Neisseria meningitidis

Revised December, 2019

Definition and History

Neisseria meningitidis (the meningococcus) is the cause of epidemic cerebrospinal fever, clusters and sporadic cases of acute bacterial meningitis, mild bacteremia to devastating septicemia, pneumonia, and, less commonly, septic arthritis, pericarditis, chronic bacteremia, conjunctivitis, epiglottitis, otitis, sinusitis, urethritis, and proctitis. Historically, half a million cases of invasive meningococcal disease occur worldwide each year, but incidence is declining owing to the widespread use of conjugate vaccines that provide herd protection, new vaccines for serogroup B, targeted and widespread antibiotic use that eliminates carriage, and other factors including reductions in population risk factors for disease such as smoking and crowding. Mortality remains at approximately 10% to 15% in developed countries and is higher, approximately 20%, in the developing world. Morbidity occurs in an additional 11% to 19% of systemically infected individuals and includes digit and limb loss, scarring, hearing loss, cognitive dysfunction, visual impairment, educational difficulties and developmental delays, motor nerve deficits, seizures, and behavioral problems.

Meningococcal disease was first clearly described in the late winter and spring in Geneva, Switzerland, in 1805, as “an epidemic outbreak of rapid onset, hemorrhagic eruption, febrile course, and high mortality with gross inflammation of the central nervous system; 33 deaths in three months were recorded.” In 1806, a similar epidemic outbreak was reported in New Bedford, Massachusetts. Subsequently, large outbreaks were reported across Europe and in the United States from 1805 through World War II. Curiously, no description of this singular epidemic disease and its distinct presentation was reported before 1805, nor were there reports of epidemics in the meningitis belt of sub-Saharan Africa before the late 1800s. This and meningococcal molecular phylogeny studies have given rise to speculation that N. meningitidis epidemics were, at the time, a new emerging disease.

Marchiafava and Celli (1884) first described intracellular oval micrococci in cerebrospinal fluid (CSF), and Anton Weichselbaum (1887) identified and cultured the organism, which he named Diplococcus intracellularis meningitidis because of the organism's presence inside neutrophils from CSF, thus establishing the etiologic relationship between N. meningitidis and epidemic meningitis. Kiefer in 1896 and Albrecht and Ghon in 1901 found that healthy persons were nasopharyngeal carriers of the meningococcus. Outbreaks of meningococcal meningitis in New York City in the early 1900s led in 1907 to the introduction of intrathecal equine serum therapy for the treatment of meningococcal meningitis by Flexner. Mortality was reduced to 40% from 75% to 85%. In 1908, Bruns and Hohn noted a close relationship between the carrier rate in a population and the onset, rise, and decline of an epidemic. Serologically different meningococci were first recognized by Dopter in 1909, and N. meningitidis was found to be distinct from the commensal Neisseria lactamica. Before and during World War I, the organism caused significant outbreaks. Glover (1917) was the first to note that carrier rates in military recruit camps increased with periods of crowding, and Gordon and Murray in 1915 developed the first meningococcal classification system (I, II, III, and IV). Later (1918), a similar system (A, B, C, D) was developed by Nicolle, Debains, and Jouan. In 1928 to 1930 and in 1941, significant US and worldwide epidemics (serogroup A) occurred. Rake (1934) further defined the epidemiology of the meningococcal carrier state. In 1937, sulfonamide therapy radically altered the outcome of meningococcal infection and replaced serum as the initial treatment. Beeson and Westerman reported on 3575 cases in England and Wales in 1939 to 1941 managed with sulfonamides; mortality was 16%. In the 1940s and 1950s, Branhan further defined meningococcal serogroups based on differences in capsular polysaccharide and developed the internationally standardized nomenclature A, B, and C, which was later expanded in the 1960s by the work of Slaterus and by the Walter Reed Institute of Medical Research to include serogroups E, X, Y, Z, and W. Later work identified serogroups H, I, K, and L. Meningococci that do not have the capacity to express capsules are commonly found as commensals in the pharynx.

Although N. meningitidis remains a devastating and worldwide cause of sepsis and meningitis, significant advances in control have been made in the past 2 decades, led by the introduction of new effective vaccines to prevent meningococcal disease. Study of the meningococcus has also led to the discovery of important insights into bacterial pathogenesis and of pathogen evolution in humans. The new meningococcal polysaccharide (MPS) conjugate vaccines against serogroups A, C, Y, X, and W (X in development), and new serogroup B vaccines, hold great promise for worldwide prevention in expanded human populations (e.g., infants and young children) and can (at least for the protein-polysaccharide conjugate vaccines) induce significant indirect effects and herd protection. Major challenges are the global implementation of meningococcal conjugate vaccines (MCVs), the full introduction and breadth of coverage of vaccines against serogroup B, the duration of protection of meningococcal vaccines, increasing antibiotic resistance in meningococci, and the emergence or reemergence in the past 2 decades of serogroups (e.g., Y, W, X) and new invasive genotypes that now cause significant endemic and epidemic meningococcal disease.

Microbiology

The meningococcus is a gram-negative diplococcus (0.6 × 0.8 µm), a β-proteobacterium, and a member of the bacterial family Neisseriaceae, which includes many commensal species (e.g., N. lactamica , Neisseria subflava , Neisseria polysaccharea ) and also the human pathogen Neisseria gonorrhoeae. The adjacent sides of the diplococcus are flattened to produce the typical biscuit or coffee bean shape. The meningococcus has a rapid autolytic rate. Lysis appears to be mediated by expression of lytic transglycosylase and cytoplasmic N -acetylmuramyl- l -alanine amidase genes and an outer membrane phospholipase, which can result in considerable size and shape variation in older cultures. The organism may produce a polysaccharide capsule; structural differences in the capsular polysaccharide are the basis of the serogroup typing system.

