Classification and Pathogenesis of Meningococcal Infections
The clinical symptoms induced by Neisseria meningitidis reflect compartmentalized intravascular and intracranial bacterial growth and inflammation. In this chapter, we describe a classification system for meningococcal disease based on the nature of the clinical symptoms. Meningococci invade the subarachnoid space and cause meningitis in as many as 50–70% of patients. The bacteremic phase is moderate in patients with meningitis and mild systemic meningococcemia but graded high in patients with septic shock. Three landmark studies using this classification system and comprising 862 patients showed that 37–49% developed meningitis without shock, 10–18% shock without meningitis, 7–12% shock and meningitis, and 18–33% had mild meningococcemia without shock or meningitis. N. meningitidis lipopolysaccharide (LPS) is the principal trigger of the innate immune system via activation of the Toll-like receptor 4-MD2 cell surface receptor complex on myeloid and nonmyeloid human cells. The intracellular signals are conveyed via MyD88-dependent and -independent pathways altering the expression of >4,600 genes in target cells such as monocytes. However, non-LPS molecules contribute to inflammation, but 10–100-fold higher concentrations are required to reach the same responses as induced by LPS. Activation of the complement and coagulation systems is related to the bacterial load in the circulation and contributes to the development of shock, organ dysfunction, thrombus formation, bleeding, and long-term complications in patients. Despite rapid intervention and advances in patient intensive care, why as many as 30% of patients with systemic meningococcal disease develop massive meningococcemia leading to shock and death is still not understood.
Key wordsMeningococcal meningitis Septicemia Classification Lipopolysaccharide Shock
Peter Kierulf, Reidun Övstebö, Berit Brusletto, Tom Eirik Mollnes, Bernt Christian Hellerud, Arne Höiby, Anne Marie Siebke Tröseid, Tom Sprong, Chris Neeleman, and Sabine de Greeff have all contributed extensively to the studies.
The studies have been financed by Ullevål University Hospital, Oslo, the Reginal Health Authority Helse Söröst, Norway, and the Dutch Organisation for Scientific Research, the Netherlands. A particular thank you to all patients, parents, and relatives who consented to participate in the studies.
- 6.de Greeff SC, de Melker HE, Schouls LM et al (2008) Pre-admission clinical course of meningococcal disease and opportunities for the earlier start of appropriate intervention: a prospective epidemiological study on 752 patients in the Netherlands, 2003-2005. Eur J Clin Microbiol Infect Dis 27:985–992PubMedCrossRefGoogle Scholar
- 20.Brandtzaeg P (2010) Meningococcal Infections. In: Warrell DA, Cox TM, Firth JD (eds) Oxford Textbook of Medicine, 5th edn. Oxford University Press, Oxford, pp 709–722Google Scholar
- 23.Ovstebo R, Brandtzaeg P, Brusletto B et al (2004) Use of robotized DNA isolation and real-time PCR to quantify and identify close correlation between levels of Neisseria meningitidis DNA and lipopolysaccharides in plasma and cerebrospinal fluid from patients with systemic meningococcal disease. J Clin Microbiol 42:2980–2987PubMedCrossRefGoogle Scholar
- 32.Sprong T, Stikkelbroeck N, van der Ley P et al (2001) Contributions of Neisseria meningitidis LPS and non-LPS to proinflammatory cytokine response. J Leukoc Biol 70:283–288Google Scholar
- 47.Steeghs L, den Hartog R, den Boer A et al (1998) Meningitis bacterium is viable without endotoxin. Nature 392:449–450Google Scholar
- 54.Christodoulides M, Heckels JE, Weller RO (2002). The role of the leptomeninges in meningococcal meningitis. In: Ferreiros C, Criado MT, and Vavquez J (eds) Emerging strategies in the fight against meningitis: molecular and cellular aspects. Horizon Scientific Press, Norfolk: pp1–34Google Scholar