Neisseria meningitidis is a common commensal bacterium of the human upper respiratory tract. Colonization infrequently leads to disseminated disease, but the resulting meningitis and sepsis can be fulminant and rapidly fatal in healthy children and adults. Among survivors, 11% to 19% are left with disabilities such as neurological deficit, hearing loss, or limb amputation.1,2 Despite advances in vaccine technology, N meningitidis remains a significant worldwide pathogen and the cause of epidemic meningitis.
Humans are the only reservoir for N meningitidis, and approximately 10% of the general population are asymptomatic, nasopharyngeal carriers. Peak colonization rates of 24% to 37% occur in healthy adolescents and young adults.4The colonization rate increases even more under conditions of crowding or during outbreaks and epidemics. The majority of these strains are not pathogenic, but carriage often results in protective, serum antibodies.1-5 Even colonization with a virulent clone infrequently leads to disease, but when dissemination occurs, it is often in the first week after acquisition.2,6 Baseline endemic disease can be punctuated with localized outbreaks or epidemics caused by virulent, genetically related (focal complex) strains.2
In the United States, the rate of meningococcal disease remained relatively stable at 0.9 to 1.5 cases per year per 100,000 population between 1960 and 1999.1 The rate of disease then declined yearly until 2004 and has remained steady through 2006 at 0.3 cases per 100,000 population.9 The prevalence of serum bactericidal antibody is lowest in infants 6 to 24 months of age, and this window of susceptibility correlates with the peak incidence of meningococcal disease.10 Rates drop during childhood, and then a second, smaller peak occurs during adolescence and early adulthood.1,9 The prevalence of meningococcal disease varies seasonally, with the highest attack rates occurring in the winter and early spring.
In the 1980s and early 1990s, most of the disease in the United States was due to serogroups B and C. Recently, group Y increased in prevalence and now accounts for about one third of the cases. Serogroup A is rarely found.1,9Epidemics have not occurred in the United States since World War II.
A multicenter surveillance study of invasive meningococcal disease in children identified 159 episodes between January 1, 2001, and March 15, 2005. The age distribution is shown in eFigure 275.2 . Sixty-six percent of the children were 5 years of age or younger.
Meningococcal disease occurs worldwide. Serogroups B and C cause most of the disease in industrialized nations, with an incidence of 1 to 3 per 100,000 population over the past 30 years. Serogroup A, and to a lesser extent C, predominate in developing countries, with a much higher incidence of 25 cases per 100,000 population.1-3,5 eFigure 275.3 shows the global serogroup distribution of invasive meningococcal disease.5
Antibody-induced, complement-mediated immune lysis is critical in host defense, and individuals who lack this ability are at increased risk. However, underlying immune defects account for only a small percentage of disease.1These include functional and anatomic asplenia as well as several genetic defects. X-linked properdin deficiency predisposes to fatal meningococcemia, and defects in the terminal complement components increase the risk for recurrent infections. Polymorphisms in genes encoding for mannose binding lectin, the Fcγ-receptor II (CD32) and III (CD16), plasminogen activator inhibitor (PAI-1), and Toll-like receptor 4 (TLR4) are associated with increased frequency or severity of disease.2,3,5,11,16
Exposure to tobacco smoke, concurrent viral infection of the upper respiratory tract, household crowding, and chronic underlying illness all increase the risk of developing disseminated disease.1,17
N meningitidis are gram-negative, aerobic diplococci that grow well on enriched medium such as chocolate or Mueller-Hinton agar in an atmosphere of 5% to 10% carbon dioxide (eFig. 275.1 ). Organisms are divided into 13 serogroups based on the structure of their capsular polysaccharide, but only 6 (A, B, C, Y, W-135, and X) account for most of the disease, with groups A, B, C, and Y predominating. Molecular subtyping methods (multilocus enzyme electrophoresis, pulsed-field gel electrophoresis, or DNA sequence analysis) are useful for the characterization of outbreaks and the identification of disease-causing clones.1,3
Meningococci are transmitted by aerosol or contact with secretions and colonize the respiratory mucosa. Focal spread can lead to respiratory tract infection, including pneumonia. Invasion through epithelial surfaces leads to bloodstream dissemination, allowing the bacteria to seed the meninges, pericardium, or large joints. The loss of protective maternal antibody renders the infant susceptible until endogenous antibody is induced by carriage of N meningitidis and Neisseria lactamica, a nonpathogenic species, as well as cross-reactive antibody induced by normal enteric organisms.2,3,5,11,16
When meningococci enter the bloodstream, they can be cleared spontaneously, resulting in transient bacteremia, or they can result in overt disease. Endotoxin is released in the form of outer membrane vesicles and induces cytokine production, shock, and disseminated intravascular coagulation (see eFig. 275.4 ).
