Neisseria meningitidis 125
125 Neisseria meningitidis
Andrew J. Pollard and Adam Finn
Neisseria meningitidis (meningococcus) is a leading cause of serious
bacterial infections in children, most commonly manifesting as purulent
meningitis or septicemia. Asymptomatic pharyngeal colonization is more
common than invasive disease, and humans are the only reservoir.1
Gaspard Vieusseux provided the first clinical description of
meningococcal disease during an outbreak in Geneva, Switzerland, as
recently as 1805,2 which was followed by epidemics across Europe for the
next 50 years. The first description in North America was in Medfield,
Massachusetts, in 1806.3 Further cases appeared in New England and
Canada during the following decade. In 1887 Anton Weichselbaum
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 PART III  Etiologic Agents of Infectious Diseases
SECTION A  Bacteria
described paired cocci inside white blood cells (WBCs) in cerebrospinal
fluid (CSF) and named the organism Diplococcus intracellularis,4 and the
organism later was reclassified as Neisseria meningitidis.
MICROBIOLOGY
N. meningitidis is a nonmotile, gram-negative coccus, usually appearing
in pairs with abutting sides flattened. The genus Neisseria also includes
N. gonorrhoeae and several commensal organisms, including N. flavescens,
N. lactamica, N. mucosa, N. sicca, and N. subflava.
N. meningitidis has complex nutritional requirements but grows well
on chocolate, blood, Mueller-Hinton, trypticase soy, and GC agar in a
humidified environment at 35°C to 37°C. N. meningitidis, like N. gonor-
rhoeae, requires additional carbon dioxide for growth. The organism is
highly susceptible to drying, cold, sunlight, and either high or low pH.
Neisseria species are differentiated initially by biochemical characteristics.
N. meningitidis can produce acid from glucose and maltose, but N. gonor-
rhoeae uses maltose alone. All neisseriae produce catalase and are oxidase
positive.
The cell envelope of N. meningitidis has 3 layers (Fig. 125.1): a cytoplas-
mic membrane, a peptidoglycan cell wall, and an outer membrane that
contains lipopolysaccharide (LPS), phospholipid, and outer membrane
proteins(OMPs). Invasive meningococci also have a polysaccharide capsule
surrounding the cell envelope that confers the capsular group, often termed
the “serogroup,” and reflecting the main typing method (i.e., serology,
used before the availability of molecular typing). The recent appearance
of invasive meningococcal disease in 1805 could indicate the acquisition of
capsule genes in the last 200 years that have conferred virulence potential
on an organism that previously was only a commensal, as well as survival
advantages the precise nature of which remains obscure.
The antigen responsible for capsular group specificity is the capsular
polysaccharide. Twelve different capsular groups of meningococci have
been identified (A, B, C, X, Y, Z, 29E, W [formerly designated W135], H,
I, J, and L), each with different saccharide subunits, but only 5 are com-
monly associated with disease: A, B, C, Y, and W (Table 125.1).5 A sixth,
capsular group X, has been associated with epidemics in sub-Saharan
Africa. The other capsular groups are responsible for occasional sporadic
cases, but these groups are isolated from asymptomatic carriers more
commonly than from people with disease.
Opa
PorB
PorA
LPS
Pilus
Capsule
Outer
membrane
Peptidoglycan
Lipoprotein cell wall
Cytoplasmic membrane
FIGURE 125.1  Surface structures of Neisseria meningitidis. LPS, lipopolysac-
charide; Opa, PorA, and PorB, outer membrane proteins. (From Pollard AJ, Levin
M. Vaccines for prevention of meningococcal disease. Pediatr Infect Dis J
2000;19:333–345, with permission.)
748
TABLE 125.1  Chemical Structure of Meningococcal Polysaccharide
Capsules
Capsular Group Chemical Structure
A N-acetyl mannosamine-1 phosphate
B α2-8 NANA
C α2-9 NANA
29E 3-deoxy-D-manno-octulosonic acid
X α1-4 N-acetyl-D-glucosamine-1 phosphate
W Copolymer of NANA with galactose
Y Copolymer of NANA with glucose
NANA, N-acetyl neuraminic acid.
Within each capsular group, serotypes and subtypes can be identified
on the basis of differences in 2 OMPs, PorB and PorA, respectively,
whereas the immunotype is defined by the LPS structure.6 More recently,
sero(sub)typing has been undertaken by molecular methods in view of
the limited availability of serologic reagents.7 With the advent of novel
vaccines based on surface proteins, antigen-gene sequence typing is
growing in importance to describe diversity and predict potential vaccine
coverage. In addition to serologic and genetic differentiation based on
surface antigens, related meningococcal isolates previously were described
by differences in the electrophoretic mobility of cytoplasmic enzymes
(multilocus enzyme electrophoresis [MLEE]) and more recently have
been described by the genetic relatedness of strains using multilocus
sequence typing (MLST),8 which defines meningococci using sequence
data from 7 housekeeping genes. Using this method, 7 hyperinvasive
lineages have been described that cause most cases of invasive meningo-
coccal disease worldwide. With the availability of low-cost, high-
throughput sequencing, routine whole-genome sequencing is now
replacing these other typing methods.
Complete genome sequences were determined for several meningo-
coccal isolates in 2000,9,10 and these isolates were shown to contain a large
number of repeating sequences. In addition, meningococcal genomes
contain multiple insertion sequences that are responsible for the uptake
of DNA from the microbial environment,11 thus allowing the addition of
new genes. For example, meningococci can acquire the capsular operon
from another capsular group and switch to expression of the donor gene
product (e.g., switch from capsular group B to capsular group C and
vice versa).11,12 Meningococci also import DNA at high rates from other
commensal Neisseria spp. during mixed colonization in the nasophar-
ynx.13 Phase variation of surface structures during colonization and
invasion can augment the foregoing mechanisms in helping evade host
responses. Variability in the expression of immunogenic proteins may be
important for persistence of the organism but has hampered vaccine
development. However, sequence data from the meningococcal genome
have been used to identify genes encoding potential vaccine candidates
that are included in the most recent generation of meningococcal vac-
cines based on surface-expressed proteins.14,15
VIRULENCE AND PATHOGENESIS
The rare episodes of invasive meningococcal disease that occur probably
do not provide any survival advantage for the meningococcus. It seems
likely that the virulence factors associated with pathogenic meningococci
have evolved as a result of a fitness advantage that they confer in the
transmission-colonization cycle that describes the organism’s normal
lifestyle and in the polymicrobial environment of the human nasophar-
ynx. The polysaccharide capsule enhances invasiveness by inhibiting
phagocytosis but may also be important, for example, for avoiding desic-
cation during transmission. Immunoglobulin (Ig) A1 protease, a neutral
endopeptidase with specific enzymatic activity against human IgA1,
appears to enhance the ability of pathogenic Neisseria to colonize mucosal
surfaces. The ability of pathogenic N. meningitidis to survive and multiply
within the human host is facilitated by the organism’s ability to extract
iron from high-affinity iron-binding proteins by means of a non–energy-
requiring cell surface mechanism.
Colonization involves a series of interactions between meningococcal
surface structures (including pili and the OMP Opa) and specific ligands

on the surface of cells in the nasopharyngeal mucosa of the human,16–18
and it must precede invasive infection. Invasion of N. meningitidis
through the nasopharyngeal mucosa into the bloodstream is incompletely
understood, but it appears to depend on phase variation of meningococ-
cal surface structures, including the capsule, and it results in the release
of endotoxin (LPS) contained in blebs formed from the outer membrane
during bacterial growth. A cascade of mediators is triggered in an inflam-
matory storm with interactions between LPS and CD14 and toll-like
receptor 4 and between lipoprotein or peptidoglycan and toll-like recep-
tor 2 at the core. The subsequent cytokine release (rather than direct
tissue injury by microbial products) is thought ultimately to produce the
features of septic shock in susceptible people. High levels of meningococ-
cal LPS are found in severe meningococcal disease and correlate strongly
with death.19 Many different genes are involved in these responses, and
various human gene polymorphisms have been associated with suscep-
tibility to meningococcal infection or severity of disease.20 Early in
meningococcal disease high levels of tumor necrosis factor-α (TNF-α),
soluble TNF-α receptor (sTNFR), interleukin-1 (IL-1), IL-1ra, IL-1β,
IL-6, IL-8, IL-10, plasminogen activator inhibitor (PAI-1), and leukemia-
inhibitory factor are detectable in blood, and elevated levels of many of
these cytokines also have been associated with disease severity or fatal-
ity.21 Indeed, the balance between these cytokines and their antagonists
may influence the outcome of meningococcal disease.22
Although during meningococcal meningitis an inflammatory cascade
of cytokines also is released in the subarachnoid space, the levels of these
cytokines are not obviously associated with death.23 Nevertheless, the
inflammatory response is thought to mediate neurologic injury in
meningococcal meningitis and can be suppressed by use of corticoste-
roids, although clinical data to support use of this adjunctive treatment
for meningococcal meningitis are limited.24,25
IMMUNITY
In 1918, Matsunami and Kolmer26 demonstrated that the bactericidal
activity of clotted whole blood from various laboratory animals was
related to the resistance of these animals to infection with N. meningitidis.
These investigators also demonstrated that the bactericidal activity of
serum from adults was greater than that from children, thus providing
the first link between serum bactericidal activity and the susceptibility of
young children to meningococcal disease. Soon afterward, Heist and
colleagues27 found individual variation in the bactericidal activity of sera
and individual susceptibility to infection. Unfortunately Heist’s own
serum contained inadequate bactericidal activity against meningococcus
to protect him, and he died of invasive meningococcal disease before the
publication of these observations.
Goldschneider and associates28,29 are credited with firmly establishing
the importance of the relationship between serum bactericidal activity
(defined as killing of meningococci after mixing with serum and exoge-
nous complement in vitro) and susceptibility to infection. These inves-
tigators showed in 1969 that susceptibility to invasion by a newly acquired
strain of N. meningitidis was associated with the absence of bactericidal
antibody against that strain,28,29 an observation reconfirmed in 2000
during an outbreak in the United Kingdom.30 This finding is further
supported by the age-specific incidence of meningococcal disease caused
by capsular groups A, B, and C, which correlates inversely with the age-
specific prevalence of protective bactericidal antibody (Fig. 125.2).29,31,32
Titers of antimeningococcal bactericidal antibody in a newborn infant
are similar to those in the mother but decline after birth and reach a nadir
at about 6 months of age, which correlates with the peak incidence of
meningococcal disease at 5 to 9 months of age.
People with hypogammaglobulinemia may have a moderately
increased rate of meningococcal infection.33,34 Conversely, serum therapy
was successfully used in the treatment of meningococcal disease before
the advent of antibiotics. The mortality rate of untreated meningococcal
disease fell from between 60% and 80% following the introduction of
therapy using horse serum shortly after 1900 to between 13% and 30%
in treated patients, depending on how promptly treatment was
initiated.35
The bactericidal activity of immune sera requires the presence of both
antibody and complement. Approximately 0.3% of patients with menin-
gococcal disease have complement deficiency36; 50% of people with a late
complement component deficiency (C5–C9) will develop meningococcal
Neisseria meningitidis 125
Maternal antibody and complement Acquired antibody and complement
Opsonophagocytosis with maternal antibody Alternative complement pathway
Alternative complement pathway Opsonophagocytosis with antibody
Alternative complement pathway
Phagocytosis without antibody
Number of cases of disease
100
with bactericidal activity
Percentage of sera
80
60
Serum bactericidal activity
40
Disease prevalence
20
0 12 24 5 8 12 15 20 25
Months Years
Age
FIGURE 125.2  Age-specific incidence of meningococcal disease contrasted with
serum bactericidal activity. (Modified from Goldschneider I, Gotschlich E, Artenstein
M. Human immunity to the meningococcus. I. The role of humoral antibodies. J
Exp Med 1969;129:1307.)
disease, and one half of these patients will have recurrent attacks, thus
highlighting the importance of complement in defense against meningo-
coccal infection.37,38 These episodes usually occur in older age groups and
often are associated with the less common capsular groups and only
rarely with capsular group B disease.36,39,40 A relative deficiency of late
complement components is observed in infancy,41 and this deficiency
may add to the susceptibility to meningococcal infection in this age
group. In contrast to people with terminal complement component
deficiency, susceptible complement-deficient people who have either
properdin or factor D deficiency have a case fatality rate of >50%,
although recurrence is rare in survivors.38,42,43
In vitro opsonophagocytosis plays a greater role in killing capsular
group B meningococci than A, C, Y, or W meningococci despite equiva-
lent C3 binding to the surface of the capsular group B and Y organisms.44
This finding may explain the relative resistance of complement-deficient
people to capsular group B infection and their susceptibility to capsular
group Y infection.
Some further data suggest that phagocytic function may be important
in immunity against meningococci. Congenital impairment of binding
by phagocytes of IgG2 also can predispose to invasive meningococcal
disease. In one study, children with fulminant meningococcal disease
were more likely than were healthy control subjects to have poor IgG2
binding by the opsonic Fc-γ receptor IIa, which is expressed by phago-
cytes.45 The decreased binding results in marked reduction in phagocy-
tosis of meningococci opsonized with IgG2, but not of those opsonized
with IgG1.
During the first 2 decades of life, most people develop bactericidal
antibody directed against the capsular polysaccharides and subcapsular
structures such as OMP and LPS, and these antibodies are thought to
mediate naturally acquired immunity.46 Of the known surface proteins
that are important in antimeningococcal immunity, PorA appears to be
the dominant immunogen (with short surface exposed segments of loop
1 and 4 of the protein containing the immunogenic epitopes), but bac-
tericidal activity mediated by these antibodies is largely strain specific.47
Within 2 weeks of asymptomatic acquisition of a meningococcus, the
titer of bactericidal antibody against the colonizing strain increases.
Cross-reacting (i.e., non–strain-specific) antibodies are directed primar-
ily against OMP and LPS antigens.
Natural immunity can develop as a result of asymptomatic coloniza-
tion with meningococci or unrelated organisms bearing cross-reactive
antigenic structures.29,48 Carriage of pathogenic meningococci in early
childhood is uncommon and therefore unlikely to be responsible for the
induction of early natural immunity.48 However, carriage of N. lactamica
and of nontypable N. meningitidis is common and induces cross-reacting
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 PART III  Etiologic Agents of Infectious Diseases
SECTION A  Bacteria
bactericidal antibodies against other strains of meningococci.49 Enteric
bacteria bear many similar surface structures that also can cross-react
with meningococci. The Escherichia coli K1 capsular polysaccharide
cross-reacts antigenically with capsular group B meningococci,50 and
E. coli K92 cross-reacts with capsular group C polysaccharide.51
The role of cell-mediated immunity in specific host responses to
meningococcus is unclear. Lymphoproliferative responses to Opa, Opc,
and PorA proteins of the bacterial outer membrane have been described,52
and age-dependent differences in the cytokine response of peripheral
blood mononuclear cells following infection have been observed.53
Although age-dependent emergence of specific mucosal T-lymphocyte
immunity to meningococcus has been demonstrated,54 evidence also
indicates that such responses may be relatively tolerant and therefore
poorly protective in the mucosa.55
EPIDEMIOLOGY
Meningococcal disease has 2 largely distinct epidemiologic patterns:
endemic and epidemic disease.
Endemic disease consists of isolated sporadic cases and occasional
small clusters of cases that are associated temporally and geographically.
This pattern appears to occur everywhere that disease surveillance per-
formed, although baseline incidence rates vary markedly among different
geographic areas within the approximate range 0.1 to 7 cases per 100,000
population per year.56 In the 1990s disease rates in the United States
were at approximately 1 per 100,000,57 falling considerably since then to
<0.2 per 100,000 (Centers for Disease Control and Prevention [CDC],
unpublished data, 2013). The exception is in the Pacific Northwest,58
where higher rates were reported in the late 1990s because of an increase
in cases caused by hyperinvasive capsular group B strains. By contrast,
during the 1990s in the British Isles, disease rates increased to >5 per
100,000, higher than in other regions of Europe,59 largely because of
a highly virulent clone bearing the capsular group C polysaccharide
capsule60 until the disease was controlled by vaccination from 1999
onward. Most cases of endemic disease occur during the winter season in
temperate climates, which may reflect an association with respiratory viral
infections.
Capsular group distribution varies with time and place. During the
late 1990s a rising incidence of capsular group C disease in Europe and
of capsular group Y in North America was reported.61 Until recently,
capsular groups B and C were the most prevalent capsular groups in most
industrialized nations, but rates of group C disease fell following intro-
duction of group C meningococcal vaccines in many countries in Europe
and in Canada and Australia,62 and group B meningococci now are the
predominant cause of disease in these regions. In the US, serogroup B
cases declined in the US to approximately 55 to 65 cases annually in
young adults 11 through 24 years of age before the availability of capsular
group B vaccines.63,64 Capsular groups A and W previously caused only a
minority of the cases of meningococcal disease in Europe and North
America in recent decades, but a sharp rise in group W cases was observed
in the UK from 2012.65 By contrast, capsular group A was the most
commonly isolated organism on both sides of the Atlantic during the
periods after World Wars I and II and in various parts of Europe, includ-
ing Finland, and in North America during the 1970s.66 Capsular group
A meningococci caused a significant amount of disease in New Zealand
during the 1980s,67 but these meningococci were replaced by high rates
of group B disease from the early 1990s,68 thus leading to a vaccine
intervention program in 2005. Outbreaks of group A meningococcal
disease in Russia69 and Poland70 highlight the proximity to western
Europe of areas with high disease prevalence.
