Targeting the Complement System in Bacterial Meningitis

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

Disclosures

Brain. 2019;142(11):3325-3337. 

In This Article

Complement Variation Studies

The complement system is often regarded as a double-edged sword (Morgan, 2015). Deficiencies in the complement system are well-known to increase the risk of bacterial infections (Brouwer et al., 2009). Terminal pathway deficiencies that inhibit MAC formation, for instance, are associated with increased susceptibility to Gram-negative bacteria such as Neisseria species. The cell wall of these bacteria is thin in comparison to Gram-positive bacteria such as S. pneumoniae, making it vulnerable for the MAC (Skarnes and Watson, 1957). Conversely, an overactive complement system, although limiting susceptibility, could result in an uncontrolled inflammatory response in patients once infected, and lead to an unfavourable outcome. It was noted more than 30 years ago that patients with invasive meningococcal disease who had a late complement deficiency had a lower mortality rate (Ross and Densen, 1984). Several studies have investigated this double-edged sword hypothesis for other complement gene variations by investigating its associations with disease course and outcome of invasive pneumococcal and meningococcal disease (Table 1) (Hibberd et al., 1999; Kronborg and Garred, 2002; Perez-Castellano et al., 2006; Faber et al., 2007; Endeman et al., 2008; Garcia-Laorden et al., 2008, 2013; Woehrl et al., 2011; Garnacho-Montero et al., 2012; Adriani et al., 2013; Brouwer et al., 2013; Lundbo et al., 2014; Bradley et al., 2015; Mills et al., 2015; Kasanmoentalib et al., 2017). Overall, patients with genetic variations associated with complement deficiencies seemed to have higher susceptibility, but inversely improved rate of favourable outcome. Results of the different reports are, however, not always similar and may differ per pathogen (Hibberd et al., 1999; Faber et al., 2007; Garnacho-Montero et al., 2012; Brouwer et al., 2013), homozygous and heterozygous deficiencies (Hellemann et al., 2007), and clinical situation (Garred et al., 2003; Fidler et al., 2004). Pathogens differ in their way of complement activation. For S. pneumoniae, mannose-binding lectin (MBL) does not function as complement activator (Ali et al., 2012). A factor compromising the interpretation of genetic variations with outcome is that a linkage disequilibrium may exist (Fijen et al., 1999; Spath et al., 1999). The most striking genetic association identified was that of a genetic variation in the C5 encoding region (rs17611), which was significantly associated with unfavourable outcome of pneumococcal meningitis, even when corrected for multiple testing, or in a multivariate regression model corrected for risk factors for poor outcome (Woehrl et al., 2011).

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