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Chapter 184 Neisseria meningitidis (Meningococcus)
Dan M. Granoff, Janet R. Gilsdorf
Neisseria meningitidis (also referred to as meningococcus) lives as a commensal in the nasopharynx of humans and is typically carried by 10% or more of the population at any one time. Relatively rarely the organism enters the bloodstream and may cause devastating disease. Why invasive meningococcal disease develops in a small proportion of exposed individuals is still largely not understood. Paradoxically, N. meningitidis also is unique for its ability to cause epidemic bacterial meningitis and sepsis. Although the last major meningococcal epidemic in the USA was in the 1940s, the organism remains an important cause of serious endemic disease in the country and of epidemic disease throughout the world. Despite advances in critical care medicine, previously healthy children and adolescents continue to succumb to fulminant meningococcal disease.
N. meningitidis is a fastidious encapsulated, oxidase-positive, aerobic diplococcus. In gram-stained specimens, the microbes appear as gram-negative, kidney-shaped pairs. There are 13 chemically and serologically distinct meningococcal capsular groups, of which five, designated A, B, C, W-135 and Y, are responsible for almost all cases of human disease. Meningococcal strains also are subclassified on the basis of antigenic variation in two porin molecules, PorB (serotype) and PorA (serosubtype). The PorA serologic classification is gradually being replaced by a parallel classification system, called variable region (VR) sequence types, which are based on amino acid variation at two surface-accessible loops on the PorA molecule. Genetic lineages of strains can be inferred from multilocus sequence typing (MLST), which is based on polymorphisms in seven housekeeping genes.
The meningococcus readily exchanges genes encoding key antigens. The characterization of strains based on the product of one or two genetic loci therefore does not provide a reliable reflection of the underlying genetic or epidemiologic relationships between isolates. In practice, a combination of MLST, capsular group, and sequence variation in several protein antigens is used to determine epidemiologic relatedness of strains. These techniques have established that endemic meningococcal disease is caused by genetically heterogeneous strains and that outbreaks are usually caused by single strains.
Meningococci are transmitted by aerosol droplets or through contact with respiratory secretions, such as through kissing or sharing a drinking glass. The organism is not thought to survive for long periods in the environment, and transmission is decreased during periods of high ambient ultraviolet B radiation. Viral respiratory infections (influenza), exposure to tobacco smoke, marijuana use, bar patronage, binge drinking, attendance at nightclubs, and freshmen college students living in dormitories are all associated with increased rates of meningococcal carriage or disease. Respiratory viruses and/or exposure to smoke may alter the mucosal surface and enhance bacterial binding and/or decrease clearance of the organism from the nasopharynx.
Meningococcal disease is a global problem. Disease incidence rates are highly cyclic. After a decade of relatively high incidence in the 1990s, rates in the USA have steadily decreased. Over the last 10 years, the annual incidence averaged ≈1- 2/100,000 population, resulting in ≈2000 to 3500 culture-confirmed cases per year. The actual number of cases likely was higher, because in countries such as the United Kingdom, where polymerase chain reaction (PCR) methods are used routinely for diagnosis of suspected cases, only 50% of PCR-confirmed cases are culture-confirmed. In the USA, most cases of meningococcal disease are sporadic. Small outbreaks in elementary or secondary schools or colleges account for <2% of all cases.
The highest age-incidence of meningococcal disease occurs in infants <1 yr old (average annual rates of 5-9/100,000 population). The high rate in this age group is not entirely understood. It may be attributable to immature alternative and lectin complement pathways and to lack of acquired serum antibodies. In the absence of immunization, incidence rates decline by age 2-4 yr (1-2/100,000), with a further decline after age 4 yr (0.5/100,000). A secondary peak in incidence occurs among adolescents (1-3/100,000), which may be related to increased exposure from social activities.
In the USA, the majority of cases of disease in the first year of life is caused by capsular group B strains. After age 1 yr, disease is roughly equally distributed among group B, C, and Y strains. In most other industrialized countries group B strains predominate at all ages, in part because of introduction of routine group C meningococcal conjugate vaccination in infants and/or toddlers. For reasons not understood, disease in children caused by group Y strains was uncommon in the USA before the 1990s and remains relatively uncommon outside the country.
