Clinical manifestations

Presentation and course

Invasive meningococcal disease most commonly presents with meningitis or meningococcemia, which may rapidly progress to purpura fulminans, shock, and death (38; 22). In a French study of invasive meningococcal disease spanning the years 2014 to 2016, most adult cases presented as meningococcal meningitis (59%), whereas the remainder presented with meningococcemia (25%), both (9%), or other and unspecified (7%) (107).

Meningococcemia may present abruptly with fever, chills, nausea, vomiting, headache, myalgias, breathing difficulty, malaise, prostration, and rash. Rash is non-blanching but somewhat variable and may be urticarial, maculopapular, or petechial. In darker-skinned people, rash may be less evident, so it is important to check the soles of the feet, the palms, and the conjunctivas (225). Limb pain with pale or cyanotic, cold extremities, hypotension, tachycardia, and prolonged capillary refill are clinical features that indicate impending shock (225). Acute fulminating cases of meningococcal septicemia (Waterhouse-Friderichsen syndrome) occur mainly in children younger than 10 years of age and are characterized by vomiting, diarrhea, extensive purpura, disseminated intravascular coagulation, cyanosis, convulsions, shock, coma, and often death within hours despite appropriate treatment; many of these cases have meningitis and adrenal insufficiency with hemorrhage into the adrenal glands or adrenal infarction.

At initial contact, fever is present in about three quarters of the cases, whereas specific symptoms, such as headache (about one third), a rash or petechiae (about one quarter), and stiffness of the neck (about one tenth), are infrequent (105). The rash may become widespread with erythematous patches or develop into bleeding spots under the skin (petechiae, ecchymoses, or purpura). There may be associated swelling, muscle pain, skin deterioration, or gangrene in the arms and legs.

Severe complications include purpura fulminans with cutaneous pain, extensive necrosis caused by disseminated intravascular coagulation, and gangrenous necrosis of the limbs. The gangrenous areas may necessitate amputation, which may involve multiple limbs.

Meningococcal meningitis may be indistinguishable from other bacterial meningitides, including Kernig and Brudzinski signs, although the classic triad of fever, neck stiffness, and change in mental status is significantly less common in patients with meningococcal meningitis (27%) than in patients with pneumococcal meningitis (58%) (220; 100).

Although less than one third of affected patients present with the classic triad of fever, nuchal rigidity, and change in mental status, nearly 90% have at least two of the following four signs on presentation: fever, nuchal rigidity, change in mental status, and rash (100). Other manifestations may include headache, photophobia, nausea, vomiting, focal neurologic findings, Kernig and Brudzinski signs, a bulging fontanelle (in children under 2 years of age), stroke, seizures, and stupor or coma (35; 219; 225). A depressed level of consciousness may indicate altered blood flow, cerebral edema, and raised intracranial pressure. Stroke due to meningococcal meningitis can result from septic arteritis, venous thrombophlebitis, or thromboembolic events (221; 222). Meningitis can have a slower onset in infants, without nuchal rigidity, but with a bulging fontanelle and nonspecific clinical findings (181).

Associated with nuchal rigidity is a characteristic contraction of neck and back muscles that sometimes develops into frank opisthotonos and is often associated with hip flexion (194; 119; 92). In extreme cases, this may progress to decerebrate posturing.

In infants younger than 6 months of age, initial symptoms are typically fever and decreased activity. Seizures occur in the majority whereas a petechial or purpuric rash develops in only about one third (106).

Most children have only nonspecific symptoms in the first 4 to 6 hours but may be close to death by 24 hours after onset. Early symptoms of sepsis (eg, leg pains, cold hands and feet, and abnormal skin color) are present in nearly three quarters (72%) of children with meningococcal disease, are common presenting symptoms, and herald progression to shock. Signs of shock include tachycardia, hypotension, toxic or moribund state, depressed level of consciousness, breathing difficulty, poor urine output, leg pain, cold extremities with unusual skin color, and prolonged capillary refill time (longer than 2 seconds) (225). In children particularly, the classic features of hemorrhagic rash, meningeal signs, and impaired consciousness develop late (with median onset between 13 and 22 hours) (211).

