Rosen Stein 2001
Rosen Stein 2001
Rosen Stein 2001
Review Article
R
EPORTS of illness resembling meningococ- adults has increased in recent years; during the period
cal disease date back to the 16th century. The from 1992 to 1996, 28 percent of affected persons
description reported by Vieusseux in 1805 is were between 12 and 29 years old.6 This change has
generally thought to be the first definitive identifica- important implications for preventive strategies.
tion of the disease,1 and the causative organism, Neis- Since the new meningococcal conjugate vaccines,
seria meningitidis, was first isolated in 1887.2 Yet me- like the currently available quadrivalent polysaccharide
ningococcal disease remains a leading cause of bacterial vaccine, will provide serogroup-specific protection, the
meningitis and sepsis in the United States and a ma- distribution of serogroups is a key factor in the design
jor cause of epidemics in sub-Saharan Africa. Short of of vaccination programs. From 1988 to 1991, most
abolishing tobacco use, which is thought to be respon- cases of meningococcal disease in the United States
sible for almost one third of cases,3 routine vaccination were due to either serogroup C or serogroup B, and
of high-risk populations is likely to be the most effec- serogroup Y accounted for only 2 percent of cases.7
tive public health strategy for controlling meningo- In recent years, the number of cases involving sero-
coccal disease. Several companies are in the final stag- group Y has increased; from 1996 to 1998, one third
es of developing and testing meningococcal conjugate of cases were due to serogroup Y, which is also more
vaccines for licensure in the United States. These vac- commonly associated with pneumonia than are sero-
cines have been developed with the techniques used groups B and C.6,8 In the 1970s, serogroup Y was
to develop Haemophilus influenzae type b conjugate also recognized as a frequent cause of sporadic disease
vaccines. Progress is also being made in the use of sub- in some U.S. populations9,10 and was associated with
capsular antigens to develop vaccines against sero- several outbreaks among military personnel.11 Similar-
group B disease, but for this serogroup, substantial ly, serogroup W-135, which is also associated with
work and probably various approaches are needed to pneumonia and which currently accounts for only
find the right one. There are formidable challenges in- 4 percent of cases in the United States,6 was reported
volved in designing strategies to introduce conjugate in 15 to 20 percent of isolates received by the Centers
vaccines, but these vaccines provide an important new for Disease Control and Prevention between 1978 and
opportunity to control and prevent meningococcal 1980.12 In 2000, an international outbreak among pil-
disease.4 grims returning from the hajj (the pilgrimage to Mec-
ca) and their close contacts, including four persons
EPIDEMIOLOGIC FEATURES OF from the United States, was due to serogroup W-135.13
MENINGOCOCCAL DISEASE Although outbreaks of serogroup A meningococcal
In the United States disease were common in industrialized countries ear-
ly in the 20th century, outbreaks as well as sporadic
Since 1960, rates of meningococcal disease in the
cases have been rare in these countries since World
United States have remained relatively stable, at ap-
War II. These changes are not completely understood
proximately 0.9 to 1.5 cases per 100,000 population
but may reflect immunologic changes in the general
per year, or 2500 to 3000 cases per year.5 Meningo-
population, the introduction of new strains of N. men-
ingitidis into populations, or cross-reactive protection
From the Meningitis and Special Pathogens Branch, Division of Bacterial provided by exposure to bacteria with a similar struc-
and Mycotic Diseases (N.E.R., B.A.P., D.S.S., T.P.), National Center for
Infectious Diseases (J.M.H.), Centers for Disease Control and Prevention;
ture (e.g., Bacillus pumilus).14
and Emory University School of Medicine (D.S.S.) — both in Atlanta. Ad- Another recent change in the epidemiology of me-
dress reprint requests to Dr. Rosenstein at the Division of Bacterial and ningococcal disease in the United States has been in
Mycotic Diseases, National Center for Infectious Diseases, Centers for Dis-
ease Control and Prevention, 1600 Clifton Rd. N.E., Mailstop C-09, At- the frequency of outbreaks. In the 1980s, outbreaks
lanta, GA 30333, or at [email protected]. of meningococcal disease were rare, but since 1991,
the frequency of localized outbreaks has increased. They are classified into serogroups according to the
These outbreaks have been caused by groups of closely immunologic reactivity of their capsular polysaccha-