Epidemic meningococcal disease in Africa has occurred predominantly
during the dry season in an east-west belt from The Gambia to Ethiopia
below the Sahara desert, with cases declining at the onset of the rainy
season.71 Epidemics also have been reported in other developing coun-
tries, including China, Nepal, Mongolia, India, and Pakistan. Rates are far
higher than endemic disease. For example, in a severe epidemic in Africa
in 1996, attack rates of up to 1 in 100 people were recorded. The pre-
dominant capsular group is A, although epidemics of capsular groups C,
W, and X have been recorded.72–74 Epidemics of disease also have occurred
in conditions of overcrowding,75 and epidemics of groups A and W have
been associated with the Hajj pilgrimage to Saudi Arabia, thus leading to
a requirement for immunization before travel.76
750
BOX 125.1  Risk Factors for Invasive Meningococcal Disease
Lack of bactericidal antibody to acquired strain
Age <1 year or 15–24 years of age
Crowded living conditions or close contact (poor housing, military
barracks, students in dormitories)
Cigarette smoking, active or passive
Previous viral respiratory infection (especially influenza)
Inherited properdin or factor D deficiency
Inherited or drug-related terminal complement component
deficiency (C5–C9)
Family or household contact of person with meningococcal
disease
Factors Influencing Disease Susceptibility
and Severity
Susceptibility
Host and pathogen factors that determine susceptibility to and occur-
rence of meningococcal disease are summarized in Box 125.1. The most
important host factor is age. The peak incidence of endemic meningococ-
cal disease occurs in the first year of life, with 35% to 40% of cases
occurring in children younger than 5 years of age.1,57,77 A review of 807
cases of meningococcal disease occurring between 1992 and 1996 in the
US found that infants <1 year of age had the highest incidence of disease,
when all capsular groups were taken together.57 The median ages for
patients with disease caused by capsular groups B, C, Y, and W in this
report were 6, 17, 24, and 33 years, respectively, an observation that may
be important for vaccine programs designed for direct effects. Thirty
percent of cases of group B meningococcal disease occurred in infants
<1 year of age, compared with 14% of cases of disease caused by other
capsular groups. Median age increases during epidemics.
Other factors predisposing to meningococcal disease are overcrowd-
ing, poverty, cigarette smoking or exposure to cigarette smoke, previous
viral respiratory tract infection, winter or dry season,78 moving into new
communities,79,80 and certain immunodeficiencies.81–88 In a case-control
study, household smoking had an odds ratio for meningococcal disease
of 4.1 (95% confidence interval [CI], 1.6 and 10.7).82 In a study of mili-
tary recruits, active or passive smoking raised the risk of carriage of
N. meningitidis.89 Coexistent colonization or infection with respiratory
viruses and Mycoplasma species was associated with meningococcal
disease in a study from Chad,84 and previous studies have implicated
influenza A as a predisposing factor.85 People of low socioeconomic status
also are more likely to be carriers and to develop disease.90
Deficiency of either antibody or complement increases the risk of
meningococcal disease. Compared with the general population, inherited
deficiency of properdin or of a terminal component of complement
(C5–C8) increases the risk of invasive meningococcal disease by 250-fold
and 600-fold, respectively,91,92 as a result of impaired bacteriolysis even in
the presence of specific antibody.93 However, the proportion of all cases
of meningococcal disease that are associated with complement deficiency
is small. Patients receiving eculizumab (Soliris, Alexion Pharmaceuticals,
New Haven, Conn), a monoclonal antibody used primarily for treatment
of atypical hemolytic uremic syndrome, increases the risk of meningo-
coccal disease including serogroup B.94 Five of 326 subjects (1.5%) in
clinical trials of eculizumab developed invasive meningococcal disease
despite previous immunization with meningococcal conjugate vaccine.94
Indications for screening for complement deficiency by performance
of total hemolytic complement activity assay are as follows: recurrence
of meningococcal disease; chronic meningococcemia; endemic disease
caused by capsular groups other than A, B, and C; and a history of a
sibling with recurrent meningococcal disease. Routine screening of all
patients with meningococcal disease for complement deficiencies prob-
ably is not indicated.95
Patients with terminal complement component deficiency should be
vaccinated with the conjugated meningococcal vaccine, which reduces
the risk of recurrent disease.96 In addition, both patients and their families

should be aware of patients’ need for prompt medical care for acute
febrile illnesses.
Studies of human single nucleotide polymorphisms have indicated
various host factors that may be associated with susceptibility to invasive
meningococcal infection, as reviewed by Emonts and coworkers.20 Poly-
morphisms in Fc-gamma receptor II and III (CD32 and CD16) are more
common in children with meningococcal disease, presumably as a result
of reduced binding of IgG2 on the surface of phagocytes.97 A multina-
tional European study showed an excess of structural variants in
mannose-binding lectin exon 1 in cases of meningococcal infection
compared with controls,98 and another study found that single nucleotide
polymorphisms in factor H binding protein were associated with
increased risk of disease.99
Seven families of genetically related N. meningitidis have been
described (the hyperinvasive lineages) that account for a majority of the
invasive infections.8 These organisms appear to be genetically stable over
time and across all geographic regions, a property indicating that they
have adapted well to a particular life cycle of colonization and transmis-
sion that maintains the persistence of the clonal group. Acquisition of a
hyperinvasive N. meningitidis increases the risk of disease.
Severity
Severity of meningococcal disease is related to host, pathogen, and other
environmental factors. Large numbers of polymorphisms in human
genes involved in inflammation, coagulation, and the immune response
have been studied, and several associations have been reported (reviewed
by Emonts and colleagues20 and Texereau and associates100). Furthermore,
some meningococcal clones have been associated with higher case fatality
rates and more severe disease.101
The delivery of early and optimal medical care compared with late
diagnosis and suboptimal medical care was associated with improved
outcome in a study of deaths in the UK. Observations on changing case
management in the UK suggest that early and rapid cardiovascular
resuscitation (particularly volume replacement) may have more impact
than early administration of antibiotics, at least in settings within an
advanced healthcare system.102–105
Transmission and Colonization
Transmission of N. meningitidis occurs by means of respiratory droplets
and requires close, direct contact. In a meta-analysis, carriage prevalence
of N. meningitidis increased through childhood from 4.5% in infants to a
peak of 23.7% in 19-year-old adults and subsequently decreased to 7.8%
in 50-year-old adults.106 Most strains recovered from carriers younger than
5 years of age are not encapsulated; carriage of encapsulated strains is
uncommon until adolescence.106,107 Capsular group B is the most frequently
isolated capsular type in carriage studies from Europe (30%–40%), fol-
lowed by capsular group Ys (10%–15%), C (5%–7%), W (3%–4%), and A
(2%).108,109 Studies conducted in the UK a decade after a high uptake
conjugate vaccine campaign for all children and adults up to the age of 23
years in 2000 to 2001 demonstrated persistently low (although not nonex-
istent) rates of group C meningococcus carriage110,111 in young people.
Carriage rates of group C meningococcus also were low in the UK before
immunization was begun, when group C cases were more frequent.112
Asymptomatic carriers are the most common sources of transmission,
and evaluation of herd immune effects following introduction of group
C meningococcal vaccines suggests that adolescents and young adults are
the main vehicles of transmission for this capsular group in the popula-
tion. Close contacts are the sources of acquisition in most individual
cases. Disease is more correctly associated with acquisition than carriage
because the incubation period is very short in most cases. Studies in
military recruits show that illness often occurs within 48 to 72 hours of
colonization.113 During outbreaks of disease in military recruits, intense
transmission occurs, so that 60% to 80% of recruits become carriers of
outbreak strains within 6 to 8 weeks of starting basic training. High colo-
nization rates have not been associated with disease outbreaks in semi-
closed civilian populations, such as colleges and universities.114,115 The
highest carriage rates are detected at the beginning of the first term in
the first year of higher education.116
When members of the households of patients with capsular group B
or C disease are studied, 20% to 40% of contacts are found to carry the
Neisseria meningitidis 125
disease strain, and secondary cases of disease occur among close contacts
at rates up to 1000 times higher than in the general population.117
With the introduction of group C meningococcal conjugate vaccine
in the UK, which included a catch-up program in children and young
adults as well as a rolling program for infants, carriage rates of groups A,
B, W, and Y remained unaffected, whereas carriage rates of group C
decreased from 0.45% to 0.15% in 15- to 17-year-old adolescents.112 This
study highlights the finding that colonization rates of disease-associated
meningococci in the general population usually are <5%,118,119 even
during outbreaks in a college or school population.120,121
Few longitudinal studies have attempted to address duration of car-
riage. A study of group A stains in Africa suggested that the organism
may persist in the nasopharynx for 3 months.122 By contrast, the median
duration of carriage of group B meningococci in another study was 9
months.123
Outbreaks
School-related outbreaks have been associated with capsular group
B meningococci,124 but most outbreaks have been caused by group C
strains.125–128 The first described outbreaks occurred in Canada in the
late 1980s, but subsequent outbreaks related to schools, colleges, and
universities have been reported from the US,57,86 the UK,120 Sweden,129
Germany,130 Spain,131 Argentina,132 and Australia.133 More recent out-
breaks caused by group B strains have occurred in universities in the US,
thus prompting mass immunization campaigns and expedited licensure
in the US of 2 meningococcal cell wall protein vaccines designed to
protect against group B disease. The number of cases in each group B
outbreak is small (<10), but in most outbreaks, the proportion of fatal
meningococcemia among cases in 15- to 24-year-old patients is high.86
Risk factors for college and university outbreaks are summarized in
Box 125.2. As in outbreaks among military recruits, the risk of non–group
B disease is greatest in first-year college students, especially those living in
dormitories.120,134–136 Meningococcal carrier rates rise rapidly in the first
few months after students arrive at college.88 The highest carriage rates
among first-year university students in the UK are during the first week
of their first term.116 These data and the higher age-specific incidence of
disease in people 15 to 19 years old,137 as well as the overrepresentation
of people between 12 and 19 years of age in cases occurring in the
school-related clusters in Canada and among freshman college dormi-
tory residents in the US, suggest that adolescents transmit meningococci
to one another.86,125 Behaviors such as kissing, smoking, and prolonged
duration of close contact in relatively small groups (at dances, parties,
and bars, as well as in dormitories) may facilitate transmission of menin-
gococci.116,138,139 However, for unexplained reasons, no second adolescent
peak in incidence is seen in some regions (e.g., Latin America).140
Although cases arising in college-related outbreaks account for only
3% of all cases in the US, the resulting disruption of college activities and
the costs of outbreak management led the American College Health
Association to recommend in 1997 that college health services alert
students and parents about the risks of meningococcal disease and the
benefits of vaccination. Following earlier recommendations concerning
polysaccharide vaccine and following vaccine licensure in 2005, the CDC
and the American Academy of Pediatrics recommended universal admin-
istration of quadrivalent conjugate meningococcal vaccine (MenACWY)
to young adolescents (at 11–12 years of age), with catch-up immuniza-
tion of students entering high school or 15-year-old adolescents and
college freshmen who will be living in dormitories.130 In 2010, the CDC
and the AAP recommended a booster dose of MenACWY at 16 years for
BOX 125.2  Risk Factors Associated With Meningococcal Disease in
College and University Outbreaks
Being a first-year student
Living in a dormitory
Attending a bar, nightclub, disco, or social function within 10 days
before onset of the index case
Smoking
Intimate kissing
751
 PART III  Etiologic Agents of Infectious Diseases
SECTION A  Bacteria

A B

C D

FIGURE 125.3  An 8-year-old boy had acute onset of fever, purpuric rash, and shock. Neisseria meningitidis was isolated from blood culture. He recovered. Typically,
petechiae and purpura are most dense on (A) buttocks (day 1), lower extremities, and (B) peripherally (day 1). (C) Tissue damage (day 4) and (D) necrosis (day 10) can
ensue. (Copyright by J.H. Brien.)

persons immunized at age 11 or 12 years to ensure persistence of protec-
tive levels of bactericidal antibody.141
CLINICAL MANIFESTATIONS
The spectrum of clinical manifestations of infection with N. meningitidis
ranges from asymptomatic carriage, the most common form of infection,
to death within hours with fulminant meningococcal septicemia (menin-
gococcemia). Meningococcal meningitis and septicemia are the most
frequently reported clinical syndromes.
“Benign or unsuspected meningococcemia” has been observed in
infants and young adults142 with a clinical presentation of fever and signs
of upper respiratory tract illness without toxicity, meningismus, or rash.
Neither clinical features nor laboratory tests reliably distinguish febrile
children with unsuspected meningococcemia (i.e., with fever but with no
characteristic rash) from those without bacteremia.143 Although some
infants eliminate unsuspected meningococcemia without antibiotic
treatment, two thirds of untreated cases progress to meningitis, fulminant
meningococcemia, or other complications.144
Several clinical algorithms for assisting in the diagnosis and manage-
ment of the child presenting with a fever and a nonblanching rash have
been described,145–149 but none has been fully, independently validated.
These algorithms may enable the clinician to improve the specificity of
the diagnosis, although loss of sensitivity for diagnosis of meningococcal
disease could obviously have serious consequences.
The rash in all forms of meningococcal disease begins as macules,
maculopapules, or urticaria but usually becomes petechial within hours.
Large purpuric lesions evolve in severe cases, but some children who die
of overwhelming sepsis may have no rash.
The more frequent clinical challenge is the child with fever and
a petechial rash (Fig. 125.3). Only 2% to 11% of children with fever
and a petechial rash have meningococcal disease; most of the remain-
ing children have a viral illness, predominantly caused by enterovirus.
Other viruses associated with petechiae include influenza and other
respiratory viruses, parvovirus, Epstein-Barr virus, cytomegalovirus,
and measles virus.150–152 Petechiae or purpura also can occur with
coagulation disorders such as congenital or acquired (after varicella
infection) proteins S or C deficiencies.153,154 Other disorders associated
with petechial rash include platelet disorders (e.g., idiopathic throm-
bocytopenic purpura, drug effects, and bone marrow infiltration),
Henoch-Schönlein purpura, connective tissue disorders, and trauma
(including nonaccidental injury in children). The differential diagnosis
of other invasive infection includes septicemia caused by pneumococci,
streptococci, staphylococci, gram-negative bacilli, or rickettsia.155,156
In the case of pneumococcal purpura fulminans, hyposplenism is an
important association.
Histologic analysis of skin lesions shows widespread endothelial
necrosis of small veins and capillaries in the dermis and subcutaneous
tissue, infiltration of neutrophils, and occlusion of damaged vessels with
platelets, WBCs, fibrin thrombi, and hemorrhage.157 Meningococci are
present within the endothelium and thrombi.
Meningitis is the most common form of invasive disease and is associ-
ated with a petechial rash in two thirds of patients.1 Headache, fever,
vomiting, irritability, photophobia, lethargy, and neck stiffness can be
present, and the Kernig sign can be positive in advanced cases in older
children. Seizures occur in as many as 20% of cases, and mental state is
altered as disease progresses. Many of the features of meningitis are not
reported by younger children, and misery can be the dominant clinical

752

feature. Infants can present with poor feeding, unconsolable irritability,
a high-pitched cry, and a bulging fontanelle.
Meningococcal septicemia is a fulminant illness characterized by the
onset of a nonspecific febrile illness followed within a few hours by rapid
deterioration. Many deaths occur within 12 hours, and almost all occur
within 48 hours, of onset. Initial symptoms include fever, headache,
myalgia, shivering, cold hands and feet, and influenza-like symptoms and
may be associated with vomiting and abdominal pain. Limb pain is a
feature in some patients. Features of shock include tachycardia, poor
peripheral perfusion, tachypnea, and oliguria. As shock progresses,
cerebral perfusion decreases, resulting in alteration in mental status
(confusion, agitation, or decreasing consciousness), multiorgan failure,
and hypotension as a preterminal event.126–161 The petechial rash can
progress rapidly to purpura and ecchymoses.
Septicemia accounts for 15% to 20% of all cases of invasive meningo-
coccal disease, but some patients also have a mixed picture of meningitis
and septicemia. Septicemia is more common in infants and young chil-
dren.162,163 The case-fatality rate exceeds 40% in older case series, although
more recent reports from specialist pediatric intensive care units in the
UK showed improved survival; the mortality rate was less than 5%, with
an emphasis on early correction of shock with volume replacement.103
Many survivors lose extremities or extensive areas of skin as a result of
vascular damage and peripheral ischemia and infarction.164–166 Predictors
of death and poor outcome include young age, absence of meningitis,
presence of coma, absence of fever, and presence of hypotension, leuko-
penia, or thrombocytopenia.167,168
Less common manifestations of invasive disease are pneumonia,
pyogenic arthritis, purulent pericarditis, myocarditis, endophthalmitis,
conjunctivitis, primary peritonitis, and osteomyelitis. The incidence of
meningococcal pneumonia is not known because the cause is confirmed
only if blood or pleural fluid culture results are positive. Compared with
patients who have meningitis or bacteremia caused by N. meningitidis,
patients with pneumonia tend to be older (94.4% are >10 years old) and
are more likely to be infected with less common capsular groups, such as
W, Y, and Z.77,169 Meningococcal conjunctivitis should be managed as
invasive disease because topical therapy does not prevent invasion, and
secondary cases can occur.
Chronic meningococcemia, first described in the early 1900s,170 is a
rare form of meningococcal infection, characterized by recurrent epi-
sodes of fever, rash, and arthralgia or arthritis and headache over weeks
to months in association with bacteremia that often clears without treat-
ment. The same strain usually is responsible for recurrent episodes, and
the patient is well between attacks.171,172 One study indicated that chronic
meningococcemia was associated with the LpxL1 mutant strain that has
a less toxic pentacylated LPS molecule.173 Chronic meningococcemia can
mimic acute rheumatic fever, bacterial endocarditis, anaphylactoid
(Henoch-Schönlein) purpura, infectious mononucleosis, disseminated
gonococcal infection, and immune-mediated vasculitis. The diagnosis is
difficult because blood culture results are positive only if the specimen is
obtained during a febrile episode. If not recognized and treated, chronic
meningococcemia can progress to meningitis or acute meningococcemia.