Meningococci can also cause other organ involvement, including vasculitis, conjunctivitis, endophthalmitis, otitis media, epiglottitis, pleurisy, pneumonia, myocarditis, pericarditis, urethritis, and arthritis. Pneumonia is more common with serogroups Y and W meningococcal disease than with other serotypes (37; 181).

Prognosis and complications

The case-fatality ratio for meningococcal disease is approximately 10% (general range from 6% to 14% though values as high as 17% have been reported for New York City from 1989 to 2000), and 11% to 26% of survivors have serious sequelae (76; 111; 36; 41; 185; 153; 35; 220; 19; 158; 196; 115; 160; 189; 193; 100; 103; 156).

The continued high case fatality is largely due to the rapid disease onset in susceptible hosts. Deaths typically occur within the first 24 hours of hospitalization and are generally associated with septic shock and severe cardiovascular and coagulation disturbances (35; 100). Mortality is significantly higher for meningococcal bacteremia (17%) than for meningococcal meningitis (approximately 3%) (185; 100). Risk factors for an unfavorable outcome include serogroup C infection, infants, young adult or college student status, advanced age, rapid progression with symptoms less than 24 hours, absence of rash or rash with more than 50 petechiae, low score on the Glasgow Coma Scale on admission, tachycardia, positive blood culture, severe septicemia with hypotension, elevated erythrocyte sedimentation rate, thrombocytopenia, acidosis, and a low cerebrospinal fluid white-cell count (220; 74; 196; 189; 193).

Long-term morbidities associated with bacterial meningitis and meningococcal septicemia include headache, hearing loss, neurologic disability (eg, focal neurologic deficits, seizures, cognitive impairment, etc.), neurodevelopment problems, renal failure, limb loss, skin complications (including scarring from necrosis), orthopedic problems (damage to bones and joints), and psychosocial problems (35; 100; 225; 224; 12; 77). In a systematic review, major sequelae (eg, cognitive deficit, bilateral hearing loss, seizures, motor deficit, visual impairment, hydrocephalus) occurred in approximately 7% of patients with meningococcal meningitis, with the risk greater in low-income countries (78). However, even in serogroup B meningococcal disease, which is the commonest cause of meningitis and septicemia in high-income countries, about one tenth of survivors have major disabling deficits, and more than one third have deficits in physical, cognitive, and psychological functioning (224). Chronic hearing impairment is the most common major sequela of meningococcal meningitis (78) and occurs in 8% to 15% of survivors (35; 100).

Biological basis

Etiology and pathogenesis

Neisseria meningitidis. Neisseria meningitidis is an aerobic gram-negative diplococcus with 13 different serogroups based on the antigenic characteristics of its capsular polysaccharide (ie, A, B, C, D, 29E, H, I, K, L, W-135, X, Y, and Z). The W-135 and 29E serogroup designations originated at the Walter Reed Army Institute of Research in the 1960s but were renamed as serogroups W and E, respectively, because the numbers are historic and supply no useful information (80; 98).

The strains most commonly implicated in systemic disease around the world are A, B, C, W, X, and Y (96). In the Americas, groups B, C, and Y are the most common serogroups implicated, and each account for about 30% of reported cases (180; 153; 117). North American outbreaks (as opposed to isolated cases) are confined primarily to serogroup C (less commonly to Y and W), although the frequency of serogroup Y outbreaks increased markedly during the 1990s (36; 37; 180; 120; 216; 153; 95; 229). Serogroups B and C are responsible for most cases in Europe (22; 104; 117), whereas serogroups A, C, and W135 predominate in Asia and Africa (117; 10).

