Time Course of Peripheral Leukocytosis and Clinical Outcomes After Aneurysmal Subarachnoid Hemorrhage

Abstract

Objective: Systemic inflammation after subarachnoid hemorrhage (SAH) is implicated in delayed cerebral ischemia (DCI) and adverse clinical outcomes. We hypothesize that early changes in peripheral leukocytes will be associated with outcomes after SAH. Methods: SAH patients admitted between January 2009 and December 2016 were enrolled into a prospective observational study and were assessed for Hunt Hess Scale (HHS) at admission, DCI, and modified Ranked Scale (mRS) at discharge. Total white blood cell (WBC) counts and each component of the differential cell count were determined on the day of admission (day 0) to 8 days after bleed (day 8). Global cerebral edema (GCE) was assessed on admission CT, and presence of any infection was determined. Statistical tests included student's t-test, Chi-square test, and multivariate logistic regression (MLR) models. Results: A total of 451 subjects were analyzed. Total WBCs and neutrophils decreased initially reaching a minimum at day 4-5 after SAH. Monocyte count increased gradually after SAH and peaked between day 6-8, while basophils and lymphocytes decreased initially from day 0 to 1 and steadily increased thereafter. Neutrophil to lymphocyte ratio (NLR) reached a peak on day 1 and decreased thereafter. WBCs, neutrophils, monocytes, and NLR were higher in patients with DCI and poor functional outcomes. WBCs, neutrophils, and NLR were higher in subjects who developed infections. In MLR models, neutrophils and monocytes were associated with DCI and worse functional outcomes, while NLR was only associated with worse functional outcomes. Occurrence of infection was associated with poor outcome. Neutrophils and NLR were associated with infection, while monocytes were not. Monocytes were higher in males, and ROC curve analysis revealed improved ability of monocytes to predict DCI and poor functional outcomes in male subjects. Conclusions: Monocytosis was associated with DCI and poor functional outcomes after SAH. The association between neutrophils and NLR and infection may impact outcomes. Early elevation in monocytes had an improved ability to predict DCI and poor functional outcomes in males, which was independent of the occurrence of infection.

Keywords: delayed cerebral ischemia; monocytes; neuroinflammation; neutrophil-to-lymphocyte ratio; subarachnoid hemorrhage.

Figure 1

Leukocyte counts stratified by occurrence of delayed cerebral ischemia (DCI). Leukocytes counts (mean and standard deviation) are shown from day of SAH (day 0) through day 8. Cells are in units of 1,000 per mm³. *P < 0.05, **P < 0.01,^†P < 0.001. Abbreviations: delayed cerebral ischemia (DCI), subarachnoid hemorrhage (SAH), white blood cells (WBC), neutrophil-to-lymphocyte ratio (NLR).

Figure 2

Leukocyte counts stratified by outcomes. Leukocyte counts (mean and standard deviation) are shown from day of SAH (day 0) through day 8. Outcome is dichotomized according to mRS good (≤ 3) or poor (≥4). *P < 0.05, **P < 0.01,^†P < 0.001. Cells are in units of 1,000 per mm³. mRS, modified Rankin Scale; SAH, subarachnoid hemorrhage; WBC, white blood cells; NLR, neutrophil-to-lymphocyte ratio.

Figure 3

Leukocyte counts stratified by infection. Leukocyte counts (mean and standard deviation) are shown from the day of SAH (day 0) through day 8. Counts are stratified by the occurrence of any infection within days 0–8. *P < 0.05, **P < 0.01,^†P < 0.001. Cells are in units of 1,000 per mm³. SAH, subarachnoid hemorrhage; WBC, white blood cells; NLR, neutrophil-to-lymphocyte ratio.

Figure 4

Leukocyte counts stratified by sex. Leukocyte counts (mean and standard deviation) are shown from the day of SAH (day 0) through day 8. Subjects are divided into males and females. *P < 0.05, **P < 0.01,^†P < 0.001. Cells are in units of 1,000 per mm³. SAH, subarachnoid hemorrhage; WBC, white blood cells; NLR, neutrophil-to-lymphocyte ratio.

Figure 5

ROC curves for DCI and mRS. ROC curves were generated for the discrimination of DCI or poor discharge mRS, with mRS dichotomized into good (0-3) and poor (–6) outcomes, using day 0 monocytes. AUC and 95%CI interval were calculated for each ROC curve. DCI, delayed cerebral ischemia; mRS, modified Rankin Scale; AUC, area under the curve.