related strains and probably represent the introduc- rides, which are the basis for currently licensed me-
tion of new clones into the population.15-17 Most of ningococcal vaccines.28 Although there are at least 13
these outbreaks have been due to serogroup C; in the serogroups, most cases of meningococcal disease are
past five years, however, there have also been outbreaks caused by serogroups A and C, for which polysac-
due to serogroup Y.16 Although such outbreaks cause charide vaccines are effective, and serogroup B, which
tremendous public concern and attract considerable at- has a polysaccharide capsule that is poorly immuno-
tention in the media, they account for only 2 to 3 per- genic in humans. The capsular polysaccharide is either
cent of the total number of cases in the United States. a homopolymer or a heteropolymer consisting of
monosaccharide, disaccharide, or trisaccharide repeat-
Worldwide ing units. The main meningococcal capsular polysac-
Serogroups A, B, and C account for most cases of charides associated with invasive disease, except for
meningococcal disease throughout the world, with serogroup A, are composed of sialic acid derivatives;
serogroups B and C responsible for the majority of the serogroup A capsule consists of repeating units of
cases in Europe and the Americas and serogroups A N-acetyl-mannosamine-1-phosphate. Meningococci
and C predominating throughout Asia and Africa.18-20 are further classified on the basis of their class 1 outer-
Israel and Sweden are the only countries other than membrane proteins (serosubtype), class 2 or 3 outer-
the United States that have reported an increase in membrane proteins (serotype), and lipooligosaccha-
serogroup Y disease.19 Serogroup B meningococcal rides (immunotype) (Fig. 2 and Table 1). Molecular
disease caused 68 percent of cases reported in Europe subtyping with the use of multilocus enzyme electro-
between 1993 and 199619 and has also caused out- phoresis, pulsed-field gel electrophoresis, or DNA-
breaks in developed countries, with attack rates of 5 to sequence analysis can be helpful in identifying closely
50 cases per 100,000 persons.21 In the late 1970s, a related strains with the potential to cause outbreaks
serogroup B strain belonging to a clonal group known and in understanding the genetic characteristics of
as ET-5 emerged, causing outbreaks in northwestern N. meningitidis.29 Meningococci also have the capac-
Europe and Central and South America.21 In the early ity to exchange the genetic material responsible for
1990s, an outbreak of serogroup B disease due to the capsule production and thereby switch from serogroup
same clonal group occurred in Oregon and Washing- B to C or vice versa.30 Capsule switching may become
ton, with a rate of 4.6 cases per 100,000 in 1994.22,23 an important mechanism of virulence with the wide-
The outbreak did not spread to other states and now spread use of vaccines that provide serogroup-specific
appears to be waning.24 In the absence of an effec- protection.
tive vaccine against serogroup B, a more widespread Humans are the only natural reservoir of N. menin-
outbreak would result in substantial morbidity and gitidis, and the nasopharynx is the site from which
mortality. meningococci are transmitted by aerosol or secretions
In the African “meningitis belt,” a region of sa- to others. Meningococci overcome host defenses and
vannah that extends from Ethiopia in the east to attach to the microvillous surface of nonciliated colum-
Senegal in the west, serogroup A meningococcal dis-
ease has posed a recurrent threat to public health for
at least 100 years.25 Rates of meningococcal disease
are several times higher in this region than in indus-
trialized countries, and the reported mortality is usu-
ally approximately 10 percent, a rate similar to that
in industrialized countries; however, because many
patients die before reaching a hospital, the true mor-
tality in the meningitis belt is probably substantially
higher.26 In addition, outbreaks occur every 8 to 12
years, frequently resulting in attack rates of 500 to
1000 cases per 100,000 population.20 In 1996, the
largest outbreak ever reported occurred in the men-
ingitis belt; the total number of cases reported to the
World Health Organization (probably a substantial
underestimate) was 152,813, with 15,783 deaths.27
MICROBIOLOGIC FEATURES
AND PATHOGENESIS
Figure 1. Neisseria meningitidis (Arrow) in Cerebrospinal Fluid
N. meningitidis are gram-negative, aerobic diplo- (Gram’s stain, ¬1000).
cocci (Fig. 1) that are best isolated on chocolate agar. The organisms are intracellular, gram-negative diplococci.