Historically, serogroup A has been most often associated with epidemics in sub-Saharan Africa and also in Asia, but serogroup C was also an important cause of outbreaks in Africa in the 1980s, and serogroup W and X have emerged as causes of significant epidemics in selected African countries since 2000 (233; 89; 209; 123; 109; 122; 154; 235). Meningitis epidemics occur annually in Africa during the dry season (January to May) and stop with the first rains (123). Serogroup W caused significant epidemics in Burkina Faso and Niger in 2001 and 2002 (205; 69; 209; 229). Although serogroup X had been a rare cause of meningitis, serogroup X was responsible for significant outbreaks of meningococcal disease in Niger, Uganda, Kenya, Togo, and Burkina Faso from 2006 to 2010 (21; 235). After gradual introduction of mass vaccination with a monovalent meningococcal A conjugate vaccine beginning in 2010, serogroup A epidemics have been eliminated (31; 07; 32). However, serogroup C, W, and X meningococci continue to circulate in African meningitis belt countries and have been responsible for focal epidemics (07; 62; 81; 177; 192). Starting in 2013, the acquisition of capsule genes and virulence factors by a strain previously circulating asymptomatically in the African population led to the emergence of a virulent strain of serogroup C Neisseria meningitidis in Niger and Nigeria (31).

Mandatory meningococcal vaccination with the quadrivalent (A,C,Y,W) vaccine has prevented pilgrimage-associated meningococcal outbreaks and significantly reduced the incidence of the disease during the Hajj (236). Serogroup W emerged as an important cause of meningococcal epidemics in Saudi Arabia, especially during the Hajj, the annual Islamic pilgrimage to Mecca (Makkah) (203; 136).

By multilocus electrophoresis, hundreds of different electrophoretic types have been identified among invasive isolates, but less than 10 “hyperinvasive lineages” are responsible for most meningococcal disease worldwide (22; 199). Most strains are not pathogenic (181; 22; 199).

Colonization of the upper respiratory tract. Neisseria meningitidis commonly colonizes the upper respiratory tract and, particularly, the microvillous surface of non-ciliated columnar mucosal cells in the nasopharynx (181). Meningococcal carriage prevalence increases through childhood from approximately 5% in infants to a peak of 24% at 19 years of age and subsequently decreases in adulthood to 8% by 50 years of age (54).

Following acquisition, N meningitidis must compete against host defenses and interactions with other microbiome members to inhabit the nasopharynx mucus (149). Pathogenic meningococci associated with invasive disease have a capsule, which protects the bacteria from desiccation and host-mediated, complement-dependent bacteriolysis and phagocytosis (181). Eventual binding of N meningitidis to the epithelial surface of the nasopharynx results in passage into the submucosa by transcytosis. Binding of N meningitidis to epithelial cells occurs by interaction of bacterial surface structures with their cognate receptors, resulting in inflammation, cellular restructuring, and transcytosis (149).

Evading host defenses. To survive in the bloodstream and proceed to transcellular invasion, N meningitidis must avoid or resist antibody- and complement-mediated killing, acquire iron, and attach to the capillary endothelial surface to form microcolonies (149).

N meningitidis uses multiple mechanisms to evade host defenses and avoid being killed by antimicrobial proteins, phagocytes, and the complement system (126; 96; 127). Such strategies include mimicry of host molecules by bacterial structures (eg, capsular proteins) as well as frequent antigenic variation (126; 96; 103). The mechanisms involved in meningococcal immune evasion and resistance against complement increase in response to an increase in ambient temperature (eg, with inflammation); the increased temperature acts as a “danger signal” for the meningococcus, which responds by enhancing its defense against human immune killing (127). Unfortunately, continuous adaptation of meningococcal surface structures has produced genetic shifts of potential vaccine-target epitopes, impeding development of a universal meningococcal vaccine that could be used against all serogroups, especially serogroup B (126; 103). In addition, the alpha-2,8-linked polysialic acid capsule modifies the interaction of serogroup B meningococci with human macrophages at multiple steps, including adherence to the macrophage surface and phagosome-lysosome fusion (176).