The pathogenesis of chronic meningococcemia is unknown, but inherited
deficiencies of terminal components of complement have been found in
some cases.174
DIAGNOSIS
The diagnosis of meningococcal disease should be made clinically, and
appropriate therapy should be instituted immediately. Microbiologic
confirmation is important for public health control, to confirm antibiotic
sensitivity, and to exclude an alternative diagnosis. Specimens from
normally sterile sites (most commonly CSF) are inoculated onto choco-
late agar and incubated in 3% to 5% carbon dioxide. Specimens from
mucosal sites are inoculated on selective media (e.g., Thayer-Martin
chocolate agar) to which vancomycin, colistin, and nystatin have been
added to inhibit growth of competing microbes. Visualization of intracel-
lular or extracellular diplococci on Gram staining of CSF, fluid from skin
lesions, or the buffy coat of blood can provide positive results immedi-
ately. Scrapings or aspirates from skin lesions also can be used for diag-
nosis (Gram stain and inoculation onto chocolate agar).
Blood culture results may be positive in 40% to 75%, and CSF culture
results are positive in 90%, of patients with meningococcal meningitis
Neisseria meningitidis 125
who have not received antibiotics. Some blood culture media contain
sodium polyanethol sulfonate, which can inhibit Neisseria spp., and these
organisms are very sensitive to a delay in transport to the microbiology
laboratory or inoculation of CSF samples onto agar. Results of Gram
stain of CSF are positive in 75% to 80% of patients with untreated cases
of meningitis, and the test has a specificity of 97%. Combining results of
blood and CSF cultures with those of the CSF Gram stain identifies 94%
of cases of meningitis. Culture of blood, CSF, and skin lesions improves
laboratory confirmation of disease. However, administration of oral or
parenteral antibiotics before specimens are obtained reduces the rate of
positive results of blood cultures to <10% and of CSF cultures to approxi-
mately 50% in patients who have meningitis.163
Detection of meningococcal antigen in CSF by latex agglutination can
be useful in patients who previously received antibiotics, but the test has
poor sensitivity and specificity, particularly for capsular group B, the
predominant cause of the disease in most industrialized countries, and
it is not recommended routinely if polymerase chain reaction (PCR) is
available as an adjunct to culture.175 PCR assays can detect meningococcal
DNA in CSF, plasma, and serum.176–178 PCR assays may use different
amplification methods and gene targets176,179; optimal PCR systems are
reported to have sensitivity and specificity of >90% and to permit diag-
nosis within 4 to 8 hours.179,180 PCR is more sensitive than blood culture,
and the proportion of laboratory-confirmed cases of meningococcal
disease is increased by 30% to 40% when PCR is included in the inves-
tigation of suspected meningococcal disease because the assay is relatively
less affected by previous antibiotic therapy.181
Lumbar puncture can be associated temporally with deterioration in
some patients with meningococcal disease, and in patients with shock the
procedure can compromise cardiovascular function.182–184 Lumbar punc-
ture is contraindicated in patients with cardiorespiratory insufficiency,
raised intracranial pressure, coagulopathy, and extensive or spreading
purpura and after convulsions until the patient’s condition is stabilized.
Lumbar puncture can be deferred until the patient’s condition is stabi-
lized, when abnormal CSF findings can confirm meningitis, and PCR can
be used to confirm the cause.
Some patients come to medical attention in a coma, and computed
tomography brain imaging may be helpful to exclude intracranial hemor-
rhage in patients in whom diagnosis is unclear. However, clinically sig-
nificant raised intracranial pressure or cerebral edema may not be evident
on computed tomography, and the decision to perform a lumbar punc-
ture instead should be based on clinical assessment.185,186
METABOLIC AND HEMATOLOGIC ABNORMALITIES
In meningococcal meningitis, the CSF WBC count, the peripheral blood
WBC count, and inflammatory markers (C-reactive protein, procalcito-
nin, and erythrocyte sedimentation rate) typically are elevated. Bio-
chemical and coagulation test results usually are normal, but inappropriate
antidiuretic hormone secretion can occur and lower the plasma sodium
concentration. The CSF shows pleocytosis with raised protein, low
glucose, and the presence of gram-negative diplococci.
In meningococcal septicemia, metabolic derangements are common
and contribute to depressed myocardial function. Hypoglycemia, hypo-
kalemia, hypocalcemia, hypomagnesemia, hypophosphatemia, and meta-
bolic acidosis are present frequently in severely affected children and
should be corrected.105,187 Renal failure, anemia, and coagulopathy also
can occur, and patients may have spontaneous pulmonary, gastric, or
cerebral hemorrhage, particularly in the presence of thrombocytopenia.
Because onset may be very rapid, normal or depressed WBC and normal
C-reactive protein values are common initially. Protein C, fibrinogen,
prothrombin, coagulation factors (V, VII, and X), and antithrombin
levels typically are depressed. Tissue factor pathway inhibitor is raised.
Coagulopathy can be corrected with fresh frozen plasma, platelets, and,
in severe cases, cryoprecipitate, to prevent life-threatening hemorrhage.
TREATMENT
Antimicrobial Agents
Use of a third-generation cephalosporin, such as ceftriaxone or cefotax-
ime, for initial therapy of suspected meningococcal disease seems prudent
because meningococcal strains that are relatively resistant to penicillin
753
 PART III  Etiologic Agents of Infectious Diseases
SECTION A  Bacteria
appear to be susceptible to these antibiotics (discussed later) and because
third-generation cephalosporins also provide coverage for Haemophilus
influenzae and most cases of Streptococcus pneumoniae. In geographic
locations where penicillin-resistant cephalosporin-resistant pneumococci
are prevalent, addition of vancomycin is recommended.
Prehospital antibiotic therapy is recommended in some countries,
especially when any delay in transfer to hospital is likely. No high-quality
studies, however, address the benefit of such an approach, and available
observational data are conflicting. Urgent transfer to a hospital may
improve outcome among patients with septicemia because fluid resusci-
tation appears to be the clinical priority.
For confirmed disease, ceftriaxone (80 mg/kg/day, maximum 4 g/day,
in 1–2 divided doses, intravenously), cefotaxime (200 mg/kg/day,
maximum 12 g/day, in 3–4 divided doses [50 mg/kg/dose], intrave-
nously), penicillin G (50 mg/kg every 4–6 hours, maximum 2.4 g every
4 hours), or chloramphenicol (100 mg/kg/day, maximum 2 g/day, 4
divided doses orally or intravenously) is effective.188 Ceftriaxone sterilizes
the CSF more rapidly than does cefotaxime, ampicillin, or chlorampheni-
col (P < 0.01), although the clinical importance is unknown.189 Many
countries recommend penicillin for confirmed disease in view of its low
cost and narrow spectrum, although penicillin, unlike the third-
generation cephalosporins, does not clear nasopharyngeal colonization.
Chloramphenicol is widely used and effective in resource-poor settings,
and it is used elsewhere in patients with severe β-lactam allergy. One
randomized controlled trial in Turkey found that necrotic skin lesions
occurred more frequently with penicillin G therapy than with ceftriaxone
(P < 0.05).190 In the UK, ceftriaxone is recommended as definitive therapy
for penicillin-susceptible organisms because it appears to be less expen-
sive when administration costs are considered, and the long half-life and
dose interval also make it easier for children who can complete treatment
as outpatients.36
Emergence of strains with increased resistance to penicillin (i.e., with
a minimum inhibitory concentration between 0.12 and 1.0 µg/mL) has
been reported from Africa, the UK, Spain, Argentina, the US, and
Canada.191 Failure of penicillin therapy for meningitis caused by such
strains is reported, but these strains remain susceptible to third-generation
cephalosporins.192 Resistance results from a genetic mutation that appears
to have been acquired from avirulent N. lactamica or other Neisseria spp.
through DNA transformation and causes alteration in penicillin-binding
protein 2. The highest prevalence of penicillin resistance has been
reported from Spain, where rates exceed 40%.193 Although the frequency
of penicillin-resistant N. meningitidis has increased in many parts of the
world, the prevalence in the US remained unchanged at 3% between 1991
and 1997,194 and it remained unreported in the Netherlands in 2012.195
Although the recommended duration of therapy for meningitis and
meningococcemia is 7 days, no high-quality studies are available to
support any specific duration of therapy. In some studies, treatment with
penicillin, chloramphenicol, or ceftriaxone for 4 to 5 days appeared to be
effective. Treatment with 1 or 2 doses of ceftriaxone or a long-acting oily
suspension of chloramphenicol, in a developing country, was shown to
be as effective as more prolonged therapy.196–203
The appropriate duration of therapy for meningococcal infections at
other sites (bone, joint, heart, lung) has not been established, although
descriptive evidence supports short-course treatment of arthritis204;
nevertheless, patients with such infections should be treated at least until
all clinical and laboratory signs of infection have resolved.
Adjunctive Therapy
The use of corticosteroid therapy for presumed meningococcal menin-
gitis is controversial because no pediatric studies have had an adequate
sample size to assess benefit, although benefit has been shown for other
bacterial causes of meningitis.205 Studies in developing countries do not
show benefit from corticosteroid therapy in bacterial meningitis.206
However, studies in adults in industrialized countries have shown benefit
in all-cause meningitis and a trend toward benefit in meningococcal
meningitis.207 If used, dexamethasone can be administered in a dose of
0.15 mg/kg 4 times daily for 4 days.
No studies of high-dose corticosteroid treatment in children with
meningococcemia or other types of shock have been conducted, but data
from adult studies showed no benefit and the potential for harm. Studies
of low (“physiologic”) doses in adults showed conflicting results, but
754
some authorities believe that replacement doses (25 mg/m2 hydrocorti-
sone 4 times daily) may be useful in children who have refractory shock
in association with impaired adrenal gland responsiveness; investigation
in Europe is ongoing.208,209
Reduced concentrations of protein C have been found in the plasma of
patients with meningococcal sepsis, and low levels are associated with an
increased risk of death. Activated protein C inhibits both inflammatory
and procoagulant pathways that are activated by the proinflammatory
cytokines released in response to sepsis and reduces mortality rates in
adults with sepsis.210 Although small controlled trials showed increased
survival in treated patients,211–213 a randomized, placebo-controlled study
of the use of activated protein C in children with severe sepsis failed to
demonstrate apparent benefit in children with septic shock, and serious
bleeding was a complication.214 Protein C is therefore not recommended.
Recombinant bactericidal permeability-increasing protein (rBPI),
which binds to endotoxin and blocks the inflammatory cascade, was
studied in a randomized, multicenter, placebo-controlled trial, but the
study was not sufficiently powered to assess a reduction in mortality rates
adequately.215,216 However, children who received rBPI had fewer amputa-
tions, decreased blood product transfusions, and improved functional
outcome, and fewer children died who received a full 24-hour infusion
of rBPI (2% rBPI vs. 6% placebo; P = 0.07).
Various other agents and other adjunctive therapies have been used or
considered in the management of septicemia including fibrinolysis,
extracorporeal membrane oxygenation, plasmapheresis, and antimedia-
tor therapy, but only the antiendotoxin antibody, HA1A, has been sub-
jected to rigorous clinical trials and did not show benefit.217 None of these
adjunctive therapies currently are recommended.
EMERGENCY MANAGEMENT
Pulmonary edema or poor pulmonary perfusion and hypoxia can
be present in patients with meningococcal septicemia and requires
elective endotracheal intubation during volume resuscitation. Intuba-
tion also is recommended if the patient is still in shock after 40 to
60 mL/kg of volume resuscitation because pulmonary edema is common
during ongoing resuscitation. After securing the airway, the 2 clinical
management priorities in children with meningococcal disease are
correction of cardiovascular shock and control of raised intracranial
pressure. Most patients die of decompensated shock, and a few die of
raised intracranial pressure. Aggressive volume resuscitation and ino-
tropic support to maintain tissue perfusion are critical to improving
survival and minimizing sequelae in patients with fulminant disease
and shock. Children with meningococcal septicemia may require fluid
replacement volumes equivalent to or several times greater than their
circulating blood volume. Fluid replacement should be administered
initially as 0.9% sodium chloride solution in a volume of 20 mL/kg
over 5 to 10 minutes and repeated until shock improves (reduction in
heart rate and increased tissue perfusion). Human albumin solution
(4.5%) is recommended as an alternative by many intensivists, but cur-
rently no data are available to guide the type of fluid to be used. If the
child is still in shock after receiving 40 to 60 mL/kg of fluid, vasoactive
therapy is required. Metabolic derangements, anemia, and coagulopathy
should be monitored and corrected as appropriate. Renal support may
be necessary. For the child with raised intracranial pressure, management
should be directed at ensuring adequate cerebral perfusion by correcting
coexistent shock and by providing neurointensive care. In patients with
meningococcal meningitis without raised intracranial pressure or inap-
propriate secretion of antidiuretic hormone, volume resuscitation should
be aggressive. No evidence supports the historical practice of fluid restric-
tion in such cases, and one study found increased rates of neurologic
sequelae among patients who had fluid restriction.218 Analysis of the
mechanisms of excess 48-hour mortality rates reported in children with
severe febrile illnesses who were given fluid boluses in a randomized trial
in Africa219 indicates that death was not primarily caused by respiratory
or neurologic events associated with fluid overload but by cardiovascular
collapse.220 Accordingly, fluid resuscitation and inotropic support remain
the standard approaches to meningococcal shock in settings where close
observation and intensive support are available.
An algorithm has been developed to assist direction of early manage-
ment in both children and adults,106,221 and updated versions are available
from the Meningitis Research Foundation website (www.meningitis.org).

OUTCOME
Mortality
The overall case-fatality rate for invasive meningococcal disease is
approximately 10%.57,179,222,223 In a case series from the Netherlands,224 the
risk of death was higher in infants <6 months of age, adolescents, and
adults >50 years of age (odds ratio, 5.1, 3.4, and 9.8, respectively) than in
children 1 to 9 years old. The risk of death was greater among female
patients (odds ratio, 2.3; 95% CI, 1.2 and 4.7).
Death or severe ischemic damage with extremity loss or extensive skin
gangrene occurs much more commonly in fulminant meningococcemia
than in meningitis. Optimized initial management and aggressive sup-
portive care in the pediatric intensive care unit of the most severely
affected patients have been associated with a reduction in mortality rates
in this group of patients from a predicted risk of death of 25% to less
than 5%.136 With prompt and appropriate antibiotic and supportive
therapy, patients with uncomplicated cases of meningococcal disease
improve rapidly. Most patients with meningitis return to a normal state
of consciousness within 2 days, are afebrile within 3 to 4 days, and show
resolution of meningismus within 4 to 5 days.
Prognostic scoring systems have been developed that use presenting
clinical signs and laboratory findings.225–227 The first of these systems
demonstrated that the combination of 3 or more of the following features
was associated with a poor prognosis: (1) petechiae for less than 12 hours
before presentation, (2) hypotension, (3) absence of meningismus, and
(4) peripheral blood WBC lower than 10,000 cells/mm3 and an erythro-
cyte sedimentation rate less than 10 mm/hr.228 The Glasgow meningococ-
cal septicemia prognostic score229 has been widely used as a research tool
but tends to overestimate mortality. The clinical utility of scoring systems
has not been fully established.
Postinfectious Inflammatory Syndromes
Various immunologic or reactive complications, such as arthritis,
cutaneous vasculitis, iritis, and pericarditis, can occur in patients with
meningococcal disease from 4 days after the onset of invasive disease
(after bacteriologic eradication). The mechanism is focal deposition of
immune complexes containing meningococcal polysaccharide antigen,
IgG, and C3 that results in acute inflammation.230 All forms of reactive
disease resolve spontaneously. Symptoms usually can be relieved by
administration of acetylsalicylic acid or nonsteroidal anti-inflammatory
agents.
The rate of reactive arthritis is 5% to 8%; reactive arthritis more
often is reported in adults than in children, and it affects medium-sized
joints preferentially.231 Fever occurs at the time of onset of joint pain,
and arthritis resolves within 6 to 10 days without residual damage. The
onset of arthritis is associated with the disappearance of meningococcal
antigen from the serum, a rise in antibody titer, and a drop in serum C3
concentration.232
Cutaneous vasculitis occurs in approximately 2% of patients, with
onset 5 to 9 days after appearance of disease.213 Small numbers of warm,
red papules appear, mainly on the extremities, and they often progress
to form bullae that rupture, leaving a shallow ulcer. Several crops of
papules can appear over 2 to 3 days. Healing occurs without scarring
in 4 to 8 days.
Inflammation of the iris or sclera occurs in approximately 1% of
patients, often in association with reactive arthritis or vasculitis.231 Reac-
tive pericarditis, characterized by chest pain, pericardial friction rub,
recurrence of fever, and sterile, nonpurulent pericardial exudate, also
can occur.233 Concurrent presence of polyarthritis and polyserositis is
common. Pericardial effusion rarely leads to tamponade or requires
drainage.
