Stroke-induced immunodepression and post-stroke infections: lessons from the preventive antibacterial therapy in stroke trial.
Infections are a leading cause of death in patients with acute CNS injury such as stroke. Recent experimental evidence indicated that stroke leads to suppression of innate and adaptive peripheral immune responses which predisposes to infection. However, less is known on phenotypic and functional immune alterations in correlation with the occurrence of infectious complications in patients with acute stroke.


METHODS
In the recently completed randomized, double blind, placebo-controlled Preventive Antibacterial Therapy in Stroke (PANTHERIS) trial on the efficacy of short-term antibacterial therapy to prevent the development of post-stroke infections, we assessed longitudinal changes in lymphocyte subpopulations and mitogen-induced lymphocytic interferon gamma (IFN)-gamma production using flow cytometry in 80 patients with acute severe stroke at days 1, 3, 8, 90 and 180 after clinical onset. Plasma interleukin (IL)-6 and IL-10 concentration as well as urinary levels of norepinephrine and cortisol was assessed within the first 8 days after stroke. Patients of the placebo and verum (moxifloxacin) treatment groups who did or did not develop infections within 11 days after stroke were compared to identify immunological changes associated with the occurrence of post-stroke infections.


RESULTS
Rapid T-lymphopenia and long-lasting suppression of lymphocytic IFN-gamma production were observed in all stroke patients. Patients of the placebo group who developed infections showed a trend toward greater decline of CD4+ Th cell counts and higher urinary levels of norepinephrine early after stroke than patients without infections. Onset of infections was accompanied with higher plasma IL-6 levels in the placebo group but not in the moxifloxacin group. In addition, an early rise in plasma IL-10 was detected in patients who developed infections despite preventive antibacterial treatment.


CONCLUSIONS
A rapid loss and functional deactivation of T cells are common changes in stroke patients consistent with immunodepression after brain ischemia. A stronger decrease in cellular immune responses and an increased sympathetic activity after stroke are associated with a higher risk of infections. Increased plasma levels of the anti-inflammatory cytokine IL-10 early after stroke may identify patients who will not respond to preventive antibacterial therapy with moxifloxacin.
Klehmet
J
J
Center of Stroke Research Berlin, Department of Neurology, Charité Universitaetsmedizin Berlin, Charitéplatz 1, 10117 Berlin, Germany. juliane.klehmet@charite.de
Harms
H
H
Richter
M
M
Prass
K
K
Volk
H D
HD
Dirnagl
U
U
Meisel
A
A
Meisel
C
C
D000900:Anti-Bacterial Agents / Q000627:therapeutic use*; D001424:Bacterial Infections / Q000188:drug therapy / Q000276:immunology* / Q000517:prevention & control*; D004311:Double-Blind Method; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D006854:Hydrocortisone / Q000032:analysis / Q000097:blood; D007108:Immune Tolerance / Q000187:drug effects / Q000276:immunology*; D007111:Immunity, Cellular / Q000276:immunology; D016867:Immunocompromised Host / Q000276:immunology; D007371:Interferon-gamma / Q000032:analysis / Q000097:blood; D007378:Interleukins / Q000032:analysis / Q000097:blood; D018655:Lymphocyte Count; D008231:Lymphopenia / Q000276:immunology* / Q000503:physiopathology; D008297:Male; D009638:Norepinephrine / Q000032:analysis / Q000097:blood; D015990:Placebo Effect; D020521:Stroke / Q000150:complications* / Q000276:immunology* / Q000503:physiopathology
D000900:Anti-Bacterial Agents; D007378:Interleukins; D007371:Interferon-gamma; D006854:Hydrocortisone; D009638:Norepinephrine