Meningococcal adhesion and invasion. Like the binding of N meningitidis to the epithelial surface of the nasopharynx, binding of N meningitidis to endothelial cells occurs by interaction of meningococcal surface structures with their cognate receptors, resulting in cortical plaque formation, transcytosis, and breakdown of tight junctions (149).

Bacterial outer membrane components are related to meningococcal adhesion and invasion. Bacterial capsular adhesion molecules (including pili and opacity-associated proteins Opa and Opc) are responsible for binding specific human membrane proteins.

Bacterial type IV pili—long retractile fibers with a diameter of 6 nm—are necessary both for adhesion to human cells and for plasma membrane remodeling (53). Remodeling of the plasma membrane of endothelial cells by N meningitidis during the blood phase of meningococcal infection is tightly linked to the amount of type IV pili expressed by the bacteria. Plasma membrane remodeling occurs independently of F-actin, along meningococcal type IV pili fibers (53).

N meningitidis produces type IV pili as a meshwork of fibers. On adhesion to the host endothelial cell, the high adhesiveness of type IV pili enables "one-dimensional membrane wetting" of the plasma membrane, thus, remodeling the membrane alongside the type IV pili fibers. As the bacteria proliferate and aggregate extracellularly, plasma membrane protrusions remain attached to type IV pili fibers and end up embedded in a dense extracellular type IV pili meshwork that provides the microcolony with sufficient mechanical coherence to resist blood flow–generated shear stress (53).

Expression of a specific human carcinoembryonic antigen-related cell adhesion molecule (CEACAM1) is necessary for binding the neisserial Opa protein adhesions, and for establishing intranasal colonization with Neisseria meningitides (114). Binding stimulates bacterial engulfment by mucosal epithelial cells, and subsequent passage of bacteria through the mucosa in phagocytic vacuoles (181). Meningococcal vascular adhesion is restricted to capillaries that exhibit transient reductions in flow (131). Initial adhesion of pathogenic strains of Neisseria meningitidis to endothelial cells relies on meningococcal type IV pili (17). The immunoglobulin superfamily member CD147, which is also known as extracellular matrix metalloproteinase inducer (EMMPRIN), is a critical host receptor for the meningococcal pilus components PilE and PilV (17). Interrupting the interaction of this endothelial receptor for bacterial adhesion potently inhibits the attachment of meningococci to human endothelial cells in vitro and prevents colonization of vessels in human brain tissue explants ex vivo and in mice in vivo (17).

Following pilus-mediated adhesion to human brain endothelial cells, N meningitidis initiates signaling cascades, which facilitate opening of intercellular junctions, allowing meningeal colonization (65). N meningitidis specifically stimulates a beta-2-adrenoceptor/beta-arrestin signaling pathway in endothelial cells, which traps beta-arrestin-interacting partners (eg, the Src tyrosine kinase and junctional proteins) under bacterial colonies; these in turn mediate cytoskeletal reorganization, which stabilizes bacterial adhesion to endothelial cells, and produce anatomical gaps used by bacteria to penetrate into tissues (65). Mutations in the N meningitidis surface-exposed proteins glyceraldehyde 3-phosphate dehydrogenase (GapA-1) and fructose-1, 6-bisphosphate aldolase also significantly affect the ability of the bacterium to adhere to human epithelial and endothelial cells (214; 215).

During meningococcal sepsis, Neisseria meningitidis accumulates in large organs (29).

Genetic traits of Neisseria meningitidis linked to phenotypic outcomes (ie, invasive meningococcal disease or carriage) have been identified (79): one gene and one non-synonymous single nucleotide polymorphism (SNP) were associated with invasive disease, and seven genes and one non-synonymous SNP were associated with carriage isolates. The gene associated with invasive disease encodes a phage transposase (NEIS1048), and the associated invasive SNP glmU S373C encodes the enzyme N-acetylglucosamine 1-phosphate (GlcNAC 1-P) uridyltransferase. In the genes fkbp, glmU, PilC, and pilE, k-mers were found that were associated with both carriage and invasive isolates, indicating that specific variations within these genes could play a role in invasiveness.

