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Background <p>Delayed cerebral ischemia (DCI) after aneurysmal subarachnoid hemorrhage (SAH) is incompletely understood and may involve intrathecal immune activation. Cytotoxic natural killer (NK) cells can rapidly respond to SAH and promote neuroinflammation, whereas regulatory T cells (Tregs) may counteract excessive immune activation. This study investigates the NK/Treg ratio in cerebrospinal fluid (CSF) and peripheral blood (PB) as a potential immunological marker associated with DCI.</p> Methods <p>In this prospective, observational, single-center study, CSF and peripheral blood samples from 21 patients with aneurysmal SAH admitted between 2023 and 2024 were analyzed. Longitudinal dynamics of NK cells and Tregs were assessed by flow cytometry at predefined time points from day 1 to day 14 after hemorrhage. The NK/Treg ratio was calculated for each compartment and time point, and its association with DCI was explored.</p> Results <p>Twenty-one patients were included, of whom 16 were female (76.2%). The mean age was 55.9 years (standard deviation [SD] 13.3). Median WFNS and modified Fisher grades at admission were 3 (range 1–5) and 3 (range 1–4), respectively. DCI occurred in 10 patients (47.6%), with a median onset of 8.5 days after hemorrhage (range 4–12). Longitudinal dynamics of NK cells and Tregs in CSF and peripheral blood were assessed using flow cytometry. On day 3, the CSF NK/Treg ratio was higher in patients who later developed DCI compared with patients without DCI (mean 5556.6 [SD 12266.0] vs. 161.8 [SD 195.2]). CSF ratios remained numerically higher at later time points, whereas changes in peripheral blood were modest. In exploratory analyses of clinical covariates, lower modified Fisher grades (1–3 vs. 4) were associated with increased NK/Treg ratios in CSF at day 1 (<i>p</i> = 0.046) and day 2 (<i>p</i> = 0.007), possibly indicating that the elevation was not merely a reflection of subarachnoid blood burden.</p> Conclusions <p>Patients who developed DCI showed an early intrathecal shift in the balance between NK cells and Tregs, reflected by a higher CSF NK/Treg ratio around day 3. This pattern was more pronounced in CSF than in peripheral blood, suggesting a compartment-specific immune alteration associated with DCI. Although the small sample size, high variability, and limited statistically significant findings preclude definitive conclusions, these data support the hypothesis that early CSF immune dysregulation may contribute to DCI after SAH. CSF-based immune profiling, including the NK/Treg ratio, may therefore represent a promising exploratory approach for DCI risk stratification. Larger prospective multicenter studies with standardized CSF sampling are required to validate these exploratory findings.</p>

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Natural killer cells and regulatory T cells in aneurysmal subarachnoid hemorrhage in peripheral blood and cerebrospinal fluid - a pilot study

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年5月29日

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  • A. Pfnür,
  • A. Bohnacker,
  • L. Dörfer,
  • A. Ziebart,
  • R. Halbgebauer,
  • M. Huber-Lang,
  • H. Tumani,
  • C. R. Wirtz,
  • T. Kapapa

摘要

Background

Delayed cerebral ischemia (DCI) after aneurysmal subarachnoid hemorrhage (SAH) is incompletely understood and may involve intrathecal immune activation. Cytotoxic natural killer (NK) cells can rapidly respond to SAH and promote neuroinflammation, whereas regulatory T cells (Tregs) may counteract excessive immune activation. This study investigates the NK/Treg ratio in cerebrospinal fluid (CSF) and peripheral blood (PB) as a potential immunological marker associated with DCI.

Methods

In this prospective, observational, single-center study, CSF and peripheral blood samples from 21 patients with aneurysmal SAH admitted between 2023 and 2024 were analyzed. Longitudinal dynamics of NK cells and Tregs were assessed by flow cytometry at predefined time points from day 1 to day 14 after hemorrhage. The NK/Treg ratio was calculated for each compartment and time point, and its association with DCI was explored.

Results

Twenty-one patients were included, of whom 16 were female (76.2%). The mean age was 55.9 years (standard deviation [SD] 13.3). Median WFNS and modified Fisher grades at admission were 3 (range 1–5) and 3 (range 1–4), respectively. DCI occurred in 10 patients (47.6%), with a median onset of 8.5 days after hemorrhage (range 4–12). Longitudinal dynamics of NK cells and Tregs in CSF and peripheral blood were assessed using flow cytometry. On day 3, the CSF NK/Treg ratio was higher in patients who later developed DCI compared with patients without DCI (mean 5556.6 [SD 12266.0] vs. 161.8 [SD 195.2]). CSF ratios remained numerically higher at later time points, whereas changes in peripheral blood were modest. In exploratory analyses of clinical covariates, lower modified Fisher grades (1–3 vs. 4) were associated with increased NK/Treg ratios in CSF at day 1 (p = 0.046) and day 2 (p = 0.007), possibly indicating that the elevation was not merely a reflection of subarachnoid blood burden.

Conclusions

Patients who developed DCI showed an early intrathecal shift in the balance between NK cells and Tregs, reflected by a higher CSF NK/Treg ratio around day 3. This pattern was more pronounced in CSF than in peripheral blood, suggesting a compartment-specific immune alteration associated with DCI. Although the small sample size, high variability, and limited statistically significant findings preclude definitive conclusions, these data support the hypothesis that early CSF immune dysregulation may contribute to DCI after SAH. CSF-based immune profiling, including the NK/Treg ratio, may therefore represent a promising exploratory approach for DCI risk stratification. Larger prospective multicenter studies with standardized CSF sampling are required to validate these exploratory findings.