By Marie Rosenthal, MS
Because it rises early after an infectious insult, interleukin-6 (IL-6) may be an effective biomarker for predicting sepsis in high-risk patients, including neonates, children and pregnant women, said Seán O. Whelan, MB, BAO, BCh, BSc, MSc, MRCPI, at ESCMID Global 2025, in Vienna (abstract O0177).
Managing sepsis is a race against time, so the clinical diagnosis of sepsis is always a challenge, but especially in these three groups, because physiologic changes can obscure its early signs, explained Dr. Whelan, a clinical microbiology trainee in Dublin.
Specific challenges include “difficulties with consensus definitions for what sepsis means in each of these populations; the presence of confounding co-pathologies that closely mimic sepsis and may be far more common than sepsis, which are difficult to try to differentiate; and then the poor performance of our currently used culture-based technologies,” he said.
“And as a result of these, it can be difficult to clinically make a risk assessment in an accurate and timely way about which patients are at high risk of poor outcome.”
Given the rapid progression of sepsis, clinicians have begun looking at diagnostic biomarkers, such as C-reactive protein (CRP), procalcitonin (PCT) and the neutrophil-to-lymphocyte ratio (NLR) to enable timely intervention. These biomarkers are used throughout the course of sepsis from diagnosis to predicting severity to monitoring, according to Dr. Whelan.
IL-6, a cytokine that has myriad pro- and anti-inflammatory effects, is gaining attention as a sepsis biomarker primarily because of its attractive dose–response relationship, according to Dr. Whelan.
While CRP and PCT secretions begin to rise “six hours or so after an infectious insult and reach their peak one or several days after, interleukin-6 begins to rise one hour after an infectious insult and peaks within six hours. So, this potentially more closely aligns with the physiological response, and therefore, may make the case for interleukin-6 being a more sensitive early diagnostic biomarker for sepsis,” he said.
In their retrospective cohort study, Dr. Whelan and his colleagues analyzed serial blood samples for one year from 252 patients (111 pediatric, 72 maternity and 69 neonatal cases) with suspected sepsis from two hospitals, Rotunda Hospital, which is a large maternity hospital that cares for more than 10,000 pregnant women each year, and Children’s Health Ireland (CHI) at Temple Street, which has a pediatric ICU, both in Dublin.
Patients were classified by infection type (bacterial, viral or no infection) and physiologic response (normal, systemic inflammatory response syndrome, sepsis and septic shock). Diagnostic accuracy was evaluated by analyzing the area under the receiver operating characteristic curve (AUROC) (ranging from 1.0, a perfect test with 100% specificity and sensitivity, to 0.5, a completely ineffective test).
They wanted to assess the diagnostic performance of IL-6 against the other biomarkers that were in use in their institutions (CRP, PCT and NLR) across the three populations.
“Specifically, we sought to look at the biomarker kinetics,” Dr. Whelan said. “So, in those who had serial sampling over time, we looked at the individual biomarker profiles of patients across physiological and etiological axes, and then we evaluated the diagnostic performance using receiver operator characteristic curves,” Dr. Whalen explained.
IL-6 consistently outperformed traditional biomarkers in distinguishing bacterial from nonbacterial infections, with AUROC values of 0.91 in children, 0.94 in the maternal patients and 0.86 in neonates. IL-6 also effectively stratified sepsis severity, distinguishing between mild infection, sepsis and septic shock, a critical marker for guiding timely and appropriate treatment.
In terms of sensitivity and specificity, IL-6 exceeded 80% in both pediatric and maternal patients, detecting bacterial infections with 91% sensitivity in children and 94% in pregnant women. In neonates, while IL-6 maintained high specificity (97.1%), its sensitivity (67.6%) was lower. These lower sensitivity and AUROC values may be partly attributable to the complexities of diagnosing neonatal sepsis, where there is no clear consensus definition, he said. The broader spectrum of presentations in neonatal sepsis also may contribute to these differences.
Dr. Whelan concluded: “This faster, steeper response makes IL-6 a promising biomarker for earlier sepsis detection.”
Dr Whelan also highlighted its growing clinical application. “IL-6 is already in routine use in our institutions, the Rotunda Hospital and Children’s Health Ireland at Temple Street, for these populations. The challenges to wider adoption have been lessened by the development of commercially available testing on commonly used platforms, which can provide real-time results. The COVID-19 pandemic accelerated this process, as IL-6 testing became more widely used in assessing patient inflammation.”
The study had limitations, he said, including that it was a two-center observational study, which may not be representative of a broader population, and some patients did not have complete serial samplings on days 0, 1 and 2, as part of their routine care.
Dr. Whelan reported no relevant financial disclosures. This study was carried out in collaboration with colleagues in the Departments of Microbiology, Chemical Pathology, Pediatric Intensive Care, Neonatology and Obstetrics & Gynecology at CHI at Temple Steet and the Rotunda Hospital, as well as the Irish Meningitis and Sepsis Reference Laboratory at CHI at Temple Street.