Cytoplasmic membrane
Periplasmic space
Cytoplasmic-membrane Outer membrane
proteins
Lipooligosaccharide
Pilus
Capsule
Outer-membrane proteins
Phospholipid
nar mucosal cells of the nasopharynx, where they mul- RISK FACTORS
tiply (i.e., colonize) (Fig. 3).31 Pili (Fig. 2) are the ma- Meningococci are diverse organisms and are usu-
jor adhesins that may target the CD46 receptor, a ally commensal bacteria in humans. Only a minority
membrane cofactor protein; subsequently, the opacity- of the nasopharyngeal isolates cause invasive disease.
associated proteins, Opa and Opc,32 bind to CD6633 Meningococci associated with invasive disease elabo-
and heparan sulfate proteoglycan receptors, respective- rate a capsule, which provides protection from desic-
ly. Binding stimulates engulfment of the meningococ- cation during transmission and aids in the evasion of
ci by epithelial cells, which may then traverse the mu- host immune mechanisms. In addition, adhesins, such
cosal epithelium through phagocytic vacuoles.31 The as pili, and specific nutrient-acquisition factors, espe-
survival of meningococci in the epithelial cells may be cially mechanisms for acquiring iron from human lac-
promoted by the IgA1 protease and by porB.34 Five toferrin, transferrin, and hemoglobin enhance their
to 10 percent of adults are asymptomatic nasopharyn- pathogenic potential.39 Finally, a major factor in the
geal carriers of strains of N. meningitidis,35,36 most of virulence of the organism is the release of outer-mem-
which are not pathogenic. In a small number of per- brane vesicles that consist of lipooligosaccharide (endo-
sons, N. meningitidis penetrates the mucosa and gains toxin), outer-membrane proteins, phospholipids, and
access to the bloodstream, causing systemic disease.37 capsular polysaccharides. The endotoxin of N. men-
In most persons, however, carriage is an immunizing ingitidis is structurally distinct from the lipooligosac-
process, resulting in a systemic protective antibody charide of enteric gram-negative bacteria.40 Menin-
response.38 gococci also undergo autolysis, releasing DNA and
cell-wall components, which induce the inflammato- is not nearly as high as that of infection with other
ry cascade. The reasons for the clonality of invasive encapsulated organisms, such as Streptococcus pneu-
isolates are not fully understood, but they may pos- moniae.46,47 Additional research is needed to clarify
sess particular virulence factors or they may have an- the role of genetic immune defects, such as polymor-
tigenic characteristics that are not recognized by the phisms in the genes for mannose-binding lectin and
host and hence escape adaptive immune mechanisms. tumor necrosis factor a, that may have major roles in
Persons who lack or have a deficiency of antibody- altering the susceptibility to meningococcal disease.48,49
dependent, complement-mediated immune lysis (bac- The acquisition of infection depends on the chance
tericidal activity) are most susceptible to meningococ- that a person will encounter and acquire a virulent bac-
cal disease.41,42 The importance of humoral immunity terium. In households where a case of meningococcal
was indirectly demonstrated in a study that showed an disease has occurred, the risk of invasive disease in fam-
inverse correlation between the age-related incidence ily members is increased by a factor of 400 to 800.9
of disease and the age-related acquisition of serum In the United States, blacks and persons of low socio-
bactericidal antibodies.42 The direct correlation be- economic status have consistently been found to be
tween susceptibility to meningococcal disease and the at higher risk for meningococcal disease than whites
absence of detectable bactericidal antibodies was fur- and persons of higher socioeconomic status.6,7 Black
ther demonstrated by the finding that military recruits race and low socioeconomic status are likely to be
who had detectable bactericidal antibodies frequently markers for differences in factors such as household
became carriers but did not contract the disease.42 Re- crowding, urban residence, and exposure to tobacco
cently, opsonophagocytic activity has been found to smoke. Active or passive exposure to tobacco smoke,
play a part in providing protection against meningo- as well as concurrent viral infection of the upper res-
coccal disease.43 piratory tract, increases the risk of meningococcal dis-
Underlying immune defects that confer a predis- ease by enhancing the formation and spread of respi-
position to invasive meningococcal infection include ratory droplets or diminishing the functional and
functional or anatomical asplenia, a deficiency of pro- mechanical integrity of the respiratory mucosa as a
perdin, and a deficiency of terminal complement com- barrier to invasion.3,50,51
ponents.44,45 Persons with these conditions have a sub- New military recruits have consistently been found
