarged liver and spleen and low blood count—who has lived in or deployed to countries l where Leishmania is endemic to seek specialized diagnostic testing from the CDC. “So you can treat to potentially save lives.”
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Mody RM, Lakhal-Naouar I, Sherwood JE, Koles NL, Shaw D, Bigley DP, Co EA, Copeland NK, Jagodzinski LL, Mukbel RM, Smiley RA, Duncan RC, Kamhawi S, Jeronimo SMB, DeFraites RF, Aronson NE. Asymptomatic Visceral Leishmania infantum Infection in US Soldiers Deployed to Iraq. Clin Infect Dis. 2019 May 30;68(12):2036-2044. doi: 10.1093/cid/ciy811. PMID: 30239631; PMCID: PMC6769235.
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de Araujo FF, Lakhal-Naouar I, Koles N, Raiciulescu S, Mody R, Aronson N. Potential Biomarkers for Asymptomatic Visceral Leishmaniasis among Iraq-Deployed U.S. Military Personnel. Pathogens. 2023 May 12;12(5):705. doi: 10.3390/pathogens12050705. PMID: 37242376; PMCID: PMC10223375.