Infection with Neisseria meningitidis most commonly manifests as asymptomatic colonization in the nasopharynx of healthy adolescents and adults. Invasive disease occurs rarely, usually presenting as either bacterial meningitis or meningococcal septicemia. Patients may also present with occult bacteremia, pneumonia, septic arthritis, conjunctivitis, and chronic meningococcemia.
Etiology and Microbiology
N. meningitidis is a gram-negative aerobic diplococcus that colonizes humans only and that causes disease after transmission to a susceptible individual. Several related organisms have been recognized, including the pathogen N. gonorrhoeae and the commensals N. lactamica, N. flavescens, N. mucosa, N. sicca, and N. subflava . N. meningitidis is a catalase- and oxidase-positive organism that utilizes glucose and maltose to produce acid.
Meningococci associated with invasive disease are usually encapsulated with polysaccharide, and the antigenic nature of the capsule determines an organism's serogroup (Table 143-1). In total, 13 serogroups have been identified (A–D, X–Z, 29E, W135, H–J, and L), but just 5 serogroups—A, B, C, Y, and W135—account for the majority of cases of invasive disease. Acapsular meningococci are commonly isolated from the nasopharynx in studies of carriage; the lack of capsule often is a result of phase variation of capsule expression, but as many as 16% of isolates lack the genes for capsule synthesis and assembly. These “capsule-null” meningococci and those that express capsules other than A, B, C, Y, and W135 are only rarely associated with invasive disease and are most commonly identified in the nasopharynx of asymptomatic carriers.
Table 143-1 Structure of the Polysaccharide Capsule of Common Disease-Causing Meningococci |Favorite Table|Download (.pdf)
Table 143-1 Structure of the Polysaccharide Capsule of Common Disease-Causing Meningococci
|Meningococcal Serogroup||Chemical Structure of Oligosaccharide||Current Disease Epidemiology|
|A||2-Acetamido-2-deoxy-D-mannopyranosyl phosphate||Epidemic disease mainly in sub-Saharan Africa; sporadic cases worldwide|
|B||α-2,8-N-acetylneuraminic acid||Sporadic cases worldwide; propensity to cause hyperendemic disease|
|C||α-2,9-O-acetylneuraminic acid||Small outbreaks and sporadic disease|
|Y||4-O-α-D-glucopyranosyl-N-acetylneuraminic acid||Sporadic disease and occasional small institutional outbreaks|
|W135||4-O-α-D-galactopyranosyl-N-acetylneuraminic acid||Sporadic disease; outbreaks of disease associated with mass gatherings; epidemics in sub-Saharan Africa|
Beneath the capsule, meningococci are surrounded by an outer phospholipid membrane containing lipopolysaccharide (LPS, endotoxin) and multiple outer-membrane proteins (Figs. 143-1 and 143-2). Antigenic variability in porins expressed in the outer membrane defines the serotype (PorB) and serosubtype (PorA) of the organism, and structural differences in LPS determine the immunotype. Serologic methods for typing of meningococci are restricted by the limited availability of serologic reagents that can distinguish among the organisms′ highly variable surface proteins. Where available, high-throughput antigen gene sequencing has superseded serology for meningococcal typing. A large database of antigen gene sequences for the outer-membrane proteins PorA, PorB, FetA, Opa, and factor H–binding protein is available online (www.neisseria.org). The number of specialized iron-regulated proteins found in the meningococcal outer membrane (e.g., FetA and transferrin-binding proteins) highlights the organisms′ dependence on iron from human sources. A thin peptidoglycan cell wall separates the outer membrane from the cytoplasmic membrane.
Electron micrograph of Neisseria meningitidis. Black dots are gold-labeled polyclonal antibodies binding surface opacity proteins. Blebs of outer membrane can be seen being released from the bacterial surface (see arrow). (Photo courtesy of D. Ferguson, Oxford University.)
Cross-section through surface structures of Neisseria meningitidis. (Reprinted with permission from Sadarangani and Pollard, 2010.)
The structure of meningococcal populations involved in local and global spread has been studied with multilocus enzyme electrophoresis (MLEE), which characterizes isolates according to differences in the electrophoretic mobility of cytoplasmic enzymes. However, this technique has mostly been replaced by multilocus sequence typing (MLST), in which meningococci are characterized by sequence types assigned on the basis of sequences of internal fragments of seven housekeeping genes. The online MLST database currently includes more than 13,000 meningococcal isolates and 7600 unique sequence types (http://pubmlst.org/neisseria/). Seven hyperinvasive lineages of N. meningitidis have been identified and are responsible for the majority of cases of invasive meningococcal disease worldwide. The apparent genetic stability of these meningococcal clones over decades and during wide geographic spread indicates that they are well adapted to the nasopharyngeal environment of the host and to efficient transmission.
The group B meningococcal genome is >2 megabases in length and contains 2158 coding regions. Many genes undergo phase variation that makes it possible to control their expression; this capacity is likely to be important in meningococcal adaptation to the host environment and evasion of the immune response. Meningococci can obtain DNA from their environment and can acquire new genes—including the capsular operon—such that a switch from one serogroup to another can occur.