Bacterium-host interactions. Bacterium-host interactions are key determinants of the clinical course and risk of fatal outcomes. The interaction of meningococci with host endothelial cells is mediated by type IV pili, which are responsible for the formation of microcolonies on the apical surfaces of the cells (pili are hairlike appendages on the bacterial surface, and type IV pili, in particular, can generate motile forces that can pull the bacteria forward like a grappling hook, so-called twitching motility) (64). A low level of bacteremia favors colonization of brain blood vessels and development of meningitis, whereas colonization of many blood vessels during high-level bacteremia results in septic shock and purpura fulminates (64). In the bloodstream, meningococci release a lipo-oligosaccharide endotoxin (structurally distinct from the endotoxin of enteric gram-negative bacteria) and other cell-wall components, which stimulate cytokine production and induce the inflammatory cascade (181). Toll-like receptor 9 (TLR9) recognizes bacterial DNA leading to intracellular inflammatory signaling, and specific TLR9 single nucleotide polymorphisms are associated with susceptibility to meningococcal meningitis (183).

High-frequency changes have been identified in pilin glycosylation patterns during Neisseria meningitidis serogroup A meningitis outbreaks in the African meningitis belt, which suggests that variation in N meningitidis protein glycosylation could be crucial for bacterial adaptation to evade herd immunity in semi-immune populations (112).

Serum bactericidal activity is dependent on the complement system (especially C2 and C5) and high antibody titers (101; 206). Therefore, terminal complement component defects and alterations in complement regulators are associated with an increased risk of developing N meningitidis infections (101). The polysaccharide capsule protects against complement-mediated bacterial killing, opsonization, and phagocytosis (206). In addition, during invasive disease, N meningitidis releases the contents of outer membrane vesicles into the bloodstream: these contents include lipo-oligosaccharide and outer-membrane proteins that confound the immune response to the bacteria (206).

After N meningitidis infection, convalescent patients develop a natural long-lasting cross-protective immunity, but the antigens that mediate this response have not been fully identified (147). One potential such antigen, GNA2132, is an N meningitidis protein of unknown function discovered by reverse vaccinology (188). GNA2132 has been shown to induce bactericidal antibodies in animal models, to induce protective immunity in humans, and to be recognized by sera of patients after meningococcal disease; because the protein binds heparin in vitro and because this property correlates with increased survival of the unencapsulated bacterium in human serum, the protein was renamed “Neisserial heparin binding antigen.”

Alternate routes of entry into CNS. N meningitidis readily infects trigeminal Schwann cells (the glial cells of the trigeminal nerve) (71). Infection of trigeminal Schwann cells may be one mechanism by which N meningitidis can invade the CNS. Infection of trigeminal Schwann cells leads to multinucleation and the appearance of atypical nuclei, with progressive increases over time in the presence of horseshoe nuclei and the budding of nuclei (71).

Meningitis and secondary brain complications. Meningococcal meningitis produces a purulent exudate over the surface of the brain and spinal cord. Leptomeningeal inflammatory infiltrates consist of neutrophilic granulocytes.

The inflammatory response produced to eradicate infectious pathogens can have further negative consequences, including ischemic stroke. Bacterial virulence factors and pathogen-associated molecular reactions cause direct damage to the blood-brain barrier and activate leukocytes to respond to the infection. Cytokine release further damages the blood-brain barrier, leads to neuronal death, and activates the coagulation cascade through the complement system. This inflammatory response causes vasculopathy and promotes coagulation of cerebral blood vessels, leading to cerebral ischemia.

Epidemiology

Humans are the only natural reservoir of Neisseria meningitidis. N meningitidis is essentially a human commensal, with the great majority of infections producing harmless nasopharyngeal colonization rather than invasive disease (104; 199; 126; 103; 206). Meningococci are transmitted person-to-person through respiratory droplets. Nasal carriage rates average about 8% to 15% (84; 181), but some studies report yields of more than 30% with nasopharyngeal swabs (165). There is a low prevalence of carriage in saliva (less than 1%), indicating that saliva contact is unlikely to transmit meningococci (165). Although meningococci can be transmitted throughout the year, most cases in developed countries occur during the winter and early spring (181; 160; 189).