Sequelae
Rates of severe and moderate neurologic sequelae after 5 years are lower
after meningitis caused by N. meningitidis (2.9% and 6.5%, respectively)
than following meningitis caused by H. influenzae (3.4% and 7.3%,
respectively) or S. pneumoniae (9.7% and 13.9%, respectively).234 In 562
cases of meningococcal disease in the Netherlands, 8.5% of survivors had
one or more sequelae, including deafness in 3.1%, motor dysfunction
Neisseria meningitidis 125
in 1.2%, and other neurologic deficits in 1.2%.225 The frequency of
sequelae did not vary significantly with the serogroup or serotype of the
pathogen or with the sex or age of the patient. A review of 471 cases of
invasive meningococcal disease in Quebec, Canada, between 1990 and
1994 demonstrated significantly higher rates of death (13.8% vs. 7.2%)
and major complications such as skin scars and amputations (15.3%
vs. 3.2%) in patients infected with group C than in those with group B
meningococcal infection, respectively.222
Psychological problems are frequently reported, and neurologic defi-
cits are found in 7% of patients.36 It is important to perform follow-up
auditory testing in all patients with meningococcal disease to identify
hearing loss (rate of occurrence 2% to 15% of cases in various studies),235
as well as to provide hearing aids and plan cochlear implantation as
necessary in a timely manner.
Perfusion of the skin and muscle can be severely compromised in
meningococcal shock, and areas affected by purpura and pressure areas
can be necrotic and at risk of secondary infection. In one study, ischemic
infarction of skin and soft tissues resulted in significant scarring or
extremity loss in 3.9% of survivors, most often after fulminant menin-
gococcemia.225 Multiple areas are involved in most patients. The limbs
are the predominant sites of damage. In a study of 21 patients with skin
infarction, the lower limbs were involved in 20, the arms in 9, the trunk
in 8, the face in 4, and the scalp and ear in 1 each.236 The mean area of
skin necrosis was 13% of total body surface area. Across several studies,
skin damage or scarring was noted in 13% of cases.36
Limb compartment syndromes often are observed during the course
of disease, and fasciotomy has been used in management in some cir-
cumstances, but its role is not established clearly.237 Except in the presence
of infection, amputations of ischemic limbs should be undertaken late to
allow maximum limb recovery before lines of viability are finalized.
Amputations are necessary in approximately 3% of cases, and a further
3% of patients have other orthopedic complications. With effective surgi-
cal treatment, rehabilitation, and support such patients can achieve a
high quality of life; clinicians therefore should not be deterred from active
management in the acute phase of the disease.238
Impaired organ perfusion results from hypovolemia, vasoconstriction,
and myocardial depression resulting in prerenal failure in some patients,
with oliguria or anuria or acute tubular necrosis. Most patients recover
without any renal support, some require hemofiltration, and rarely
permanent renal failure ensures.
PREVENTION
Management of Contacts
Household and kissing contacts of a patient with meningococcal disease
are at significantly increased risk of meningococcal disease (Box
125.3).86,239,240 The incidence of disease in household contacts, although
BOX 125.3  Contacts of a Patient With Meningococcal Disease Who
Are at Increased Risk of Disease
Household members
Childcare center and nursery school contacts
School or college contacts during outbreak
Anyone directly exposed to a patient’s oral secretions through
mouth kissing or the sharing of food, drinks, utensils, glasses,
water bottles, or anything that has been in the mouth of the
patient
Healthcare personnel exposed directly to the patient’s oral
secretions through mouth-to-mouth resuscitation, or
endotracheal intubation or tube management in the first 2 days
of therapy without wearing a surgical maska
a
Healthcare workers without such exposure are not at increased risk.
Adapted from Advisory Committee on Immunization Practices. Prevention and control of
meningococcal disease: recommendations of the Advisory Committee on Immunization Prac-
tices (ACIP). MMWR Morb Mortal Wkly Rep 2000;49:1; and Pollard A, Begg N. Meningococcal
disease and healthcare workers. BMJ 1999;319:1147.
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 PART III  Etiologic Agents of Infectious Diseases
SECTION A  Bacteria
still low, is 500 to 1000 times that in the general population.241 In sporadic
cases of disease, 1% to 3% of households have 1 or more secondary cases
of disease within 30 days of onset of the index case if no intervention
occurs.242 Approximately 20% of secondary cases are coprimary infec-
tions (i.e., occurring on the same day as the index case); 30% of secondary
cases occur in the first week, 20% in the second week, and 30% in weeks
3 to 8 after the index case. Because of the rapid onset in 50% of related
cases, early antibiotic prophylaxis when indicated, education, and close
follow-up of contacts to ensure rapid intervention if they experience
febrile illness are important. Culture of specimens from contacts usefully
does not inform management.
Trials of mass prophylaxis with sulfadiazine in military recruit camps
during World War II suggested efficacy for eradication of carriage and
interruption of epidemics. However, mass prophylaxis has not been
effective in other situations,243 and usually it is avoided. The emergence
of worldwide resistance of capsular groups A, B, and C to sulfonamide
drugs after 1963 led to the investigation of other agents for use in eradica-
tion of meningococcal carriage as a means of prophylaxis. Efficacy
against all capsular groups has been noted for rifampin, minocycline,
ceftriaxone, ciprofloxacin, and ofloxacin. Minocycline rarely is used for
prophylaxis because of its high rate of adverse effects (dizziness, nausea,
and vomiting).
Rifampin is the only agent that has been studied widely, but it has the
following disadvantages: (1) the eradication rate is only 80% to 85%;
(2) adverse effects occur in 25% of patients; (3) 4 doses are required;
(4) rifampin is expensive and not readily available; and (5) a liquid
suspension is not always available for children.241 Moreover, emergence
of resistance to rifampin can occur rapidly. Ceftriaxone, administered as
a single intramuscular injection, has been shown to be >97% effective
in eradicating carriage.244 Additional advantages are single-dose therapy
and safety during pregnancy. Disadvantages are the pain associated
with intramuscular injection and potential adverse effects on mucosal
flora related to broad-spectrum activity. Ciprofloxacin and ofloxacin
effectively eradicate meningococcal carriage after a single oral dose.245–248
However, fluoroquinolones are not approved for use in pregnant
women, and the use of these drugs is restricted in children in some
countries.
All contacts must be treated immediately and concurrently for
maximal impact on secondary cases. Otherwise, untreated carriers could
infect contacts who have already completed prophylaxis. Treatment of
patients with index cases with ceftriaxone also eradicates carriage.
Patients who are treated with antibiotics not known to eradicate carriage
should receive appropriate prophylaxis before hospital discharge to
prevent reintroduction of the pathogen into the household or
community.
Details of prophylactic regimens are given in Table 125.2. Prophylaxis
is not routinely recommended for the following: (1) school, church, or
community contacts; or (2) medical personnel caring for the patient,
except for those who have unusual, direct exposure to respiratory secre-
tions through mouth-to-mouth resuscitation, or intubation or suction-
ing without wearing a mask.249 Prophylaxis is recommended for infants
and young children who have been in close contact with affected people
in daycare centers.
TABLE 125.2  Chemoprophylaxis Regimens for Contacts of Patients
of Meningococcal Disease
Antibiotic Dose
Rifampin 10 mg/kg per dose (maximum dose 600 mg) PO every 12
hours for 4 doses (for infants <1 month of age, 5 mg/kg
per dose)
Ceftriaxone Single injection of 125 mg for <15 years and 250 mg for
≥15 yearsa
Ciprofloxacin 20 mg/kg (max 500 mg) >1 month of agea
a
From American Academy of Pediatrics Committee on Infectious Diseases.
Red Book: 2015 Report of the Committee on Infectious Diseases, 30th ed. Elk Grove, IL,
American Academy of Pediatrics, 2015.
IM, intramuscularly; PO, by mouth.
756
Immunization
Polysaccharide Vaccines
Vaccines composed of purified capsular polysaccharide of large molecu-
lar size have been developed against capsular groups A, C, W, and Y and
have been formulated as monovalent A and C, bivalent A/C, and quad-
rivalent A,C,W,Y vaccines (PsACWY). The major vaccine-related deter-
minants of immunogenicity are the molecular size and dose of the
vaccine, and the major host factor is age.250,251 Currently licensed vaccines
contain 50 µg of each capsular group polysaccharide per dose. Vaccines
are safe, with rare reports of serious systemic events.251–254 Benign febrile
seizures have been reported rarely in young children who have undergone
vaccination with bivalent group A and group C vaccine.255 Transient local
reactions, such as erythema and tenderness, can occur at the site of
injection. These reactions are more common after quadrivalent vaccine
(30% to 40%) than after monovalent group A or C vaccines (8% to 10%).
In US adults vaccinated with PsACWY, bactericidal antibodies directed
at group A and C polysaccharides peaked at 1 month, declined after 2
years, but remained higher than baseline for 10 years after vaccination.256
In rural Nigeria, however, increases in antibody to group A polysaccha-
ride were not sustained 2 years after vaccination.257
Protection induced by meningococcal vaccine is capsular group spe-
cific. Group A vaccine is effective in preventing disease in all age groups
(Box 125.4). Two doses administered 2 to 3 months apart in infants 3 to
18 months of age (or 1 dose in older children and adults) have a protec-
tive efficacy >95%.66,67 Group A vaccine appears to be effective in termi-
nating epidemics of group A disease, although logistical challenges limit
the impact of this approach. However, because duration of protection
against invasive disease in adults does not appear to last more than 3 to
5 years, PsA vaccine is not recommended for routine use.
Immunization with the PsC vaccine has been >90% effective in pre-
venting disease in young adults, and its routine use in the military elimi-
nated outbreaks of group C disease.258,259 However, PsC vaccine is poorly
immunogenic in infants. Repeated doses of group C vaccine, unlike
group A vaccine, do not cause an anamnestic response at any age. Indeed,
1 dose of PsC vaccine was shown to induce immunologic hyporespon-
siveness to subsequent doses in infants, toddlers, and adults.251,260–262 The
duration and clinical relevance of such hyporesponsiveness are uncertain,
but the phenomenon can last several years in recipients.249,263
Group Y and group W polysaccharide vaccines are immunogenic in
children older than 12 to 24 months of age. Proof of efficacy has not been
obtained, mainly because of the absence of epidemics caused by groups
W or Y until more recent W outbreaks.65,264,265
The polysaccharide vaccines largely have been superseded by the gly-
coconjugate vaccines.
Conjugate Vaccines
Conjugation of group A, C, W, and Y polysaccharides to proteins such as
CRM197 (CRM), tetanus toxoid (TT), or diphtheria toxoid (D) achieves
similar or greater immunogenicity and duration of protection in infants,
children, adolescents, and adults without increases in reactogenicity,
compared with the much larger doses in plain polysaccharide
vaccines.260–268 Moreover, the conjugated vaccines induce immunologic
memory,261,263 unlike polysaccharide vaccines, and can overcome the
hyporesponsiveness induced by previous doses of some polysaccharide
vaccines.262,269 Conjugated group C vaccines also have been shown to
induce salivary IgG and IgA antibodies in infants vaccinated at 2, 3, and
4 months of age,270 adolescents,271 and young adults,272 and general use
of the vaccine is associated with reduction in carriage rates.112
Because of a significant rise in the incidence of group C disease, a mass
immunization program was started in November 1999 in the UK with
meningococcal conjugate C (MenC) vaccines from 3 manufacturers.273
Vaccination was offered first to infants <1 year of age and adolescents 15
to 17 years of age, the age groups at highest risk. Subsequently, vaccine
was offered to all children and young adults <24 years of age. The cam-
paign was highly effective both as a result of direct protection of individual
people and perhaps more as a result of community (herd) protection
through reduction in transmission of the organism.112,274,275
MenC vaccines have been licensed and used in many other countries
on the basis of the efficacy demonstrated in the UK, by using either a

BOX 125.4  Recommended Uses of Meningococcal Vaccines
RECOMMENDED USES
Routine immunization of infants or toddlers with monovalent
capsular group C meningococcal conjugate vaccine (MenC)
recommended in some countries (currently not available in the
United States) with booster doses increasingly advised in
adolescence to maintain individual protection and herd immunity
Routine immunization of children at 11 or 12 years of age and with
catch-up immunization of those through 18 years of age, using a
quadrivalent conjugate capsular group ACYW vaccine
(MenACYW), recommended in the US. Booster doses of
MenACYW for adolescents advised in some countries with
established MenC programs in early childhood.
Routine immunization of infants with MenB vaccine recommended in
the United Kingdom (2-, 4-, and 12-month schedule) and some
subcountry regions of Europe and Canada (2-, 4-, 6-, and
12-month schedule) (2 MenB are licensed currently in the US)
Immunization of at-risk populations for control of outbreaks caused
by capsular groups contained in vaccine
Immunization with relevant meningococcal vaccines of travelers to
an epidemic area (see Table 125.3 for US recommendations)
Routine immunization in high-risk setting with MenACWY or MenB
vaccines, or both (see Table 125.3 for US recommendations)
Immunization of children with special high-risk conditions:
■ UK recommendations: Persistent complement
deficiencies at 9 months of age and children with other
high-risk conditions such as asplenia at 2 years of age,
with MenACWY in a 2-dose series 3 months apart. MenB
vaccine also advised for these populations in some countries
2- or 3-dose infant schedule or a single-dose toddler schedule with a
catch-up campaign.62,276 Data from the UK show that persistence of
antibody after primary infant immunization is poor, and effectiveness
data indicate that protection wanes to 0 by 1 year after completion of the
3-dose infant schedule.274 In response to this finding, the UK Department
of Health announced the addition of a booster dose of MenC vaccine in
2006 to be administered in the second year of life. However, more recent
studies suggest that persistence of functional antibody is poor even after
this booster dose given at 1 year of age.277 By contrast, persistence of
antibody is more sustained after primary immunization of children who
are older than 10 years of age.278 Furthermore, a marked response to a
booster and persistence of antibody occur for at least 1 year if the booster
is administered beyond 6 years of age.279 Booster doses in adolescents now
have been implemented or are being considered in several countries with
an infant MenC program. Vaccination of this age group appears likely to
interrupt transmission of MenC bacteria, and thus introduction of
boosters should maintain the community protection induced following
the mass campaigns at the time of vaccine introduction. In a study of 53
people who developed invasive group C meningococcal disease despite
receipt of MenC vaccine, antibody response to disease was consistent
with an anamnestic response, a finding indicating that persistence of
antibody may be a better correlate of long-term protection than priming
for immune memory.280
In 2005, MenACYW-D (Menactra, Sanofi Pasteur, Swiftwater, PA) was
licensed and recommended for universal use in the US in children at the
age of 11 years.139 Preliminary data from the CDC in 2010 indicated a
vaccine effectiveness of 75% (95% CI, 17 to 93).281 Cases of Guillain-
Barré syndrome (GBS) occurring within 6 weeks of receipt were reported
soon after implementation of MenACYW-D for adolescents. Ongoing
investigations since then in the US, as well as surveillance in Canada,
describe no excess cases or rare excess cases over that predicted, and most
experts no longer consider GBS to be a risk of the vaccine.282,283 MenA-
CYW-CRM (GSK vaccines, Rixsensart, Belgium) was launched in 2010
in Europe and North America, and MenACYW-TT (Pfizer Vaccines, Pearl
River, NY) is also available in some regions. In view of their immunologic
advantages, the MenACYW conjugate vaccines should replace the plain
Neisseria meningitidis 125
■ US recommendations: Persistent complement
deficiencies, functional or anatomic asplenia, HIV
infection, or risk during a community outbreak
attributable to vaccine serogroup (beginning at 2 months
of age for HibMenCY-TT [MenHibRix, GlaxoSmithKline,
Philadelphia, Pa] or MenACWY-CRM [GlaxoSmithKline];
beginning at 9 months after primary pneumococcal conjugate
vaccines for MenACWY-D [Menactra, Sanofi Pasteur,
Swiftwater, Pa])
■ Travel to or residence in country where meningococcal
disease is hyperendemic or epidemic (beginning at 2
months of age for MenACWY-CRM and 9 months of age for
MenACWY-D) (see Table 125.3 for US MenB
recommendations)
REVACCINATION
Routine booster immunization of adolescents at 16 years of age
who received MenACYW at 11 or 12 years of age or at 18 years
of age for those who received MenACYW at 13 or 14 years of
age. No booster recommended routinely for persons who
received MenACYW at ≥15 years of age
Booster immunization of persons in high-risk groups every 5 years
(with first booster after 3 years in those immunized at <2 years of
age who continue to be at high risk of disease)
Recommendations for boosters of MenB vaccine pending
CONTRAINDICATIONS
Severe reaction (anaphylaxis) to previous dose of vaccine
polysaccharide vaccines for all indications in children and adults.
MenACYW vaccines are recommended universally at 11 years and from
2 months of age for those at increased risk of meningococcal disease.141
Waning of bactericidal antibody following MenACWY immunization
given at 11 or 12 years of age led to the US recommendation in 2010 for
a second dose at 16 years of age, or at 18 years of age if the primary dose
was given at 13 through 15 years of age.141 In countries with established
monovalent C conjugate vaccination programs in early childhood the
quadrivalent MenACWY vaccine or the monovalent MenC vaccine is
being introduced to overcome waning population immunity among
adolescents, as described earlier. The former approach has the advantage
of maintaining control of capsular group C disease and protecting the
vaccinated teenagers from A, Y, and W infection while also inducing
community protection to prevent disease caused by all 4 groups across
ages.