Up to 500,000 cases of meningococcal disease are thought to occur worldwide each year, and ∼10% of the individuals affected die. There are several patterns of disease: epidemic, outbreak (small clusters of cases), hyperendemic, and sporadic or endemic.
Epidemics have continued since the original descriptions of meningococcal disease, especially affecting the sub-Saharan meningitis belt of Africa, where tens to hundreds of thousands of cases (caused mainly by serogroup A but also by serogroups W135 and X) may be reported over a season and rates may be as high as 1000 cases per 100,000 population. Serogroup A epidemics took place in Europe and North America after the First and Second World Wars, and serogroup A outbreaks have been documented over the past 30 years in New Zealand, China, Nepal, Mongolia, India, Pakistan, Poland, and Russia.
Clusters of cases occur where there is an opportunity for increased transmission—i.e., in (semi-)closed communities such as schools, colleges, universities, military training centers, and refugee camps. Recently, such clusters have been especially strongly linked with a particular clone (sequence type 11) that is mainly associated with the serogroup C capsule. Wider and more prolonged community outbreaks (hyperendemic disease) due to single clones of serogroup B meningococci account for ≥10 cases per 100,000. Regions affected in the past decade include the U.S. Pacific Northwest, New Zealand (both islands), and the province of Normandy in France.
Most countries now experience predominantly sporadic cases (0.3–5 cases per 100,000 population), with many different disease-causing clones involved and usually no clear epidemiologic link between one case and another. The disease rate and the distribution of meningococcal strains vary in different regions of the world and also in any one location over time. For example, in the United States, the rate of meningococcal disease fell from 1.2 cases per 100,000 population in 1997 to <0.4 case per 100,000 in 2007 (Fig. 143-3). Meningococcal disease in this country was previously dominated by serogroups B and C; however, serogroup Y emerged during the 1990s and became more common than serogroup C in 2007. In contrast, rates of disease in England and Wales rose to >5 cases per 100,000 during the 1990s because of an increase in cases caused by the ST11 serogroup C clone. As a result of a mass immunization program against serogroup C in 1999, almost all cases in the United Kingdom are now attributed to serogroup B (Fig. 143-4).
Meningococcal disease in the United States over time. (Adapted from ABC Surveillance data, Centers for Disease Control and Prevention; www.cdc.gov.)
Global distribution of meningococcal serogroups, 1999–2009.
Factors Associated with Disease Risk and Susceptibility
The principal determinant of disease susceptibility is age, with the peak incidence in the first year of life (Fig. 143-5). The susceptibility of the very young presumably results from an absence of specific adaptive immunity in combination with very close contact with colonized individuals, including parents. Compared with other age groups, infants appear to be particularly susceptible to serogroup B disease: >30% of serogroup B cases in the United States occur during the first year of life. In the early 1990s in North America, the median ages for patients with disease due to serogroups B, C, Y, and W135 were 6, 17, 24, and 33 years, respectively.
Age distribution of serogroups B and C meningococcal disease in England and Wales, 1998/1999. (Health Protection Agency, UK; www.hpa.org.uk.)
After early childhood, a second peak of disease occurs in adolescents and young adults (15–25 years of age) in Europe and North America. It is thought that this peak relates to social behaviors and environmental exposures in this age group, as discussed below. Most cases of infection with N. meningitidis in developed countries today are sporadic, and the rarity of the disease suggests that individual susceptibility may be important. A number of factors probably contribute to individual susceptibility, including the host's genetic constitution, environment, and contact with a carrier or a case.
The best-documented genetic association with meningococcal disease is complement deficiency, chiefly of the terminal complement components (C5–9), properdin, or factor D; such a deficiency increases the risk of disease by up to 600-fold and may result in recurrent attacks. Complement components are believed to be important for the bactericidal activity of serum, which is considered the principal mechanism of immunity against invasive meningococcal disease. However, when investigated, complement deficiency is found in only a very small proportion of individuals with meningococcal disease (0.3%). Conversely, 7–20% of persons whose disease is caused by the less common serogroups (W135, X, Y, Z, 29E) have a complement deficiency. Complement deficiency appears to be associated with serogroup B disease only rarely. Individuals with recurrences of meningococcal disease, particularly those caused by non-B serogroups, should be assessed for complement deficiency by measurement of total hemolytic complement activity. There is also limited evidence that hyposplenism (through reduction in phagocytic capacity) and hypogammaglobulinemia (through absence of specific antibody) increase the risk of meningococcal disease. Genetic studies have revealed various associations with disease susceptibility, including complement and mannose-binding lectin deficiency, single-nucleotide polymorphisms in Toll-like receptor (TLR) 4 and complement factor H, and variants of Fc gamma receptors.