Because the meningococcus is considered fastidious, appropriate media and growth conditions are necessary. On solid media, the meningococcus grows as a round, colorless-to-gray, nonpigmented, nonhemolytic colony that is 1 to 5 mm in diameter. Colonies are convex and, if large amounts of polysaccharide are present, can appear to be mucoid rather than smooth. Optimal growth conditions are achieved in a moist environment at 35°C to 37°C under an atmosphere of 5% to 10% carbon dioxide. The meningococcus will grow well on a number of medium bases, including blood agar base, trypticase soy agar, supplemented chocolate agar, and Mueller-Hinton agar. Classic confirmation of this organism in clinical specimens has depended on a positive oxidase test (the meningococcus contains cytochrome oxidase in its cell wall) and a series of carbohydrate fermentations. The meningococcus will metabolize glucose and maltose to acid without gas formation and fails to metabolize sucrose or lactose. The expanded use of molecular methods based on a variety of polymerase chain reaction (PCR) techniques has confirmed and supplemented cultures in the diagnosis of patients infected with the meningococcus. This is particularly true for clinical specimens from patients treated with antibiotics before cultures are obtained.

Biology and Pathogenesis

The dynamic pathobiology of N. meningitidis resembles the story of “Dr. Jekyll and Mr. Hyde.” As an obligate human pathogen with no other reservoir, the organism is an ancient common human commensal that can be carried for months, most often in the human nasopharynx. Cross-sectional studies in multiple populations project an estimated 230 million to more than 1 billion meningococcal carriers worldwide (3%–25% of populations). Carriage is an immunizing process, often resulting in natural protective immunity. In contrast, the meningococcus is a devastating human pathogen, historically causing approximately 500,000 cases of invasive meningococcal disease worldwide annually, with high mortality and morbidity and with increased incidence in often otherwise healthy children and adolescents.

Meningococcal biology and pathogenesis can be defined by three interrelated components: (1) N. meningitidis human-to-human transmission, acquisition, and colonization; (2) virulence factors that facilitate these events and invasive meningococcal disease; and (3) human “host” susceptibility to invasive meningococcal disease. Each of these areas has implications for prevention strategies.

The potential virulence of N. meningitidis (defined as the ability to cause invasive disease) differs extensively among meningococcal strains. Unencapsulated strains rarely cause invasive disease, but even among encapsulated strains there is considerable variability in virulence. Organism characteristics that facilitate survival during invasive disease and/or that also promote transmission and acquisition will increase disease incidence. Meningococcal disease patterns and incidence vary dramatically, both geographically and over time in populations. This is related to the appearance and disappearance in populations of invasive meningococci of specific genotypes designated as clonal complexes (CCs), often but not exclusively associated with a specific capsular polysaccharide. Currently, 12 genomic CC types (see “ Epidemiology ”) cause most endemic and epidemic invasive meningococcal disease worldwide. The genomic population structure of colonizing meningococci is considerably more diverse. One approach to the assessment of meningococcal virulence relates the number of cases in a population due to a specific clade or CC to the number of carriers of that clade or CC. This can range from much less than 1 case per 10,000 carriers to more than 1 case per 10 to 20 carriers for highly virulent CCs. For example, the case-to-carrier ratio is much higher for serogroup A CCs or serogroup C, CC ST-11, than for serogroup X or serogroup Y meningococci, presumably reflecting a marked difference in meningococcal virulence.

The meningococcus has a single chromosome of 2.1 to 2.3 megabases. The first whole-genomic sequences were from serogroup B and serogroup A strains and were reported in 2000. With high-throughput whole-genome sequencing (WGS), the number of genomes as gap-closed, as finished genomes, or now more commonly as incomplete or draft genomes is rapidly increasing in available databases ( http://neisseria.org/nm/genomes ; http://patricbrc.org/portal/portal/patric/Home ; http://PuBMLST.org ). The Neisseria PubMLST database contains genetic data for a collection of over 50,000 isolates and over 19,000 genomes that represent the total known diversity of Neisseria species ( http://PuBMLST.org ). The core genome consists of 1300 to 1600 genes and differs by 3% to 5% from other sequenced strains, with the meningococcal “pan genome” estimated at more than 2500 genes. The overall G and C content is 51%, but low G and C regions suggest horizontal transfer and contain genes that are important in pathogenesis. Work has identified a transcriptome of approximately 1100 transcribed open reading frames per strain with over 300 operons. The genome encodes core metabolic, fitness, and key virulence factors, including capsular polysaccharide, a requirement for virtually all invasive meningococcal disease and the basis for serogrouping; lipooligosaccharide (LOS), a lipopolysaccharide molecule without repeating O side chains and the basis for immunotyping; the pilus organelle complex that facilitates motility and initiates attachment; and other virulence-associated outer membrane proteins (PorA, PorB, Opc, Opa, NadA, FetA, FHbp), which are the basis for serotyping and serosubtyping ( Fig. 211.1 ). Repetitive nucleotide sequences and polymorphic regions are present, usually in large heterogeneous arrays, suggesting active areas of genetic recombination. Transformation is the major means of horizontal gene transfer and a source of strain diversity. Over 1900 copies of the Neisseria uptake sequence (5′-GCCGTCTGAA-3′) ease Neisseria spp. DNA exchange by transformation and homologous recombination. Recombination events are recognized, including transfer of DNA including complete genes between meningococci, gonococci, and commensal Neisseria spp. and other bacteria. The genome is modified and regulated at multiple levels. Genetic switches involved in gene regulation include small noncoding regulatory RNAs, CRISPR (clustered regularly interspaced short palindromic repeats), slipped-strand mispairing of repetitive nucleotides, global protein regulators of promoters (e.g., fur ), intergenic recombination, IS (insertion sequence) element movement, methylation, hypermutator phenotypes, and two-component systems regulation. There are large genetic islands (e.g., IHT-A1 [8.5 kb], IHT-A2 [5.4 kb], IHT-B [17.1 kb], IHT-C [32.6 kb], IHT-E) in different meningococcal strains containing bacteriophages, phage elements and remnants, and many restriction enzymes related to CC genomic structure virulence factors and other genes to encoding surface proteins. For example, the IHT-A2 locus encodes an ABC transporter homologue and a secreted protein and the IHT-C locus encodes 30 open reading frames, including toxin homologues, a bacteriophage, and potential virulence proteins. Although one bacteriophage has been proposed as a marker of virulence, the current evidence is that no specific virulence gene pool is exclusively present in all N. meningitidis strains from hyperinvasive lineages.

