Blocking of leukocyte accumulation in the cerebrospinal fluid augments bacteremia and increases lethality in experimental pneumococcal meningitis

Abstract

The role of leukocyte accumulation in the cerebrospinal fluid (CSF) in the evolution of the pathophysiological changes that occur in bacterial meningitis is unclear. Here, we investigate how leukocyte recruitment to the CSF, modulated by the leukocyte blocker fucoidin, affects the extent of brain damage and outcome in pneumococcal meningitis in rats treated with ceftriaxone from 28 h after infection. Rats treated with fucoidin from time of infection had an excess risk of a fatal outcome compared to rats not receiving fucoidin (25 / 63 versus 5 / 34, p = 0.012), whereas the risk of cortical damage in surviving animals was comparable (16 / 44 versus 9 / 29, p = 0.8). Pre-treatment with fucoidin attenuated CSF pleocytosis 24 h after infection (median 400 versus 800 × 10 6 cells/l, p = 0.01) without affecting CSF bacterial counts (2.3 × 10 5 versus 3.6 × 10 5 CFU/ml, p = 0.54). A significant increase in blood bacterial counts was found among rats pre-treated with fucoidin (median 9.6 × 10 2 versus 5.2 × 10 2 CFU/ml, p = 0.03). Furthermore, blood bacterial count was found to be an important predictor of fatal outcome as shown by multivariate logistical regression analysis (OR 4.43, 95% CI [1.16–17.0] p = 0.03). In summary, blocking leukocyte entry to the central nervous system in experimental pneumococcal meningitis compromises the survival prognosis but does not affect the risk of brain damage or level of infection in this compartment. Conversely, poorer prognosis was associated with an increase in bacterial load in blood, suggesting that leukocyte blockage affects the host's ability to control systemic infection.