Prospects for control of epidemic group A meningococcal disease in
the meningitis belt of Africa have been enhanced by an alliance between
the World Health Organization (WHO) and the Program for Appropri-
ate Technology in Health (PATH) to develop a monovalent capsular
group A meningococcal vaccine for Africa, funded by the Bill & Melinda
Gates Foundation. Vaccine program implementation began across the
meningitis belt of Africa during 2010, and results indicate a decline in
disease among vaccinated populations.284
Development of a polysaccharide vaccine against group B meningo-
cocci, the major cause of endemic disease, is thwarted by the relative lack
of immunogenicity of the B polysaccharide in humans.285 Because B
polysaccharide has structural and immunologic identity with sugars
decorating the neural cell adhesion molecule, a membrane glycoprotein
on human neurons in the developing brain, such antibodies have the
potential to be autoreactive and thus harmful.286 Field trials of a vaccine
containing outer membrane vesicles (OMVs) (blebs of bacterial outer
membrane containing OMPs, lipid, and LPS) derived from a Norwegian
outbreak strain reduced the incidence of group B disease among school-
children aged 14 to 16 years by 53%.287 A Cuban OMV vaccine from a
local outbreak strain may have had somewhat greater efficacy in Cuba,288
but it did not perform so well when tested in other settings against
757
 PART III  Etiologic Agents of Infectious Diseases
SECTION A  Bacteria
heterologous strains. OMV vaccines may have limited utility for endemic
disease because the bactericidal antibody elicited appears to be limited
largely to the immunodominant strain-specific PorA proteins. However,
this property makes OMV vaccine ideal for control of an outbreak caused
by a single clone, such as in New Zealand, in which a single group B clone
caused a prolonged epidemic starting in the early 1990s. An OMV vaccine
based on the outbreak strain was first used in 2004 with high apparent
effectiveness,289 and the program was discontinued in 2008. Since the
vaccine campaign, most cases caused by the outbreak strain have been
among unvaccinated people, a finding suggesting that the vaccine may
still be providing some protection in the population.290
Development of a more comprehensive capsular group B vaccine has
been an important public health goal, and many vaccine candidates have
been considered over the past 3 decades, as reviewed by Sadarangani
and Pollard.291 Data from the genome-sequencing projects have provided
information about novel vaccine candidates,14 and 2 vaccines have been
licensed by various regulatory authorities: a 4-component vaccine con-
taining meningococcal factor H binding protein, neisserial adhesion A,
neisserial heparin binding antigen, and the New Zealand outbreak strain
OMV (MenB-4C); and a 2-component vaccine containing 2 variants
of meningococcal factor H binding protein (2fHbp) (MenB-FHbp).
Data from studies of these vaccines in adults and children indicate
that the vaccines induce bactericidal antibody against strains bearing
the antigens contained in the vaccine and provide in vitro evidence
of potential cross-protection to other endemic strains of meningococci
that contain and express variants of the vaccine antigens.292–296 MenB-4C
has been developed both for infants and adolescents (as with other
meningococcal vaccines) and has waning of antibody after vaccination
in early childhood, although this characteristic is variable among the
vaccine components,297–300 and persistence of immunity is better among
adolescents. Some evidence indicated an impact of MenB-4C vaccine
on carriage of the organism in the oropharynx in a study of university
students, but uncertainty remains about whether this effect is sufficient
to induce community protection.110 MenB-4C (GSK) was introduced
into the UK infant immunization program for all infants at 2, 4, and 12
months of age in September 2015, and it has been used for university
and community outbreaks of disease in the US and Canada, respectively.
Early data from the UK program indicate vaccine effectiveness (VE)
of 82.9% (95%, CI 24.1–95.2) against all capsular group B disease in
infants, which is presumed to be an underestimate of true VE since
the vaccine is not expected to cover all circulating strains. Two group
B meningococcal vaccines (MenB-FHbp [Trumenba, Pfizer, New York,
Key Points: Diagnosis, Management, and Prevention of Neisseria meningitidis Infection
MICROBIOLOGY
• Catalase-positive, oxidase-positive, piliated Gram-negative
coccus that oxidizes glucose and maltose
• Outer phospholipid membrane contains endotoxin and
various outer membrane proteins that are subject to phase
variation.
• Can be surrounded by a polysaccharide capsule or acapsulate;
5 capsule “capsular groups” associated with most global
disease: A, B, C, Y, and W
• Grows well on chocolate or blood agar; enhanced growth in
humidified carbon dioxide environment
EPIDEMIOLOGY
• Highest rate of colonization (up to 40%) in adolescents and
young adults; colonization rare in children <10 years of age
• Respiratory route of transmission
• Peak of disease in children <2 years of age and smaller peak in
adolescence
• Risk of disease increased by smoking (active and passive),
overcrowding, previous viral respiratory tract infection, winter or
dry season, moving into new communities, complement
deficiency, and various human single nucleotide polymorphisms.
758
TABLE 125.3  Increased Risk Groups Recommended for the
Different Meningococcal Vaccine
MenACWY MenB
a
Complement deficiency Complement deficiencya
Anatomic or functional aspleniab Anatomic or functional aspleniab
HIV infection
Outbreak caused by MenACWYc Outbreak caused by MenBc
Microbiologistsd Microbiologistsd
Travelers e
—
First-year college studentsf —
Military recruits —
a
Inherited or chronic deficiencies of C3, C5-9, properdin, factor D, or factor H or eculizumab
(Soliris) use.
b
Includes sickle cell disease.
c
The Centers for Disease Control and Prevention defines outbreaks and those at risk: http://
www.cdc.gov/meningococcal/downloads/interim-guidance.pdf.
d
Only microbiologists who routinely work with Neisseria meningitidis.
e
To areas with hyperendemic or epidemic meningococcal disease.
f
Unvaccinated or inadequately vaccinated first-year college students who live in residence
halls.
MenACWY, quadrivalent meningococcal A, C, Y, W conjugate vaccine; MenB, meningococcal
B vaccine.
NY] for a 3-dose series and MenB-4C [Bexsero, GlaxoSmithKline] for a
2-dose series) were licensed by the US Food and Drug Administration
by an accelerated pathway in 2014 and 2015 for children and adults 10
through 25 years of age. The AAP and the CDC recommend use of MenB
vaccine for high-risk groups (Table 125.3). The current low number of
N. meningitidis B cases in the US makes universal recommendation of
MenB vaccines cost prohibitive. Despite outbreaks of group B on US
college campuses, the incidence of disease in college students (0.09 per
100,000) is similar to or lower than the incidence in all 18 through 23
year olds (0.14 per 100,000) (CDC, unpublished data), thus precluding a
recommendation of MenB vaccine for college students alone.94 Approval
was based on clinical trial immunogenicity data rather than clinical
efficacy.
All references are available online at www.expertconsult.com.
• Capsular group distribution varies over time and with geographic
location: B and C (where vaccine has not been introduced)
account for most disease in Europe; B, C, and Y in North
America; and capsular group A in Africa and Asia.
• In developed countries most cases are sporadic but small
clusters can occur (mostly capsular group C strains). Epidemics
of disease can occur (mainly capsular group A, with some X or
W) in developing countries, especially the meningitis belt of Africa.
CLINICAL FEATURES
• Four presentations, all of which are most often associated with a
nonblanching (petechial or purpuric) rash:
■ Meningitis with a mortality rate <5%
■ Septic shock (meningococcemia or meningococcal
septicemia) with a high mortality rate
■ A mixed picture of meningitis and shock
■ Bloodstream infection without shock or meningitis
• Death usually is caused by cardiovascular collapse in patients
with septic shock or, rarely, by raised intracranial pressure in
patients with meningitis.
• Complications include the following: a self-limiting inflammatory
reactive syndrome; neurologic sequelae (including deafness).
 Key Points: Diagnosis, Management and Prevention of Neisseria meningitidis Infection—cont’d
following meningitis; and limb, digit, and skin scarring or loss
after septic shock
DIAGNOSIS
• Microbiologic diagnosis usually is made by Gram stain
of CSF or culture of blood (automated culture system)
or CSF
• PCR of blood or CSF can yield higher rate of identification
(especially with receipt of antibiotic before sampling)
TREATMENT
• Ceftriaxone is recommended as empiric therapy for suspected
cases
• Urgent management of shock includes volume replacement
therapy and supportive care (mechanical ventilation and
inotropic drugs)
• Meningococcal meningitis should be managed with antibiotics
and maintenance fluids with careful assessment for coexistent
shock or raised intracranial pressure
DURATION OF THERAPY
• Duration of therapy should be 5 to 7 days, but some studies
suggest that as little as 1 dose of an appropriate antibiotic may
be sufficient
• Response to therapy usually is rapid
CSF, cerebrospinal fluid; PCR, polymerase chain reaction.
KEY REFERENCES
2. Vieusseaux G. Mémoire sur le maladie qui a régné à Genève au printemps de 1805.
J Med Chir Pharm 1805;2:163–165.
27. Heist GD, Solis-Cohen S, Solis-Cohen M. A study of the virulence of meningococci
for man and of human susceptibility to meningococcic infection. J Immunol
1922;7:1–33.
28. Goldschneider I, Gotschlich E, Artenstein M. Human immunity to the meningococ-
cus. I. The role of humoral antibodies. J Exp Med 1969;129:1307–1326.
29. Goldschneider I, Gotschlich E, Artenstein M. Human immunity to the meningococ-
cus. II. Development of natural immunity. J Exp Med 1969;129:1327–1348.
107. Pollard AJ, Britto J, Nadel S, et al. Emergency management of meningococcal
disease. Arch Dis Child 1999;80:290–296.
108. Christensen H, May M, Bowen L, et al. Meningococcal carriage by age: a systematic
review and meta-analysis. Lancet Infect Dis 2010;10:853–861.
VACCINE PREVENTION
• Monovalent capsular group C meningococcal conjugate vaccines
(MenC) are widely used in Europe, Australia, and Canada for
routine immunization of infants or toddlers and are highly
effective, although more recent data suggest that an adolescent
booster is required to maintain population immunity
• Quadrivalent meningococcal A, C, Y, W conjugate vaccines
(MenACYW) are used routinely in North America for adolescent
immunization and are now recommended in many countries for
high-risk groups and travelers (as young as 2 months of age)
and are being adopted to replace MenC as an adolescent
booster outside the US
• Booster doses of MenACYW are recommended in the US for
high-risk children and persons immunized at <15 years of age
• Capsular group B outer membrane vesicle (OMV) vaccines have
been used successfully for outbreaks involving single clones but
are not suitable for endemic, polyclonal disease
• Two novel capsular group B vaccines (MenB-4C, 2-dose series;
MenB-FHbp, 3-dose series) aimed at broad capsular group B
coverage have been licensed for people ≥10 years of age.
Recommendations in the US are limited to at-risk patients and
outbreak settings, and the vaccines can be given at 16 through
23 years of age at “clinical discretion”
112. Read RC, Baxter D, Chadwick DR, et al. Effect of a quadrivalent meningococcal
ACWY glycoconjugate or a serogroup B meningococcal vaccine on meningo-
coccal carriage: an observer-blind, phase 3 randomised clinical trial. Lancet
2014;384:2123–2131.
136. Harrison L, Dwyer D, Maples C, et al. Risk of meningococcal disease in college
students. JAMA 1999;281:1906–1910.
277. Trotter CL, Andrews NJ, Kaczmarski EB, et al. Effectiveness of meningococ-
cal serogroup C conjugate vaccine 4 years after introduction. Lancet 2004;364:
365–367.
295. Gossger N, Snape MD, Yu LM, et al; European MenB Vaccine Study Group.
Immunogenicity and tolerability of recombinant serogroup B meningococcal
vaccine administered with or without routine infant vaccinations according to
different immunization schedules: a randomized controlled trial. JAMA 2012;307:
573–582.

REFERENCES
1. Gold R. Clinical aspects of meningococcal disease. In: Vedros N (ed) Evolution of
Meningococcal Disease, Vol. 2. Boca Raton, FL, CRC Press, 1987, p 69.
2. Vieusseaux G. Mémoire sur le maladie qui a régné à Genève au printemps de 1805.
J Med Chir Pharm 1805;2:163–165.
3. Danielson L, Mann E. The history of a singular and very mortal disease, which lately
made its appearance in Medfield. Med Agric Reg 1806;1:65.
4. Weichselbaum A. Ueber die Aetiologie der akuten Meningitis cerebro-spinalis.
Fortschr Med 1887;5:573–583, 620–626.
5. Vedros N. Development of meningococcal serogroups. In: Vedros N (ed) Evolution
of Meningococcal Disease, Vol. 2. Boca Raton, FL, CRC Press, 1987, p 33.
6. Frasch C. Development of meningococcal serotyping. In: Vedros N (ed) Evolution
of Meningococcal Disease, Vol. 2. Boca Raton, FL, CRC Press, 1987, p 39.
7. Vogel U, Claus H. Molecular epidemiology of Neisseria meningitidis. Front Biosci
2003;8:E14–E22.
8. Maiden MC, Bygraves JA, Feil E, et al. Multilocus sequence typing: a portable
approach to the identification of clones within populations of pathogenic micro-
organisms. Proc Natl Acad Sci USA 1998;95:3140–3145.
9. Parkhill J, Achtman M, James K, et al. Complete DNA sequence of a serogroup A
strain of Neisseria meningitidis Z2491. Nature 2000;404:502–506.
10. Tettelin H, Saunders N, Heidelberg J, et al. Complete genome sequence of Neisseria
meningitidis serogroup B strain MC58. Science 2000;287:1809–1815.
11. Kriz B, Svandova E, Musilek M. Antimeningococcal herd immunity in the Czech
Republic: influence of an emerging clone, Neisseria meningitidis ET-15/37. Epide-
miol Infect 1999;123:193–200.
12. Smith J, Lehmann A, Lie L, et al. Outbreak of meningococcal disease in western
Norway due to a new serogroup C variant of the ET-5 clone: effect of vaccination
and selective carriage eradication. Epidemiol Infect 1999;123:373–382.
13. Linz B, Schendker M, Zhu P, et al. Frequent interspecific genetic exchange between
commensal neisseriae and Neisseria meningitidis. Mol Microbiol 2000;35:1049–1058.
14. Pizza M, Scarlato V, Masignani V, et al. Identification of vaccine candidates
against serogroup B meningococcus by whole-genome sequencing. Science
2000;287:1815–1820.
15. Kelly DF, Rappuoli R. Reverse vaccinology and vaccines for serogroup B Neisseria
meningitidis. Adv Exp Med Biol 2005;568:217–223.
16. DeVoe IW. The meningococcus and mechanisms of pathogenicity. Microbiol Rev
1982;46:162–190.
17. Virji M, Makepeace K, Ferguson DJ, et al. Meningococcal Opa and Opc proteins:
their role in colonization and invasion of human epithelial and endothelial cells.
Mol Microbiol 1993;10:499–510.
18. Bradley CJ, Griffiths NJ, Rowe HA, et al. Critical determinants of the interactions
of capsule-expressing Neisseria meningitidis with host cells: the role of receptor
density in increased cellular targeting via the outer membrane Opa proteins. Cell
Microbiol 2005;7:1490–1503.
19. Brandtzaeg P, Kierulf P, Gaustad P, et al. Plasma endotoxin as a predictor of
multiple organ failure and death in systemic meningococcal disease. J Infect Dis
1989;159:195–204.
20. Emonts M, Hazelzet JA, de Groot R, et al. Host genetic determinants of Neisseria
meningitidis infections. Lancet Infect Dis 2003;3:565–577.
21. Riordan FA, Marzouk O, Thomson AP, et al. Proinflammatory and anti-
inflammatory cytokines in meningococcal disease. Arch Dis Child 1996;75:453–454.
22. Girardin E, Roux-Lombard P, Grau GE, et al. Imbalance between tumour necrosis
factor-alpha and soluble TNF receptor concentrations in severe meningococcaemia.
The J5 Study Group. Immunology 1992;76:20–23.
23. Waage A, Brandtzaeg P, Halstensen A, et al. The complex pattern of cytokines
in serum from patients with meningococcal septic shock: association between
interleukin 6, interleukin 1, and fatal outcome. J Exp Med 1989;169:333–338.
24. Gupta S, Tuladhar AB. Does early administration of dexamethasone improve
neurological outcome in children with meningococcal meningitis? Arch Dis Child
2004;89:82–83.
25. van de Beek D, de Gans J, Tunkel AR, et al. Community-acquired bacterial menin-
gitis in adults. N Engl J Med 2006;354:44–53.
26. Matsunami T, Kolmer JA. The relation of the meningococcidal activity of the blood
to resistance to virulent meningococci. J Immunol 1918;111:201–212.
27. Heist GD, Solis-Cohen S, Solis-Cohen M. A study of the virulence of meningococci
for man and of human susceptibility to meningococcic infection. J Immunol
1922;7:1–33.
28. Goldschneider I, Gotschlich E, Artenstein M. Human immunity to the meningococ-
cus. I: The role of humoral antibodies. J Exp Med 1969;129:1307–1326.
29. Goldschneider I, Gotschlich E, Artenstein M. Human immunity to the meningococ-
cus. II: Development of natural immunity. J Exp Med 1969;129:1327–1348.
30. Jones G, Williams J, Christodoulides M, et al. Lack of immunity of university
students before an outbreak of serogroup C meningococcal infection. J Infect Dis
2000;181:1172–1175.
31. Trotter C, Borrow R, Andrews N, et al. Seroprevalence of meningococcal serogroup
C bactericidal antibody in England and Wales in the pre-vaccination era. Vaccine
2003;21:1094–1098.
32. Pollard AJ, Ochnio J, Ho M, et al. Disease susceptibility to ST11 complex meningo-
cocci bearing serogroup C or W135 polysaccharide capsules, North America. Emerg
Infect Dis 2004;10:1812–1815.
33. Salit IE. Meningococcemia caused by serogroup W135: association with hypogam-
maglobulinemia. Arch Intern Med 1981;141:664–665.
34. Hobbs JR, Milner RD, Watt PJ. Gamma-M deficiency predisposing to meningococ-
cal septicaemia. Br Med J 1967;4:583–586.
Neisseria meningitidis 125
35. Swartz MN. Bacterial meningitis: a view of the past 90 years. N Engl J Med
2004;351:1826–1828.