The major virulence factor for invasive disease produced by the meningococcal genome is capsular polysaccharide. Serologic typing and the biochemical composition of capsular polysaccharides have classified N. meningitidis capsular polysaccharides into a total of 13 serogroups (A, B, C, D, E, H, I, K, L, W, X, Y, and Z), with A, B, C, E, H, I/K, L, W, X, Y, and Z now confirmed genetically. However, six capsular serogroups (A, B, C, W, X, and Y) cause almost all invasive meningococcal disease. Serogroups B and C capsular polysaccharides are sialic acid homopolymers of (α2→8) and (α2→9) linkages, respectively, whereas serogroups Y and W are alternating units of d -glucose or d -galactose and sialic acid, respectively. Serogroup A N. meningitidis expresses a homopolymeric (α1→6) N -acetyl mannosamine-1-phosphate capsule, whereas serogroup X expresses (α1→4) linked N -acetyl- d -glucosamine-1-phosphate. Capsular polysaccharides provide antiadherent properties, thereby promoting meningococcal spread from mucosal surfaces, and provide protection in intracellular environments and against complement-mediated killing.

Capsule is produced by a 30-kb region containing the IHT-A1 genetic island with genes for capsule biosynthesis, assembly, and transport. The island has been lost or never acquired in commensal Neisseria species, such as N. lactamica, the pathogen N. gonorrhoeae, and many commensal N. meningitidis ; but recent work shows evidence of a cps locus in some commensals such as N. subflava . The acquisition or reacquisition and evolution of this genetic island was a key to the emergence of invasive meningococcal disease. Capsule subunit and polymer biosynthesis, acetylation, assembly, protection from degradation, and transport to the cell surface are encoded by genes of the region. The region is related to capsule encoding islands in Pasteurella and other bacterial species. The different capsule structures are the result of evolutionary divergent biosynthesis, polymerization, or acetylation genes found in the capsule locus.

The serogroup B polysaccharide capsule ([α2→8]-linked polysialic acid) is similar to the capsular polysaccharides of Escherichia coli K1, Pasteurella haemolytica A2, Moraxella nonliquefaciens, and human polysialic acid structures, such as the neural cell adhesion molecule (NCAM). Due to NCAM similarity, the serogroup B capsule is poorly immunogenic as an antigen in humans and animals.

Capsule, as with many other meningococcal virulence factors, is subject to genetic regulation. On↔off phase variation, regulation of amount of capsule expressed, and modifications to structure (e.g., capsule acetylation) are well described. Thermoregulation of capsule expression (increased capsule expression at 37°C due to RNA thermosensors in the cps operon) is reported. Meningococci “capsule switching” resulting in structural change also occurs, providing a mechanism of immune escape. Gene conversion by transformation and homologous recombination of the capsule locus was first noted in a serogroup B outbreak in the United States in the 1990s ; otherwise identical serogroup C expressing strains appeared during the outbreak. Similarly, CC, ST-11 serogroup W N. meningitidis outbreaks associated first with the Hajj in 2000 and 2001 and more recently with other CC, ST-11 W clades were likely the result of distant capsule switching events from ST-11 serogroup C ancestors. In large meningococcal isolate collections, capsule switching events are detected in approximately 3% of isolates.

Type IV pili (see Fig. 211.1 ) are complex surface appendages requiring at least 23 proteins (e.g., PilE, PilC, secretin, PilT, PilQ), either as structural components of the organelle or required for biogenesis. Pili are anchored in the outer membrane and radiate, through an oligomeric ring, several thousand nanometers from the meningococcal surface (see Fig. 211.1 ). The major subunit may undergo O -linked glycosylation. Pili and accessory proteins (e.g., PilX) facilitate meningococcal aggregation and initial attachment and anchoring to human epithelial or endothelial cells. Through cycles of polymerization and depolymerization that produce retraction and extension, pili are responsible for “twitching motility” (1–2 µm/sec). Pilus attachment to human cells initiates localized remolding of the human cell cytoskeleton. Pili also facilitate aggregation and microcolony formation but, when glycosylated, promote meningococcal disaggregation and dissemination. Pili are also necessary for DNA transformation.

The endotoxin of N. meningitidis, an LOS, lacks O -side chains and has a lipid A structure distinct from gram-negative enterics. This LOS can mimic the i and I human blood group antigens. LOS also is an important virulence factor, influencing cell damage, meningococcal attachment and invasion of host cells, and complement-mediated killing. Mass spectrometry analysis of the structure of LOS shows highly phosphorylated lipid A forms that influence innate immune responses and clinical outcomes. The release of LOS during bloodstream or CSF invasion is a key factor in meningococcal sepsis and meningitis. Serum or CSF levels of LOS are directly correlated with the severity of meningococcal sepsis and meningitis. For example, when LOS levels exceed 100 ng/L, septic shock and/or death are highly correlated. LOS stimulates chemokine and cytokine release systemically by binding Toll-like receptor 4 (TLR4) on macrophages and other cells and stimulating MyD88-independent and MyD88-dependent pathways, resulting in tumor necrosis factor-α (TNF-α), interleukin (IL)-1β, monocyte chemoattractant protein 1 (MCP-1), macrophage inflammatory protein-3α (MIP-3α), IL-6, IL-8, IL-10, MCP-5, and release of other chemokines and cytokines. LOS also downregulates genes involved in oxidative phosphorylation and mitochondrial function in human cells. Non-LPS molecules can contribute to inflammation, but 10-fold to 100-fold higher concentrations are required to reach the same responses as those induced by LOS.

Outer membrane porins are involved in host-cell interactions and are targets for bactericidal antibodies. PorB, which is the major outer membrane porin, inserts in membranes, induces Ca ²⁺ influx, and activates Toll-like receptor 2 (TLR2) and cell apoptosis. PorA is a second important porin and a major target of meningococcal outer membrane vesicle (OMV) vaccines including OMV in one of the new MenB vaccines. Meningococci also express variable proteins such as Opa and Opc, which are important in adherence and host cell interactions. Another important outer membrane protein, a principal target for the new MenB meningococcal vaccines, is the factor H binding protein (FHbp), a lipoprotein involved in meningococcal resistance to complement-mediated killing. Other outer membrane vaccine-targeted proteins include neisserial adhesin A (NadA), a mediator of adhesion and cell invasion; and neisserial heparin binding antigen (NHBA), also involved in adhesion and in protection against complement-mediated killing.