Factors that increase the chance of a susceptible individual acquiring N. meningitidis via the respiratory route also increase the risk of meningococcal disease. Acquisition occurs through close contact with carriers as a result of overcrowding (e.g., in poor socioeconomic settings, in refugee camps, during the Hajj pilgrimage to Mecca, and during freshman-year residence in college dormitories) and certain social behaviors (e.g., attendance at bars and nightclubs, kissing). Secondary cases may occur in close contacts of an index case (e.g., household members and persons kissing the infected individual); the risk to these contacts may be as high as 1000 times the background rate in the population. Factors that damage the nasopharyngeal epithelium also increase the risk of both colonization with N. meningitidis and invasive disease. The most important of these factors are cigarette smoking (odds ratio, 4.1) and passive exposure to cigarette smoke. In addition, recent viral respiratory tract infection, infection with Mycoplasma species, and winter or the dry season have been associated with meningococcal disease; all of these factors presumably either increase the expression of adhesion molecules in the nasopharynx, thus enhancing meningococcal adhesion, or facilitate meningococcal invasion of the bloodstream.
N. meningitidis has evolved as an effective colonizer of the human nasopharynx, with asymptomatic infection rates of >25% described in some series of adolescents and young adults and among residents of crowded communities. Point-prevalence studies reveal widely divergent rates of carriage for different types of meningococci. This variation suggests that some types may be adapted to a short duration of carriage with frequent transmission to maintain the population, while others may be less efficiently transmitted but may overcome this disadvantage by colonizing for a long period. Despite the high rates of carriage among adolescents and young adults, only ∼10% of adults carry meningococci, and colonization is very rare in early childhood. Many of the same factors that increase the risk of meningococcal disease also increase the risk of carriage, including smoking, crowding, and respiratory viral infection. Colonization of the nasopharynx involves a series of interactions of meningococcal adhesins (e.g., Opa proteins and pili) with their ligands on the epithelial mucosa. N. meningitidis produces an IgA1 protease that is likely to reduce interruption of colonization by mucosal IgA.
Colonization should be considered the normal state of meningococcal infection, with an increased risk of invasion the unfortunate consequence (for both host and organism) of adaptations of hyperinvasive meningococcal lineages. The meningococcal capsule is an important virulence factor: acapsular strains rarely cause invasive disease. The capsule provides resistance to phagocytosis and may be important in preventing desiccation during transmission between hosts. Antigenic diversity in surface structures and an ability to vary levels of their expression have probably evolved as important factors in maintaining meningococcal populations within and between individual hosts.
Invasion through the mucosa into the blood occurs rarely, usually within a few days of acquisition of an invasive strain by a susceptible individual. Only occasional cases of prolonged colonization prior to invasion have been documented. Once the organism is in the bloodstream, its growth may be limited if the individual is partially immune, although bacteremia may allow seeding of another site, such as the meninges or the joints. Alternatively, unchecked proliferation may continue, resulting in high bacterial counts in the circulation. During growth, meningococci release blebs of outer membrane (Fig. 143-1) containing outer-membrane proteins and endotoxin (LPS). Endotoxin binds cell-bound CD14 in association with TLR4 to initiate an inflammatory cascade with the release of high levels of various mediators, including tumor necrosis factor α, soluble tumor necrosis factor receptor, interleukin (IL) 1, IL-1 receptor antagonist, IL-1β, IL-6, IL-8, IL-10, plasminogen-activator inhibitor 1 (PAI-1), and leukemia inhibitory factor. Soluble CD14-bound endotoxin acts as a mediator of endothelial activation. The severity of meningococcal disease is related both to the levels of endotoxin in the blood and to the magnitude of the inflammatory response. The latter is determined to some extent by polymorphisms in the inflammatory response genes (and their inhibitors), and the release of the inflammatory cascade heralds the development of meningococcal septicemia (meningococcemia). Endothelial injury is central to many clinical features of meningococcemia, including increased vascular permeability, pathologic changes in vascular tone, loss of thromboresistance, intravascular coagulation, and myocardial dysfunction. Endothelial injury leads to increased vascular permeability (attributed to loss of glycosaminoglycans and endothelial proteins), with subsequent gross proteinuria. Leakage of fluid and electrolytes into the tissues from capillaries leads to hypovolemia, tissue edema, and pulmonary edema. Initial compensation results in vasoconstriction and tachycardia, although cardiac output eventually falls. While resuscitation fluids may restore circulating volume, tissue edema will continue to increase, and, in the lung, the consequence may be respiratory failure.
Intravascular thrombosis (caused by activation of procoagulant pathways in association with upregulation of tissue factor on the endothelium) occurs in some patients with meningococcal disease and results in purpura fulminans and infarction of areas of skin or even of whole limbs. At the same time, multiple anticoagulant pathways are downregulated through loss of endothelial thrombomodulin and protein C receptors and decreases in levels of antithrombin III, protein C, protein S, and tissue factor pathway inhibitor. Thrombolysis is also profoundly impaired in meningococcal sepsis through the release of high levels of PAI-1.
Shock in meningococcal septicemia appears to be attributable to a combination of factors, including hypovolemia, which results from the capillary leak syndrome secondary to endothelial injury, and myocardial depression, which is driven by hypovolemia, hypoxia, metabolic derangements (e.g., hypocalcemia), and cytokines (e.g., IL-6). Decreased perfusion of tissues as a result of intravascular thrombosis, vasoconstriction, tissue edema, and reduced cardiac output in meningococcal septicemia can cause widespread organ dysfunction, including renal impairment and—later in the disease—a decreased level of consciousness due to central nervous system involvement.