Most cases of invasive disease occur in children and young adults (111; 185). The highest rates are among infants under 6 months of age, who have the lowest serum bactericidal antibody titers because they do not have meningococcal-specific maternal bactericidal antibodies (206). Although rates of disease are highest among children under 2 years of age (and especially in infants younger than 6 months), almost two thirds of meningococcal disease in the United States occurs in those older than 10 years. Infants under 1 year of age have the highest incidence of meningococcal disease (5.38 cases per population of 100,000) (55). Adolescents and young adults continue to have the second-highest disease incidence from N meningitidis infection (27).

Worldwide there are 1.2 million cases of invasive meningococcal disease, with some 135,000 deaths annually.

Meningococcal disease is the leading infectious cause of death in early childhood (171).

Even though the incidence of invasive meningococcal disease is declining in some populations, there has been an opposing trend of decreasing rates of penicillin susceptibility (18).

As part of the Global Burden of Disease Study 2019, the global, regional, and national burden of meningitis and its etiologies were evaluated for 1990 to 2019 (88). In 2019, there were an estimated 236,000 deaths and 2.51 million incident cases due to meningitis globally; the burden was greatest in children younger than 5 years old, with 112,000 deaths and 1.28 million incident cases. Tremendous variation exists in regional risks from meningitis in children younger than 5 years old. Age-standardized mortality rates decreased from 7.5 per 100,000 population in 1990 to 3.3 per 100,000 population in 2019. The proportion of total all-age meningitis deaths in 2019 attributable to N meningitidis was 13.6%. Between 1990 and 2019, the number of deaths due to N meningitidis among children younger than 5 years old declined by 72%, but N meningitidis still accounts for the most cases of bacterial meningitis in this age group and the second-highest number of deaths from bacterial meningitis in this age group (after Streptococcus pneumoniae).

Risk factors for invasive meningococcal disease. Risk factors for invasive meningococcal disease are outlined in the table below (38; 40; 41; 83; 57; 181; 120; 216; 199; 232; 201; 91; 75).

Table 1. Risk Factors for Invasive Meningococcal Disease

Meningococcal serogroup trends. In non-African countries over the 50-year period from 1966 to 2017, the predominant serogroup in most outbreaks was serogroup C (61%), followed by serogroup B (29%), serogroup A (5%), and serogroup W135 (4%) (223). Outbreaks showed a peak in the colder months of both the northern and southern hemispheres (223). In Eastern Europe, the predominate serogroups are B and C, followed by A, and cases attributable to serogroups W, X and Y are emerging (14; 23).

Serogroups B, C, and Y are the major causes of meningococcal disease in the United States, with each responsible for about one third of cases (19). However, the proportion of cases caused by each serogroup varies by age. Among infants, most cases are caused by serogroup B (19). In contrast, for persons older than 10 years, more than three quarters of cases are caused by serogroups C, Y, or W, all of which are included in licensed vaccines in the United States (19). In 2016, a serogroup C meningococcal disease outbreak occurred in Southern California, primarily affecting homosexual men (157).

From 2014 to 2018, 822 cases of serogroup A, C, W, and Y meningococcal disease were reported in the Netherlands, of which 34 (4%) were in patients who previously received at least one dose of MenACWY vaccine (23 were up to date on MenACWY vaccine, per recommendations) (20). A significantly higher proportion of vaccinated patients were people living with HIV compared to unvaccinated patients. Eight of the 34 vaccinated patients were immunosuppressed, including five with HIV, one taking eculizumab, and two taking other immunosuppressive medications.

