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REDUCING THE IMPACT
OF MENINGOCOCCAL
DISEASE IN ADOLESCENTS
AND YOUNG ADULTS
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FACULTY
William Schaffner, MD, Chairman
Lee H. Harrison, MD
Sheldon L. Kaplan, MD
Elizabeth Miller, MD
Walter A. Orenstein, MD
Georges Peter, MD
Nancy E. Rosenstein, MD
National
Foundation for
Infectious
Diseases
This CME activity has been planned and produced in accordance with the Essential Areas and Policies
of the Accreditation Council for Continuing Medical Education (ACCME), and is made possible by an
unrestricted educational grant to the National Foundation for Infectious Diseases from sanofi pasteur.
Issued: July 2005
Release Date: July 2005
Expiration Date: July 2007
Estimated Time to
Complete Activity: 1.5 hours
se
as
es
FACULTY
William Schaffner, MD, Chairman
Professor and Chair, Department of Preventive Medicine
Professor of Medicine (Infectious Diseases)
Vanderbilt University School of Medicine
Nashville, Tennessee
Lee H. Harrison, MD
Professor of Medicine
Infectious Diseases Epidemiology Research Unit
University of Pittsburgh School of Medicine
Pittsburgh, Pennsylvania
Sheldon L. Kaplan, MD
Professor and Vice Chairman for Clinical Affairs
Department of Pediatrics
Baylor College of Medicine
Houston, Texas
Elizabeth Miller, MD
Head of the Immunisation Department
Communicable Disease Surveillance Centre
Health Protection Agency Centre for Infections
London, England
Walter A. Orenstein, MD
Director, Vaccine Policy and Development
Associate Director, Emory Vaccine Center
Emory University School of Medicine
Atlanta, Georgia
Georges Peter, MD
Professor, Department of Pediatrics
Brown Medical School
Founding Director, Division of Pediatric Infectious Diseases
Rhode Island Hospital
Providence, Rhode Island
Nancy E. Rosenstein, MD
Chief, Meningitis and Special Pathogens Branch
Division of Bacterial and Mycotic Diseases
National Center for Infectious Diseases
Centers for Disease Control and Prevention
Atlanta, Georgia
REDUCING THE IMPACT OF
MENINGOCOCCAL DISEASE IN
ADOLESCENTS AND YOUNG ADULTS
Continuing Medical Education Information
1
Introduction
3
Epidemiology of Meningococcal Disease
5
Transmission and Pathogenesis: Examining Risk Factors
7
U.S. Immunization Recommendations
8
Presentations, Progression and Sequelae
11
Conclusion
15
References
16
Self-Assessment Examination
18
CME Evaluation
19
Copyright © 2005 by National Foundation for Infectious Diseases.
All Rights Reserved.
CONTINUING MEDICAL EDUCATION INFORMATION
Target Audience
the Centers for Disease Control and Prevention’s Advisory
Primary care physicians, pediatricians, infectious
Committee on Immunization Practices and the scientific
disease specialists, college health professionals and
data that provide rationale for an immunization strategy
public health officials responsible for or interested in
designed to lessen the burden of meningococcal disease.
communicable diseases.
Educational Format
Statement of Need
This activity was developed by the faculty based on a
Meningococcal disease causes substantial morbidity and
literature review and personal knowledge and expertise
mortality. Cyclical trends in disease epidemiology suggest
about meningococcal disease.
that persons across many age groups may be at increased
risk of disease and severe complications, including death.
1
U.S. immunization policy and recommendations changed
Evaluation and Exam
following approval of a conjugate meningococcal vaccine
A course evaluation form and self-assessment examination
for use in persons aged 11 to 55 years. All physicians and
at the end of this monograph will provide participants
public health officials interested in communicable
with the opportunity to critique the program content and
diseases should be aware of the new recommendations by
method of delivery, identify future educational needs and
possible bias in the presentation materials and complete
the self-assessment examination to receive CME credits.