Since World War II, disease from group A strains has been largely confined to developing countries. The highest incidence of group A disease is in sub-Saharan Africa, with annual endemic rates of 10-25/ 100,000. Every 7 to 10 yr this region experiences large group A pandemics with annual rates as high as 1000/100,000. The onset of cases in the sub-Saharan region typically begins during the dry season and subsides with the rainy season, and may reemerge the following dry season. Endemic and epidemic meningococcal disease in this region has also been caused by group W-135 and X strains. These strains are infrequent causes of disease in other areas of the world, although W-135 isolates have been associated with outbreaks among pilgrims returning from the Hajj.
After exposure to meningococci, attachment of an organism to nasopharyngeal mucosal cells is mediated by specific bacterial adhesins. Multiple adhesins have been identified, but among the most important are pili and two opacity-associated proteins, Opa and Opc. CD46 and other, unidentified host cell receptors mediate pilus attachment. Opa and Opc interact with heparin sulfate proteoglycans and extracellular matrix proteins such as fibronectin and vitronectin. There are also specific receptor interactions, the most important being carcino-embryonic antigen cell adhesion molecule (CEACAM) proteins. Contact between the bacteria and host cells initiates internalization of the bacteria within membrane-bound vesicles. These molecular events lead to replication of the organism and establishment of an asymptomatic carrier state.
Although carriage can persist for weeks to months, onset of invasive meningococcal disease usually occurs within a few days to a week after acquisition of the organism. Development of disease depends on the virulence of the organism, innate susceptibility of the host, and presence or absence of serum antibodies capable of activating complement-mediated bacteriolysis and/or opsonophagocytosis. The strains responsible for invasive disease are always encapsulated and are usually derived from a limited number of so-called hypervirulent genetic lineages. Although these strains can be found in asymptomatic carriers, the majority of carrier strains either are nonencapsulated or are encapsulated organisms derived from diverse genetic lineages, many of which rarely cause disease.
The most important virulence determinant is the presence of a capsular polysaccharide, which enhances resistance of the organism to killing by normal human serum and helps resist opsonophagocytic killing. Additionally, endotoxin (lipopolysaccharide) has an essential role in stimulating cytokines and activating coagulation and bleeding, which are the clinical hallmarks of severe meningococcal sepsis. The ability of the organism to scavenge iron from human transferrin and lactoferrin and to bind human factor H (fH), a downregulating molecule in the complement cascade, are additional important mechanisms that allow meningococci to evade innate host defenses and to survive and grow in human serum or blood.
The severity of meningococcal disease is related to the circulating level of endotoxin in the bloodstream. During bacterial growth, outer membrane blebs, which are rich in endotoxin, are released. Meningococcal endotoxin is composed of lipopolysaccharide—also referred to as lipo-oligosaccharide (LOS) because of the presence of repeating short saccharides instead of long-chain saccharides characteristic of endotoxins of many other gram-negative bacteria. The lipid A portion of meningococcal LOS is responsible for the toxicity of the molecule, which is sensed by host cells through Toll-like receptors (TLRs), most notably TLR4 in association with an accessory protein, MD-2. Stimulation of TLR4 activates genes via pathways related to nuclear factor-κB (NF-κB), which leads to production of multiple proinflammatory cytokines including tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), IL-6, and IL-8. Subsequently both the extrinsic (by way of induction of tissue factor expression on endothelial cells and monocytes) and intrinsic pathways of coagulation are activated. Progression of capillary leak and disseminated intravascular coagulopathy (DIC) can lead to multiple organ system failure, septic shock, and death. Following initiation of antibiotic therapy, circulating LOS and TNF-α levels can increase transiently as a result of rapid bacterial lysis, which then decreases with clearance of viable microbes. Activation of the complement and clotting cascades can continue well beyond this point, especially in fulminant cases.
Diffuse vasculitis and DIC are common with meningococcemia. Leukocyte-rich fibrin clots are seen in small vessels, including arterioles and capillaries. The resulting focal hemorrhage and necrosis that initially manifest as purpura in the skin may occur in any organ. The heart, central nervous system, skin, mucous and serous membranes, and adrenal glands are affected in most fatal cases, and microbes are often present in these lesions. Myocarditis is present in >50% of patients who die of meningococcal disease. Diffuse adrenal hemorrhage without vasculitis, the Waterhouse-Friderichsen syndrome, is common during fulminant meningococcemia. Meningitis is characterized by acute inflammatory cells in the leptomeninges and perivascular spaces. Focal cerebritis is uncommon.