Meningococcal disease can manifest as several different clinical syndromes as summarized in Table 275-1. Meningitis without shock occurs in about 50% of cases (higher in developing countries) and is indistinguishable from other forms of purulent meningitis (see Chapter 231).
Bacteria are isolated from the blood in up to 75% of cases. This can present as occult bacteremia in young children being evaluated for fever without a source or as transient bacteremia associated with fever and a nonspecific rash. Meningococcal sepsis occurs in 5% to 10% of patients and is characterized by fever and petechial or purpuric rash (Fig. 275-1). This can progress to fulminant meningococcal septicemia (purpura fulminans). Patients present with severe, persistent shock with little or no signs of meningitis. The development of a profound inflammatory response leads to progressive circulatory collapse; severe coagulopathy; and impaired pulmonary, renal, and adrenal function. Disseminated intravascular coagulation results in thrombotic lesions in the skin, limbs, kidneys, adrenals (Waterhouse-Friderichsen syndrome), and choroid plexus and lungs: Multiorgan failure ensues. Vascular complications often lead to limb amputation and extensive skin loss1,3 (eFig. 275.5 ).
Pneumonia occurs in 5% to 15% of patients with disseminated meningococcal disease and tends to occur in older children. Other, less common, respiratory tract infections include otitis media and epiglottitis. Focal infections occur less frequently and include septic arthritis, purulent pericarditis, conjunctivitis, urethritis, osteomyelitis, primary peritonitis, and endophthalmitis. Chronic meningococcemia is a rare manifestation that can last weeks to months and is characterized by prolonged intermittent fevers, rash, and arthralgias1,3 (eFig. 275.6 ).
Table 275-1. Infectious Syndromes Associated with Meningococcal Disease*
Meningococcemia (purpura fulminans and the Waterhouse-Friederichsen syndrome)
Respiratory tract infection
*More than one syndrome may be present in an individual patient.
Modified with permission from Rosenstein NE, et al. Meningococcal disease. N Engl J Med. 2001;344:1378-1388.
FIGURE 275-1. Macular (A) and nonblanching petechial (B and C) rashes in meningococcal disease. (Source: Used with permission from Stephens DS, Greenwood B, Brandtzaeg P. Epidemic meningitis, meningococcaemia, and Neisseria meningitidis. Lancet. 2007;369:2196-2210.)
The culture of N meningitidis from a normally sterile site remains the cornerstone of diagnosis. In the absence of antibiotic treatment, the blood culture is positive in 40% to 75% and the cerebrospinal fluid (CSF) culture in 80% to 90% of cases.18,19 Once antibiotics have been initiated, the sensitivity of a culture rapidly decreases.20 The Gram stain of CSF remains important in the evaluation of a patient with meningitis and can rapidly and accurately determine the diagnosis.1,21
The detection of meningococcal polysaccharide antigen in CSF can be a useful adjunct to diagnosis, and commercial kits are available. These tests, the most common being latex agglutination, have been reported to be rapid, specific, and sensitive for serogroups A and C, but are unreliable for serogroup B.19 The Practice Guideline Committee of the Infectious Diseases Society of America (IDSA) does not recommend routine use of latex agglutination for the rapid identification of the bacterial etiology of meningitis because of evidence that testing does not appear to modify the decision to initiate antibiotics and because false-positive results have been reported. The test may be most useful in the setting of pretreatment with antibiotics and a negative CSF Gram stain and culture result.21 Antigen detection tests of blood and urine are also unreliable.1
Recently, polymerase chain reaction (PCR) has emerged as a very useful tool in the diagnosis of meningococcal disease and has the advantage of being rapid and more sensitive than culture or antigen detection. Since viable bacteria are not necessary, PCR is less affected by pretreatment with antibiotics. A prospective study of children found that real-time PCR of blood and CSF had a sensitivity of 96%, specificity of 100%, positive predictive value of 100%, and negative predicted value of 99%.22 PCR has been widely used in the United Kingdom since 1996, and a large number of cases are diagnosed by PCR without culture.3,23
