601 CURRENT TOPIC Arch Dis Child: first published as 10.1136/adc.88.7.601 on 1 July 2003. Downloaded from Pathophysiology of meningococcal meningitis and septicaemia N Pathan, S N Faust, M Levin ............................................................................................................................. Arch Dis Child 2003;88:601–607 Neisseria meningitidis is remarkable for the diversity of The human immune system has a number of interactions that the bacterium has with the human host, different mechanisms to limit the growth of meningococci in blood. Both the older innate ranging from asymptomatic nasopharyngeal immune system and acquired immunity through colonisation affecting virtually all members of the antibodies, T and B cells play a role. The population; through focal infections of the meninges, epidemiology of meningococcal disease clearly indicates that the development of specific anti- joints, or eye; to the devastating and often fatal body is the most important immunoprotective syndrome of meningococcal septic shock and purpura mechanism.78 The peak incidence of the disease fulminans. occurs in the first year of life following the loss of maternal antibody; the disease becomes progres- .......................................................................... sively less common throughout childhood and is extremely rare in adults, a pattern suggestive of a n the past few decades, considerable progress major role for acquired immunity through anti- has been made in understanding the complex bodies. The studies of Goldschneider and Gottlieb Iinteraction of host and pathogen, and the established that the age related incidence of the pathophysiology underlying both meningococcal disease in the population is related to the septicaemia and meningitis. This increased un- presence of bactericidal antibodies in serum.7 derstanding has resulted in improved manage- Although antibody appears to be the primary ment of the disorder, and is likely to lead to the protective mechanism, there is also evidence that introduction of new forms of treatment innate immune mechanisms are important in protecting infants, particularly in the window of HOST PATHOGEN INTERACTION: time between colonisation of the nasopharynx COLONISATION, INVASION, AND and the development of protective immune SURVIVAL IN THE BLOODSTREAM response. All three components of the comple- The reasons why invasive disease occurs in a very ment pathway—classical pathway through anti- http://adc.bmj.com/ small percentage of individuals are not well body; alternative pathway through properdin; understood. A variety of factors including preced- and the newly discovered mannose binding lectin ing viral infections, inhalation of dry dusty air, or pathway—are important in the protection against exposure to passive smoking have been associated meningococcal disease. Individuals deficient in with invasive disease.1 terminal components of the complement path- The meningococcus is able to adhere to way, as well as those with properdin deficiency, non-ciliated epithelial cells through a number of suffer recurrent infection.910 Individuals with adhesion factors, including pili.2 The bacterium mutations in the mannose binding lectin gene on October 1, 2021 by guest. Protected copyright. has a number of mechanisms enabling it to avoid have an increased risk of meningococcal disease host immunological mechanisms in the na- but appear less likely to suffer recurrent infec- sopharynx, including production of IgA tions once antibodies have developed.11 protease,3 production of factors which inhibit cili- ary activity,4 and the possession of a polysaccha- ACTIVATION OF THE HOST IMMUNE ride capsule which promotes adherence and RESPONSE 5 inhibits opsonophagocytosis. The organism also A large body of evidence now indicates that much undergoes notable variation in the level of of the damage to host tissues is caused by activa- expression or structure of a variety of surface tion of host immune mechanisms (fig 1). antigens, including proteins and endotoxin, Although there are likely to be numerous See end of article for which enables the bacterium to evade the host bacterial factors that can trigger the host immune authors’ affiliations immune response. In the case of group B menin- response, endotoxin appears to be the most ....................... gococci, the polysaccharide structure is non- important. The studies of Brandtzaeg et al clearly Correspondence to: immunogenic, because of structural similarity established that the severity of meningococcal Prof. M Levin, Department with the human neural cell adhesion molecule septicaemia was directly related to levels of circu- 6 of Paediatrics, Faculty of (NCAM). lating endotoxin.12 The characteristic property of