December 5, 2024 | Researchers from Simon Fraser University in Burnaby, Canada, and the University of British Columbia in Vancouver, Canada, have discovered a genetic signature in newborn infants that can predict neonatal sepsis before symptoms show. Neonatal sepsis is difficult to diagnose because of the nonspecific clinical signs that are often considered typical behavior issues in newborns, such as difficulty feeding and irritability. Therefore, most infants are not diagnosed until they start developing or have acquired the disease.
The team originally set out to study immunity and immune responses in newborns, specifically factors that result in the successful vaccination of newborns. They took blood samples from 720 newborns at birth and then one, three, or seven days after birth. The population was from the Medical Research Council (MRC) Unit – The Gambia, headed by Beate Kampmann, professor of pediatric infection and immunity at the London School of Hygiene and Tropical Medicine and a co-senior author of the study. Because newborns are tiny and have underdeveloped immune systems, the research team was only able to take small amounts of blood samples. In order to better examine the samples, the team used RNA sequencing (RNA-seq) to analyze changes in gene expression. It was through these gene expression changes that the team measured and determined changes associated with early-onset neonatal sepsis—and made their accidental discovery. The gene signature (HSPH1, BORA, NCAPG2, PRIM1) was developed and validated.
Within this sample population, 21 newborns were diagnosed with either blood culture-proven bacterial sepsis with a clinically proven pathogen or clinically diagnosed sepsis with negative blood culture but displaying fever, excessive crying, poor feeding, vomiting, convulsions, and other symptoms that would indicate sepsis (EBioMedicine, DOI: 10.1016/j.ebiom.2024.105411). These infants initially appeared healthy at birth but developed the disease within 28 days.
“A certain number of them had what they call early onset sepsis, which is sepsis in the first week of life,” explains co-senior author Dr. Robert E.W. Hancock, professor of microbiology and immunology at UBC. “This provided us with an ability to look for predictive markers of sepsis because the infants were apparently healthy at day zero… but acquired sepsis sometime in the first week.”
He also notes a surprising discovery during the study. There was a programmed set of changes that occurred in the babies, regardless if they came from MRC Unit – The Gambia or the Papua New Guinea Institute of Medical Research. There were two prominent changes going on. The first was the infants developing a mature immune response possibly due to the challenges of the environment they were born into, and the second was how the high stress levels around birth decreased over time with lots of changes going on, which reflects about one in five of all the genes that are expressed in the infant.
“There is a lot of stuff happening in these infants in the first week of life,” says Dr. Hancock. “We call that the development program, and… when these infants get sepsis, that program is substantially altered.” He also expresses concern over figuring out why infants that develop neonatal sepsis tend to have altered development, including altered learning abilities.
The Impact on Neonatal Sepsis Treatment
In Western countries such as Canada and the US, neonatal sepsis is not as common compared to lower- and middle-income countries. However, physicians can “overreact” to uncertainties about whether a newborn is acquiring or will acquire sepsis, starting babies on antibiotics prematurely, which can affect the infant’s development.
However, this predictive genetic signature can provide a clearer picture of the baby’s health and condition, “[signaling] physicians what they should do and how they should manage the patient—in this case, the baby.”
Despite the opportunities with diagnoses and treatment options that this genetic expression provides, it does not address another major issue. For lower- and middle-income countries, resources and treatment options are limited compared to their higher-income counterparts. Because of this, only babies that are definitively diagnosed with neonatal sepsis or showing a very high probability of the disease would need to be prioritized.
The sample size was quite small, including its validation cohort. With that said, the discovery of the gene expression is enough for the team to get a lead. The researchers have plans to expand the study to thousands of participants in order to validate the signature and gather more information. Dr. Hancock states that testing for the gene signature would be easier, now that they can use PCR. Instead of looking at all genes, this allows focus on the “signature” genes. The team can eventually use point-of-care devices that only require a drop of blood and generate results in as little as 30 minutes. Dr. Hancock also mentions that there are now handheld devices that are even more convenient and provide results in as little as 10-15 minutes.
For now, the team is focused on finding funding, but “the objective is important enough that we hope that we’ll have success in doing that.”