Iron is necessary for meningococcal survival, colonization, and infection. The meningococcus scavenges iron from the human proteins transferrin, lactoferrin, and hemoglobin through a series of highly evolved, surface-exposed receptors and TonB-derived energy. More than 80 genes are regulated by the iron-responsive repressor Fur. Meningococcal iron-acquiring proteins include HmbR (hemoglobin), TbpA and TbpB (transferrin), HbpA and HbpB (lactoferrin), and HpnA and HpnB (hemoglobin-haptoglobin complex) and FetA (ferric enterobactin receptor). Iron-loaded animals are more susceptible to fatal meningococcal infection. New putative iron acquisition proteins, adhesion or invasion proteins, and toxin proteins have been identified in meningococcal genome searches.

Meningococcal Colonization and Transmission

The dynamic life cycle of N. meningitidis is shown in Fig. 211.2 . The human nasopharynx is the most frequent site of meningococcal colonization and carriage and the major source of transmission to other humans. The human nasopharynx, optimal for N. meningitidis growth, has a CO ₂ content of 3% to 4%; high, 75% to 80%, humidity; and a temperature of 34°C. Colonization is a complex process of meningococcal interaction with upper respiratory mucosa. The initial adherence of meningococci is facilitated by type IV pili, which may recognize integrin α-chains or other receptors. Surface movement, proliferation, aggregation, and microcolony formation are facilitated on mucosal surfaces by type IV pili–induced twitching motility involving pilus retraction, and the phase variation of glycan decorations on pili. Meningococci attach to nonciliated nasopharyngeal epithelial cells and induce apical cortical plaques (see Figs. 211.2 and 211.3A ), which anchor the organisms against loss by mucus and ciliary action and promote the formation of meningococcal microcolonies and biofilms (see Fig. 211.3A ). This process is mediated by close adherence involving the meningococcal outer membrane ligands (Opc, Opa, LOS, NadA, and others) and the human host receptors such as carcinoembryonic antigen–related cell adhesion molecules (CEACAMs) and integrins, leading to cortical actin polymerization and plaque formation (see later). The induction of cortical plaques also leads to internalization of meningococci within epithelial cells, a site where capsule is advantageous for survival. Cell entry is a potential pathway to mucosal invasion and access to the bloodstream. Capsule expression and glycan expression on pili result in meningococcal disaggregation and spread along and from mucosal surfaces.

As previously noted, meningococci are common commensals, colonizing 3% to 25% of human populations worldwide. Carriage rates are low in infants and young children and highest in adolescents and in closed populations, but there is considerable global diversity. Carriage may be transient or prolonged (e.g., months). Carriage does not directly predict an outbreak or the course of the outbreak, but “if there are no carriers, there are no cases.” Although usually less than 1% of persons exposed develop invasive disease, expanded transmission of meningococci with the capacity to cause disease will result in increased incidence. Transmission is by direct contact with respiratory secretions or by inhalation of large respiratory droplet nuclei that travel approximately 1 meter (3 feet); respiratory droplets may increase in low-humidity environments. Meningococci are fastidious but can survive for hours or more on innate surfaces. Factors that influence meningococcal transmission and carriage include crowding or close contact, exposure through migration or travel (e.g., the Hajj), season, active and passive smoking, party or club attendance, male sex, and respiratory coinfections. The human upper respiratory microbiome also influences meningococcal colonization (e.g., the presence of N. lactamica is negatively correlated with meningococcal carriage). A challenge in understanding the dynamics of meningococcal carriage has been the variable expression of capsule or other virulence factors detected with serologic technologies in colonizing isolates. WGS is a more accurate approach to characterizing meningococcal carriage isolates.

The meningococcal inoculum required for nasopharyngeal colonization or needed to cause invasive disease is not known. However, data from experimental N. gonorrhoeae urethral infections in male subjects revealed a median infective dose (ID ₅₀ ) of approximately 10 ⁵ colony-forming units of gonococci, which could be further reduced to approximately 3 × 10 ² if gonococci obtained from the initial passage after infection were used. In settings of very high exposure (e.g., military recruits), the acquisition of meningococci in the nasopharynx is transient (or not detected) in about 40% of individuals; in approximately 33%, the period of nasopharyngeal colonization and carriage is brief (i.e., days to weeks); and in approximately 25%, meningococcal carriage becomes fully established and can last 9 to 15 months or longer. Meningococci that gain access to the bloodstream may cause a transient or mild bacteremia but also the clinical syndromes of septicemia and meningitis described later. Invasive meningococcal disease usually occurs 1 to 14 days after mucosal acquisition. Cofactors associated with invasive meningococcal disease are respiratory tract infections (e.g., from mycoplasma, or influenza and other viral agents), active and passive smoking, and environmental damage to the upper respiratory tract (e.g., from low humidity, dusty winds of the Harmattan in Africa). N. meningitidis also has the capacity to damage respiratory epithelial cells, can cause a pharyngitis, and can spread to adjacent mucosal surfaces of the upper respiratory tract to produce focal respiratory infections (e.g., pneumonia in up to 10% of presentations) but is an uncommon cause of otitis media or sinusitis. Meningococcal pneumonia and conjunctivitis are also recognized as portals of entry for systemic disease.

Once in the bloodstream, type IV pili facilitate meningococcal attachment to peripheral vascular endothelial cells. This results in the formation of microcolonies on vascular endothelium, the activation of signaling pathways in endothelial cells and formation of cortical plaques, and meningococcal entry into endothelial cells. A humanized mouse model shows meningococcal adherence only to human vessels. Adherence results in extensive damage, inflammation, and development of a purpura at these sites. The specific steps in brain and other microvascular endothelial cortical plaque formation have been dissected and involve the recruitment and activation of the β ₂ -adrenoreceptor and CD147 in hetero-oligomeric complexes, the accumulation of ezrin and ezrin-binding receptors, β-arrestins and β-arrestin–binding molecules such as Src and VE-cadherin, and the activation of the cortactin/Arp2/3 complex, leading to actin polymerization, membrane protrusions, and cortical plaque formation (see Fig. 211.3B ). In brain microvascular endothelium there is also breakdown of tight junctions between endothelial cells, which also may allow meningococci to cross the blood-brain barrier and gain access to the subarachnoid space.