Medicine, Imperial College While the events which enable certain strains of Science, Technology & Medicine, Norfolk Place, of meningococci to pass through the nasopharyn- London W2 1PG, UK; geal membrane into the bloodstream remain ................................................. [email protected] poorly understood, it is clear that survival in the Abbreviations: CSF, cerebrospinal fluid; IL, interleukin; bloodstream, and the ability to multiply to high Accepted NCAM, neural cell adhesion molecule; PAI, plasminogen 21 December 2002 numbers, are an essential requirement for severe activator inhibitor; TFPI, tissue factor pathway inhibitor; ....................... disease to occur. TNF, tumour necrosis factor www.archdischild.com 602 Pathan, Faust, Levin Arch Dis Child: first published as 10.1136/adc.88.7.601 on 1 July 2003. Downloaded from Figure 1 The inflammatory cascade in meningococcal septicaemia. meningococci to release blebs of outer membrane vesicles, lining in sepsis probably enable proteolytic enzymes to be which are rich in endotoxin, probably plays an important part released, which damage the endothelial surface.20 http://adc.bmj.com/ in releasing large quantities of endotoxin into the 13 bloodstream. MICROVASCULAR INJURY IN MENINGOCOCCAL Endotoxin is bound to a circulating plasma protein called SEPSIS endotoxin binding protein. The interaction between endotoxin There is now considerable evidence that indicates that the and endotoxin binding protein alters the conformation of major pathophysiological event occurring in meningococcal endotoxin to enable increased binding to and activation of septicaemia, which explains most of the severe physiological 14 macrophages and other inflammatory cells. The principle consequences of the disease, is related to a profound change in on October 1, 2021 by guest. Protected copyright. cellular receptor for endotoxin is CD14, but a range of other the normal finely regulated functions of the microvasculature. endotoxin sensors on cell surfaces exist, including the toll like The vascular endothelial surface is a highly specialised organ, receptors, which are also important in activation of host regulating vascular permeability and presenting a thrombo- inflammatory cells.15 16 A soluble form of CD14 also acts as the resistant, non-reactive surface to circulating blood cells. These receptor for endotoxin on endothelial surfaces. Endotoxin highly specialised properties are lost during the inflammatory binding to these cells triggers an intense inflammatory process, occurring on entry of meningococci into the process. Macrophages undergo activation to produce a range bloodstream. The complex physiology of meningococcal sepsis of proinflammatory cytokines, including tumour necrosis fac- is largely explained by four basic processes affecting the tor α (TNFα) and interleukin 1β (IL-1β). Increased production microvasculature: of interferon γ by T cells and natural killer cells occurs, and the (1) Increased vascular permeability interferon γ in turn enhances production of TNF by the mac- (2) Pathological vasoconstriction and vasodilatation rophage. A number of studies have documented high levels of cytokines including TNFα, IL-1β, IL-6, IL-8, GM-CSF, IL-10, (3) Loss of thromboresistance and intravascular coagulation and interferon γ in meningococcal sepsis.17–19 In general (4) Profound myocardial dysfunction. cytokine levels are closely correlated with disease severity and These events are largely responsible for the development of risk of death. shock and multiorgan failure. Neutrophils appear to be activated both through the effects of endotoxin and through complement mediated stimuli. Increased vascular permeability and the capillary leak Neutrophils undergo a respiratory burst with the production syndrome of reactive oxygen species, as well as undergoing degranula- Hypovolaemia appears to be the most important early event tion and the release of a range of inflammatory proteins, pro- leading to shock and is a direct result of a gross increase in teases, and other enzymes, which can degrade tissues. Close vascular permeability. The inflammatory process induced by proximity and attachment of neutrophils to the endothelial meningococci results in a major change in the permeability www.archdischild.com Pathophysiology of meningococcal meningitis and septicaemia 603 Figure 2 (A) The inflammatory, coagulation, and fibrinolytic pathways are linked at many levels, Arch Dis Child: first published as 10.1136/adc.88.7.601 on 1 July 2003. Downloaded from leading to organ failure and eventually death. (B) The coagulation and fibrinolytic pathways rely on the function of endothelial proteins and protein complexes. Dysfunctional regulatory mechanisms in meningococcal disease include endothelial (protein