OBJECTIVES
After completing the monograph, physicians will
be able to:
Accreditation
This activity has been planned and implemented in
• Discuss the epidemiology of meningococcal
disease in terms of age, serogroup and
geographic distribution;
accordance with the Essential Areas and Policies of the
Accreditation Council for Continuing Medical Education
(ACCME) by the National Foundation for Infectious
Diseases (NFID). NFID is accredited by the ACCME to
• Describe clinical presentations of
meningococcal disease;
provide Continuing Medical Education (CME) for
physicians. NFID takes responsibility for the content,
quality and scientific integrity of the CME activity.
• Outline U.S. immunization recommendations;
NFID designates this CME activity for a maximum of 1.5
• Compare features of conjugate and
polysaccharide vaccines.
credits toward the AMA Physician’s Recognition Award of
the American Medical Association. Each physician should
claim only those hours of credit that he/she actually spent
on the educational activity.
Commercial Support
Disclaimer
This CME activity is made possible by an unrestricted
Any procedures, medications or other courses of diagnosis
educational grant from sanofi pasteur to the National
or treatment discussed or suggested in this activity should
Foundation for Infectious Diseases.
not be used by clinicians without evaluation of their
patient’s condition, possible contraindications or dangers
in use, review of any applicable manufacturer’s product
Financial Disclosures
information and comparison with recommendations of
Lee H. Harrison, MD, has a financial interest/relationship
other authorities.
with sanofi pasteur in the form of research support,
consulting, and speaking fees.
Release date: July 2005
Expiration date: July 2007
Sheldon L. Kaplan, MD, has a financial interest/relationship
with sanofi pasteur in the form of a research grant, stipend
and/or fellowship.
2
Elizabeth Miller, MD, has a financial interest/relationship
with Chiron, Wyeth Pharmaceuticals and Baxter in the
form of provision of meningococcal surveillance reports
for submission to licensing authorities.
Walter A. Orenstein, MD, has no significant financial interests
or relationships to disclose in relation to this program.
Georges Peter, MD, has no significant financial interests or
relationships to disclose in relation to this program.
Nancy E. Rosenstein, MD, has no significant financial interests
or relationships to disclose in relation to this program.
William Schaffner, MD, has no significant financial interests
or relationships to disclose in relation to this program.
© National Foundation for Infectious Diseases,
4733 Bethesda Avenue, Suite 750, Bethesda, Maryland, 20814
INTRODUCTION
Following approval of the first conjugate vaccine
11 to 18 years of age (CDC. Unpublished data).2 The
against meningococcal disease, the Centers for Disease
annual disease rate generally ranges from 0.9 to 1.5
Control and Prevention’s (CDC) Advisory Committee
cases per 100,000, but clearly the overall and age-specific
on Immunization Practices (ACIP) has broadened its
incidence rates are markedly cyclical.
meningococcal disease vaccination
recommendations.1
The ACIP recommends routine vaccination of young
adolescents with the meningococcal conjugate vaccine at
the pre-adolescent health care visit (11-12 years of age).
Meningococcal Disease
Immunization Recommendations
For those persons who have not previously received the
meningococcal conjugate vaccine, ACIP recommends
vaccination before high-school entry (approximately 15
years of age). Routine vaccination is also recommended for
college freshmen living in dormitories. By 2008, the goal
will be routine vaccination of all adolescents beginning
3
In addition to the ACIP, other important groups have
issued recommendations regarding meningococcal
disease vaccination. These may be reviewed at the
following Web addresses:
Advisory Committee on Immunization Practices
www.cdc.gov/mmwr/PDF/rr/rr5407.pdf
at 11 years of age.
This document describes meningococcal disease
epidemiology and disease burden among children,
adolescents and young adults in the U.S. It also discusses
prevention strategies for meningococcal disease, with a
focus on recommended use of the quadrivalent conjugate
American Academy of Family Physicians
www.aafp.org/x34406.xml
American Academy of Pediatrics
www.cispimmunize.org/pro/pdf/aapmengpolicy.pdf
American College Health Association
www.acha.org/projects_programs/men.cfm
meningococcal vaccine. An overview of the meningococcal
conjugate vaccination program in the United Kingdom,
implemented in 1999, provides an example of the benefits
of widespread conjugate immunization across a population.