Bacteria that reach the meninges cause a local inflammatory response, with release of a spectrum of cytokines similar to that seen in septicemia, that presents clinically as meningitis and is believed to determine the severity of neuronal injury. Local endothelial injury may result in cerebral edema and rapid onset of raised intracranial pressure in some cases.
As discussed above, the most common form of infection with N. meningitidis is asymptomatic carriage of the organism in the nasopharynx. Despite the location of infection in the upper airway, meningococcal pharyngitis is rarely reported; however, upper respiratory tract symptoms are common prior to presentation with invasive disease. It is not clear whether these symptoms relate to preceding viral infection (which may promote meningococcal acquisition) or to meningococcal acquisition itself. After acquiring the organism, susceptible individuals develop disease manifestations in 1–10 days (usually <4 days, although colonization for 11 weeks has been documented).
Along the spectrum of presentations of meningococcal disease, the most common clinical syndromes are meningitis and meningococcal septicemia. In fulminant cases, death may occur within hours of the first symptoms. Occult bacteremia is also recognized and, if untreated, progresses in two-thirds of cases to focal infection including meningitis or septicemia. Meningococcal disease may also present as pneumonia, pyogenic arthritis or osteomyelitis, purulent pericarditis, endophthalmitis, conjunctivitis, primary peritonitis, or (rarely) urethritis. Perhaps because it is difficult to diagnose, pneumococcal pneumonia is not commonly reported but is associated with serogroups Y, W135, and Z and appears most often to affect individuals >10 years of age.
A nonblanching rash (petechial or purpuric) develops in >80% of cases of meningococcal disease; however, the rash is often absent early in the illness. Usually initially blanching in nature (macules, maculopapules, or urticaria) and indistinguishable from more common viral rashes, the rash of meningococcal infection becomes petechial or frankly purpuric over the hours after onset. In the most severe cases, large purpuric lesions develop (purpura fulminans). Some patients (including those with overwhelming sepsis) may have no rash. While petechial rash and fever are important signs of meningococcal disease, fewer than 10% of children (and, in some clinical settings, fewer than 1% of patients) with this presentation are found to have meningococcal disease. Most patients presenting with a petechial or purpuric rash have a viral infection (Table 143-2). The skin lesions exhibit widespread endothelial necrosis and occlusion of small vessels in the dermis and subcutaneous tissues, with a neutrophilic infiltrate.
Table 143-2 Common Causes of Petechial or Purpuric Rashes |Favorite Table|Download (.pdf)
Table 143-2 Common Causes of Petechial or Purpuric Rashes
|Influenza and other respiratory viruses|
|Deficiency of protein C or S (including postvaricella protein S deficiency)|
|Platelet disorders (e.g., idiopathic thrombocytopenic purpura, drug effects, bone marrow infiltration)|
|Henoch-Schönlein purpura, connective tissue disorders, trauma (including nonaccidental injuries in children)|
|Pneumococcal, streptococcal, staphylococcal, or gram-negative bacterial sepsis|
Meningococcal meningitis commonly presents as nonspecific manifestations, including fever, vomiting, and (especially in infants and young children) irritability, and is indistinguishable from other forms of bacterial meningitis unless there is an associated petechial or purpuric rash, which occurs in two-thirds of cases. Headache is rarely reported in early childhood but is more common in later childhood and adulthood. When headache is present, the following features, in association with fever or a history of fever, are suggestive of bacterial meningitis: neck stiffness, photophobia, decreased level of consciousness, seizures or status epilepticus, and focal neurologic signs. Classic signs of meningitis, such as neck stiffness and photophobia, are often absent in infants and young children with bacterial meningitis.
While 30–50% of patients present with a meningitis syndrome alone, up to 40% of meningitis patients also present with some features of septicemia. Most deaths from meningococcal meningitis alone (i.e., without septicemia) are associated with raised intracranial pressure presenting as a reduced level of consciousness, relative bradycardia and hypertension, focal neurologic signs, abnormal posturing, and signs of brainstem involvement—e.g., unequal, dilated, or poorly reactive pupils; abnormal eye movement; and impaired corneal responses (Chap. 274).
Meningococcal septicemia alone accounts for up to 20% of cases of meningococcal disease. The condition may progress from early nonspecific symptoms to death within hours. Mortality rates among children with this syndrome have been high (25–40%), but aggressive management (as discussed below) may reduce the figure to <10%. Early symptoms are nonspecific and suggest an influenza-like illness with fever, headache, and myalgia accompanied by vomiting and abdominal pain. As discussed above, the rash, if present, may appear to be viral early in the course until petechiae or purpuric lesions develop. Purpura fulminans occurs in severe cases, with multiple large purpuric lesions and signs of peripheral ischemia. Surveys of patients have indicated that limb pain, pallor (including a mottled appearance and cyanosis), and cold hands and feet may be prominent. Shock is manifested by tachycardia, poor peripheral perfusion, tachypnea, and oliguria. Decreased cerebral perfusion leads to confusion, agitation, or decreased level of consciousness. With progressive shock, multiorgan failure ensues; hypotension is a late sign in children, who more commonly present with compensated shock. Poor outcome is associated with an absence of meningismus, hypotension, young age, coma, relatively low temperature (< 38oC), leukopenia, and thrombocytopenia. Spontaneous hemorrhage (pulmonary, gastric, or cerebral) may result from consumption of coagulation factors and thrombocytopenia.