About 10% of cases of meningococcal meningitis are caused by naturally occurring LOS mutants with penta-acylated instead of hexa-acylated lipid A. The penta-acylated mutant is poorly recognized by human TLR4 and, as a result, has attenuated endotoxin activity. Patients with meningitis caused by penta-acylated mutant strains are reported to have milder clinical syndromes, including decreased coagulopathy, than patients infected by strains that have the more common form of LOS with hexa-acylated lipid A.
Naturally acquired serum antibodies to meningococci are elicited by asymptomatic carriage of pathogenic and nonpathogenic strains as well as by carriage of antigenically related species such as Neisseria lactamica. Bactericidal antibodies are produced against capsular polysaccharide and outer membrane proteins. Immunoglobulin M (IgM), IgG, and IgA responses are induced within a few weeks after nasopharyngeal colonization. Ongoing natural exposures may help maintain immunity.
The role of complement-mediated serum bactericidal antibodies is protective in military recruits exposed to epidemic group C meningococcal disease. Recruits with serum bactericidal titers of 1 : 4 or greater were protected from disease. The importance of serum bactericidal antibody also is underscored by a greatly increased risk of acquiring meningococcal disease in persons with inherited late complement component deficiencies (C5-C9), who lack bactericidal activity because of an inability to form a complement membrane attack complex. However, vaccine-induced antibodies in patients with late complement component deficiencies have opsonic activity, and in one study, meningococcal polysaccharide vaccination decreased the incidence of meningococcal disease among C5-C9 deficient individuals. These observations support an independent contribution of opsonophagocytic activity to protection against meningococcal disease and provide the rationale for the recommendation to immunize complement-deficient patients with meningococcal vaccines.
Persons with inherited deficiencies of properdin, factor D, or terminal complement components have up to a 1000-fold higher risk for development of meningococcal disease than complement-sufficient persons. The risk of meningococcal disease is also increased in patients with acquired complement deficiencies associated with diseases such as nephrotic syndrome, systemic lupus erythematosus, and hepatic failure.
Among persons with complement deficiencies, meningococcal disease is more prevalent during late childhood and adolescence, when carriage rates are higher than in children <10 yr; meningococcal infections may be recurrent. Although meningococcal disease can occasionally be overwhelming in patients with late complement component deficiency, cases are more typically described as being less severe than in complement-sufficient persons, perhaps reflecting the fact that these cases are often caused by unusual capsular groups such as W-135 and X. Although protective against early infection, extensive complement activation and bacteriolysis may contribute to the pathogenesis of severe disease once bacterial invasion has occurred.
A large number of host genetic factors appear to affect the risk and/or severity of meningococcal disease. The molecules implicated involved polymorphisms at epithelial surfaces, the complement cascade, pattern recognition receptors, clotting factors, or inflammatory mediators. To date, the strongest associations implicate genetic variation in complement regulators, particularly genes encoding mannose-binding protein (MBL), which is part of the lectin complement pathway, or in factor H, which is a down-regulator in the complement cascade. Factor H binds specifically to the surface of N. meningitidis, which enhances resistance to complement-killing of the bacteria and is critical for evasion of host defenses. Most other studies to identify susceptibility genes enrolled relatively small numbers of patients, and the results have not yet been confirmed or validated. Children with the IgG receptor allotype, FcγRIIa R/R131 (i.e., homozygous for arginine at position 131) are reported to have increased severity of meningococcal disease. One reason may be that neutrophils with this Fc receptor allotype exhibit less effective opsonophagocytosis than those with allotypes containing histidine at this position. Plasminogen activator converts plasminogen into its active form, plasmin, which elicits fibrinolysis. Functional polymorphisms in the promoter region of the gene for plasminogen-activator-inhibitor-1, which result in higher inhibitor levels and decreased fibrinolysis, have been associated with increased severity of meningococcal disease. The presence of factor V Leiden, which is known to increase the risk of thrombosis, also may exacerbate meningococcal purpura fulminans.
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