Pathogenesis and pathophysiology of bacterial meningitis

INTRODUCTION — From its original recognition in 1805 until the early 1900s, bacterial meningitis due to Haemophilus influenzae and Streptococcus pneumoniae was virtually 100 percent fatal. In 1913, Simon Flexner's introduction of intrathecal meningococcal antiserum decreased the mortality of meningococcal meningitis from 75 to 31 percent, but the clinical outcome did not dramatically improve for all three meningeal pathogens until the advent of systemic antimicrobial therapy in the 1930s [1].

Despite the effectiveness of antibiotics in clearing bacteria from the cerebrospinal fluid (CSF), bacterial meningitis in adults continues to cause significant morbidity and mortality worldwide. As an example, in the largest prospective study to date of 1412 episodes of community-acquired bacterial meningitis, the case-fatality rate was 17 percent, and unfavorable outcomes occurred in 38 percent [2]. (See "Neurologic complications of bacterial meningitis in adults".)

The pathogenesis and pathophysiology of bacterial meningitis involve a complex interplay between virulence factors of the pathogens and the host immune response [3,4]. Much of the damage from this infection is believed to result from cytokines released within the CSF as the host mounts an inflammatory response. (See "Neurologic complications of bacterial meningitis in adults".)

The clinically important issues related to the pathogenesis and pathophysiology of bacterial meningitis will be reviewed here. The clinical features, treatment, prognosis, and prevention of bacterial meningitis in adults and children and issues related to chronic and recurrent meningitis are discussed separately. (See "Clinical features and diagnosis of acute bacterial meningitis in adults" and "Initial therapy and prognosis of community-acquired bacterial meningitis in adults" and "Treatment of bacterial meningitis caused by specific pathogens in adults" and "Bacterial meningitis in children older than one month: Clinical features and diagnosis" and "Bacterial meningitis in children older than one month: Treatment and prognosis" and "Approach to the patient with chronic meningitis" and "Approach to the adult with recurrent infections", section on 'Meningitis'.)

PATHOGENESIS — Bacterial meningitis develops when virulence factors of the pathogen overcome host defense mechanisms [3,5].

The pathogenesis of bacterial meningitis for the most common meningeal pathogens (S. pneumoniae, Neisseria meningitidis, H. influenzae, Group B streptococcus [GBS], Escherichia coli) have four main processes [3,4]:

●Colonization of respiratory, gastrointestinal, or lower genital tract

●Invasion of the bloodstream

●Survival in the bloodstream

●Entry into the subarachnoid space

(See "Microbiology and pathobiology of Neisseria meningitidis" and "Epidemiology of Neisseria meningitidis infection".)

Colonization of mucous membranes — Many of the major meningeal pathogens possess surface components, such as fimbriae or pili, which enhance mucosal colonization. The main requirement for meningococcal adhesion is type IV pili, which adhere via various receptors including platelet-activating factor receptor (PAFR), beta-2 adrenergic receptors, and CD147 [5]; the outer membrane proteins (OpC and OpA) have also been proposed to contribute to the maintenance of adhesion [3]. In S. pneumoniae, the three receptors that are responsible for adhesion to epithelial surfaces are PAFR, laminin receptors, and polymeric immunoglobulin receptor [6]. Colonization of the host mucosal epithelium is facilitated by evasion of mucosal secretory immunoglobulin A (IgA) through pathogen secretion of IgA protease [7]. IgA protease inactivates the mucosal antibody and facilitates bacterial attachment to host epithelial cells. After successful colonization, invasion occurs across the epithelium via intracellular or intercellular pathways that are mediated by specific binding adhesins of the bacterial surface, many of which are localized to pili in gram-negative pathogens [8]. After attachment and aggregation of N. meningitidis, organisms detach from the aggregates to systematically invade the host by means of a transcellular pathway that crosses the respiratory epithelium [9]. Surface encapsulation may also be an important virulence factor for nasopharyngeal colonization and systemic invasion of meningeal pathogens.

Invasion of bloodstream — Colonization with the meningeal pathogens is much more common than invasion of the bloodstream and subsequent meningitis. Bloodstream invasion is most likely mediated by an interaction of environmental, host factors, and genetic factors of the pathogens [4]. Environmental factors include prior viral infection (eg, influenza), smoking, and alcohol abuse while host factors include asplenia, complement deficiency, antibody deficiency, and immunosuppressive therapy or conditions [6].

Genetic factors related to host response to bacterial infections that have been described to predispose to infection are single-nucleotide polymorphisms (SNPs) in nuclear factor kB inhibitor alpha in pneumococcal meningitis [6] or deficiencies in interleukin-1 receptor-associated kinase 4, myeloid differentiation primary response protein 88, and SNPs in pattern recognition receptor genes, such as Toll-like receptor 9 [6,10]. Furthermore, multilocus sequence typing has described hyperinvasive strains of N. meningitidis [11], S. pneumoniae [12], GBS [13], and E. coli [14].