Chronic meningococcemia, which is rarely recognized, presents as repeated episodes of petechial rash associated with fever, joint pain, features of arthritis, and splenomegaly that may progress to acute meningococcal septicemia if untreated. During the relapsing course, bacteremia characteristically clears without treatment and then recurs. The differential diagnosis includes bacterial endocarditis, acute rheumatic fever, Henoch-Schönlein purpura, infectious mononucleosis, disseminated gonococcal infection, and immune-mediated vasculitis. This condition has been associated with complement deficiencies in some cases and with inadequate sulfonamide therapy in others.
Postmeningococcal Reactive Disease
In a small proportion of patients, an immune complex disease develops ∼4–10 days after the onset of meningococcal disease, with manifestations that include a maculopapular or vasculitic rash (2% of cases), arthritis (up to 8% of cases), iritis (1%), pericarditis, and/or polyserositis associated with fever. The immune complexes involve meningococcal polysaccharide antigen and result in immunoglobulin and complement deposition with an inflammatory infiltrate. These features resolve spontaneously without sequelae. It is important to recognize this condition since a new onset of fever and rash can lead to concerns about relapse of meningococcal disease and unnecessarily prolonged antibiotic treatment.
Like other invasive bacterial infections, meningococcal disease may produce elevations of the white blood cell (WBC) count and of values for inflammatory markers (e.g., C-reactive protein and procalcitonin levels or the erythrocyte sedimentation rate). Values may be normal or low in rapidly progressive disease, and lack of these elevations does not exclude the diagnosis. However, in the presence of fever and a petechial rash, these elevations are suggestive of meningococcal disease. In patients with severe meningococcal septicemia, common laboratory findings include hypoglycemia, acidosis, hypokalemia, hypocalcemia, hypomagnesemia, hypophosphatemia, anemia, and coagulopathy.
Although meningococcal disease is often diagnosed on clinical grounds, in suspected meningococcal meningitis or meningococcemia, blood should routinely be sent for culture to confirm the diagnosis and to facilitate public health investigations; blood cultures are positive in up to 75% of cases. Culture media containing sodium polyanethol sulfonate, which may inhibit meningococcal growth, should be avoided. Meningococcal viability is reduced if there is a delay in transport of the specimen to the microbiology laboratory for culture or in plating of cerebrospinal fluid (CSF) samples. In countries where treatment with antibiotics before hospitalization is recommended for meningococcal disease, the majority of clinically suspected cases are culture negative. Real-time polymerase chain reaction (PCR) analysis of whole-blood samples increases the diagnostic yield by >40%, and results obtained with this method may remain positive for several days after administration of antibiotics. Indeed, in the United Kingdom, more than half of clinically suspected cases are currently identified by PCR.
Unless contraindications exist (raised intracranial pressure, uncorrected shock, disordered coagulation, thrombocytopenia, respiratory insufficiency, local infection, ongoing convulsions), lumbar puncture should be undertaken to identify and confirm the etiology of suspected meningococcal meningitis, whose presentation cannot be distinguished from that of meningitis of other bacterial causes. Some authorities have recommended a CT brain scan prior to lumbar puncture because of the risk of cerebral herniation in patients with raised intracranial pressure. However, a normal CT scan is not uncommon in the presence of raised intracranial pressure in meningococcal meningitis, and the decision to perform a lumbar puncture should be made on clinical grounds. CSF features of meningococcal meningitis (elevated protein level and WBC count, decreased glucose level) are indistinguishable from those of other types of bacterial meningitis unless a gram-negative diplococcus is identified. (Gram's staining is up to 80% sensitive for meningococcal meningitis.) CSF should be submitted for culture (sensitivity, 90%) and (where available) PCR analysis. CSF antigen testing with latex agglutination is insensitive and should be replaced by molecular diagnosis when possible.
Lumbar puncture should generally be avoided in meningococcal septicemia, as positioning for the procedure may critically compromise the patient's circulation in the context of hypovolemic shock. Delayed lumbar puncture may still be useful when the diagnosis is uncertain, particularly if molecular technology is available.
In other types of focal infection, culture and PCR analysis of normally sterile body fluids (e.g., synovial fluid) may aid in the diagnosis. Although some authorities have recommended cultures of scrapings or aspirates from skin lesions, this procedure adds little to the diagnostic yield when compared with a combination of blood culture and PCR analysis. Urinary antigen testing is also insensitive, and serologic testing for meningococcal infection has not been adequately studied. Because N. meningitidis is a component of the normal human nasopharyngeal flora, identification of the organism on throat swabs has no diagnostic value.
Treatment: Meningococcal Infections
Death from meningococcal disease is associated most commonly with hypovolemic shock (meningococcemia) and occasionally with raised intracranial pressure (meningococcal meningitis). Therefore, management should focus on the treatment of these urgent clinical issues in addition to the administration of specific antibiotic therapy. Delayed recognition of meningococcal disease or its associated physiologic derangements, together with inadequate emergency management, is associated with poor outcome. Since the disease is rare, protocols for emergency management have been developed (see www.meningitis.org).
