++
Neisseriameningitidis 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. Children
and young adults bear the burden of disease.
++
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.4 The
colonization rate increases even more under conditions of crowdingin
which people from diverse regions are brought together, such as
with military recruits, pilgrims, and prisoners, 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 Serum
bactericidal antibody that activates complement has been shown to
be responsible for blocking the dissemination of meningococci from
the nasopharynx.7,8 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, or 2500 to 3000 cases per year.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.1,9 Epidemics have not occurred
in the United States since World War II, but Rosenstein et al1,11 reported
that beginning in 1991, the frequency of focal outbreaks has increased and
is caused by groups of closely related strains, predominantly serogroups
C and Y. While these outbreaks generate anxiety and media attention,
they account for only 2% to 3% of the yearly disease.1
++
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 275.1. 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.1-3,5eFigure 275.2 shows the global serogroup
distribution of invasive meningococcal disease.5
++
++
Serogroup A causes the highest incidence of disease. Sub-Saharan
Africa, known as the meningitis belt, experiences yearly outbreaks during
the dry season.1-3,5,13 Epidemics, with rates up
to 1000 cases per 100,000 population, have occurred every 5 to 12
years in this region, spreading from east to west. They are responsible
for about 3000 to 10,000 deaths annually.13 Serogroup
A epidemics have also occurred in China and Russia.1-3,5,13
++
Serogroup B is associated with a lower incidence of disease but
has been associated with prolonged outbreaks in Europe, Cuba, South America,
and New Zealand.2,3,5 Serogroup C has caused major
epidemics in sub-Saharan Africa and Brazil and also focal outbreaks
in Canada and western Europe.2,3,5 Serogroup W-135
has emerged as a cause of outbreaks associated with the Hajj (pilgrimage
to Mecca) and in Africa, with a recent epidemic in Burkina Faso.3,5,14,15 Previously
rare, serogroup X has emerged as the cause of a recent epidemic
in Niger.13,14
++
Underlying immune defects increase the risk of invasive meningococcal
disease but account for only a small percentage of disease.1 These
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 (C5 to C9) increase
the risk for recurrent infections. Polymorphisms in genes encoding for
mannosebinding 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 Several
studies have looked at the risk of meningococcal disease in college
students in the United States and the United Kingdom. While the
risk was higher for US college students residing in dormitories compared
to those residing in other types of accommodations, the overall
incidence among college students was similar or slightly lower than
that seen in the general population of similar age.17 In
the United Kingdom, college students had higher rates of meningococcal disease
compared with nonstudents, and risk was associated with residence
in dormitories.17
++
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.1 These 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. 275.3). 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 and shock. Bacteria undergo
autolysis and release DNA and cell wall components that induce the
inflammatory cascade. Disseminated intravascular coagulation is
a result of excessive activation of the coagulation system and downregulation
of the fibrinolytic system by endotoxin.1,3 An excellent
review of the pathophysiology of meningococcal sepsis is presented
by Stephens et al3 and in eFigure 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). Fever, headache,
and neck stiffness are sometimes accompanied by photophobia, nausea,
and altered mental status. Infants often present with irritability
and lethargy and occasionally a bulging anterior fontanel.
++
++
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) and is associated with rapid growth of meningococci
in the bloodstream, resulting in very high concentrations of organisms
and endotoxin. 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).
++
++
A recent study12 of 159 children with disseminated
meningococcal disease found that meningitis was the most common
manifestation, accounting for 70% of cases. Twenty-seven
percent of the children had bacteremia alone, with 16% of
these being fulminant and 14% being occult. Four children
had pneumonia and 1 had septic arthritis. On admission, 55% of
the children had petechiae, 38% had purpura, and 10% were
hypotensive. Laboratory evaluation revealed that 6% had
a platelet count under 100,000/mm3 and
5% were neutropenic (absolute neutrophil count < 1500/mm3).
CSF parameters were characteristic of bacterial meningitis. Of the
children, 26% required mechanical ventilation. The mean
duration of fever after initiation of antibiotics was 1.9 days,
and 90% were afebrile by day 5.12
++
The culture of N meningitidis from a normally sterile
site, including blood, CSF, and less frequently, synovial, pleural,
and pericardial fluid, 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 Up to 75% of
cases of meningitis will have a positive culture result in the absence
of antibiotics.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. Most MICs of penicillin have ranged
from 0.06 to 0.8 μg/mL.25 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). For
children 1 month of age or older without head trauma, neurosurgery,
or a foreign body, vancomycin and a third-generation cephalosporin
(ceftriaxone or cefotaxime) are recommended.21 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 multicenter surveillance study of invasive meningococcal
disease in children12 found an overall mortality
of 8%, which varied by age. Children who were 11 years
of age or older had a higher mortality rate of 21% compared
with a rate of 4.8% for children younger than 11 years
of age. Hearing loss occurred in 12.5% of children with
meningitis. Other less common sequelae included limb amputation,
skin necrosis, ataxia, and hemiplegia.12
++
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 The
risk of secondary disease is highest in the first 7 days of illness in
the index patient, and 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 Failure
of prophylaxis due to rifampin resistance has been reported but
remains rare.1,28
++
+++
Meningococcal
Vaccines
++
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 (MCV4) is
licensed for individuals 2 to 55 years of age. For current recommendations
regarding vaccination, see Chapter 244. Vaccine recommendations
were published in 2005 by the American Academy of Pediatrics29 and revised
in 2007 by the CDC Advisory Committee on Immunization Practices.30 It
is now recommended that all persons aged 11 to 18 years of age receive
1 dose of MCV4 at the earliest opportunity. New recommendations regarding
children aged 2 to 10 years may be forthcoming. Routine immunization
for persons aged 19 to 55 years is recommended for those at increased
risk of meningococcal disease: college freshman living in dormitories, microbiologists
routinely exposed to N meningitidis, military recruits,
persons with terminal complement component deficiencies, persons with
anatomic or functional asplenia, and travelers to or residents of
countries in which N meningitidis meningitis is
hyperendemic or epidemic.30 The meningococcal polysaccharide
vaccine is considered an acceptable alternative for short-term protection
against meningococcal disease (3 to 5 years).30
++
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