36. National Collaborating Centre for Women’s and Children’s Health. Bacterial
Meningitis and Meningococcal Septicaemia: Management of Bacterial Meningitis
and Meningococcal Septicaemia in Children and Young People Younger Than 16
Years in Primary and Secondary Care. London, Royal College of Obstetricians and
Gynaecologists, 2010.
37. D’Amelio R, Agostoni A, Biselli R, et al. Complement deficiency and antibody
profile in survivors of meningococcal meningitis due to common serogroups in
Italy. Scand J Immunol 1992;35:589–595.
38. Ross SC, Densen P. Complement deficiency states and infection: epidemiology,
pathogenesis and consequences of neisserial and other infections in an immune
deficiency. Medicine (Baltimore) 1984;63:243–273.
39. Petersen BH, Lee TJ, Snyderman R, et al. Neisseria meningitidis and Neisseria
gonorrhoeae bacteremia associated with C6, C7, or C8 deficiency. Ann Intern Med
1979;90:917–920.
40. Fijen CA, Kuijper EJ, Hannema AJ, et al. Complement deficiencies in patients over
ten years old with meningococcal disease due to uncommon serogroups. Lancet
1989;2:585–588.
41. Lassiter HA, Watson SW, Seifring ML, et al. Complement factor 9 deficiency in the
serum of neonates. J Infect Dis 1992;166:53–57.
42. Densen P. Complement deficiencies and meningococcal disease. Clin Exp Immunol
1991;86(suppl 1):57–62.
43. Platonov AE, Beloborodov VB, Vershinina IV. Meningococcal disease in patients
with late complement component deficiency: studies in the USSR. Medicine
(Baltimore) 1993;72:374–392.
44. Ross SC, Rosenthal PJ, Berberich HM, et al. Killing of Neisseria meningitidis by
human neutrophils: implications for normal and complement-deficient individu-
als. J Infect Dis 1987;155:1266–1275.
45. Bredius R, Derkx B, Fijen C, et al. Fc receptor IIa (CD32) polymorphism in
fulminant meningococcal septic shock in children. J Infect Dis 1994;170:848–853.
46. Pollard AJ, Frasch C. Development of natural immunity to Neisseria meningitidis.
Vaccine 2001;19:1327–1346.
47. Jones G, Christodoulides M, Brooks JL, et al. Dynamics of carriage of Neisseria
meningitidis in a group of military recruits: subtype stability and specificity of the
immune response following colonization. J Infect Dis 1998;178:451–459.
48. Gold R, Lepow M, Goldschneider I, et al. Carriage of Neisseria meningitidis and
Neisseria lactamica in infants and children. J Infect Dis 1978;137:112.
49. Kim J, Mandrell R, Griffiss J. Neisseria lactamica and Neisseria meningitidis share
lipooligosaccharide epitopes but lack common capsular and class 1, 2 and 3 protein
epitopes. Infect Immun 1989;57:602.
50. Kasper DL, Winkelhake JL, Zollinger WD, et al. Immunochemical similarity
between polysaccharide antigens of Escherichia coli 07: K1(L):NM and group B
Neisseria meningitidis. J Immunol 1973;110:262–268.
51. Glode MP, Robbins JB, Liu TY, et al. Cross-antigenicity and immunogenicity
between capsular polysaccharides of group C Neisseria meningitidis and of Esch-
erichia coli K92. J Infect Dis 1977;135:94–104.
52. Wiertz EJ, Delvig A, Donders EM, et al. T-cell responses to outer membrane
proteins of Neisseria meningitidis: comparative study of the Opa, Opc, and PorA
proteins. Infect Immun 1996;64:298–304.
53. Pollard AJ, Galassini R, Rouppe van der Voort EM, et al. Cellular immune responses
to Neisseria meningitidis in children. Infect Immun 1999;67:2452–2463.
54. Davenport V, Guthrie T, Findlow J, et al. Evidence for naturally acquired
T cell–mediated mucosal immunity to Neisseria meningitidis. J Immunol
2003;171:4263–4270.
55. Hallissey CM, Heyderman RS, Williams NA. Human tonsil-derived dendritic cells
are poor inducers of T cell immunity to mucosally encountered pathogens. J Infect
Dis 2014;209:1847–1856.
56. European Union Invasive Bacterial Infections Surveillance Network. Invasive Neis-
seria meningitidis in Europe—2002. http://www.hpa-bioinformatics.org.uk/euibis/
meningo/meningo_statistics.htm.
57. Rosenstein N, Perkins B, Stephens D, et al. The changing epidemiology of
meningococcal disease in the United States, 1992–1996. J Infect Dis 1999;180:
1894–1901.
58. Swartley JS, Marfin AA, Edupuganti S, et al. Capsule switching of Neisseria menin-
gitidis. Proc Natl Acad Sci USA 1997;94:271–276.
59. Hubert B, Caugant DA. Recent changes in meningococcal disease in Europe. Euro
Surveill 1997;2:69–71.
60. Connolly M, Noah N. Is group C meningococcal disease increasing in Europe? A
report of surveillance of meningococcal infection in Europe 1993–6. European
Meningitis Surveillance Group. Epidemiol Infect 1999;122:41–49.
61. Rosenstein NE, Perkins BA, Stephens DS, et al. The changing epidemiol-
ogy of meningococcal disease in the United States, 1992–1996. J Infect Dis
1999;180:1894–1901.
62. Snape MD, Pollard AJ. Meningococcal polysaccharide-protein conjugate vaccines.
Lancet Infect Dis 2005;5:21–30.
63. American Academy of Pediatrics. Committee on Infectious Diseases. Serogroup B
meningococcal vaccines: policy statement. Pediatrics 2016;138:pii: e20161890.
64. MacNeil JR, Rubin L, Folaranmi T, et al. Use of serogroup B meningococcal vaccines
in adolescents and young adults: recommendations of the Advisory Committee
on Immunization Practices, 2015. MMWR Morb Mortal Wkly Rep 2015;64:
1171–1176.
65. Ladhani SN, Beebeejaun K, Lucidarme J, et al. Increase in endemic Neisseria
meningitidis capsular group W sequence type 11 complex associated with severe
invasive disease in England and Wales. Clin Infect Dis 2015;60:578–585.
759.e1
 PART III  Etiologic Agents of Infectious Diseases
SECTION A  Bacteria
66. Peltola H, Makela P, Kayhty H, et al. Clinical efficacy of meningococcus group A
capsular polysaccharide vaccine in children three months to five years of age. N
Engl J Med 1977;297:686–691.
67. Lennon D, Gellin B, Hood D, et al. Successful intervention in a group A meningo-
coccal outbreak in Auckland, New Zealand. Pediatr Infect Dis J 1992;11:617–623.
68. Dyet K, Devoy A, McDowell R, et al. New Zealand’s epidemic of meningococ-
cal disease described using molecular analysis: implications for vaccine delivery.
Vaccine 2005;23:2228–2230.
69. Achtman M, van der Ende A, Zhu P, et al. Molecular epidemiology of serogroup A
meningitis in Moscow, 1969 to 1997. Emerg Infect Dis 2001;7:420–427.
70. World Health Organization Department of Communicable Disease Surveillance
and Response. WHO Report on Global Surveillance of Epidemic-Prone Infec-
tious Diseases. 2000. http://www.who.int/csr/resources/publications/surveillance/
Meningitis.pdf.
71. Moore P. Meningococcal meningitis in sub-Saharan Africa: a model for the epi-
demic process. Clin Infect Dis 1992;14:515–525.
72. Boisier P, Nicolas P, Djibo S, et al. Meningococcal meningitis: unprecedented inci-
dence of serogroup X-related cases in 2006 in Niger. Clin Infect Dis 2007;44:657–663.
73. Gagneux SP, Hodgson A, Smith TA, et al. Prospective study of a serogroup X
Neisseria meningitidis outbreak in Northern Ghana. J Infect Dis 2002;185:618–626.
74. Njanpop-Lafourcade BM, Parent du Chatelet I, Sanou O, et al. The establishment
of Neisseria meningitidis serogroup W135 of the clonal complex ET-37/ST-11 as
an epidemic clone and the persistence of serogroup A isolates in Burkina Faso.
Microbes Infect 2005;7:645–649.
75. Baker M, McNicholas A, Garrett N, et al. Household crowding a major risk factor
for epidemic meningococcal disease in Auckland children. Pediatr Infect Dis J
2000;19:983–990.
76. Lingappa JR, Al-Rabeah AM, Hajjeh R, et al. Serogroup W-135 meningococcal
disease during the Hajj, 2000. Emerg Infect Dis 2003;9:665–671.
77. Pastor P, Medley F, Murphy T. Meningococcal disease in Dallas County, Texas:
results of a six-year population-based study. Pediatr Infect Dis J 2000;19:324–348.
78. Greenwood B. The epidemiology of acute bacterial meningitis in tropical Africa.
In: William JD, Burnie J (eds) Bacterial Meningitis. London, Academic Press, 1987,
pp 61–91.
79. Berild D, Gedde-Dahl TW, Abrahamsen T. Meningococcal disease in the Norwegian
Armed Forces 1967–1979: some epidemiological aspects. NIPH Ann 1980;3:23–30.
80. Neal KR, Nguyen-Van-Tam J, Monk P, et al. Invasive meningococcal disease among
university undergraduates: association with universities providing relatively large
amounts of catered hall accommodation. Epidemiol Infect 1999;122:351–357.
81. Stanwell-Smith R, Stuart J, Hughes A, et al. Smoking, the environment and menin-
gococcal disease: a case control study. Epidemiol Infect 1994;112:315–328.
82. Thomas J, Bendana N, Waterman S, et al. Risk factors for carriage of meningococ-
cus in the Los Angeles County men’s jail system. Am J Epidemiol 1991;133:286–295.
83. Hubert B, Watier L, Garnerin P, et al. Meningococcal disease and influenza-like
syndrome: a new approach to an old question. J Infect Dis 1992;166:542–545.
84. Moore P, Hierholkzer J, DeWitt W, et al. Respiratory viruses and Mycoplasma as cofac-
tors for epidemic group A meningococcal meningitis. JAMA 1990;264:1271–1275.
85. Cartwright K, Jones D, Smith A, et al. Influenza A and meningococcal disease.
Lancet 1991;338:554–557.
86. Advisory Committee on Immunization Practices. Prevention and control of menin-
gococcal disease: recommendations of the Advisory Committee on Immunization
Practices (ACIP). MMWR Recomm Rep 2000;49(RR-07):1–20.
87. Neal K, Nguyen-Van-Tam J, Jeffrey N, et al. Changing carriage rate of Neisseria men-
ingitidis among university students during the first week of term: cross sectional
study. BMJ 2000;320:846–849.
88. Fitzpatrick P, Salmon R, Hunter P, et al. Risk factors for carriage of Neisseria
meningitidis during an outbreak in Wales. Emerg Infect Dis 2000;6:65–69.
89. Riordan T, Cartwright K, Andrews N, et al. Acquisition and carriage of meningo-
cocci in marine commando recruits. Epidemiol Infect 1998;121:495–505.
90. Stuart JM, Cartwright KA, Dawson JA, et al. Risk factors for meningococcal disease:
a case control study in south west England. Community Med 1988;10:139–146.
91. Fijen C, Kuijper E, te Bulte M, et al. Assessment of complement deficiency in patients
with meningococcal disease in the Netherlands. Clin Infect Dis 1999;28:98–105.
92. Densen P. Complement deficiencies and meningococcal disease. Clin Exp Immunol
1991;86(suppl 1):57–62.
93. Nicholson A, Lepow I. Host defense against Neisseria meningitidis requires a
complement-dependent bactericidal activity. Science 1979;205:298–299.
94. http://www.soliris.net/resources/pdf/soliris_pi_mg.pdf.
95. Hoare S, El-Shazali O, Clark JE, et al. Investigation for complement deficiency
following meningococcal disease. Arch Dis Child 2002;86:215–217.
96. Platonov AE, Vershinina IV, Kuijper EJ, et al. Long term effects of vaccination of
patients deficient in a late complement component with a tetravalent meningococ-
cal polysaccharide vaccine. Vaccine 2003;21:4437–4447.
97. Bredius RG, Derkx BH, Fijen CA, et al. Fc gamma receptor IIa (CD32) poly-
morphism in fulminant meningococcal septic shock in children. J Infect Dis
1994;170:848–853.
98. Faber J, Scheussleer T, Finn A, et al. Age-dependent association of human mannose-
binding lectin mutations with susceptibility to invasive meningococcal disease in
childhood. Pediatr Infect Dis J 2007;26:243–246.
99. Davila S, Wright VJ, Khor CC, et al; International Meningococcal Genetics Consor-
tium. Genome-wide association study identifies variants in the CFH region associ-
ated with host susceptibility to meningococcal disease. Nat Genet 2010;42:772–776.
100. Texereau J, Pene F, Chiche JD, et al. Importance of hemostatic gene polymor-
phisms for susceptibility to and outcome of severe sepsis. Crit Care Med
2004;32(suppl):S313–S319.
759.e2
101. Read RC. Neisseria meningitidis: clones, carriage, and disease. Clin Microbiol Infect
2014;20:391–395.
102. Ninis N, Phillips C, Bailey L, et al. The role of healthcare delivery in the outcome of
meningococcal disease in children: case-control study of fatal and non-fatal cases.
BMJ 2005;330:1475.
103. Booy R, Habibi P, Nadel S, et al. Reduction in case fatality rate from menin-
gococcal disease associated with improved healthcare delivery. Arch Dis Child
2001;85:386–390.
104. Thorburn K, Baines P, Thomson A, et al. Mortality in severe meningococcal disease.
Arch Dis Child 2001;85:382–385.
105. Pollard AJ, Britto J, Nadel S, et al. Emergency management of meningococcal
disease. Arch Dis Child 1999;80:290–296.
106. Christensen H, May M, Bowen L, et al. Meningococcal carriage by age: a systematic
review and meta-analysis. Lancet Infect Dis 2010;10:853–861.
107. Gold R, Goldschneider I, Lepow ML, et al. Carriage of Neisseria meningitidis and
Neisseria lactamica in infants and children. J Infect Dis 1978;137:112–121.
108. Claus H, Maiden MC, Wilson DJ, et al. Genetic analysis of meningococci carried
by children and young adults. J Infect Dis 2005;191:1263–1271.
109. Yazdankhah SP, Kriz P, Tzanakaki G, et al. Distribution of serogroups and genotypes
among disease-associated and carried isolates of Neisseria meningitidis from the
Czech Republic, Greece, and Norway. J Clin Microbiol 2004;42:5146–5153.
110. Read RC, Baxter D, Chadwick DR, et al. Effect of a quadrivalent meningococcal
ACWY glycoconjugate or a serogroup B meningococcal vaccine on meningo-
coccal carriage: an observer-blind, phase 3 randomised clinical trial. Lancet
2014;384:2123–2131.
111. Jeppesen CA, Snape MD, Robinson H, et al. Meningococcal carriage in adolescents
in the United Kingdom to inform timing of an adolescent vaccination strategy. J
Infect 2015;71:43–52.
112. Maiden MC, Stuart JM. Carriage of serogroup C meningococci 1 year after menin-
gococcal C conjugate polysaccharide vaccination. Lancet 2002;359:1829–1831.
113. Edwards E, Devine L, Sengbush C, et al. Immunological investigations of menin-
gococcal disease. Scand J Infect Dis 1977;9:105–110.
114. Ala’Aldeen DA, Neal KR, Ait-Tahar K, et al. Dynamics of meningococcal long-term
carriage among university students and their implications for mass vaccination. J
Clin Microbiol 2000;38:2311–2316.
115. Jones GR, Williams JN, Christodoulides M, et al. Lack of immunity in university
students before an outbreak of serogroup C meningococcal infection. J Infect Dis
2000;181:1172–1175.
116. Neal KR, Nguyen-Van-Tam JS, Jeffrey N, et al. Changing carriage rate of Neis-
seria meningitidis among university students during the first week of term: cross
sectional study. BMJ 2000;320:846–849.
117. Cooke RP, Riordan T, Jones DM, et al. Secondary cases of meningococcal infection
among close family and household contacts in England and Wales, 1984–7. BMJ
1989;298:555–558.
118. Froholm L, Holton E, Poolman J, et al. Typing of Norwegian meningococcal isolates
and possible implications for serogroup B vaccination. In: Schoolnik G (ed) The
Pathogenic Neisseriae. Washington, DC, American Society for Microbiology, 1985,
p 541.
119. Poolman J, Jonsdottir K, Jones M, et al. Meningococcal serotypes and serogroup B
disease in north-west Europe. Lancet 1986;2:555.
120. Gilmore A, Jones G, Barker M, et al. Meningococcal disease at the University of
Southampton: outbreak investigation. Epidemiol Infect 1999;123:185–192.
121. Smith J, Lehmann A, Lie L, et al. Outbreak of meningococcal disease in western
Norway due to a new serogroup C variant of the ET-5 clone: effect of vaccination
and selective carriage eradication. Epidemiol Infect 1999;123:373–382.
122. Blakebrough IS, Greenwood BM, Whittle HC, et al. The epidemiology of infections
due to Neisseria meningitidis and Neisseria lactamica in a northern Nigerian com-
munity. J Infect Dis 1982;146:626–637.
123. De Wals P, Gilquin C, De Maeyer S, et al. Longitudinal study of asymptomatic
meningococcal carriage in two Belgian populations of schoolchildren. J Infect
1983;6:147–156.
124. Samuelsson S, Ege P, Berthelsen L, et al. An outbreak of serogroup B:15:P1.16
meningococcal disease, Frederiksborg County, Denmark, 1987–9. Epidemiol Infect
1992;108:19–30.
125. Gold R. Meningococcal disease in Canada: 1991–92. Can J Public Health
1992;83:5–8.