Airway patency may be compromised if the level of consciousness is depressed as a result of shock (impaired cerebral perfusion) or raised intracranial pressure; this situation may require intervention. In meningococcemia, pulmonary edema and pulmonary oligemia (presenting as hypoxia) require oxygen therapy or elective endotracheal intubation. In cases with shock, aggressive fluid resuscitation (with replacement of the circulating volume several times in severe cases) and inotropic support may be necessary to maintain cardiac output. If shock persists after volume resuscitation at 40 mL/kg, the risk of pulmonary edema is high, and elective intubation is recommended to improve oxygenation and decrease the work of breathing. Metabolic derangements including hypoglycemia, acidosis, hypokalemia, hypocalcemia, hypomagnesemia, hypophosphatemia, anemia, and coagulopathy should be anticipated and corrected. In the presence of raised intracranial pressure, management includes correction of coexistent shock and neurointensive care to maintain cerebral perfusion.
Empirical antibiotic therapy for suspected meningococcal disease consists of a third-generation cephalosporin such as ceftriaxone [75–100 mg/kg per day (maximum, 4 g/d) in one or two divided IV doses] or cefotaxime [200 mg/kg per day (maximum, 8 g/d) in four divided IV doses] to cover the various other (potentially penicillin-resistant) bacteria that may produce an indistinguishable clinical syndrome. Although unusual in most countries, reduced meningococcal sensitivity to penicillin (a minimal inhibitory concentration of 0.12–1.0 μg/mL) has been reported from Africa, the United Kingdom, Spain, Argentina, the United States, and Canada.
Both meningococcal meningitis and meningococcal septicemia are conventionally treated for 7 days, although courses of 3–5 days may be equally effective. Furthermore, a single dose of ceftriaxone or an oily suspension of chloramphenicol has been used successfully in resource-poor settings. No data are available to guide the duration of treatment for meningococcal infection at other foci (e.g., pneumonia, arthritis); antimicrobial therapy is usually continued until clinical and laboratory evidence of infection has resolved.
The use of glucocorticoids for adjunctive treatment of meningococcal meningitis remains controversial since no relevant studies have had sufficient power to determine true efficacy. One large study in adults did indicate a trend toward benefit, and in clinical practice a decision to use glucocorticoids usually precedes a definite diagnosis. Therapeutic doses of glucocorticoids are not recommended in meningococcal septicemia, but many intensivists recommend replacement glucocorticoid doses for patients who have refractory shock in association with impaired adrenal gland responsiveness. Various other adjunctive therapies for meningococcal disease have been considered, but few have been subjected to clinical trials and none can currently be recommended. An antibody to LPS (HA1A) failed to confer a demonstrable benefit. Recombinant bactericidal/permeability-increasing protein was tested in a study that had inadequate power to show an effect on mortality rates; however, there were trends toward lower mortality rates among patients who received a complete infusion, and this group also had fewer amputations, fewer blood-product transfusions, and a significantly improved functional outcome. Given that protein C concentrations are reduced in meningococcal disease, the use of activated protein C has been considered since a survival benefit was demonstrated in adult sepsis trials; however, trials in pediatric sepsis (of particular relevance for meningococcal disease) found no benefit and indicated a potential risk of bleeding complications with use of activated protein C.
The postmeningococcal immune-complex inflammatory syndrome has been treated with nonsteroidal anti-inflammatory agents until spontaneous resolution occurs.
About 10% of patients with meningococcal disease die despite the availability of antimicrobial therapy and other intensive medical interventions. The most common complication of meningococcal disease (10% of cases) is scarring after necrosis of purpuric skin lesions, for which skin grafting may be necessary. The lower limbs are most often affected; next in frequency are the upper limbs, the trunk, and the face. On average, 13% of the skin surface area is involved. Amputations are necessary in ∼2% of survivors of meningococcal disease because of a loss of tissue viability after peripheral ischemia or compartment syndromes. Unless there is local infection, amputation should usually be delayed to allow the demarcation between viable and nonviable tissue to become apparent. Approximately 4% of patients with meningococcal disease suffer hearing loss, and 7% have neurologic complications. In one study, pain was reported by 21% of survivors. In some investigations, the rate of complications is higher for serogroup C disease (mostly associated with the ST11 clone) than for serogroup B disease. In patients with severe hypovolemic shock, renal perfusion may be impaired and prerenal failure is common, but permanent renal replacement therapy is rarely needed.
Several studies suggest adverse psychosocial outcomes after meningococcal disease, with reduced quality of life, lowered self-esteem, and poorer neurologic development, including increased rates of attention deficit/hyperactivity disorder and special educational needs. Other studies have not found evidence of such outcomes.