stantially elevated risk of meningococcal infection, but to have a higher risk of both sporadic meningococcal
infections in such persons account for only a small disease and outbreaks of disease than other military
proportion of cases. Those infected with the human personnel or the general population.52 The increased
immunodeficiency virus are probably also at increased risk is probably related to crowded living conditions
risk for sporadic meningococcal disease, but the risk among persons from various geographic areas who
have diverse strains of N. meningitidis. Recent studies longed, intermittent fevers, rash, arthralgias, and head-
have also shown that college freshmen living in dor- aches.55
mitories have an elevated risk of disease, perhaps for Before the 1920s, meningococcal disease was fatal
similar reasons, but overall, U.S. college students are in up to 70 percent of cases.62 The use of serum ther-
not at higher risk for meningococcal disease than oth- apy and the discovery of sulfonamides and other anti-
er people of similar age.53,54 microbial agents led to a substantial decline in case
fatality rates. Despite treatment with appropriate an-
CLINICAL MANIFESTATIONS timicrobial agents and optimal medical care, the over-
One of the challenges of diagnosing meningococ- all case fatality rates have remained relatively stable
cal disease is that its clinical manifestations (Table 2) over the past 20 years, at 9 to 12 percent, with a rate
are difficult to distinguish from those of more com- of up to 40 percent among patients with meningococ-
mon but less serious illnesses. Meningeal infection, re- cal sepsis.5 Eleven to 19 percent of survivors of menin-
sulting from hematogenous spread, occurs in about gococcal disease have sequelae, such as hearing loss,
50 percent of patients6 and is similar to other forms neurologic disability, or loss of a limb.63,64
of acute purulent meningitis, with a sudden onset of
headache, fever, and stiffness of the neck, sometimes DIAGNOSIS
accompanied by nausea, vomiting, photophobia, and The classic laboratory diagnosis of meningococcal
an altered mental status. In infants, meningeal infec- disease has relied on bacteriologic culture, but the sen-
tion may have a slower onset, with nonspecific signs sitivity of culture may be low, especially when per-
and without stiffness of the neck; a bulging fontanelle formed after the initiation of antibiotic treatment.65
is occasionally noted. N. meningitidis can be isolated Gram’s staining of cerebrospinal fluid is still considered
from the bloodstream in up to three quarters of pa- an important method for rapid and accurate identi-
tients, but meningococcal sepsis, which is also called fication of N. meningitidis.66 Nonculture methods,
meningococcemia, occurs in only 5 to 20 percent of such as the use of commercially available kits to detect
patients.6,55 Meningococcemia is characterized by an polysaccharide antigen in cerebrospinal fluid, have
abrupt onset of fever and a petechial or purpuric rash, been used to enhance the laboratory diagnosis. These
which may progress to purpura fulminans, and is of- methods are rapid and specific and can provide a sero-
ten associated with the rapid onset of hypotension, group-specific diagnosis, but false negative results are
acute adrenal hemorrhage (the Waterhouse–Frider- common, especially in cases of serogroup B disease.67
ichsen syndrome), and multiorgan failure.55 Antigen tests of urine or serum are unreliable for the
Pneumonia occurs in 5 to 15 percent of patients diagnosis of meningococcal disease. Serologic testing,
with invasive meningococcal disease.8,56 Meningococ- primarily with enzyme-linked immunosorbent assays,
cal pneumonia may not always be diagnosed, because can be used as part of the evaluation if meningococcal
isolation of the organism from sputum does not dis- disease is suspected but should not be used to estab-
tinguish persons who are carriers of the bacteria from lish the diagnosis.68 Polymerase-chain-reaction (PCR)
those with pneumonia caused by N. meningitidis and analysis offers the advantages of detecting serogroup-
because physicians may not consider the organism as specific N. meningitidis DNA and of not requiring live
a possible cause of pneumonia.11,57,58 Much less fre- organisms for a positive result. PCR tests for N. men-
quently, other syndromes are associated with menin- ingitidis are not commercially available in the United
gococcal disease, including conjunctivitis,59 otitis States, but this approach has been widely used in the
media, epiglottitis, arthritis,60 urethritis, and pericardi- United Kingdom since late 1996, and in 1998, 35 per-
tis.6,61 In rare cases, patients may present with chronic cent of cases of meningococcal disease in the United
meningococcemia, a syndrome characterized by pro- Kingdom were confirmed by PCR alone (Kaczmarski
Figure 3 (facing page). Colonization of Neisseria meningitidis in the Nasopharynx and Entry into the Bloodstream and Cerebrospinal
Fluid.