The antibiotics penicillin, cefotaxime, ceftriaxone, and chloramphenicol are effective in treating meningococcal infections although decreased susceptibility to penicillin has been reported worldwide. This decreased susceptibility to penicillin is due to production of altered penicillin-binding protein 2. The clinical relevance of this intermediate resistance is uncertain, as both failure and success in treatment have been reported.1 US surveillance studies reported that 3% to 30% of strains showed intermediate resistance to penicillin.24,25 Decreased susceptibility to penicillin has been reported worldwide and varies by country. In 1997, some areas of Spain reported that more than 55% of strains were not fully penicillin susceptible. High-level penicillin resistance (MIC ≥ 1 μg/mL), β-lactamase–producing strains, and chloramphenicol resistance remain rare.3
Rapid initiation of antibiotics is crucial in the treatment of meningococcal disease as CSF is sterilized within 3 to 4 hours after starting intravenous antibiotics and plasma endotoxin levels fall by 50% within 2 hours. Antibiotic treatment does not lead to the Jarisch-Herxheimer reaction.3 Empirical antimicrobial therapy for purulent meningitis is based on age and predisposing factors (see Chapter 231). Once N meningitidis is isolated, susceptibility testing should guide therapy. Standard therapy for a strain fully susceptible to penicillin (MIC < 0.1 μg/mL) is penicillin or ampicillin. Alternative antibiotics are ceftriaxone, cefotaxime, and chloramphenicol. Ceftriaxone or cefotaxime is recommended in patients with meningitis strains resistant to penicillin (MIC ≥ 0.1 μg/mL). Alternative antibiotics are chloramphenicol and meropenem.21 Five to seven days of intravenous antibiotic is recommended.21,26
With the advent of antibiotics in the 20th century, the mortality rate for meningococcal disease declined dramatically, but has since remained stable at 9% to 12%. The mortality rate for meningococcal sepsis is much higher and reaches 40%. Of survivors, 11% to 19% are left with sequelae including hearing loss, neurological disability, or need for limb amputation.1 Immune-mediated complications such as pericarditis and arthritis can occur several days after the onset of illness when the patient is otherwise improving.
The risk of meningococcal disease is increased among close contacts. Hence, chemoprophylaxis is indicated for household members, childcare center contacts, and anyone directly exposed to the patient’s oral secretions (eTable 275.1 ) beginning 7 days before onset of illness in the index patient.17,26 Chemoprophylaxis should be given as soon as possible, preferably within 24 hours of diagnosis.1,26 Nasopharyngeal cultures are not useful in determining the need for prophylaxis.1,26 Rifampin, ciprofloxacin, and ceftriaxone have been shown to be effective.27 Rifampin is given 10 mg/kg (maximum 600 mg) orally every 12 hours to children 1 month of age or older for 2 days. In infants younger than 1 month of age, each dose is reduced to 5 mg/kg. Rifampin is not recommended for pregnant women. Ceftriaxone is given in a single intramuscular dose of 125 mg for children younger than 15 years of age and 250 mg for individuals 15 years of age or older. For nonpregnant individuals 18 years of age or older, ciprofloxacin in a single 500-mg oral dose is also an acceptable alternative.26 Treatment of meningococcal disease with antibiotics other than ceftriaxone or other third-generation cephalosporins might not reliably eradicate nasopharyngeal carriage, and the index patient should receive chemoprophylaxis before discharge.17
In the United States, there are 2 licensed meningococcal vaccines.29 One containing capsular polysaccharides A, C, Y, and W-135 is licensed for individuals older than 2 years of age. A meningococcal polysaccharide (A/C/Y/W-135) and protein conjugate vaccine is licensed for individuals 2 to 55 years of age. For current recommendations regarding vaccination, see Chapter 244.
In the United Kingdom, a C polysaccharide conjugate vaccine was introduced in 2000 and was indicated for all children and young adults. The vaccine was highly effective in reducing the rate of serogroup C disease (90% vaccine effectiveness at 3 years for children aged 11 to 18 years). Herd immunity reduced by more than 50% the rates of serogroup C carriage and disease in nonvaccinated individuals. The United Kingdom now recommends the vaccine be given at 3 and 4 months of age with a booster dose at 12 months of age.3
The development of a vaccine to prevent serogroup B meningococcal disease remains problematic because polysialyl structures identical to the group B capsular polysaccharide are found on human tissue, including neural cells. The B polysaccharide is nonimmunogenic at any age. Alternative vaccine components are being investigated and include outer membrane proteins, vesicles, and lipooligosaccharide.3