Several prognostic scoring systems have been developed to identify patients with meningococcal disease who are least likely to survive. Factors associated with a poorer prognosis are shock; young age (infancy), old age, and adolescence; coma; purpura fulminans; disseminated intravascular coagulation; thrombocytopenia; leukopenia; absence of meningitis; metabolic acidosis; low plasma concentrations of antithrombin and proteins S and C; high blood levels of PAI-1; and a low erythrocyte sedimentation rate or C-reactive protein level. The Glasgow Meningococcal Septicaemia Prognostic Score is probably the best-performing scoring system studied so far and may be clinically useful for severity assessment in meningococcal disease. However, scoring systems do not direct the clinician to specific interventions, and the priority in management should be recognition of compromised airways, breathing, or circulation and direct, urgent intervention. Most patients improve rapidly with appropriate antibiotics and supportive therapy. Fulminant meningococcemia is more likely to result in death or ischemic skin loss than is meningitis; optimal emergency management may reduce mortality rates among the most severely affected patients.
Since mortality rates in meningococcal disease remain high despite improvements in intensive care management, immunization is the only rational approach to prevention on a population level. Secondary cases are common among household and “kissing” contacts of cases, and secondary prophylaxis with antibiotic therapy is widely recommended for these contacts (see below).
Purified capsular polysaccharide has been used for immunization since the 1960s. Meningococcal polysaccharide vaccines are currently formulated as either bivalent (serogroups A and C) or quadrivalent (serogroups A, C, Y, and W135), with 50 μg of each polysaccharide per dose. Local reactions (erythema, induration, and tenderness) may occur in up to 40% of vaccinees, but serious adverse events (including febrile convulsions in young children) are very rarely reported. In adults, the vaccines are immunogenic, but immunity appears to be relatively short-lived (with antibody levels above baseline for only 2–10 years), and booster doses do not induce a further rise in antibody concentration. Indeed, a state of immunologic hyporesponsiveness has been widely reported to follow booster doses of plain polysaccharide vaccines. The repeating units of these vaccines cross-link B cell receptors to drive specific memory B cells to become plasma cells and produce antibody. Because polysaccharides are T cell–independent antigens, no memory B cells are produced after immunization, and the memory B cell pool is depleted such that fewer polysaccharide-specific cells are available to respond to a subsequent dose of vaccine (Fig. 143-6). The clinical relevance of hyporesponsiveness is unknown. Plain polysaccharide vaccines generally are not immunogenic in early childhood, possibly because marginal-zone B cells are involved in polysaccharide responses and maturation of the splenic marginal zone is not complete until 18 months to 2 years of age. The efficacy of the meningococcal serogroup C component is >90% in young adults; no efficacy data are available for the serogroup Y and W135 polysaccharides in this age group.
A. Polysaccharides from the encapsulated bacteria that cause disease in early childhood stimulate B cells by cross-linking the BCR and driving the production of immunoglobulins. There is no production of memory B cells, and the B cell pool may be depleted by this process such that subsequent immune responses are decreased. B. The carrier protein from protein-polysaccharide conjugate vaccines is processed by the polysaccharide-specific B cell, and peptides are presented to carrier peptide–specific T cells, with the consequent production of both plasma cells and memory B cells. BCR, B cell receptor; MHC, major histocompatibility complex; TCR, T cell receptor. (Reprinted from Pollard et al, 2009.)
Group A meningococcal polysaccharides are exceptional in that they are effective in preventing disease at all ages. Two doses administered 2–3 months apart to children 3–18 months of age or a single dose administered to older children or adults has a protective efficacy rate of >95%. The vaccine has been widely used in the control of meningococcal disease in the African meningitis belt. The duration of protection appears to be only 3–5 years.
There is no meningococcal serogroup B plain polysaccharide vaccine because α-2,8-N-acetylneuraminic acid is expressed on the surface of neural cells in the fetus such that the B polysaccharide is perceived as “self” and therefore is not immunogenic in humans.
The poor immunogenicity of plain polysaccharide vaccines in infancy has been overcome by chemical conjugation of the polysaccharides to a carrier protein (CRM197, tetanus toxoid, or diphtheria toxoid). Conjugates that contain monovalent serogroup C polysaccharide and quadrivalent vaccines with A, C, Y, and W135 polysaccharides have been developed, as have vaccines including various other antigen combinations. After immunization, peptides from the carrier protein are conventionally believed to be presented to peptide-specific T cells in association with major histocompatibility complex (MHC) class II molecules (some recent data suggesting that carrier protein peptide may actually be presented in association with an oligosaccharide and MHCII) by polysaccharide-specific B cells; the result is a T cell–dependent immune response that allows production of antibody and generation of an expanded B cell memory pool. Unlike responses to booster doses of plain polysaccharides, responses to booster doses of conjugate vaccines have the characteristics of memory responses. Indeed, conjugate vaccines overcome the hyporesponsiveness induced by plain polysaccharides by replenishing the memory pool. The reactogenicity of conjugate vaccines is similar to that of plain polysaccharide vaccines.
The first widespread use of serogroup C meningococcal conjugate vaccine (MenC) came in 1999 in the United Kingdom after a rise in serogroup C disease. A mass vaccination campaign involving all individuals <19 years of age was undertaken, and the number of cases fell from >1000 in 1999 to just 28 in 2006. The effectiveness of the immunization program was attributed both to direct protection of immunized persons and to reduced transmission of the organism in the population as a result of decreased rates of colonization among the immunized (herd immunity). Data on immunogenicity and effectiveness have shown that the duration of protection is short when the vaccine is administered in early childhood; thus booster doses are needed to maintain population immunity. In contrast, immunity after a dose of vaccine given in adolescence appears to be prolonged.