Meningococcal disease is associated with an overall case
fatality rate of 10% to 14%.1 Fatality rates can vary widely,
Meningococcal disease is a potentially life-threatening
however, depending on prevalence of the disease, the nature
infection caused by the bacterium Neisseria meningitidis.
of the infection and societal conditions.5 Case fatality rates
It affects 1,400 to 2,800 persons in the U.S. annually.1
generally increase with age,6 but again, aberrations have
Most cases are sporadic; less than 5% occur in outbreaks.2,3
been noted. During a decade-long span ending in 2002,
Incidence is highest in children less than 2 years of age,
CDC surveillance reported fatality rates of 12% in those
but approximately 50% of cases occur in those over 15
aged 10 to 17 years and 14% in those aged 14 to 24 years
years. Temporal and geographic peaks have been noted,
(CDC. Unpublished data).2 Beyond mortality, meningococcal
however, in various age groups. A study in Maryland found
disease is also associated with substantial long-term
that in the 1990s, 30% of cases occurred in adolescents
morbidity. Of those who survive, 11% to 19% have
and young
adults.4
During the same period (1991 to
2002), 13% to 14% of disease countrywide was in persons
permanent sequelae, such as hearing loss, brain damage,
renal failure or limb amputation.1,7,8
Five clinically relevant meningococcal serogroups, A,
and college students who wish to reduce their risk of
B, C, Y and W-135, are responsible for nearly all disease
meningococcal disease may elect to be vaccinated.
worldwide. Currently, serogroups B, C and Y cause the
majority of U.S. infections; serogroup A is extremely rare
Widespread conjugate meningococcal vaccination should
in the U.S. and W-135 causes a very small proportion of
decrease the risk of meningococcal disease in adolescents
infections. However, serogroup distribution has changed
and adults. Expectations for conjugate vaccines are based
over time. Serogroup Y caused only 2% of U.S. cases in
on recent experience. In the U.K., widespread use of
the early 1990s but 39% of cases from 1996 to 2001 (this
conjugate meningococcal C vaccines has led to sharp
specific change appears to be confined to the U.S. thus
decreases in meningococcal C disease (which was respon-
far). Serogroup distribution also varies by
age.3
Serogroup
sible for 30% to 40% of cases in the U.K.), reduction in
B is the most common serogroup in infants, serogroup
bacterial carriage and consequent reduction in incidence
C is most common in adolescents and young adults and
in unimmunized persons.9,10 In the U.S., universal use
serogroup Y causes the majority of cases in those aged
of conjugate Haemophilus influenzae type b (Hib) and
65 years and
older.2
Similar fluctuations in serogroups are
seen worldwide.
pneumococcal vaccines has led to sharp decreases in
meningitis cases caused by these bacteria.11,12 Because
of these immunization successes, meningococcal disease
A quadrivalent conjugate meningococcal vaccine
is now the most common cause of bacterial meningitis
(MCV4), approved for use in persons aged 11 to 55 years
among children over 2 years of age, adolescents and young
(Menactra®, sanofi
adults in the U.S.11
pasteur), is a key addition to existing
meningococcal disease prevention measures.1 Like the
polysaccharide vaccine, which has been licensed in the
United States since 1978, the quadrivalent conjugate offers
Several factors make meningococcal
protection against four serogroups of N. meningitidis
disease a matter of public health importance.
(A, C, Y, W-135), the bacteria that cause meningococcal
First, it is a communicable disease
disease. Successful conjugate vaccine technology, however,
offers additional benefits compared with polysaccharide
associated with notable morbidity and
vaccines, including improved duration of protection,
mortality. Second, isolated meningococcal
induction of immunologic memory, booster responses and
cases and outbreaks often cause serious
reduction in nasopharyngeal bacterial carriage.
medical and social stress in communities and
Routine vaccination is also recommended for groups that
are associated with increased costs — both
have elevated risk. These groups include microbiologists
economic and social. Finally, each case of
who are routinely exposed to isolates of N. meningitidis;
meningococcal disease requires a public
persons who travel to or reside in countries in which
health response (i.e., identification of close
N. meningitidis is epidemic; military recruits; and those
with complement deficiency or functional or anatomic
asplenia. In addition to these groups, all other adolescents
contacts for prophylaxis).
