Baseline T-helper-related immune measures and subsequent infectious events in children with newly diagnosed malignancies: an exploratory prospective cohort study

To evaluate whether baseline T-helper-related immune measures, derived from plasma T-helper-associated cytokines, are associated with subsequent infectious events in children with newly diagnosed malignancies. In this exploratory prospective cohort study, 65 children with cytopenia and suspected hematologic malignancies were enrolled. Malignancy was confirmed in 49 patients, and ruled out in 16, who served as a malignancy-free comparison group providing a non-malignant baseline reference for the immune measures. Plasma T-helper-associated cytokines were measured using a bead-based multiplex immunoassay and were used to derive T-helper-related immune measures (multi-cytokine indices calculated as the summed concentrations of subset-defining cytokines for T-helper 1 (Th1), Th2, and Th17, and single-cytokine axis measures for Th9 and Th22). These pathways were selected because they cover the principal, non-redundant arms of T-helper antimicrobial defense: Th1 against intracellular pathogens, Th17 and Th22 against extracellular bacteria/fungi and at the mucosal barrier, and Th2/Th9 in type-2 and regulatory roles, making their coordinated activity biologically suited to capture infection susceptibility in children who are starting chemotherapy. Samples were obtained at three time points — baseline before chemotherapy, after induction, and during maintenance — so that baseline measures could be tested for association with subsequent infectious events (primary analysis) and their trajectories described over treatment (exploratory analysis). Patients with malignancies were monitored for chemotherapy-associated infections. Associations between baseline T-helper-related immune measure tertiles and the infectious event index were examined using logistic regression models adjusted for age and sex. At baseline, T-helper-related immune measures in children with malignancy were higher than those in the non-malignant comparator reference, and children who later developed infectious events showed the greatest deviation from baseline. Among the 49 children with confirmed malignancies, 40 developed at least one infectious event over a mean follow-up of approximately 42 months, and 9 remained free of infection. Baseline Th9-axis measurements were the most strongly associated with subsequent infectious events. Compared with the first tertile, the second and third tertiles were associated with higher odds of infectious events after adjusting for age and sex (adjusted odds ratio (aOR): 4.86, 95% confidence interval (CI) [1.14, 20.71] and aOR: 6.91, 95% CI [1.48, 32.29], respectively). The upper tertiles of the Th1, Th2, and Th17 indices and the Th22-axis measure also showed higher odds estimates, although the confidence intervals were wide. In an exploratory longitudinal analysis, baseline immune measures tended to be higher in children who later developed infectious events, with trajectories converging between the groups during follow-up. In this exploratory cohort, higher baseline T-helper-related immune measures, particularly those of the Th9-axis, were associated with subsequent infectious events. Because multiple measures were examined without correction for multiple comparisons, these findings are preliminary and require validation in larger cohorts before any role in infection risk assessment can be considered. Not applicable. What is Known • Children with newly diagnosed malignancies are highly susceptible to infection during chemotherapy. • Conventional and single cytokine biomarkers inconsistently predict the risk of infection across treatment phases. What is New • Higher baseline T-helper-related immune measures, particularly Th9-axis measures, were associated with a higher likelihood of subsequent infectious events. • Grouped T-helper-based measures tracked the link between baseline immune activity and subsequent infection more consistently than single cytokines, a hypothesis-generating finding that warrants validation in larger cohorts.