126. Ronne T, Lind I, Buhl L, et al. Recurrent localized outbreaks of group C meningo-
coccal disease and selective vaccination programmes. J Microbiol 1986;51:221.
127. Morrow H, Slaten D, Reingold A, et al. Risk factors associated with a school-
related outbreak of serogroup C meningococcal disease. Pediatr Infect Dis J 1990;9:
394–398.
128. Gully P. Canada: meningococcal disease. Lancet 1992;339:920.
129. Riesbeck K, Orvelid-Mölling P, Fredlund H, et al. Long-term persistence of a
discotheque-associated invasive Neisseria meningitidis group C strain as proven
by pulsed-field gel electrophoresis and porA gene sequencing. J Clin Microbiol
2000;38:1638–1640.
130. Hauri A, Ehrhard I, Frank U, et al. Serogroup C meningococcal disease outbreak
associated with discotheque attendance during carnival. Epidemiol Infect
2000;124:69–73.
131. Fernandez S, Arreaza L, Santiago I, et al. Carriage of a new epidemic strain of
Neisseria meningitides and its relationship with the incidence of meningococcal
disease in Galicia, Spain. Epidemiol Infect 1999;123:349–357.
132. Cookson S, Corrales J, Lotero J, et al. Disco fever: epidemic meningococcal
disease in northeastern Argentina associated with disco patronage. J Infect Dis
1998;178:266–269.

133. Australian Meningococcal Surveillance Programme. Annual report of the
Australian meningococcal surveillance programme – 1997. Commun Dis Intell
1998;22:205–211.
134. Harrison L, Dwyer D, Maples C, et al. Risk of meningococcal disease in college
students. JAMA 1999;281:1906–1910.
135. Harrison L. Preventing meningococcal infection in college students. Clin Infect Dis
2000;30:648–651.
136. Neal K, Nguyen-Van-Tam J, Monk P, et al. Invasive meningococcal disease among
university undergraduates: association with universities providing relatively large
amounts of catered hall accommodation. Epidemiol Infect 1999;122:351–357.
137. Berg S, Trollfor B, Alesti K, et al. Incidence, serogroups and case fatality rate of
invasive meningococcal infections in a Swedish region 1975–1989. Scand J Infect
Dis 1992;24:333.
138. Bruce MG, Rosenstein NE, Capparella JM, et al. Risk factors for meningococcal
disease in college students. JAMA 2001;286:688–693.
139. Bilukha OO, Rosenstein N. Prevention and control of meningococcal disease.
Recommendations of the Advisory Committee on Immunization Practices (ACIP).
MMWR Recomm Rep 2005;54(RR-07):1–21.
140. Ibarz-Pavón AB, Lemos AP, Gorla MC, et al. Laboratory-based surveillance of
Neisseria meningitidis isolates from disease cases in Latin American and Caribbean
countries, SIREVA II 2006-2010. PLoS ONE 2012;7:e44102.
141. Centers for Disease Control and Prevention. Updated recommendations for use
of meningococcal conjugate vaccines: Advisory Committee on Immunization
Practices (ACIP), 2010. MMWR Morb Mortal Wkly Rep 2011;60:72–76.
142. Baltimore R, Hammerschlag M. Meningococcal bacteremia: clinical and serological
studies of infants with mild illness. Am J Dis Child 1977;92:25.
143. Kupperman N, Malley R, Inkelis S, Fleisher G. Clinical and hematologic features do
not reliably identify children with unsuspected meningococcal disease. Pediatrics
1999;103:e20. http://www.pediatrics.org/cgi/content/full/103/2/e20/.
144. Wang V, Malley R, Fleisher G, et al. Antibiotic treatment of children with unsus-
pected meningococcal disease. Arch Pediatr Adolesc Med 2000;154:556–560.
145. Close RM, Ejidokun OO, Verlander NQ, et al. Early diagnosis model for meningitis
supports public health decision making. J Infect 2011;63:32–38.
146. Carrol ED, Newland P, Riordan FA, et al. Procalcitonin as a diagnostic marker of
meningococcal disease in children presenting with fever and a rash. Arch Dis Child
2002;86:282–285.
147. Wells LC, Smith JC, Weston VC, et al. The child with a non-blanching rash: how
likely is meningococcal disease? Arch Dis Child 2001;85:218–222.
148. Nielsen HE, Andersen EA, Andersen J, et al. Diagnostic assessment of haemorrhagic
rash and fever. Arch Dis Child 2001;85:160–165.
149. Brogan PA, Raffles A. The management of fever and petechiae: making sense of
rash decisions. Arch Dis Child 2000;83:506–507.
150. Mandl KD, Stack AM, Fleisher GR. Incidence of bacteremia in infants and children
with fever and petechiae. J Pediatr 1997;131:398–404.
151. Baker RC, Seguin JH, Leslie N, et al. Fever and petechiae in children. Pediatrics
1989;84:1051–1055.
152. Van Nguyen Q, Nguyen EA, Weiner LB. Incidence of invasive bacterial disease in
children with fever and petechiae. Pediatrics 1984;74:77–80.
153. Levin M, Eley BS, Louis J, et al. Postinfectious purpura fulminans caused by an
autoantibody directed against protein S. J Pediatr 1995;127:355–363.
154. Inbal A, Kenet G, Zivelin A, et al. Purpura fulminans induced by disseminated
intravascular coagulation following infection in 2 unrelated children with double
heterozygosity for factor V Leiden and protein S deficiency. Thromb Haemost
1997;77:1086–1089.
155. Jacobs R, Hsi S, Wilson C, et al. Apparent meningococcemia: clinical features
of disease due to Haemophilus influenzae and Neisseria meningitidis. Pediatrics
1983;72:469–472.
156. Nguyen Q, Nguyen E, Weiner L. Incidence of invasive bacterial disease in children
with fever and petechiae. Pediatrics 1984;74:77–80.
157. Sotto M, Langer B, Hoshino S, de Brito T. Pathogenesis of cutaneous lesions in acute
meningococcemia in humans: light, immunofluorescent, and electron microscopic
studies in skin biopsy specimens. J Infect Dis 1976;133:506–514.
158. Täuber M, Moser B. Cytokines and chemokines in meningococcal inflammation:
biology and clinical implications. Clin Infect Dis 1999;28:1–12.
159. Hazelzet J, de Groote R, van Mierlo G, et al. Complement activation in relation
to capillary leakage in children with septic shock and purpura. Infect Immun
1998;66:5350–5356.
160. Thiru Y, Pathan N, Bignall S, et al. A myocardial cytotoxic process is involved
in the cardiac dysfunction of meningococcal septic shock. Crit Care Med
2000;28:2979–2983.
161. Oragui E, Nadel S, Kyd P, Levin M. Increased excretion of urinary glycosaminogly-
cans in meningococcal septicemia and their relationship to proteinuria. Crit Care
Med 2000;28:3002–3008.
162. de Morais J, Munford R, Risi J, et al. Epidemic disease due to serogroup C Neisseria
meningitidis in Sao Paulo, Brazil. J Infect Dis 1974;129:568–571.
163. Geiseler P, Nelson K, Levin S, et al. Community-acquired purulent meningitis: a
review of 1316 cases during the antibiotic era. Rev Infect Dis 1980;2:725–745.
164. McManus M, Churchwell K. Coagulopathy as a predictor of outcome in menin-
gococcal sepsis and the systemic inflammatory response syndrome with purpura.
Crit Care Med 1993;21:706–711.
165. Davies M, Nadel S, Habibi P, et al. The othopaedic management of peripheral
ischemia in meningococcal septicaemia in children. J Bone Joint Surg Br
2000;82:383–386.
166. Potokar TS, Oliver DW, Russell R, Hall PN. Meningococcal septicaemia and plastic
surgery: a strategy for management. Br J Plast Surg 2000;53:142–148.
Neisseria meningitidis 125
167. Peters MJ, Ross-Russell RI, White D, et al. Early severe neutropenia and thrombo-
cytopenia identifies the highest risk cases of severe meningococcal disease. Pediatr
Crit Care Med 2001;2:225–231.
168. Lodder MC, Schildkamp RL, Bijlmer HA, et al. Prognostic indicators of the outcome
of meningococcal disease: a study of 562 patients. J Med Microbiol 1996;45:16–20.
169. Winstead J, McKinsey D, Tasker S, et al. Meningococcal pneumonia: characteriza-
tion and review of cases seen over the past 25 years. Clin Infect Dis 2000;30:87–94.
170. Dock W. Intermittent fever of seven months duration due to meningococcemia.
JAMA 1922;83:399–400.
171. Benoit F. Chronic meningococcemia: case report and review of the literature. Am
J Med 1963;35:103–112.
172. Leibel R, Fangman J, Ostrovsky M. Chronic meningococcemia in childhood. Am J
Dis Child 1974;127:94–98.
173. Van Der Ley P. Naturally occurring lipid A variants among meningococcal car-
riage and disease isolates. Presented at the 17th International Pathogenic Neisseria
Conference, Banff, Canada, 2010:abstract OM12.
174. Adams E, Hustead S, Rubin P, et al. Absence of the seventh component of comple-
ment in a patient with chronic meningococcemia presenting as vasculitis. Ann
Intern Med 1983;99:35.
175. Kaplan S. Antigen detection in cerebrospinal fluid: pros and cons. Am J Med
1983;75(suppl 1B):109.
176. Guiver M, Borrow R, Marsh J, et al. Evaluation of the Applied Biosystems automated
Taqman polymerase chain reaction system for the detection of meningococcal
DNA. FEMS Immunol Med Microbiol 2000;28:173–179.
177. Porritt RJ, Mercer JL, Munro R. Detection and serogroup determination of Neis-
seria meningitidis in CSF by polymerase chain reaction (PCR). Pathology 2000;32:
42–45.
178. Seward RJ, Towner KJ. Evaluation of a PCR-immunoassay technique for detec-
tion of Neisseria meningitidis in cerebrospinal fluid and peripheral blood. J Med
Microbiol 2000;49:451–456.
179. Ragunathan L, Ramsay M, Borrow R, et al. Clinical features, laboratory findings and
management of meningococcal meningitis in England and Wales: report of a 1997
survey—meningococcal meningitis: 1997 survey report. J Infect 2000;40:74–79.
180. Carrol E, Thomson A, Shears P, et al. Performance characteristics of the polymerase
chain reaction assay to confirm clinical meningococcal disease. Arch Dis Child
2000;83:271–273.
181. Pollard AJ, Probe G, Trombley C, et al. Evaluation of a diagnostic polymerase chain
reaction assay for Neisseria meningitidis in North America and field experience
during an outbreak. Arch Pathol Lab Med 2002;126:1209–1215.
182. Nadel S, Britto J, Booy R, et al. Avoidable deficiencies in the delivery of health care
to children with meningococcal disease. J Accid Emerg Med 1998;15:298–303.
183. Rennick G, Shann F, de Campo J. Cerebral herniation during bacterial meningitis
in children. BMJ 1993;306:953–955.
184. Dezateux CA, Dinwiddie R, Helms P, Matthew DJ. Recognition and early manage-
ment of Reye’s syndrome. Arch Dis Child 1986;61:647–651.
185. Heyderman RS, Robb SA, Kendall BE, Levin M. Does computed tomography have a
role in the evaluation of complicated acute bacterial meningitis in childhood? Dev
Med Child Neurol 1992;34:870–875.
186. Hasbun R, Abrahams J, Jekel J, Quagliarello VJ. Computed tomography of the
head before lumbar puncture in adults with suspected meningitis. N Engl J Med
2001;345:1727–1733.
187. Nadel S, Levin M, Habibi P. Treatment of meningococcal disease in childhood. In:
Cartwright K (ed) Meningococcal Disease. Chichester, John Wiley and Sons, 1995,
pp 207–243.
188. Prasad K, Kumar A, Singhal T, et al. Third generation cephalosporins versus con-
ventional antibiotics for treating acute bacterial meningitis. Cochrane Database Syst
Rev 2008;(1):CD001832.
189. Peltola H, Anttila M, Renkonen OV. Randomised comparison of chloramphenicol,
ampicillin, cefotaxime, and ceftriaxone for childhood bacterial meningitis. Lancet
1989;8650:1281–1287.
190. Tuncer AM, Gur I, Ertem U, et al. Once daily ceftriaxone for meningococcemia and
meningococcal meningitis. Pediatr Infect Dis J 1988;7:711–713.
191. Campos J, Trujillo G, Seuba G, Rodriguez A. Discriminative criteria for Neisseria
meningitidis isolates that are moderately susceptible to penicillin and ampicillin.
Antimicrob Agents Chemother 1992;36:1028–1031.
192. Turner P, Southern K, Spencer N, Pullen H. Treatment failure in meningococcal
meningitis. Lancet 1990;335:732–733.
193. Saez-Nieto J, Lujan R, Berron S, et al. Epidemiology and molecular basis of
penicillin-resistant Neisseria meningitidis in Spain: a 5-year history (1985–1989).
Clin Infect Dis 1992;14:394–402.
194. Rosenstein N, Stocker S, Popovic T, et al. Antimicrobial resistance of Neisseria
meningitidis in the United States, 1997. Clin Infect Dis 2000;30:212–213.
195. Bijlsma MW, Bekker V, Brouwer MC, et al. Epidemiology of invasive meningococcal
disease in the Netherlands, 1960–2012: an analysis of national surveillance data.
Lancet Infect Dis 2014;14:805–812.
196. Rivard GE, David M, Farrell C, et al. Treatment of purpura fulminans in meningo-
coccemia with protein C concentrate. J Pediatr 1995;126:646–652.
197. Whittle HC, Davidson NM, Greenwood BM, et al. Trial of chloramphenicol for
meningitis in northern savanna of Africa. Br Med J 1973;3:379–381.
198. MacFarlane JT, Anjorin FI, Cleland PG, et al. Single injection treatment of
meningococcal meningitis. 1. Long-acting penicillin. Trans R Soc Trop Med Hyg
1979;63:693–697.
199. Wali S, Macfarlane J, Wier W, et al. Single injection treatment of meningococ-
cal meningitis. 2. Long-acting chloramphenicol. Trans R Soc Trop Med Hyg
1979;73:698–702.
759.e3
 PART III  Etiologic Agents of Infectious Diseases
SECTION A  Bacteria
200. Pecoul B, Varaine F, Keita M, et al. Long acting chloramphenicol versus intravenous
ampicillin for treatment of bacterial meningitis. Lancet 1991;338:862–866.
201. World Health Organization. Antimicrobial and Support Therapy for Bacterial
Meningitis in Children: Report of the Meeting of 18–20 June 1997, Geneva, Swit-
zerland. Report no. WHO/EMC/BAC/98.2. Geneva, World Health Organization,
1998. http://www.who.int/csr/resources/publications/meningitis/whoemcbac982
.pdf?ua=1.
202. World Health Organization. Control of Epidemic Meningococcal Disease.
WHO Practical Guidelines, 2nd ed. Report No. WHO/EMC/BAC/98.3. Geneva,
World Health Organization, 1998. http://www.who.int/csr/resources/publications/
meningitis/whoemcbac983.pdf?ua=1.
203. Nathan N, Borel T, Djibo A, et al. Ceftriaxone as effective as long-acting chloram-
phenicol in short-course treatment of meningococcal meningitis during epidemics:
a randomised non-inferiority study. Lancet 2005;366:308–313.
204. Cabellos C, Nolla JM, Verdaguer R, et al. Arthritis related to systemic menin-
gococcal disease: 34 years’ experience. Eur J Clin Microbiol Infect Dis 2012;31:
2661–2666.
205. McIntyre PB, Berkey CS, King SM, et al. Dexamethasone as adjunctive therapy in
bacterial meningitis: a meta-analysis of randomized clinical trials since 1988. JAMA
1997;278:925–931.
206. Molyneux EM, Walsh AL, Forsyth H, et al. Dexamethasone treatment in child-
hood bacterial meningitis in Malawi: a randomised controlled trial. Lancet
2002;360:211–218.
207. van de Beek D, de Gans J, McIntyre P, Prasad K. Steroids in adults with acute
bacterial meningitis: a systematic review. Lancet Infect Dis 2004;4:139–143.
208. Hatherill M, Tibby SM, Hilliard T, et al. Adrenal insufficiency in septic shock. Arch
Dis Child 1999;80:51–55.
209. van Woensel JB, Biezeveld MH, Alders AM, et al. Adrenocorticotropic hormone and
Cortisol levels in relation to inflammatory response and disease severity in children
with meningococcal disease. J Infect Dis 2001;184:1532–1537.
210. Bernard GR, Vincent JL, Laterre PF, et al. Efficacy and safety of recombinant human
activated protein C for severe sepsis. N Engl J Med 2001;344:699–709.
211. Hinds CJ. Treatment of sepsis with activated protein C. BMJ 2001;323:881–882.
212. Bernard GR, Vincent J-L, Laterre R-F, et al. Efficacy and safety of recombinant
human activated protein C for severe sepsis. N Engl J Med 2001;344:699–709.
213. de Kleijn ED, de Groot R, Hack CE, et al. Activation of protein C following infusion
of protein C concentrate in children with severe meningococcal sepsis and purpura
fulminans: a randomized, double-blinded, placebo- controlled, dose-finding study.
Crit Care Med 2003;31:1839–1847.
214. US Food and Drug Administration. Safety Alert: Xigris [drotrecogin alfa(activated)].
2005.
215. Levin M, Quint PA, Goldstein B, et al. Recombinant bactericidal/permeability-
increasing protein (rBPI21) as adjunctive treatment for children with severe
meningococcal sepsis: a randomised trial. rBPI21 Meningococcal Sepsis Study
Group. Lancet 2000;356:961–967.