N. meningitidis enters the nasopharynx and attaches to nonciliated epithelial cells, probably through the binding of the pili to the
CD46 receptor (a membrane cofactor protein) and the subsequent binding of opacity-associated proteins, Opa and Opc, to the
CD66e (carcinoembryonic antigen) and heparan sulfate proteoglycan receptors, respectively. The attached organisms are engulfed
by the cells, enter phagocytic vacuoles, and may then pass through the cells. IgA1 protease (an outer-membrane protein) cleaves
lysosome-associated membrane protein and may promote the survival of N. meningitidis in epithelial cells. PorB (another outer-
membrane protein) crosses the cell membrane and arrests the maturation of the phagosome. In the bloodstream, the organisms
release endotoxin in the form of blebs (vesicular outer-membrane structures) that contain 50 percent lipooligosaccharide and 50
percent outer-membrane proteins, phospholipids, and capsular polysaccharide. The endotoxin and probably other components
stimulate cytokine production and the alternative complement pathway. N. meningitidis crosses the blood–brain barrier endothe-
lium by entering the subarachnoid space, possibly through the choroid plexus of the lateral ventricles.
cell components
Alternative
Host-cell cytokine complement
Blood production pathway
vessel
endothelium
Cerebrospinal
N. meningitidis fluid N. meningitidis
vaccine has induced a serogroup-specific response in would prefer to have a single formulation for use
animals.96 Use of serogroup B polysaccharide vaccines throughout the world. Conjugate meningococcal vac-
in humans has been limited because of the theoretical cines would need to include a serogroup A component
risk that these vaccines will overcome immune toler- to maximize their effect on the control of disease in
ance and induce autoimmunity, and further develop- Africa and therefore the global burden of the disease.
ment must be undertaken carefully.
Another approach to serogroup A and C polysac- CONCLUSIONS
charides has been the use of peptides that mimic the Despite our improved understanding of the epide-
capsular polysaccharide in complex with or conjugated miologic features and pathogenesis of meningococcal
to potent carrier-protein molecules in order to elicit a disease, risk factors, and advances in diagnosis and
T-cell–dependent response.103 In addition, the recent treatment, the disease remains a leading cause of men-
completion of the genomic sequencing of a serogroup ingitis and sepsis. Routine vaccination of high-risk
B meningococcus may make it possible to identify nov- populations is a reasonable public health strategy for
el surface proteins that could be effective vaccines.104 controlling meningococcal disease, but the shortcom-
As with H. influenzae type b conjugate vaccines, ings of the quadrivalent polysaccharide vaccine limit
serogroup A, C, Y, and W-135 meningococcal poly- its usefulness. New serogroup B vaccines, now being
saccharides have been chemically conjugated to car- developed, are unlikely to be available in the next five
rier proteins. These meningococcal conjugate vaccines years. How well meningococcal conjugate vaccines will
induce a T-cell–dependent response, resulting in an work, especially with respect to the duration of pro-
improved immune response in infants, priming im- tection and herd immunity, remains unclear, and there
munologic memory, and leading to a booster response are unresolved strategic issues concerning formulations
to subsequent doses.89 These vaccines are expected to and target age groups. The greatest challenges may
provide long-lasting immunity even when given as a be integrating these vaccines into an already compli-
series in infancy, and they may provide herd immu- cated immunization schedule in the United States and
nity through protection from nasopharyngeal carriage. making them available, despite costs that may be rel-
Clinical trials of these vaccines are ongoing.105-107 In atively high, in sub-Saharan Africa. Although the prob-
the United Kingdom, where the rate of serogroup C lems are by no means solved, conjugate meningococ-
meningococcal disease ranges from 1.4 to 2.0 cases cal vaccines have the potential to provide greatly
per 100,000 population per year and where menin- improved control of meningococcal disease through-
gococcal disease is the leading cause of death from out the world.
infection among young children (Stuart J: personal
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