Experimental studies of pneumococcal meningitis.

This thesis summarizes experimental meningitis research conducted at Statens Serum Institut in collaboration with the Copenhagen HIV programme and the Danish Research Centre for Magnetic Resonance between 2001 and 2007. Previous experimental studies had shown that the host inflammatory response in invasive infections contributed significantly to an extremely poor outcome despite initiation of efficient antimicrobial chemotherapy. Consequently, we aimed to investigate and clarify how the course of disease in pneumococcal meningitis was modulated by local meningeal inflammation and concomitant systemic infection and inflammation. Experimental studies were based on the development of a rat model of pneumococcal meningitis, refined and optimized to closely resemble the human disease, mimicking disease severity, outcome, focal- and global brain injury and brain pathophysiology. These endpoints were evaluated by the development of a clinical score system, definition of outcomes and measurement of hearing loss by otoacoustic emission. The investigation of in-vitro and in-vivo brain pathology with histology and MRI revealed an injury pattern similar to that found clinically. Additionally, MRI enabled the study of parameters closely related to the cerebral pathophysiology of meningitis (brain oedema, blood brain barrier (BBB) permeability, focal brain injury and hydrocephalus). Modulation of the inflammatory host response was achieved by initiation of treatment prior to infection: 1) G-CSF treatment increased the peripheral availability of leukocytes, 2) Selectin blocker fucoidin attenuated meningeal leukocyte accumulation and 3) A serotype specific Ab augmented systemic pneumococcal phagocytosis. The studies revealed a dual role of the inflammatory response in pneumococcal meningitis. Whilst focal brain injury appeared to result from local meningeal infectious processes, clinical disease severity and outcome appeared determined by systemic infection. Furthermore systemic disease contributed significantly to BBB permeability and brain ventricle expansion. Ventricle expansion was also associated with clinical appearance. An augmented systemic host response limited pneumococcal bacteraemia and protected from fatal outcome, but did not reduce occurrence of focal brain injury. Thus, our findings suggest that meningitis sequelae arise from local disease complications whereas fatal outcome is accelerated by systemic infection. Understanding of the relationship and interplay between septicaemia, intracranial pressure, ventricle expansion and brain edema could help optimize the treatment of these disease complications by, for example, improved systemic infection control. New therapeutic approaches to improve survival and neurological outcome from pneumococcal meningitis may be achieved through identification of the pathogen factors that initiate and prolong extensive systemic and local inflammation. Investigation of genomic differences and protein expression between pneumococcal serotypes or between identical serotypes with different virulence are considered crucial to this progress. Future progress may also be achieved by disease prevention with pneumococcal vaccines. Randomized trials of treatment strategies including bacteriostatic agents, antioxidants or more specific anti-inflammatory agents are realistic possibilities in the near future.