216. Giroir BP, Scannon PJ, Levin M. Bactericidal/permeability- increasing protein:
lessons learned from the phase III, randomized, clinical trial of rBPI21 for
adjunctive treatment of children with severe meningococcemia. Crit Care Med
2001;29(suppl):S130–S135.
217. Derkx B, Wittes J, McCloskey R. Randomized, placebo- controlled trial of HA-1A, a
human monoclonal antibody to endotoxin, in children with meningococcal septic
shock. European Pediatric Meningococcal Septic Shock Trial Study Group. Clin
Infect Dis 1999;28:770–777.
218. Maconochie I, Baumer H, Stewart ME. Fluid therapy for acute bacterial meningitis.
Cochrane Database Syst Rev 2008;(1):CD004786.
219. Maitland K, Kiguli S, Opoka RO, et al; FEAST Trial Group. Mortality after fluid
bolus in African children with severe infection. N Engl J Med 2011;364:2483–2495.
220. Maitland K, George EC, Evans JA, et al; FEAST trial group. Exploring mechanisms
of excess mortality with early fluid resuscitation: insights from the FEASTtrial.
BMC Med 2013;11:68.
221. Heyderman RS. Early management of suspected bacterial meningitis and
meningococcal septicaemia in immunocompetent adults: second edition. J Infect
2005;50:373–374.
222. Erickson L, De Wals P. Complications and sequelae of meningococcal disease in
Quebec, Canada, 1990–1994. Clin Infect Dis 1998;26:1159–1164.
223. Peltola H. Burden of meningitis and other severe bacterial infections of children in
Africa: implications for prevention. Clin Infect Dis 2001;32:64–75.
224. Scholten R, Bijlmer H, Valkenburg H, Dankert J. Patient and strain characteristics
in relation to the outcome of meningococcal disease: a multivariate analysis.
Epidemiol Infect 1994;112:115–124.
225. Sinclair J, Skeoch C, Hallworth D. Prognosis of meningococcal septicaemia [letter].
Lancet 1987;2:38.
226. Thomson A, Sills J, Hart C. Validation of the Glasgow meningococcal septicemia
prognostic score: a 10-year retrospective survey. Crit Care Med 1991;19:26–30.
227. Castellanos-Ortega A, Delgado-Rodriguez M. Comparison of the performance of
two general and three specific scoring systems for meningococcal septic shock in
children. Crit Care Med 2000;28:2967–2973.
228. Stiehm E, Damrosch D. Factors in the prognosis of meningococcal infection. J
Pediatr 1966;68:457–467.
229. Sinclair J, Skeoch C, Hallworth D. Prognosis of meningococcal septicaemia. Lancet
1987;3:38.
230. Greenwood B, Whittle H, Bryceson A. Allergic complications of meningococcal
disease. II. Immunological investigations. Br Med J 1973;2:737–740.
231. Whittle H, Abdullahi M, Fakunle F, et al. Allergic complications of meningococcal
disease. I. Clinical aspects. Br Med J 1973;2:733–737.
759.e4
232. Greenwood B, Onyewotu I, Whittle H. Complement and meningococcal infection.
Br Med J 1976;1:797–799.
233. Blaser M, Reingold A, Alsever R, Hightower A. Primary meningococcal pericarditis:
a disease in adults associated with serogroup V Neisseria meningitidis. Rev Infect
Dis 1984;6:625–632.
234. Bedford H, de Louvois J, Halket S, et al. Meningitis in infancy in England and Wales:
follow up at age 5 years. BMJ 2001;323:533–536.
235. Scottish Intercollegiate Guidelines Network. Management Of Invasive Menin-
gococcal Disease in Children and Young People: A National Clinical Guideline.
Edinburgh, Scottish Intercollegiate Guidelines Network, 2008.
236. Davies MS, Nadel S, Habibi P, et al. The orthopaedic management of periph-
eral ischaemia in meningococcal septicaemia in children. J Bone Joint Surg Br
2000;82:383–386.
237. Hudson D, Goddard E, Millar K. The management of skin infarction after menin-
gococcemia in children. Br J Plast Surg 1993;46:243–246.
238. Allport T, Read L, Nadel S, Levin M. Critical illness and amputation in meningococ-
cal septicemia: is life worth saving? Pediatrics 2008;122:629–632.
239. Advisory Committee on Epidemiology. Guidelines for control of meningococcal
disease. Can Commun Dis Rep 1994;20:17–27.
240. Pollard A, Begg N. Meningococcal disease and healthcare workers. BMJ
1999;319:1147–1148.
241. Schwartz B. Chemoprophylaxis for bacterial infections: principles of and applica-
tion to meningococcal infections. Rev Infect Dis 1991;13(suppl 2):S170.
242. Munford R, Taunay AD, de Morais J, et al. Spread of meningococcal infection
within households. Lancet 1974;1:1275–1278.
243. Shehab S, Keller N, Barkay A, et al. Failure of mass antibiotic prophylaxis to control
a prolonged outbreak of meningococcal disease in an Israeli village. Eur J Clin
Microbiol Infect Dis 1998;17:749–753.
244. Schwartz B, Al-Tobaiqi A, Al-Ruwais A, et al. Comparative efficacy of ceftriaxone
and rifampicin in eradicating pharyngeal carriage of group A Neisseria meningitidis.
Lancet 1988;1:1239–1242.
245. Dworzack D, Sanders C, Horowitz E, et al. Evaluation of single dose ciprofloxacin in
the eradication of Neisseria meningitidis from nasopharyngeal carriers. Antimicrob
Agents Chemother 1988;32:1740–1741.
246. Gaunt PN, Lambert BE. Single dose ciprofloxacin for the eradication of pharyngeal
carriage of Neisseria meningitidis. J Antimicrob Chemother 1988;21:489.
247. Gaunt PN. Ciprofloxacin vs. ceftriaxone for eradication of meningococcal carriage.
Lancet 1988;2:218–219.
248. Gilja O, Halstensen A, Digranes A, et al. Use of single dose ofloxacin to eradicate
tonsillopharyngeal carriage of Neisseria meningitidis. Antimicrob Agents Che-
mother 1993;37:2024–2026.
249. Stuart JM, Gilmore AB, Ross A, et al. Preventing secondary meningococcal disease
in health care workers: recommendations of a working group of the PHLS menin-
gococcus forum. Commun Dis Public Health 2001;4:102–105.
250. Gotschlich E, Rey M, Triau R, et al. Quantitative determination of the human
immune response to immunization with meningococcal vaccines. J Clin Invest
1972;51:89–96.
251. Gold R, Lepow M, Goldschneider I, et al. Clinical evaluation of group A and group C
meningococcal polysaccharide vaccines in infants. J Clin Invest 1975;56:1536–1547.
252. Artenstein M, Gold R, Zimmerly J, et al. Cutaneous reactions and antibody
responses to meningococcal group C polysaccharide vaccine in man. J Infect Dis
1970;121:372–377.
253. Lepow M, Beeler J, Randolph M, et al. Reactogenicity and immunogenicity of a
quadrivalent combined meningococcal polysaccharide vaccine in children. J Infect
Dis 1986;154:1033–1036.
254. Peltola H, Safary A, Käyhty H, et al. Evaluation of two tetravalent (ACYW135)
meningococcal vaccines in infants and small children: a clinical study comparing
immunogenicity of O-acetyl-negative and O-acetyl-positive group C polysaccha-
rides. Pediatrics 1985;76:91–96.
255. Novelli V, Dawod S, Ali M, et al. Febrile seizures after immunization with menin-
gococcal A+C vaccine. Pediatr Infect Dis J 1989;8:250–251.
256. Zangwill K, Stout R, Carlone G, et al. Duration of antibody response after
meningococcal polysaccharide vaccination in US Air Force personnel. J Infect Dis
1994;169:847–852.
257. Greenwood B, Whittle H, Bradley A, et al. The duration of the antibody response
to meningococcal vaccination in an African village. Trans R Soc Trop Med Hyg
1980;74:756–760.
258. Artenstein M, Gold R, Zimmerly J, et al. Prevention of meningococcal disease by
group C polysaccharide vaccine. N Engl J Med 1970;282:417–420.
259. Artenstein M, Winter P, Gold R, Smith C. Immunoprophylaxis of meningococcal
infection. Mil Med 1974;139:91–95.
260. Twumasi PA Jr, Kumah S, Leach A, et al. A trial of a group A plus group C menin-
gococcal polysaccharide-protein conjugate vaccine in African infants. J Infect Dis
1995;171:632–638.
261. MacDonald N, Halperin S, Law B, et al. Induction of immunologic memory by
conjugated vs. plain meningococcal C polysaccharide vaccine in toddlers. JAMA
1998;280:1685–1689.
262. Richmond P, Kaczmarski E, Borrow R, et al. Meningococcal C polysaccharide
vaccine induces immunologic hyporesponsiveness in adults that is overcome by
meningococcal C conjugate vaccine. J Infect Dis 2000;181:761–764.
263. MacLennan J, Obaro S, Deeks J, et al. Immune response to revaccination with
meningococcal A and C polysaccharides in Gambian children following repeated
immunisation during early childhood. Vaccine 1999;17:3086–3093.
264. Kelly D, Pollard AJ. W135 in Africa: origins, problems and perspectives. Travel Med
Infect Dis 2003;1:19–28.

265. Barra GN, Araya PA, Fernandez JO, et al. Molecular characterization of invasive
Neisseria meningitidis strains isolated in Chile during 2010–2011. PLoS ONE
2013;8:e66006.
266. Richmond P, Goldblatt D, Fusco P, et al. Safety and immunogenicity of a new
Neisseria meningitidis serogroup C-tetanus toxoid conjugate vaccine in healthy
adults. Vaccine 1999;18:641–646.
267. Campagne G, Garba A, Fabre P, et al. Safety and immunogenicity of three doses
of a Neisseria meningitidis A+C diphtheria conjugate vaccine in infants in Niger.
Pediatr Infect Dis J 2000;19:144–150.
268. Pollard A, Levin M. Vaccines for prevention of meningococcal disease. Pediatr Infect
Dis J 2000;19:333–345.
269. MacDonald N, Law B, Danzig L, Granoff D. Can meningococcal C conjugate
vaccine overcome immune hyporesponsiveness induced by previous administra-
tion of plain polysaccharide vaccine? JAMA 2000;283:1826–1827.
270. Zhang Q, Pettitt E, Burkinshaw R, et al. Mucosal immune responses to menin-
gococcal conjugate polysaccharide vaccines in infants. Pediatr Infect Dis J
2002;21:209–213.
271. Zhang Q, Choo S, Everard J, et al. Mucosal immune responses to meningococcal
group C conjugate and group A and C polysaccharide vaccines in adolescents. Infect
Immun 2000;68:2692–2697.
272. Zhang Q, Lakshman R, Burkinshaw R, et al. Primary and booster mucosal immune
responses to meningococcal group A and C conjugate and polysaccharide vac-
cines administered to university students in the United Kingdom. Infect Immun
2001;69:4337–4341.
273. Communicable Disease Surveillance Centre. Vaccination programme for group C
meningococcal infection is launched. Commun Dis Rep CDR Wkly 1999;9(261):264.
274. Trotter CL, Andrews NJ, Kaczmarski EB, et al. Effectiveness of meningococcal
serogroup C conjugate vaccine 4 years after introduction. Lancet 2004;364:365–367.
275. Communicable Disease Surveillance Centre. Meningococcal disease falls in vaccine
recipients. Commun Dis Rep CDR Wkly 2000;10:133, 136.
276. National Advisory Committee on Immunization. Statement on recommended use
of meningococcal vaccines. Can Commun Dis Rep 2001;27:2–36.
277. Borrow R, Andrews N, Findlow H, et al. Kinetics of antibody persistence following
administration of a combination meningococcal serogroup C and Haemophilus
influenzae type b conjugate vaccine in healthy infants in the United Kingdom
primed with a monovalent meningococcal serogroup C vaccine. Clin Vaccine
Immunol 2010;17:154–159.
278. Snape MD, Kelly DF, Lewis S, et al. Sero-protection against serogroup C meningo-
coccal disease in adolescents in the United Kingdom: an observational study. BMJ
2008;336:1487–1491.
279. Perrett KP, Winter AP, Kibwana E, et al. Antibody persistence after serogroup C
meningococcal conjugate immunization of United kingdom primary-school
children in 1999–2000 and response to a booster: a phase 4 clinical trial. Clin
Infect Dis 2010;50:1601–1610.
280. Auckland C, Gray S, Borrow R, et al. Clinical and immunologic risk factors for
meningococcal C conjugate vaccine failure in the United Kingdom. J Infect Dis
2006;194:1745–1752.
281. MacNeil J, Cohn AC, Mair R, et al. Interim analysis of the effectiveness of quadri-
valent meningococcal conjugate vaccine (MenACYW-D): a matched case-control
study. MeningNet Partners Active Bacterial Core Surveillance (ABCs) Team. Pre-
sented at the 17th International Pathogenic Neisseria Conference. Canada, Banff,
2010:abstract OM10.
282. Centers for Disease Control and Prevention. Update: Guillain-Barre syndrome
among recipients of Menactra® meningococcal conjugate vaccine—United
States, June 2005–September 2006. MMWR Morb Mortal Wkly Rep 2006;41:
1120–1124.
Neisseria meningitidis 125
283. DeWals P, Deceuninck G, Boucher RM, et al. Risk of Guillain-Barre syndrome
following serogroup C meningococcal conjugate vaccine in Quebec, Canada. Clin
Infect Dis 2008;46:e75–e77.
284. Perkins BA. Prospects for prevention of meningococcal meningitis. Lancet
2001;358:255–256.
285. Wyle F, Artenstein M, Brandt B, et al. Immunologic responses of man to group B
meningococcal polysaccharide vaccines. J Infect Dis 1972;126:514–521.
286. Jennings H. Capsular polysaccharides as vaccine candidates. Curr Top Microbiol
Immunol 1990;150:97–127.
287. Bjune G, Høiby E, Grønnesby J, et al. Effect of outer membrane vesicle vaccine
against group B meningococcal disease in Norway. Lancet 1991;338:1093–1096.
288. Tappero J, Lagos R, Ballesteros A, et al. Immunogenicity of 2 serogroup B outer-
membrane protein meningococcal vaccines: a randomized controlled trial in Chile.
JAMA 1999;281:1520–1527.
289. Galloway Y, Stehr-Green P, McNicholas A, et al. Use of an observational cohort
study to estimate the effectiveness of the New Zealand group B meningococcal
vaccine in children aged under 5 years. Int J Epidemiol 2009;38:413–418.
290. MenAfriCar Consortium. The diversity of meningococcal carriage across the
African meningitis belt and the impact of vaccination with a group a meningococ-
cal conjugate vaccine. J Infect Dis 2015;212:1298–1307.
291. Sadarangani M, Pollard AJ. Serogroup B meningococcal vaccines: an unfinished
story. Lancet Infect Dis 2010;10:112–124.
292. Gossger N, Snape MD, Yu LM, et al; European MenB Vaccine Study Group. Immu-
nogenicity and tolerability of recombinant serogroup B meningococcal vaccine
administered with or without routine infant vaccinations according to different
immunization schedules: a randomized controlled trial. JAMA 2012;307:573–582.
293. Vesikari T, Esposito S, Prymula R, et al; EU Meningococcal B Infant Vaccine Study
group. Immunogenicity and safety of an investigational multicomponent, recombi-
nant, meningococcal serogroup B vaccine (4CMenB) administered concomitantly
with routine infant and child vaccinations: results of two randomised trials. Lancet
2013;381:825–835.
294. Santolaya ME, O’Ryan ML, Valenzuela MT, et al; V72P10 Meningococcal B
Adolescent Vaccine Study group. Immunogenicity and tolerability of a multi-
component meningococcal serogroup B (4CMenB) vaccine in healthy adolescents
in Chile: a phase 2b/3 randomised, observer-blind, placebo-controlled study. Lancet
2012;379:617–624.
295. Richmond PC, Marshall HS, Nissen MD, et al; 2001 Study Investigators. Safety,
immunogenicity, and tolerability of meningococcal serogroup B bivalent recombi-
nant lipoprotein 2086 vaccine in healthy adolescents: a randomised, single-blind,
placebo-controlled, phase 2 trial. Lancet Infect Dis 2012;12:597–607.
296. Marshall HS, Richmond PC, Nissen MD, et al. A phase 2 open-label safety and
immunogenicity study of a meningococcal B bivalent rLP2086 vaccine in healthy
adults. Vaccine 2013;31:1569–1575.
297. Snape MD, Philip J, John TM, et al. Bactericidal antibody persistence two years fol-
lowing immunization with two investigational serogroup B meningococcal vaccines
at 6, 8 and 12 months and immunogenicity of pre-school booster doses: a follow-on
study to a randomized clinical trial. Pediatr Infect Dis J 2013;32:1116–1121.
298. Snape MD, Saroey P, John TM, et al. Persistence of bactericidal antibodies fol-
lowing early infant vaccination with a serogroup B meningococcal vaccine and
immunogenicity of a preschool booster dose. CMAJ 2013;185:E715–E724.
299. McQuaid F, Snape MD, John TM, et al. Persistence of bactericidal antibodies to 5
years of age following immunization with serogroup B meningococcal vaccines at
6, 8, 12 and 40 months of age. Pediatr Infect Dis J 2014;33:760–766.
300. Santolaya ME, O’Ryan M, Valenzuela MT, et al. Persistence of antibodies in adoles-
cents 18-24 months after immunization with one, two, or three doses of 4CMenB
meningococcal serogroup B vaccine. Hum Vaccin Immunother 2013;9:2304–2310.
759.e5