4
EPIDEMIOLOGY OF MENINGOCOCCAL DISEASE
N. MENINGITIDIS
is a commensal bacterium of the human
The distribution of serogroups causing meningococcal
nasopharynx that infrequently causes invasive disease.
Up to 10% to 30% of adolescents and young
disease (A, B, C, Y, W-135) varies over time and by
adults13-15
geographic location.2 From 1988 through 1991, most U.S.
and 19% to 39% of adult males (military recruits)15 are
cases of meningococcal disease were caused by serogroups
asymptomatic, transient nasopharyngeal carriers of N.
B and C, with serogroup Y accounting for only 2% of
meningitidis, although most carry nonpathogenic strains.
cases.3 More recently (1996 through 2001), serogroup Y
Asymptomatic carriage rates in young children are much
lower (< 2%).14,15 Some carriers develop protective
disease caused the largest proportion of cases (39%),
followed by serogroup C (31%) and serogroup B (23%).2
antibodies against the organism.16 In a minority of
exposed individuals, N. meningitidis penetrates the
Although serogroup W-135 is relatively uncommon in the
nasopharyngeal mucosa, reaches the bloodstream and
U.S. and was not previously known to cause outbreaks, it
causes systemic
disease.17
played a major role in an outbreak during the Hajj pilgrimage
to Mecca in 2000. Four cases of W-135 meningococcal
disease were identified in pilgrims returning to the U.S.
varied between 0.9 and 1.5 cases per 100,000 persons
from Saudi Arabia and their close contacts.18
for 4 decades. Although meningococcal disease occurs
throughout the year, incidence peaks in late winter and
early
spring.11
Serogroup A was a common cause of U.S. epidemics early
Rates of meningococcal disease are highest
in the last century, but has been rare since World War II.
in infancy with a second spike in incidence in adolescence,
with a peak at around 18 years of age (Figure
1).2,6
Serogroups A and C continue to predominate throughout
Asia and Africa,19 with serogroup A remaining the major
Invasive Meningococcal Disease by Age and Sex in the U.S., 1992-1996
responsible for a large meningitis outbreak in Burkina
5
Incidence per 100,000
Figure 1:
cause of meningococcal disease in sub-Saharan Africa
(the “meningitis belt”).20,21 Even so, serogroup W-135 was
Male
Female
4
3
Faso in 2002.22 The diversity in geographic distribution of
15
meningococcal serogroups causing disease, while
10
unexplained, is important given the ease and frequency
of travel and potential exposure to serogroups other than
5
those common to one’s region of residence.
0
≤3
4-5
6-11
12-15
16-19
20-23
Age group (months)
2
Overall, serogroups B, C and Y cause a substantial proportion of disease across all ages, but specific distribution
1
varies by age group.3 Recent U.S. data (2002) show that
Age (years)
Rates of meningococcal disease were adjusted for race.
Source: Rosenstein6
≥85
80-84
75-79
70-74
65-69
60-64
55-59
50-54
45-49
40-44
35-39
30-34
25-29
20-24
15-19
10-14
5-9
infants and toddlers experience a higher proportion of
0-4
Incidence per 100,000
5
The rate of meningococcal disease in the U.S. generally
serogroup B disease than older age groups (Figure 2).2
Among young adults (18 to 34 years old), serogroup C is
the most common (48% of cases) and in those 65 years
and older, serogroup Y is most common (62%). In a
The cyclic nature of disease and
prospective surveillance study of U.S. college students
with meningococcal infection during the 1998–1999
school year, serogroup C was the most common (48% of
isolates for which serogroup data were available), followed
changing distribution of serogroups,
combined with frequency of travel
by B, Y and W-135 (28%, 19% and 1%, respectively).23
worldwide, underscore the need
N. meningitidis is an aerobic, gram-negative
for a prevention strategy that
diplococcus. The bacterium has an outer membrane
that is surrounded by a protective polysaccharide
incorporates all major serogroups.
capsule. Thirteen antigenically and chemically
unique polysaccharide capsules have been identified
and form the basis of serogroup classification of
the organism. Five serogroups — A, B, C, Y and
6
W-135 — cause nearly all cases of invasive
meningococcal disease.