Epidemiology

The epidemiology of meningococcal disease is dynamic. The rates of disease are influenced by the virulence of circulating strains, environmental and host factors influencing transmission, carriage and disease, population immunization, and other prevention strategies. Meningococcal isolates have been historically classified by serologic typing based on the biochemical composition of the capsular polysaccharide. Serogroups A, B, C, E, H, I/K, L, W, X, Y, and Z are confirmed genetically ; however, six serogroups (A, B, C, W, X, and Y) currently cause almost all worldwide life-threatening disease.

Outer membrane protein serotyping and serosubtyping and LOS immunotyping have also been used, especially for serogroup B meningococcal strains. Genomic typing (e.g., multilocus sequence typing [MLST]) and whole-genome comparisons have unlocked a broader understanding of the global epidemiology of meningococcal disease. With MLST, meningococcal isolates are classified into different sequence types (STs) and CCs based on polymorphisms in seven housekeeping genes considered not to be under selective pressure. CCs ST-5 and ST-7 (serogroup A); ST-41/44, ST-32, ST-18, ST-269, ST-8, and ST-35 (serogroup B); ST-11 (serogroups C, W, or B); ST-23 and ST-167 (serogroup Y); and ST-181 (serogroup X) meningococci cause almost all invasive meningococcal disease ; but other new genotypes associated with disease continued to emerge (e.g., ST-10217, serogroup C in Africa ; ST-4821, serogroups C and B in China ). The emergence of rapid WGS as an epidemiologic technique and tool for better understanding pathogenesis has further defined meningococcal strain relatedness, diversity, and virulence.

Meningococcal disease is worldwide ( Fig. 211.4 ), but with significant differences in serogroup/CC predominance. Incidence also varies in populations over time. Disease can be epidemic, endemic (sporadic), or hyperendemic. Meningococcal epidemiology is affected by the sequence types and serogroups circulating, by age and other host susceptibility (e.g., the frequency in the population of complement deficiencies), by the widespread use of antibiotics that eradicate the meningococcal carrier state, and by vaccines. The introduction of polysaccharide vaccines in the 1970s decreased the incidence of meningococcal disease through widespread use in the military, in sub-Saharan Africa, in China, and in countries associated with the Hajj and Umrah pilgrimages. More recently, the A, C, W, Y MCVs that both induce individual protection and interfere with transmission resulting in herd protection have had greater impact. Other changes in populations (e.g., in strain- or clonal group–specific immunity) and other environmental factors (e.g., crowding, smoking, humidity, dust, viral, or mycoplasmal coinfections) also influence the incidence of meningococcal transmission and disease.

Meningococcal disease epidemiology dramatically changed in industrialized nations after World War II. ^a

a References , 539.

Before and during this war, large serogroup A outbreaks occurred in the United States, Europe, Asia, South America, and Africa that were cyclical, having peaks and troughs every 5 to 12 years. These large serogroup A outbreaks dominated meningococcal disease throughout the world in the 19th and first half of the 20th centuries; disappeared from the United States, Western Europe, and Japan after World War II; but continued in parts of Asia, South America, and sub-Saharan Africa. For example, before and during World War II the incidence of meningococcal disease in the United States was 3 to 4 per 100,000 population, with episodic serogroup A outbreaks raising the incidence to 8 to 17 per 100,000. With the disappearance of serogroup A outbreaks and serogroup A carriage for reasons that are not well understood, overall attack rates in the United States declined to 1.7 per 100,000 population by the mid-1990s, but with periodic “hyperendemic” fluctuations in the incidence of B, C, or Y meningococcal disease. In the United Kingdom, incidence decreased from more than 5 per 100,000 population in the 1990s to less than 3 per 100,000 population after the virtual elimination of serogroup C disease as a result of the introduction of C specific conjugate vaccines (see later). However, in 2010 the rates of serogroup W ST-11 disease began to increase in the United Kingdom. The increase is associated with the emergence of new ST-11 serogroup W sublineages with severe disease, often in adolescents and older adults, and clinical presentations that include pneumonia, gastroenteritis (nausea, vomiting, diarrhea), septic arthritis, and epiglottitis or supraglottitis. The W:CC 11 lineages have appeared globally, causing increased disease in South America, Canada, Europe, China, Australia, and sub-Saharan Africa. These events have led to the increasing use of A, C, W, Y conjugate vaccines in many countries.

Although increases in W:CC 11 disease have occurred, the overall meningococcal disease incidence and carriage rates in many industrialized countries’ populations have continue to decline ^b

b References .

(in the United States in 2015 the invasive meningococcal disease incidence was 0.12 per 100,000). In Japan, rates of disease are now <0.04 per 100,000 (and carriage rates are 0.4%), with a high percentage of the remaining meningococcal disease occurring in complement-deficient individuals.

In the United States, serogroups B (ST-41/44, ST-32), Y (ST-23), and C (ST-11), although declining in incidence, continue to cause most (87%) of the meningococcal disease. The United States saw the emergence in the early 1970s and again in the mid-1990s into the 2000s of serogroup Y (ST-23) disease. Serogroup Y disease incidence peaked in 1997, accounting for approximately 50% of reported cases, in contrast to approximately 2% in the early 1990s. Almost all of the serogroup Y meningococcal disease in the United States in the 1990s was caused by ST-23 CC strains. In 1998, a carriage study of high school students from counties in the metropolitan area of Atlanta, Georgia, found the rate of meningococcal carriage to be 7.7%; and of these isolates, 48% were serogroup Y. However, in 2006–07, a similar carriage study in high school students found a much lower carriage rate of less than 3% and a much lower proportion of serogroup Y carriage. The lower frequency of serogroup Y and overall meningococcal carriage correlated with the decline in invasive serogroup Y cases after 1998. However, serogroup Y continues to cause disease in the US population and is seen globally.

The overall declines in disease also continue to be interrupted by localized serogroup C outbreaks in the United States and Europe, such as in MSM ; or by serogroup B outbreaks in communities and institutions such as on college campuses. The increased serogroup C rates in MSM compared with non-MSM populations led to specific targeting of educational and vaccination efforts in New York City and in other locations.

