Rapid Diagnostic Test Helps Distinguish between Severe and Uncomplicated Malaria in Africa

Ross Boyce, M.D., MS.c., studies mosquito-borne illnesses in Africa.

Ross Boyce, M.D., MS.c., studies mosquito-borne illnesses in Africa.

Malaria is a leading cause of death for children living in Sub-Saharan Africa. Many children in rural areas seek care at local community health clinics, but these clinics lack reliable tests to distinguish severe and uncomplicated malaria. Working at a health center in rural Uganda, researchers from the University of North Carolina at Chapel Hill demonstrated for the first time the potential of using a low-cost, routinely available rapid diagnostic test to detect severe malaria in children.

These findings were published in the journal Clinical Infectious Diseases.

“In many areas of rural areas of sub-Saharan Africa, malaria is inevitable. Children will be infected,” said Ross Boyce, M.D., MS.c., study author and a fellow in the UNC Division of Infectious Diseases. “Ensuring that those with the most severe form of the disease are quickly identified and treated, even when hours from the nearest hospital, is critically important to reducing the number of deaths.”

Over a period of six months, a total of 2,678 children with fever underwent testing for malaria using a rapid diagnostic test at the Bugoye Level III Health Center in the Kasese District of Western Uganda. Nearly half tested positive for malaria and 83 satisfied criteria for severe malaria. The sensitivity and specificity of the rapid diagnostic test for detecting severe malaria was 97.6 percent. The test was especially sensitive for children less than 5 years of age. Knowing when a child is suffering from severe malaria allows for a referral to a health center better equipped to handle the disease’s grave manifestations.

“Rapid diagnostic tests have been around for awhile, and are generally considered standard of care in most malaria-endemic settings,” said Boyce. “However, what we’ve done is show that these relatively simple tests can be used in new ways to provide important information beyond just a positive or negative result. While it’s not perfect, the approach could help first-line healthcare workers – many of who have no formal medical training – make potentially lifesaving triage decisions.”

Boyce said further work is needed to validate and operationalize diagnostic and treatment algorithms so as not to overwhelm fragile referral networks.

Investigators from the UNC School of Medicine collaborated with colleagues at Mbarara University of Science and Technology in Uganda and Harvard Medical School in Boston. This research was funded by the Harvard Global Health Initiative, the Thrasher Research Fund, Standard Diagnostics and Abbott Point of Care.

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Vorinostat Renders Dormant HIV Infection Vulnerable to Clearance

Julia Sung, M.D.

Julia Sung, M.D.

The ability for HIV to hide in the body in a dormant state makes curing the 40 million people living with the virus a challenge. Researchers at the University of North Carolina at Chapel Hill have shown the drug Vorinostat reverses this latency, causing resting CD4 T-cells to express HIV. The investigators have developed an assay that detects antigen production and includes immune effectors capable of clearing the virus. These results were published in EBioMedicine.

Vorinostat produces a window of vulnerability in the HIV reservoir by triggering viral antigen production. The team developed the latency clearance assay (LCA) to measure the amount of antigen activity Vorinostat produces. The assay also includes immune effectors capable of clearing the cells expressing the viral antigen.

“Measuring a latency reversing agent’s ability to induce relevant HIV production is technically challenging,” said Julia Sung, M.D., the study’s lead author and an assistant professor of medicine in the UNC Division of Infectious Diseases. “Using a latency clearance assay, we have detected the ability of Vorinostat, a latency reversing agent under clinical investigation, to induce recognizable levels of HIV protein on the cell surface allowing for subsequent clearance of infected cells.”

The optimal combination of latency-reversing agents and clearance strategies will be needed to cure HIV. The team says their assay can be used to evaluate these combinations in future studies.

The team at UNC collaborated with colleagues at MacroGenics, Inc., and Children’s National Medical Center on this study. The National Institutes of Health funded this research.

Ebola Detected in Semen of Survivors Two Years after Infection

DavidWohlCropEbola virus RNA can persist in the semen of survivors more than two years after the onset of infection researchers at the University of North Carolina at Chapel Hill have found. The research team, which included investigators from Ohio-based Clinical Research Management and the ELWA Hospital in Liberia also observed the detection of Ebola virus RNA in the semen of men who had previously had a negative test of their semen in some cases.

