Neisseria Meningitidis Infections

Definition

Neisseria meningitidis (the meningococcus) is the cause of epidemic bacterial meningitis, fulminant sepsis (meningococcemia), milder bacteremia, and, less commonly, focal infections (such as pneumonia, septic arthritis, purulent pericarditis, urethritis, and conjunctivitis).

The Pathogen

N. meningitidis is an aerobic, diplococcal gram-negative β-proteobacterium and a member of the family Neisseriaceae, which also includes Neisseria gonorrhoeae ( Chapter 275 ), the cause of gonorrhea. The meningococcus is a frequent commensal of the human upper respiratory tract but can also cause local and devastating invasive human disease. Human mucosal surfaces, most commonly the nasopharynx but sometimes the rectum and urogenital tract, are the important reservoirs. In addition to commensal unencapsulated meningococci, there are 12 confirmed serogroups of N. meningitidis , based on different capsular polysaccharide structures. However, only 6 groups (A, B, C, W, X, and Y) cause almost all invasive meningococcal disease globally ( Fig. 274-1 ). Highly pathogenic meningococci are also distinguished by capsule expression and by genetically defined clonal complexes and genotypes that can emerge and spread worldwide.

Epidemiology

The meningococcus can cause sporadic disease, case clusters, epidemics, and pandemics of meningitis and septicemia and less commonly of pneumonia and other local infections. In the pre-vaccine era, an estimated 500,000 to 1 million cases occurred worldwide each year, but the incidence has been dramatically lowered, related to the widespread use of vaccines. The greatest burden of disease is in sub-Saharan Africa, where endemic rates of disease have been 3 to 10 per 100,000 population, but rates were 1 per 1000 population during the historic cyclic pandemics that occurred every 8 to 10 years. The introduction in 2010 of a new meningococcal conjugate vaccine for group A (MenAfriVac) eliminated group A outbreaks in the region, but less severe outbreaks of group C, X, and W continue.

Overall incidence has declined, aided by the expanded use of the meningococcal ACWY conjugate and group B directed vaccines, and the decline has been accelerated by containment measures for severe acute respiratory syndrome coronavirus 2 (SARS-CoV2; Chapter 336 ). Nevertheless, meningococcal disease remains sporadic (incidence less than 0.1 to 2 per 100,000 population), with focal outbreaks/clusters in the United States, Canada, Mexico, Europe, Japan, Australia, China, Russia, South America (Chile, Brazil, Argentina), India, Southeast Asia, and other countries. Organization-based and university outbreaks are mostly caused by group B, whereas group C is the primary cause of community-based outbreaks. Meningococcal disease has its highest incidence in children below age 4 years (often group B) and in adolescents; but in sporadic settings, half of all cases occur in adults.

Asymptomatic carriage in the oropharynx is much more common (about 7-10% among adolescents ages 15 to 19 years in developed countries) than symptomatic infection, and the prevalence of meningococcal carriage is declining in many populations. Asymptomatic carriage has been linked to social behavior (e.g., attendance at pubs or clubs, intimate kissing, cigarette smoking, or exposure to passive smoke). Carriage, which can be transient or persist for days, weeks, or months, is an immunizing event leading to protective immunity (e.g., serum bactericidal activity against the meningococcus).

Pathobiology

N. meningitidis is transmitted among humans through close contact by large respiratory droplets or saliva. Colonization of the upper respiratory or other mucosal surfaces (e.g., nasopharynx) by N. meningitidis is the first step in establishing a human carrier state. Acquisition of meningococci through contact with secretions can be transient, lead to prolonged nasopharyngeal carriage, or result in invasive disease. The inoculum size needed for transmission is unknown. Invasive meningococcal disease usually occurs within 1 to 14 days after acquisition. Meningococci can also spread from the nasopharynx to adjacent epithelial surfaces, where they infrequently cause local infections, including pneumonia, sinusitis, and otitis media. Meningococci also can be found in the conjunctivae, urogenital tract, and rectum, and they may be transmitted sexually.

Initial contact of meningococci with mucosal epithelial cells is mediated by type IV pili. These structures provide mobility (“twitching motility”) to penetrate mucus and are the initial adhesins for human epithelial cells. Meningococci proceed to proliferate and form small microcolonies on the surface of human nonciliated epithelial cells. They can disseminate from colonies by post-translational glycan modifications of pili and migrate to adjacent cells by the pili-mediated motility. Close adherence of meningococci to the host epithelial cells results in the formation of epithelial cell cortical plaques and leads to the recruitment of factors ultimately responsible for the formation and extension of host epithelial cell pseudopodia that can tightly bind the meningococcus. Intimate meningococcal association with the epithelial cell is mediated by the meningococcal surface components, including opacity proteins Opa and Opc with CD66/carcinoembryonic antigen–related cell adhesion molecules and integrins, respectively, on the surface of the human cell. Other meningococcal epithelial cell mediators include the meningococcal adhesin NadA and meningococcal lipo-oligosaccharide. The formation of epithelial cell membrane protrusions and pseudopodia stems from the organization of specific molecular complexes involving the linkers ezrin and moesin along with the clustering of several membrane-integral proteins, including CD44, intracellular adhesion molecule 1, and cortical actin polymerization. These events can lead to internalization of N. meningitidis in epithelial cells ( E-Fig. 274-1 ). Intracellular meningococci reside within a membranous vacuole and are capable of translocating across the epithelial layer. Meningococci are capable of intracellular replication (in part because of the protective capsule), can survive under microaerophilic conditions, use lactate as a carbon source, and have the capacity to acquire iron through specialized transport systems.