In South and Latin America (in particular, Brazil and Chile), serogroup W:CC 11 is currently a major cause of disease, followed by serogroups B and C. In Europe, serogroups B (ST-41/44, ST-32, ST-18, ST-269, ST-8), W (ST-11), C (ST-11), and Y (ST-23) currently predominate; in Russia, serogroups B, C, A, W, and Y; in China and Mongolia, serogroups C, W, B, and A; in India and Nepal, serogroups A, C, and B ; in Oceania, serogroups W, B, Y, and C; in the Middle East and North Africa, serogroups W, B, A, and Y; and in sub-Saharan Africa, serogroups C (ST-10217), W (ST-11), and X (ST-181). Serogroup Y CC ST-11 and ST-167 have been increasingly reported in South Africa, Israel, parts of Europe, and Japan.

Serogroup A is historically associated with the highest incidence and largest epidemics of meningococcal disease, especially meningitis. Serogroup A global pandemics in the 20th century were caused by five major ST CCs (e.g., ST-5, ST-7). Three pandemic waves arising in China and spreading to Russia, the Middle East, Africa, and globally were recorded in the 1960s to 1970s, 1980s, and into the 1990s. Serogroup A strains are genetically distinct from other meningococci and appear to have evolved from a common ancestor in the 19th century. In sub-Saharan countries of Africa, extending from Senegal and The Gambia in the west to Ethiopia, Eritrea, and northern Kenya in the east, a region known as the African meningitis belt, large periodic epidemics of serogroup A meningococcal disease occurred every 5 to 12 years from the late 1800s to 2010. Virulent meningococci may have been first introduced into the region by returning Hajj pilgrims. The size of these epidemics was enormous. In major African epidemics, the attack rate ranged from 100 to 800 per 100,000 population during epidemics, and individual communities have reported rates as high as 1 per 100. ^c

c References .

Between 1988 and 1997, 704,000 cases and more than 100,000 deaths were reported; from 1996 to 1997, more than 300,000 cases and 30,000 deaths, the largest serogroup A epidemic year ever recorded, with spread to countries south of the meningitis belt (e.g., Rwanda, Burundi, Tanzania, Zambia, and the Central African Republic); between 1998 and 2002, 224,000 cases; and, in 2009, 88,199 meningococcal meningitis cases occurred in the belt.

The CCs, ST-5 and ST-7, were responsible for these global serogroup A pandemics, the African meningitis belt outbreaks, endemic serogroup A meningococcal disease in the belt, and the worldwide cases of serogroup A disease. The epidemics in the meningitis belt have been linked to environmental factors, such as climatic changes (dry season, “dust” and winds of the Harmattan), coinfections, poor living conditions, overcrowded housing, travel and population displacements, and specific population immunologic susceptibility. ^d

d References .

Disease in this region predominantly occurs in the dry season (December to June), ending during the intervening rainy season. Respiratory droplets that facilitate meningococcal transmission have higher density in the dry season. Although serogroup W, X, and rarely C had had caused epidemic outbreaks in sub-Saharan populations, serogroup A epidemic meningococcal disease was a major public health threat in the meningitis belt and other areas of the developing world. Over the past 2 decades, great strides have been made in development and implementation of serogroup A–directed MCVs. The successful introduction beginning in 2010 of a new serogroup A MCV, MenAfriVac (Serum Institute of India, Pune, India), in sub-Saharan Africa (see “ Meningococcal Conjugate Vaccines ”) has radically altered meningococcal disease in this region. The serogroup A conjugate vaccine has been introduced into the 26 countries in the African meningitis belt, resulting in a remarkable decline in the burden of disease. However, the region does continue to see serogroup C meningococcal disease, with two large outbreaks in Nigeria and Niger, serogroup W in Ghana and Burkina Faso, and serogroup X in Burkina Faso, Chad and Togo. This is a consequence of bacterial evolution rather than serogroup replacement. The cost of vaccination remains a primary obstacle to further progress against other serogroups in the African belt, but a low-cost pentavalent meningococcal conjugate A, C, W, X,Y is in development, projected for implementation in 2020 or 2021.

The epidemiology of meningococcal disease in parts of Africa outside the meningitis belt is not as well defined. In a report from rural Mozambique, the average incidence of endemic meningococcal disease was 11.6 per 100,000, with both sepsis and meningitis identified and with W (ST-11) as a major cause. It is important to note that epidemics of S. pneumoniae meningitis (serotype 1, ST 217 CC) are also reported in the meningitis belt, and febrile encephalopathy due to malaria can mimic meningococcal meningitis. More longitudinal and laboratory-based surveillance is needed in Africa.

As noted, serogroup W has emerged in the past 2 decades as a cause of global epidemic outbreaks of considerable size. In 2000 and 2001 several hundred pilgrims attending the Hajj in Saudi Arabia were infected with N. meningitidis serogroup W. Then in 2002, serogroup W emerged in Burkina Faso, striking 13,000 people and killing 1500. Global spread with secondary cases from these epidemics was also observed. The outbreaks were caused by W (ST-11) strains closely related to ST-11 serogroup C strains. Serogroup X (ST-181) has caused localized outbreaks in certain African countries, including Kenya, Niger, and Ghana, but has rarely been a cause of meningococcal disease outside Africa. Curiously, serogroup B disease is quite rare in sub-Saharan Africa but does cause significant disease in South Africa.

Serogroup B is the major cause of prolonged outbreaks, hyperendemic disease, and endemic (sporadic) meningococcal disease, especially in infants and young children in developed countries. Serogroup B epidemic outbreaks have also occurred worldwide and are usually of lower overall incidence compared with serogroup A outbreaks, but can reach levels of 20 to 45 per 100,000 in highly affected populations, as was seen in Pacific Islanders and Maoris in New Zealand and in infants. Serogroup B outbreaks can persist over many years. The serogroup B (ST-32) outbreaks of meningococcal disease in the US Pacific Northwest from 1988 to approximately 2007 and in New Zealand in 1992 to 2003 are examples. Recently in the United States, college campuses have been sites of a series of serogroup B meningococcal outbreaks (13 from 2008 to 2017).

There is greater genetic diversity, and thus antigenic diversity, in serogroup B strains that cause meningococcal disease. Most serogroup B disease is caused by seven major ST CCs: ST-41/44, ST-32 (members of these first two complexes account for over two-thirds of serogroup B disease), ST-18, ST-35, ST-269, ST-8, and ST-11. However, several other STs are found in collections of serogroup B isolates, and novel serogroup B strains can cause disease worldwide. The diversity of CCs causing serogroup B disease has presented a challenge to control through vaccination, because the B capsule structure has identity to human polysialic acid determinants. Also, ST-11 isolates, a CC usually associated with serogroup C, can express the serogroup B capsule as a result of “capsule switching,” allowing escape from vaccine-induced or natural protective immunity. This escape mechanism has raised concerns about serogroup B replacement as a threat to the effectiveness of meningococcal A, C, Y, and W conjugate vaccines.