Key aspects of recent global meningococcal disease epidemiology include the following: (1) Serogroups A, B, C, W, and Y remain dominant, but there have been recent global increases in serogroup W disease, meningococcal antimicrobial resistance, and meningococcal urethritis; (2) Unvaccinated populations have experienced disease resurgences following the lifting of COVID-19 restrictions; (3) Elevated invasive meningococcal disease rates are seen among infants and young children, adolescents/young adults, and older adults; and (4) Demonstrably effective vaccines against all five major disease-causing serogroups are available, and their prophylactic use is effective against invasive meningococcal disease, including cases with antimicrobial resistance (23).

United States. The incidence of meningococcal disease peaks in late winter to early spring (01). Attack rates are highest among infants 3 to 12 months of age.

The annual incidence in the United States decreased from 0.92 cases per population of 100,000 in 1998 to 0.33 cases per 100,000 in 2007 (55). Before the introduction of the quadrivalent meningococcal conjugate vaccine, the incidence of meningococcal disease in the United States decreased to a historic low, but no further significant decrease in serogroup C or Y meningococcal disease has been observed after the introduction of the quadrivalent meningococcal conjugate vaccine among those aged 11 to 19 years (ie, when assessed for 2006 to 2007, compared with 2004 to 2005) (55).

The vast majority of cases (95% to 98%) are sporadic (104; 19). However, outbreaks of meningococcal disease in the United States have been occurring with increasing frequency since 1990 (19). Meningococcal disease outbreaks are particularly likely in semi-closed communities, such as daycare centers, schools, colleges, nursing homes, and military recruit camps (22; 19). Almost all secondary cases in an outbreak occur within 8 days of the index case (104).

The emergence of beta-lactamase-positive and ciprofloxacin-resistant meningococci in the United States is a major concern (13).

In 2022, concurrent outbreaks of invasive meningococcal disease, hepatitis A, and mpox were identified in Florida, primarily among men who have sex with men (73). The invasive meningococcal disease outbreak in Florida involved 44 cases and was associated with Neisseria meningitidis serogroup C (sequence type 11, clonal complex 11). In comparison, the hepatitis A outbreak in Florida involved 153 cases and the mpox outbreak in Florida involved 2845 cases. The invasive meningococcal disease and hepatitis A outbreaks were concentrated in Central Florida and peaked from March to June, whereas the mpox cases were more heavily concentrated in South Florida and had a peak incidence in August. HIV infection was more common among mpox cases (52%) than among invasive meningococcal disease (34%) or hepatitis A (21%) cases.

Europe. Incidence rates are higher in Europe (1.01 per population of 100,000 per year) than in the United States, but some European countries have also documented a declining incidence of invasive meningococcal disease as a consequence of improved vaccines (particularly with the introduction of effective meningococcal conjugate vaccines in the 1990s) or broader penetration of vaccination (18; 132; 164).

Patients admitted to hospitals for invasive meningococcal disease between 2014 and 2016 were selected from the French hospital discharge database (107). Of the 1344 patients identified, about 30% of cases were in children younger than 5 years old and 25% in children aged 10 to 24 years. There is a seasonal variation in the incidence of meningococcal meningitis, with cases increasing in March and April (107). Most patients presented with meningococcal meningitis (59%), 25% with meningococcemia, and 9% with both. The case fatality rate during the index hospitalization was 6%. About 15% of patients had at least one sequela at hospital discharge.

In Spain, the average hospitalization rate for meningococcal infection was 1.64 hospitalizations per 100,000 inhabitants from 1997 through 2018, with a significant declining trend over that interval (226). Hospitalization rates of meningococcal infection, meningococcal meningitis, and meningococcemia all declined from 1997 to 2018. Hospitalizations for meningococcal infection decreased significantly with increasing age and were concentrated in young children, with almost half (46%) in children under 5 years of age (46%). The hospitalization rates reached 29 per 100,000 and 24 per 100,000 in children under 1 and 2 years of age, respectively. The case fatality rates overall were 7.5% for meningococcal infection, 4.0% for meningococcal meningitis, and 9.6% for meningococcemia. Case fatality rates increased with increasing age. Thirty percent of the deaths occurred in children under 5 years of age, and more than half occurred in adults.