Damage to the mucosal surface by coinfections, drying (e.g., very low humidity), or smoke exposure may increase the risk for meningococcal carriage and invasion. Meningococci may cross mucosal surfaces, enter the blood stream to cause bacteremia, and, in some individuals, produce systemic infections. Asymptomatic meningococcal carriage also has been linked to status as a secretor of glycoprotein ABO blood group antigens, which are water soluble. Similar molecular interactions noted for meningococci and epithelial cells also occur with endothelial cells, and meningococci can translocate across the blood-meninges barrier, possibly at the choroid plexus or by the opening of intercellular junctions, and proliferate in the subarachnoid space, thereby causing meningitis. In the vasculature and cerebrospinal fluid (CSF), high levels of multiplying bacteria lead to an intense inflammatory response, with pronounced increases in concentrations of tumor necrosis factor-α, interleukins (1β, 6, 8, and 10), other chemokines, and inflammatory mediators.

Meningococcal resistance to complement-mediated lysis or phagocytosis is due to the expression of the capsule, lipo-oligosaccharide, and several surface-exposed proteins (factor H–binding protein, NspA, Opc, NalP). Meningococcal endotoxin released in blebs plays a major role in the inflammatory events of meningococcemia and meningococcal meningitis. Meningococcal lipid A is responsible for much of the biologic activity and toxicity of meningococcal endotoxin. Activation of toll-like receptor 4 (TLR-4) by endotoxin requires association with the accessory protein MD-2, an N -glycosylated 19- to 27-kD protein expressed in both a soluble and a membrane-bound form. Binding of endotoxin to MD-2 in association with TLR-4 leads to dimerization or oligomerization of two or more TLR-4s, subsequent cellular activation, and cytokine and chemokine release.

The absence of protective bactericidal antibodies is the most important predisposing risk factor for systemic meningococcal disease, but complement deficiencies (congenital or acquired such as with the complement inhibitors eculizumab and ravulizumab [ Chapter 29 ]), genetic polymorphisms, and other host cofactors can contribute to meningococcal disease and disease severity. Disappearance of protective maternal antibodies increases the risk in older infants and young children. Congenital and acquired antibody deficiencies also increase risk. Opsonization and phagocytic function also contribute to meningococcal host defense mechanisms, as shown by disease reduction after meningococcal vaccination in individuals with terminal complement deficiencies ( Chapter 37 ). Rapidly progressive, fatal meningococcemia can arise in patients without properdin, and there is a marked risk for recurrent meningococcal infections in individuals with defects in the terminal complement pathway (C5-C9) and C3 deficiency.

Polymorphisms in genes coding for the Fcγ-receptor II (CD32), Fcγ-receptor III (CD16), mannose-binding lectin, TLR-4, and the β ₂ -adrenoceptor gene have been associated with increased risk. Plasminogen activator inhibitor 1 concentrations appear to affect the severity and mortality of meningococcal sepsis, thereby suggesting that impaired fibrinolysis is an important factor in its pathophysiology. Meningococcal disease is also linked to immunosuppressive disorders, such as nephrotic syndrome ( Chapter 107 ), congenital or acquired hypogammaglobulinemia ( Chapter 231 ), splenectomy, and human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome (AIDS; Chapter 358 ) (about a 10-fold increased risk for sporadic meningococcal disease). However, there has not been a documented increase in epidemic outbreaks of meningococcal disease in countries with high rates of HIV infection.

Meningococci can multiply rapidly in the vascular compartment, with an estimated doubling time of 30 to 45 minutes in some patients, or in the CSF. The release of high levels of inflammatory mediators such as meningococcal endotoxin in the circulation or CSF triggers an exaggerated release of chemokines, cytokines, bradykinin, and nitric oxide. Vascular dilation, hypovolemia, capillary leak, and pronounced reduction in myocardial function are the result. At a later stage, substantial complement activation contributes to the altered endothelial barrier function and relaxation of the smooth muscles in the vessel wall through the generation of high levels of anaphylatoxins (C3a and C5a). The capillary leak syndrome results in an increased flux of albumin and water across the altered capillary wall to the extravascular space. Circulatory collapse and multiorgan dysfunction are the primary causes of death due to meningococcemia. In meningitis, morbidity and death are due predominantly to cerebral edema.