Targeting the Complement System in Bacterial Meningitis

Diederik L.H. Koelman; Matthijs C. Brouwer; Diederik van de Beek


Brain. 2019;142(11):3325-3337. 

In This Article


There is a multitude of evidence that confirms the importance of complement system activation in bacterial meningitis. Patients with genetic complement deficiencies, and/or lower complement levels in the CSF tend to have favourable outcome. Experimental animal studies have increasingly shown the important regulatory function of the complement system in spurring the inflammatory response in bacterial meningitis. Amongst all complement components, C5a was most significantly associated with unfavourable outcome, both the genetic variation in complement component 5 gene and the anaphylatoxin C5a concentration in the CSF. The experimental results of targeting anaphylatoxin C5a production have been very promising. Three separate experimental studies significantly favoured treatment with C5 monoclonal antibodies, one of which was a randomized investigator-blinded trial. C5 monoclonal antibodies also showed to be beneficial when given in adjunction to the standard treatment regimen with antibiotics and dexamethasone as proposed in the current ESCMID guideline for acute bacterial meningitis (van de Beek et al., 2016b). Specific targeting of the anaphylatoxin C5a or its receptor C5aR, therefore, emerges as the most promising treatment target. Targeting the initiating pathways, C3 or C5 all have their caveats, mainly due to the opsonophagocytosis deficits, complement bypass routes, and/or inhibiting MAC formation. The promising results of the experimental models warrant the initiation of a randomized clinical phase IIb or III trial with concomitant genetic profiling of host and pathogen to determine its interactions with complement intervention to allow for future patient stratification. Possible candidates for clinical trials are currently IFX-1 (InflaRx), ALXN1007 (Alexion), Avacopan/CCX168 (Chemocentryx), and IPH5401 (Innate Pharma). The initiation of clinical trials and the clinical use of complement-targeted therapies for bacterial meningitis may be further spurred in the future when more economical therapeutic options have become available.