In Italy, admissions for invasive meningococcal disease continue to be highest for infants, but this group has seen steady declines from 2015 to 2019 (208). The percentage of hospitalized patients who died from “meningeal syndrome” remained below 5% from 2015 to 2019, although the trend is worsening, whereas the percentage of hospitalized patients who died from “septic shock” with or without meningitis has been between 10% to 25% from 2015 to 2019, with 2019 being the worst year.

Southeastern European countries (Croatia, the Czech Republic, Greece, Hungary, Poland, Romania, Serbia, Slovenia, and Ukraine) had lower vaccination rates than the European average (217). The age distribution of invasive meningococcal disease cases was highest in infants and children, and most of these countries also had a further peak in adolescents and young adults. Across these nine countries between 2010 and 2020, the largest contributors to invasive meningococcal disease were serogroups B and C.

Africa. The major burden of invasive meningococcal disease is in nonindustrialized countries: in particular, Africa has been, and remains, the continent most affected by invasive meningococcal disease. Formerly heavily concentrated in the region of the "meningitis belt" of sub-Saharan Africa, invasive meningococcal disease now extends outside of its historical limits, involving more forested regions in the central and southern parts of the continent (eg, Burundi, Rwanda, the Republic of Tanzania in the Greater Lakes area, and South Africa) (01; 229; 137; 143).

In Africa, in the interval from 1928 to 2018 (excluding 1948–1957, years for which data were unavailable), very high case counts (> 50,000) occurred in 1946, 1970, 1978, 1981, 1986, 1988–89, 1991–2, 1995–7, 2003, and 2009 (137). Very high death counts (> 5000) occurred in 1945–6, 1996–7, and 2003. Death counts were extremely high (> 15,000) in 1945, 1996, and 2003. Very high rates occurred in the meningitis belt but extended well beyond it during some periods (137).

Outside of the African meningitis belt, case counts were below 70,000 for all countries in the interval from 1928 to 2018 (excluding 1948–1957, years for which data were unavailable) but were highest in Ghana and RD-Congo (République démocratique du Congo, or the Democratic Republic of Congo) (137). Death counts were also highest in these two countries, although the case fatality rate was higher in RD-Congo than in Ghana.

Among cases of meningococcal meningitis in Africa from 2000 to 2017, the most common serotypes were (in descending order) W, C, A, and X (137).

Table 2. Confirmed Cases of Meningitis and the Responsible Pathogens, Africa, 2000 to 2017

Serotypes W and C together accounted for almost half (48%) of all meningitis cases in Africa in this interval, with the remainder as follows: S pneumoniae (24%), other serotypes of N meningitidis (19%), H influenza (3%), and other (5%). In Africa during the 20th century, serogroup A was responsible for up to 80% to 85% of meningococcal meningitis cases, but since 2000, other serogroups (including W, X, and C) have also been responsible for epidemics (137). The distribution of pathogens changed after the introduction of the MenAfrivac vaccine, which targeted N meningitidis serotype A (developed for use in sub-Saharan Africa for children and adults between 9 months and 29 years of age) (137). The impact of the MenAfrivac vaccine on the distribution of responsible pathogens within the African meningitis belt can also be seen spatially.

The African “meningitis belt.” Peak incidence rates of invasive meningococcal disease approach 1000 per 100,000 per year in the "African meningitis belt" of sub-Saharan Africa (144; 206). In the “meningitis belt,” outbreaks of serogroup A meningitis usually start in the dry season (28; 123; 109). Large epidemic waves occur in this area with a periodicity of 5 to 14 years, corresponding to molecular changes in the expression of capsular or subcapsular antigens (209; 109). The last large-scale meningitis epidemic in the African meningitis belt occurred in 2009 with 80,000 cases and 4300 deaths (10). During the 2013 epidemic season from January through June, there were 12,464 suspected meningitis cases and 1131 deaths (case fatality rate of 9.1%) reported from 18 African countries (10). The irregular timing of meningitis epidemics results from the interaction between changes in immunity and seasonal changes in the transmissibility of infection (