Intravascular survival — Following invasion and entry into the bloodstream, the polysaccharide capsule of the main meningeal pathogens (S. pneumoniae, N. meningitidis, H. influenzae, GBS, and E. coli) serves as the main line of defense by inhibiting the surface depositions of adhesins (eg, complement factors) thus preventing phagocytosis [4]. The meningococcal capsule can also inhibit the classical complement pathway by decreasing the surface deposition of the complement component C-4 binding protein [15]. Complement factor H is a complement regulatory protein inhibiting alternative pathway activation with low levels associated with mortality in pneumococcal meningitis [16]. In addition to the capsule, several bacterial surface molecules such as factor H binding protein, neisserial surface protein A, and porin B in N. meningitidis target specific complement components [17]. The pathogens avoid the bactericidal activity of complement, survive in the bloodstream, and cross the blood-brain barrier into the cerebrospinal fluid (CSF).

Meningeal invasion — Bacterial penetration to the subarachnoid space is facilitated by the duration and degree of bacteremia and occurs by the interaction of bacteria with the endothelial cells of the blood-CSF barrier in the postcapillary veins [6]. More recent studies suggest that counteracting targets contributing to the bacterial invasion of the blood-brain barrier may improve outcomes [6].

In both H. influenzae and S. pneumoniae, there is evidence that the choroid plexus may be the site of the initial entry of the bacteria into the ventricle with subsequent spread throughout the CSF [18,19]. Adhesion to the laminin receptors on the brain endothelial cells is mediated by the binding of the bacterial adhesins: the pneumococcal surface protein for S. pneumoniae and the outer membrane protein porin A for N. meningitidis [20]. The process of adhesion also involves the PAFR on the endothelial cell surfaces facilitating the invasion by S. pneumoniae (through transcellular mechanism) and N. meningitidis (via paracellular passage) [21]. After adhesion, N. meningitidis utilizes its type IV pilus to activate beta2-adrenoreceptors to organize cortical plaques that prevents complement-mediated lysis and facilitates the opening of the interendothelial junctions that allows for the paracellular migration of the bacteria into the CSF [22].

Upon successful invasion of the CSF, bacteria can multiply to high concentrations within hours (eg, up to 10⁷ organisms per milliliter) because of inadequate humoral immunity in the CSF [3]. Specifically, low concentrations of immunoglobulin and complement within human CSF (usually 1000-fold lower than serum) result in poor opsonic activity, successful bacterial replication, and the subsequent development of inflammation [23]. Despite an early influx of leukocytes in bacterial meningitis, host defenses in CSF remain suboptimal because of the lack of functional opsonic and bactericidal activity.

The accumulation of neutrophils in the CSF is mainly driven by the anaphylatoxin complement component 5a (C5a) and is correlated with disease severity and outcomes. The use of C5a receptor blockers is a promising adjunctive therapy, as they reduce inflammation and improve outcomes [24]. An additional complement-blocking target (mannose-binding lectin-associated serine protease 2 [MASP-2]) by monoclonal antibodies has also been found to attenuate the inflammatory response in pneumococcal meningitis [25].

PATHOPHYSIOLOGY — The clinical disease observed when bacteria enter the cerebrospinal fluid (CSF) is a result of a complex interaction of components of the bacteria and the host inflammatory response. This interaction influences both the blood-brain barrier and neuronal integrity.

Contribution of cell wall components — As bacteria begin to die, especially after the exposure to antibiotic therapy, bacterial fragments interact with pattern recognition receptors that trigger the host immune response [26]. In experimental animal models, subcapsular bacterial surface components are most important for the induction of CSF inflammation and blood-brain barrier injury. As an example, purified pneumococcal cell wall but not purified capsular polysaccharide induced CSF inflammation similar to live pneumococci when experimentally injected into the cisterna magna of rabbits [27]. Both teichoic acid and peptidoglycan, which are cell wall constituents, were able to provoke this inflammatory response, although the kinetics of the response differed (maximal response to teichoic acid at 5 hours and to peptidoglycan between 5 and 24 hours) [28]. Immune recognition of these bacterial components results in a strong inflammatory response, leading to blood-brain barrier impairment due to recruitment of leukocytes, vascular deregulation, vasculitis, and occlusion of vessels, which cause increased intracranial pressure [5]. In patients with pneumococcal meningitis, high pneumococcal cell wall burden as measured by CSF lipoteichoic acid has been correlated with adverse clinical outcomes [29].

Generation of inflammatory cytokines — Inhibition of many steps in the inflammatory cascade, such as neutrophil recruitment, improves the clinical outcome in meningitis by reducing neuronal loss [5]. The only clinically-proven adjunctive therapy to ameliorate this inflammatory response and to improve mortality in high-income countries with pneumococcal meningitis is dexamethasone [30,31]. After the recommendation of using adjunctive dexamethasone by the Infectious Diseases Society of America in adults with bacterial meningitis [32], studies in the Netherlands and in the United States have documented a significant reduction in mortality in pneumococcal meningitis [30,31]. (See "Initial therapy and prognosis of community-acquired bacterial meningitis in adults", section on 'Adjunctive dexamethasone'.)

