Abstract
Background and Purpose: Stroke induces immediate profound alterations of the peripheral immune system rendering patients more susceptible to post-stroke infections. The precise mechanisms maintaining stroke-induced immune alterations (SIIA) remain unknown. High-Mobility-Group-Protein B1 (HMGB-1) is elevated for at least 7 days post-stroke and has been suggested to mediate SIIA. Patients with rapid clinical recovery of neurological deficits rarely develop severe infections. We therefore investigated whether rapid neurological recovery (either spontaneous or secondary to neurovascular recanalization therapy) alters the course of SIIA. National Institutes of Health Stroke Scale (NIHSS) served as surrogate marker for neurological improvement.Methods: Fluorescence-activated cell sorting was used to define leukocyte subpopulations. C-reactive protein (CRP), procalcitonin (PCT), HMGB-1, GM-CSF; IFN-β, IFN-γ, IL-1β, IL-1RA, IL-2, IL-4, IL-5, IL-6, IL-10, IL-12, IL-17, IL-17F, IL-18, TNF-α, MIF, IL-8, MCP-1, MCP-4, MIP-3α, MIP-3β, Eotaxin, soluble IL-6 receptor, E-selectin, and P-selectin were analyzed by ELISA or Multiplex Assays. Serum miRNA expression changes were analyzed by qPCR.Results: Cellular parameters were similar in the improved and non-improved cohort on admission. In patients with rapid clinical recovery absolute and relative leukocyte, neutrophil, and lymphocyte numbers normalized promptly overnight. In contrast, HMGB-1 serum levels did not differ between the two groups. Nine miRNA were found to be differentially expressed between improved and non-improved patients.Conclusions: SIIA are detectable on admission of acute stroke patients. While it was assumed that post-stroke immunosuppression is rapidly reversed with improvement this is the first data set that shows that improvement actually is associated with a rapid reversal of SIIA demonstrating that SIIA require a constant signal to persist. The observation that HMGB-1 serum concentrations were similar in improved and non-improved cohorts argues against a role for this pro-inflammatory mediator in the maintenance of SIIA. Serum miRNA observed to be regulated in stroke in other publications was counter regulated with improvement in our cohort.
Highlights
Post-stroke infections, predominantly pneumonia, are associated with increased mortality and impaired neurological outcome. It has been clearly shown in both experimental stroke and stroke patients that these infections are closely related to stroke-induced immune alterations (SIIA) of the peripheral immune system [1, 2]
If SIIA were self-maintained after the induction within the initial hours of stroke, the time course of cellular changes should be similar in patients with rapid neurological recovery compared to those with persistent neurological deficits
All patients who improved rapidly after stroke according to our definition received some form of treatment, either mechanical thrombectomy or systemic thrombolysis with recombinant tissue plasminogen activator (rtPA) or both, while in the groups without rapid improvement only 63% of patients received some form of treatment
Summary
Post-stroke infections, predominantly pneumonia, are associated with increased mortality and impaired neurological outcome. Stroke volume and stroke severity on admission as determined by NIHSS are associated with post-stroke infections [6] and patients with transitory ischemic attacks have significantly fewer infectious complications and show a milder immune response after stroke compared to patients with complete stroke [7] and it is likely that patients with initially severe ischemic stroke that improve after hyperacute treatment have a reduced risk of infections and will show milder immune alterations after stroke To date it is unknown how SIIA are maintained and how they are reversed. National Institutes of Health Stroke Scale (NIHSS) served as surrogate marker for neurological improvement
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