The first quadrivalent conjugate meningococcal vaccine containing A, C, Y, and W135 polysaccharides conjugated to diphtheria toxoid was initially recommended for all children >11 years of age in the United States in 2005. In 2007 the license was extended to high-risk children 2–10 years of age. In the same year, the vaccine was licensed in Canada for persons 2–55 years of age. Uptake was slow, but preliminary data suggest an efficacy rate of >80%. Limited data from the U.S. Vaccine Adverse Events Reporting System indicated that there might be a short-term increase in the risk of Guillain-Barré syndrome after immunization with the diphtheria conjugate vaccine; however, further investigation has not confirmed this finding. Another quadrivalent conjugate vaccine (CRM197 carrier protein) was licensed in 2010 in both Europe and North America, and a third vaccine is in late-stage development.
A monovalent serogroup A vaccine was developed and licensed in 2010 and is being rolled out in several countries in sub-saharan Africa. The goal for this vaccine is control of epidemic meningococcal disease in the African meningitis belt.
Vaccines Based on Subcapsular Antigens
The lack of immunogenicity of the serogroup B capsule has led to the development of vaccines based on subcapsular antigens. Various surface components have been studied in early-phase clinical trials. Outer-membrane vesicles (OMVs) containing outer-membrane proteins, phospholipid, and lipopolysaccharide can be extracted from cultures of N. meningitidis by detergent treatment (Fig. 143-7). OMVs prepared in this way were used in efficacy trials with a Norwegian outbreak strain and reduced the incidence of group B disease among 14- to 16-year-old schoolchildren by 53%. Similarly, OMV vaccines constructed from local outbreak strains in Cuba and New Zealand have had reported efficacy rates of >70%. These OMV vaccines appear to produce strain-specific immune responses, with only limited cross-protection, and are therefore best suited to clonal outbreaks (e.g., those in Cuba and New Zealand as well as others in Norway and the province of Normandy in France).
Illustration of meningococcal outer-membrane vesicle containing outer-membrane structures.
Several purified surface proteins have been evaluated in phase 1 clinical trials but have not yet been developed further because of variability or poor immunogenicity (e.g., transferrin-binding proteins, neisserial surface protein A). Other vaccine candidates have been identified since sequencing of the meningococcal genome. A combination vaccine that includes the New Zealand OMV vaccine and three proteins (neisserial adhesin A, factor H–binding protein, and neisserial heparin-binding antigen) is immunogenic in infancy and was recently submitted for licensure. Finally, a highly immunogenic vaccine based on two variants of factor H–binding protein is undergoing clinical evaluation.
Close (household and kissing) contacts of individuals with meningococcal disease are at increased risk (up to 1000 times the rate for the general population) of developing secondary disease; a secondary case follows as many as 3% of sporadic cases. About one-fifth of secondary cases are actually co-primary cases—i.e., cases that occur soon after the primary case and in which transmission is presumed to have originated from the same third party. The rate of secondary cases is highest during the week after presentation of the index case. The risk falls rapidly but remains above baseline for up to 1 year after the index case; 30% of secondary cases occur in the first week, 20% in the second week, and most of the remainder over the next 6 weeks. In outbreaks of meningococcal disease, mass prophylaxis has been used; however, limited data support population intervention, and significant concerns have arisen about adverse events and the development of resistance. For these reasons, prophylaxis is usually restricted to (1) persons at greatest risk who are intimate and/or household contacts of the index case and (2) health care workers who have been directly exposed to respiratory secretions. In most cases, members of wider communities (e.g., at schools or colleges) are not offered prophylaxis.
The aim of prophylaxis is to eradicate colonization of close contacts with the strain that has caused invasive disease in the index case. Prophylaxis should be given to all contacts at the same time to avoid recolonization by meningococci transmitted from untreated contacts and should also be used as soon as possible to treat early disease in secondary cases. If the index patient is treated with an antibiotic that does not reliably clear colonization (e.g., penicillin), he or she should be given a prophylactic agent at the end of treatment to prevent relapse or onward transmission. Although rifampin has been most widely used and studied, it is not the optimal agent because it fails to eradicate carriage in 15–20% of cases, rates of adverse events have been high, compliance is affected by the need for four doses, and emerging resistance has been reported. Ceftriaxone as a single IM or IV injection is highly (97%) effective in carriage eradication and can be used at all ages and in pregnancy. Reduced susceptibility of isolates to ceftriaxone has occasionally been reported. Ciprofloxacin or ofloxacin is preferred in some countries; this agent is also highly effective and can be administered by mouth but is not recommended in pregnancy. Resistance to fluoroquinolones has been reported in some meningococci in North America, Europe, and Asia.
In documented serogroup A, C, Y, or W135 disease, contacts may be offered immunization (preferably with a conjugate vaccine) in addition to chemoprophylaxis to provide protection beyond the duration of antibiotic therapy. Mass vaccination has been used successfully to control disease during outbreaks in closed communities (educational and military establishments) as well as during epidemics in open communities.