Vaccines have only recently become available for the routine prevention of serogroup B disease. OMV vaccines were initially developed for control of serogroup B clonal outbreaks (see “Serogroup B Vaccines”) such as in 2004 in the New Zealand serogroup B outbreak. A serogroup B outer membrane protein–containing vaccine, VA-MenGOC-BC (Finlay Institute, Havana, Cuba), was also extensively used in Cuba and Latin America. New approaches to serogroup B vaccines based on conserved outer membrane proteins are now approved and in use in Europe, Canada, Australia, the United States, and other countries (see “Serogroup B Vaccines”).

Serogroup C (predominantly CC ST-11) continues to account for significant meningococcal disease, especially in older children and adolescents and young adults throughout the world. Increases in serogroup C meningococcal disease were seen in the United States and Europe in the 1980s and 1990s. In response, the meningococcal serogroup C conjugate vaccines were developed and first introduced in the United Kingdom in 1999. After serogroup C conjugate vaccine introduction, serogroup C invasive disease rapidly declined in the United Kingdom and in other European countries, but it has not been eliminated.

In the United States, surveillance including Active Bacterial Core surveillance (ABCs), a prospective laboratory- and population-based surveillance system, has tracked invasive bacterial pathogens, including N. meningitidis. This surveillance has documented the contribution of the Haemophilus influenzae type b capsular conjugate vaccines, the pneumococcal conjugate vaccines, and the MCVs to the marked decline in bacterial meningitis in the United States. However, N. meningitidis remains an important cause of bacterial meningitis and septicemia in infants, children, and adults. In the United States, it has been the second most common cause of community-acquired adult bacterial meningitis.

Based on this recent detailed surveillance, the incidence of meningococcal disease in the United States in the last quarter-century peaked at 1.7 per 100,000 population in the mid-1990s and since has continually declined; it was 0.35 per 100,000 in 2007, and in 2015 it was at a historic low of 0.12 per 100,000 population, a decrease of greater than 92%. From 2006 to 2015, a total of 7924 cases of meningococcal disease were reported in the United States; 14.9% of these cases were fatal. “Sporadic” cases accounted for 98% of cases, but molecular typing is better defining invasive isolate relatedness in communities. The incidence of meningococcal disease varies by season, with more cases occurring during January through March (34.7 % of cases) and the fewest cases occurring during August and September (11.2% of cases). The incidence of meningococcal disease in 2006 through 2015 by state ranged from 0.13 cases per 100,000 population to 0.79 cases per 100,000 population (median, 0.25 per 100,000). The incidence was highest in Oregon (0.79 cases per 100,000 population), reflecting the persistence of the longstanding serogroup B ST-32 strains in the region. The incidence of serogroup B–specific meningococcal disease was 0.31 cases per 100,000 population in Oregon, compared with 0.07 cases per 100,000 population in the other states.

Although the highest attack rates occur in the very young (<1 year old, 2.45 per 100,000), 73% of cases of invasive meningococcal disease in the United States occur in adolescents and adults. The rates of meningococcal disease have declined in all age groups in the United States since the mid-to-late 1990s. Male patients accounted for 50.6% of cases. Female patients were significantly older than male patients (median age, 35 years in female patients compared with 22 years in male patients). The incidence of meningococcal disease among black persons was 0.27 cases per 100,000 population, compared with 0.20 cases per 100,000 population among white persons and 0.20 cases per 100,000 population among other race categories combined. The distribution of serogroups causing disease has also shifted in the United States. From 2006 to 2015, serogroup B caused 35.8% of all meningococcal disease, serogroup C was responsible for approximately 22.8% of endemic disease, and case clusters and local outbreaks and serogroup Y caused 28.5% of cases. The case-fatality rates of serogroups C (20.2%) and W (20.9%) were higher than those of serogroup B (11.5%) or serogroup Y (13.7%).

Clinical Manifestations and Pathophysiology

The common presentations of invasive meningococcal disease are meningococcemia and acute meningitis. In several large series of cases, predominantly of serogroup B or C disease in industrialized settings, 40% to 65% of patients presented with meningitis, 10% to 20% had fulminant meningococcemia with shock but without meningitis, 7% to 12% had both meningitis and fulminant meningococcemia, and 18% to 33% had bacteremia without shock or meningitis. Less common presentations are primary pneumonia (up to 10%, especially with serogroup Y), septic arthritis (2%), purulent pericarditis, chronic meningococcemia, gastroenteritis, conjunctivitis, epiglottitis, sinusitis, otitis, urethritis, and proctitis . Rare presentations include necrotizing fasciitis. Invasive disease often occurs in otherwise healthy individuals and is difficult to identify early. In part, this is because sporadic meningococcal disease is not common and the classic clinical features of disease (e.g., petechial or purpuric rash, meningismus, and impaired consciousness) often appear late in the illness.

In fulminant meningococcemia, the time window between the progression from initial symptoms to death can be narrow (hours). In a study by Thompson and colleagues, nonspecific symptoms, such as fever, loss of appetite, nausea and vomiting, and sometimes diarrhea (which may have been preceded by a coryza and pharyngitis), occur in the first 4 to 6 hours, with more severe symptoms developing by 8 hours, such as leg pains, cold hands and feet, labored breathing, abnormal skin color, and rash; the median time to hospital admission was 19 hours, and by 24 hours, individuals can be dead or moribund. Physicians and health care providers should be alert to the concern of parents or relatives about the abrupt or rapid deterioration of a patient. Major complications of meningococcemia and/or meningococcal meningitis are necrosis and limb or digit loss, scarring, cranial nerve palsies (mostly commonly eighth nerve loss resulting in deafness), postinfectious immune complex–mediated polyarticular arthritis or pericarditis, long-term learning and cognitive disabilities, seizures, motor deficits, and chronic renal dysfunction. The overall case-fatality rate, despite antibiotics and aggressive support, remains at approximately 10% to 15% in developed countries.