These findings led the study team to suggest revision of the 2016 World Health Organization guidelines relating to the sexual transmission of Ebola, which calls for men who survive Ebola virus disease (EVD) to undertake measures such as abstinence and the use of condoms for at least 12 months after the onset of EVD or until their semen has tested negative for Ebola virus RNA twice. The study results were published in Open Forum Infectious Diseases.

Listen to an interview with Voice of America Africa about the study’s results.

Male participants enrolled in a longitudinal cohort study of Ebola survivors in Monrovia, Liberia, consented to donating semen. Of the 149 men who provided samples, 13 tested positive for Ebola virus RNA. Of these 13 men, 11 had positive results even two years after the onset of Ebola infection.

“Our finding of long term persistence and intermittent detection of viral RNA in semen suggests we need to change how we think about Ebola as it is no longer only an acute illness, but also one with potential long term effects,” said William A. Fischer II, M.D., an assistant professor in the UNC Division of Pulmonary and Critical Care Medicine and the study’s co-author. “It is becoming clear that in some survivors, evidence of the virus can linger in the male genital tract for long periods of time with important potential implications for transmission.”

Fischer notes that while there has been documented sexual transmission of Ebola earlier after acute infection, it is not known whether the presence of RNA serves as a correlate for infectious virus and if transmission this far out is possible.

The study team also reports that the men whose samples tested positive for Ebola virus RNA were more likely to be older than those with a negative result. Those who had Ebola virus RNA detected in their semen also complained of vision problems at a higher rate than male survivors without evidence of Ebola virus RNA in their semen. The researchers recommend future studies investigate the source of viral persistence and whether the detection of viral RNA signifies the presence of infectious virus.

The large Ebola outbreak in West Africa in 2014 to 2015 was devastating to the people in West Africa and beyond, said David A. Wohl, M.D., professor of Infectious Diseases at UNC and study co-author.

“However, the scale of the epidemic has allowed for researchers to gain better insights into the Ebola virus, including the potential persistence of the virus in certain compartments of the body, such as the genital tract,” Wohl said.

The researchers stress that such studies must be conducted in a way that empowers the Ebola survivor community and avoids further stigmatization.

The Bill and Melinda Gates Foundation and the National Institutes of Health supported this study.

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Co-Infection with Two Common Gut Pathogens Worsens Malnutrition in Mice

Luther Bartelt, M.D., helped develop a new laboratory mouse model to study malnutrition.

Luther Bartelt, M.D., helped develop a new laboratory mouse model to study malnutrition.

Two gut pathogens commonly found in malnourished children combine to worsen malnutrition and impair growth in laboratory mice, according to new research published in PLOS Pathogens.

Malnourished children often face infection with pathogenic microbes that colonize the intestines. These infections disrupt healthy gut microbial communities and harm metabolism and immune system function, worsening malnutrition and impairing children’s growth and development. However, the precise effects of co-infection with multiple pathogens in malnourished children are poorly understood.

To gain new insights, Luther Bartelt, M.D., instructor in the Division of Infectious Diseases at the University of North Carolina at Chapel Hill and colleagues developed a new laboratory mouse model of co-infection during malnutrition. They fed weaned mice a protein-deficient diet and infected them with Giardia lamblia and, two weeks later, enteroaggregative Escherichia coli (EAEC) — two of the pathogens most commonly found in malnourished children.

“We observed unique inflammatory and metabonomic consequences of Giardia and EAEC infections, not only separately, but also during co-infection,” Bartelt said. “These findings inform our understanding of similar perturbations seen in malnourished children, and change how we think about mechanisms driving multi-enteropathogen-associated enteropathy.”

The researchers used an array of analytical tools—including stool and urine analysis, flow cytometry, light microscopy, nuclear magnetic resonance spectroscopy, and 16S rRNA analysis — to observe the wide-ranging effects of this sequential co-infection.

They found that Giardia and EAEC combined to increase weight loss in the young mice. This appeared to be a result of both impaired metabolism and worsened immune system function in the mucosal lining of the mice’s intestines. Co-infection also amplified protein breakdown by gut microbes and simultaneously interfered with the ability for the mouse metabolism to adapt to protein deficiency.

These findings and future studies in similar co-infection mouse models could help reveal new insights that cannot be gleaned from single-pathogen studies alone. They could also help inform ongoing long-term studies of malnutrition in children and, ultimately, the development of new treatments or better combinations of existing treatments to restore healthy gut conditions in malnourished children.

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