Acute splenic responses in patients with ischemic stroke and intracerebral hemorrhage

Abstract

Animal models provide evidence of spleen mediated post-stroke activation of the peripheral immune system. Translation of these findings to stroke patients requires estimation of pre-stroke spleen volume along with quantification of its day-to-day variation. We enrolled a cohort of 158 healthy volunteers and measured their spleen volume over the course of five consecutive days. We also enrolled a concurrent cohort of 158 stroke patients, measured initial spleen volume within 24 h of stroke symptom onset followed by daily assessments. Blood samples for cytokine analysis were collected from a subset of patients. Using data from healthy volunteers, we fit longitudinal quantile regression models to construct gender and body surface area based normograms of spleen volume. We quantified day-to-day variation and defined splenic contraction. Based on our criteria, approximately 40% of stroke patients experienced substantial post-stroke reduction in splenic volume. African Americans, older patients, and patients with past history of stroke have significantly higher odds of post-stroke splenic contraction. All measured cytokine levels were elevated in patients with splenic contraction, with significant differences for interferon gamma, interleukin 6, 10, 12, and 13. Our work provides reference standards for further work, validation of pre-clinical findings, and characterization of patients with post-stroke splenic contraction.

Keywords: Acute stroke; brain ischemia; cerebrovascular disease; immunology; intracerebral hemorrhage.

Figure 1.

Day-to-day correlational pattern observed for spleen volumes of individual healthy volunteers. The axes represent spleen volume calculated as volume = length × width × thickness × π/6. P: Pearson correlation coefficient (p value for all comparison < 0.001).

Figure 2.

Median spleen volume for healthy volunteers plotted for each day of observation. Bars indicate interquartile range.

Figure 3.

Box and Whisker plot for spleen volumes of female and male healthy volunteers at five sequential days of observation. Each box represents the median with 25^th and 75^th percentile. The bars at the end of whiskers represent upper and lower adjacent lines. Adjacent line distance has been calculated as h-spread ± 2 steps, where h-spread is the difference between 25^th and 75^th percentile and step is 1.5 × h-spread. One outlier observation greater than 500 cm³ has not been shown to maintain proportional graphical scale, though all values were used for calculation. The solid red line in each sub-graph represents the overall median volume for females and males, respectively.

Figure 4.

Body surface area (BSA)-based normograms for males (a—left panel) and females (b—right panel) showing estimated spleen volume for 10^th, 25^th, 50^th, 75^th, and 90^th percentiles. BSA Cat: BSA Category.

Figure 5.

Comparison of mean cytokine levels for patients with (n = 15) and without (n = 22) splenic contraction. Cytokines were measured at two time points, the mean of two readings is compared. Lines indicate standard error. Different scale of measurement used for IL 4 and IL 10. GM CSF: granulocyte monocyte colony stimulating factor, INF: interferon, TNF: tumor necrosis factor, IL: interleukin. *Indicates statistical significance.