Although the clinical features of meningococcal disease are similar in all epidemiologic situations, the number of patients who have a specific clinical presentation can vary from outbreak to outbreak for reasons that are not well understood. For example, meningitis is the major presentation, and septicemia is recorded less frequently during serogroup A epidemics in the African meningitis belt in comparison with patients in industrialized countries.

Meningococcemia

In 10% to 20% of cases, septicemia with shock is the dominant clinical picture and presentation is acute, with sudden-onset fever, generalized malaise, weakness, cold extremities and skin pallor, leukocytosis or leukopenia, rash, headache and/or drowsiness, and hypotension. A petechial or purpuric rash, a classic sign of meningococcal septicemia, is seen in 40% to 80% of cases of meningococcemia but may be difficult to detect initially. A maculopapular blanching rash can also be an early sign in the disease, can progress to a petechial or purpuric rash, or can persist in 13%. Median time from onset to admission for meningococcemia in two studies was 13 hours and 12 hours, which is less than half the time recorded for patients with meningitis. Generalized muscle tenderness may also be an important differential sign. Occasionally the pain from these myalgias is quite intense and causes the patient considerable discomfort. Clinical signs of meningeal irritation are usually absent, few meningococci are present in CSF, and CSF pleocytosis is negligible.

A rapid proliferation of meningococci in the circulation characterizes meningococcal septicemia (including the classic Waterhouse-Friderichsen syndrome with adrenal hemorrhage) ( Figs. 211.5 to 211.7 ), resulting in very high concentrations of bacteria (10 ⁵ –10 ⁸ /mL) and meningococcal endotoxin (10 ¹ –10 ³ endotoxin units [EU]/mL). Cases with fatal outcome have higher concentrations of meningococcal endotoxin in plasma than mild cases, and these patients are sicker than survivors. The adherence of intact meningococci and/or OMVs to the microvasculature and association with macrophages and mononuclear cells in fulminant meningococcemia is striking. Expression of human CD46 by macrophages may accelerate inflammatory responses on meningococcal infection or LOS stimulation. The rapid bacterial growth in the bloodstream causes an exaggerated and destructive intravascular inflammatory response, leading to progressive circulatory collapse and severe coagulopathy. There is also evidence of meningococcal proliferation and massive local inflammatory response in specific organs. Shock all too frequently dominates the clinical picture. Patients can present with severe, persistent shock that lasts more than 24 hours or until death. The patient is poorly responsive, and peripheral vasoconstriction is present, with cyanotic, poorly perfused extremities. Arterial blood gas analysis demonstrates evidence of acidosis in the range of pH 7.25 to 7.3, and, depending on the degree of shock, anoxia may manifest with an arterial oxygen pressure below 70 mm Hg.

Patients develop impaired renal, adrenal, and pulmonary function and disseminated intravascular coagulation (DIC), with thrombotic lesions in the skin, limbs, kidneys, adrenals, choroid plexus, heart, and occasionally the lungs. Clinical evidence of DIC includes increasing petechiae within prescribed areas, gastric or gingival bleeding, or oozing at sites of venipuncture or intravenous infusions. Myocardial dysfunction is also well described in adults and children with meningococcemia. Postmortem studies by Hardman and by Gore and Saphir indicated that myocarditis of varying degrees of severity is present in more than half the patients who die of meningococcal disease. The hypotension and vascular complications can lead to extensive scarring and loss of digits or limbs, and survivors can be severely handicapped.

Mild or transient bacteremia without sepsis is a presentation in less than 5% of cases. Admission or emergency evaluation is often for an upper respiratory tract illness, fever, or presumed viral exanthema. After recovery in 2 to 5 days and frequently after release without specific antimicrobial therapy, the unexpected results of blood cultures are reported as positive for N. meningitidis. In one study, Sullivan and LaScolea reported that the levels of bacteremia in this presentation were low, from 22 to 325 organisms per milliliter of blood. Meningococcal disease in terminal complement-deficient patients is also often milder and associated with a lower mortality for reasons that are not well understood (see “Complement Deficiency and Meningococcal Disease”). Also, patients with isolates with LOS lipid A mutations have less rash and coagulopathy.

Complement Deficiency and Meningococcal Disease (See also Chapter 9 )

The importance of the human complement system in protection against meningococcal infections is well recognized, in particular the risk for C5 to C9 deficiencies of the terminal pathway complement pathway, properdin (factor P, a promoter of the alternative pathway of complement and link to innate NK cell activity) deficiency, and C3 deficiency. Up to 39% of individuals with late complement deficiency and 6% with properdin deficiency develop systemic meningococcal infections. Terminal complement deficiency is associated with a 1400- to 10,000-fold increase in development of meningococcal disease, and 40% to 50% of patients have recurrent infections. Vaccinating individuals deficient in late complement components may shift the burden of host defense from serum bactericidal activity (SBA) to opsonophagocytosis and confer protection.

Studies by Lim and coworkers first demonstrated an absence of the sixth complement component as a risk factor for meningococcal disease, and Alper and associates noted that a patient with recurrent meningococcal disease lacked C3. Human deficiency of C8 was found in persons with meningococcal infections, disseminated gonococcal infection, and gonococcal meningitis. Ellison and coworkers evaluated the complement system in 20 patients with first episodes of serious systemic meningococcal infection. Six of 20 (30%) had a complement deficiency. Three had deficiencies in a terminal complement protein or proteins, and three had deficiencies of multiple factors associated with underlying disease states. Densen and coworkers studied a family with properdin deficiency whose members had a high rate of fatal meningococcal disease ; about 50% of properdin-deficient individuals develop invasive meningococcal disease.

Complement deficiency is also a factor in the risk for meningococcal disease associated with systemic lupus erythematous and C3 and C4 nephritic factor (autoantibody) states, such as in glomerulonephritis and in patients in whom the complement inhibitor eculizumab is used. The role of complement in meningococcal infections has been reviewed by Densen and by Ram and colleagues. The role of the lectin complement activation pathway in meningococcal disease is controversial. Data have supported the hypothesis that MBL polymorphisms may play a role in susceptibility to meningococcal disease in early childhood or even colonization, but data from large case-control studies revealed that MBL2 structural polymorphisms do not predispose children or adults to invasive meningococcal disease.