Other promising adjunctive therapies that have been evaluated in the animal model include complement inhibitors (eg, anti-C5 antibodies), matrix-metalloproteinase inhibitors (eg, doxycycline), and nonbacteriolytic antibiotics (eg, daptomycin) but need validation in clinical studies [33].

Surface bound Toll-like receptors and cytosolic nucleotide-binding oligomerization domain-like receptors act as sensors for cytoplasmic pathogen-associated molecular patterns and stimulate the inflammatory response [6]. Proinflammatory cytokines such as tumor necrosis factor alpha, interleukin (IL)-6, and IL-1beta are released in higher quantities in pneumococcal meningitis than in other meningeal pathogens and can explain with worse prognosis seen with this pathogen [34]. Matrix metalloproteinase-9 is released from leukocytes in the CSF and is involved in increasing proinflammatory cytokines, degradation of extracellular matrix components, and recruiting more leukocytes into the CSF [3]. Patients with pneumococcal meningitis also show higher levels of matrix metalloproteinases, anti-inflammatory cytokines (eg, IL-10 and transforming growth factor-beta), and chemokines (eg, IL-8, macrophage inflammatory protein-1a, and monocyte chemoattractant protein-1) [5]. High bacterial density and bacterial breakdown products that may also be generated after treatment with bacteriolytic antibiotics promote higher concentrations of inflammatory mediators, which lead to a higher likelihood of neurologic sequelae and severe disease. These cytokines act in conjunction with bacterial surface components, such as lipopolysaccharides, to induce the synthesis of adhesive glycoproteins on the luminal surface of cerebral endothelium [35,36]. These adhesive glycoproteins, such as selectins and intercellular adhesion molecule-1, facilitate localized adhesion and diapedesis of neutrophils into the CSF. Some experimental evidence suggests that use of nonbacteriolytic antibiotics, which reduce the proinflammatory response triggered by cell-wall components, prevent neuronal damage [37], although more studies are needed.

Once inflammation is initiated, a series of injuries occur to the endothelium of the blood-brain barrier (eg, separation of intercellular tight junctions) that result in vasogenic brain edema, loss of cerebrovascular autoregulation, and increased intracranial pressure [6]. The clinical expressions of these pathophysiologic events are the neurologic complications of meningitis including coma, hydrocephalus, seizures, deafness, and motor, sensory, and cognitive deficits. Histopathologically, autopsy studies show brain edema, hydrocephalus, petechial hemorrhages, necrotic lesions in the cortical and subcortical structures, loss of myelinated fibers in the white matter, and hippocampal apoptosis [38]. (See "Neurologic complications of bacterial meningitis in adults".)

SUMMARY

●The pathogenesis and pathophysiology of bacterial meningitis involve a complex interplay between virulence factors of the pathogens and the host immune response. Much of the damage from this infection is believed to result from cytokines released within the cerebrospinal fluid (CSF) as the host mounts an inflammatory response. (See 'Introduction' above.)

●Bacterial meningitis develops when virulence factors of the pathogen overcome host defense mechanisms. For the most common pathogens causing bacterial meningitis in adults, such as Streptococcus pneumoniae and Neisseria meningitidis, meningeal invasion is related to several virulence factors that allow the bacteria to colonize host mucosal epithelium, invade and survive within the bloodstream, cross the blood-brain barrier, and multiply within the CSF. (See 'Pathogenesis' above.)

●In experimental animal models, subcapsular bacterial surface components are most important for the induction of CSF inflammation and blood-brain barrier injury. (See 'Contribution of cell wall components' above.)

●Some studies suggest that the mechanism by which these meningeal pathogens induce an inflammatory response and blood-brain barrier injury is through the in situ generation of inflammatory cytokines (eg, interleukin-1 [IL-1], IL-6, and tumor necrosis factor-alpha) and matrix metalloproteinases within the CSF. (See 'Generation of inflammatory cytokines' above.)

●Once inflammation is initiated, a series of injuries occur to the endothelium of the blood-brain barrier (eg, separation of intercellular tight junctions) that result in vasogenic brain edema, loss of cerebrovascular autoregulation, and increased intracranial pressure. This results in localized areas of brain ischemia, cytotoxic injury, and neuronal apoptosis. (See 'Generation of inflammatory cytokines' above.)

●Dexamethasone in adults with pneumococcal meningitis in resource-rich countries is the only clinically proven adjunctive therapy to reduce mortality, but other therapies such as matrix metalloproteinase inhibitors, anti-C 5 antibodies, monoclonal antibodies targeting mannose-binding lectin-associated serine protease 2 (MASP-2), and nonbacteriolytic antibiotics show promising results in the animal model. (See 'Generation of inflammatory cytokines' above and "Initial therapy and prognosis of community-acquired bacterial meningitis in adults", section on 'Adjunctive dexamethasone'.)