Figure 2:
Serogroup Distribution of Invasive Meningococcal Disease by Age Group
in the U.S. – Active Bacterial Core Surveillance 2002
B
Other
Y
C
100
90
Percent of Cases
80
70
60
50
40
30
20
10
0
≤1
2-4
5-17
18-34
Age (years)
Source: ABCs2
35-49
50-64
≥65
TRANSMISSION AND PATHOGENESIS: EXAMINING RISK FACTORS
transmission of N. MENINGITIDIS occurs by droplet aero-
Likewise, certain environmental factors have been
solization (e.g., coughing or sneezing) or direct contact
shown to increase the risk of meningococcal disease.
with secretions from the nasopharynx of colonized persons.
The infection rate (secondary infection) is 500- to
Whether the organism remains a colonizer of the
800-fold greater in household contacts exposed to a
nasopharynx or crosses the mucosal barrier and gains
person who has a sporadic meningococcal infection
access to the bloodstream, central nervous system and/or
than in the general population.34 Increased risk of
other organs depends on both specific bacterial virulence
meningococcal infection among military recruits35 and
factors (e.g., fimbriae, polysaccharide capsule, IgA
college freshmen living in dormitories23 is likely a
protease) and host defense mechanisms (e.g., mucosal
consequence of crowded living conditions.
epithelium, secretory IgA, serum antibody, ciliary activity,
complement, blood-brain barrier).24
In the U.S., higher rates of meningococcal disease have
been observed in black persons and persons of low
7
Various medical conditions increase the risk of
socio-economic status, which are likely surrogate risk
developing meningococcal disease. Persons with immature
markers (e.g., for household crowding and exposure to
or dysfunctional humoral immunity are most susceptible
tobacco smoke) rather than inherent genetic risk factors
to meningococcal
infection.25,26
Immune defects that
for disease.36 Active smoking and passive exposure to
predispose to meningococcal disease include functional
tobacco smoke increase the risk of illness, most likely by
or anatomical asplenia, deficiency of properdin and
increasing the creation and dissemination of respiratory
mannose-lectin binding protein and terminal complement
droplets or compromising the respiratory mucosa as a
components.27-29 Antecedent
barrier to microbial invasion.37 During outbreaks, bar or
respiratory tract infection
also has been associated with increased risk of
meningococcal disease.30,31 Finally, evidence indicates
nightclub attendance and alcohol consumption have
been identified as risk factors for infection.38-40
genetic risk factors may increase susceptibility to
meningococcal infection.32,33
Once N. meningitidis enters the nasopharynx, the organism
attaches to and multiplies on nonciliated epithelial cells.
Increased risk of meningococcal
infection among military recruits
and college freshmen living in
dormitories is likely a consequence
of crowded living conditions.
Some exposed individuals become asymptomatic
nasopharyngeal carriers of N. meningitidis,13,14 which is
an immunizing event. In less than 1% of colonized persons,
N. meningitidis penetrates the nasopharyngeal mucosa and
causes a systemic infection.17 In the bloodstream, the
organism can rapidly produce and release endotoxin,
which stimulates cytokine production and the alternative
complement pathway.7 In about half of bacteremic
persons, N. meningitidis crosses the blood-brain barrier
into the cerebrospinal fluid (CSF), and meningitis follows.
U.S. IMMUNIZATION RECOMMENDATIONS
The quadrivalent meningococcal conjugate vaccine
coverage among adolescents. A routine visit at 11-12 years
(MCV4, Menactra®)
of age to assess immunization status and other preventive
is recommended for routine vaccination
(Table 1) of young adolescents at the pre-adolescent
health care visit (11-12 years of
age).1
For those persons
who have not previously received MCV4, vaccination is
services is recommended by the ACIP, American Academy
of Pediatrics (AAP), American Academy of Family Physicians
(AAFP) and the American Medical Association (AMA).41
recommended before high-school entry (approximately
15 years of age). Also, if not previously vaccinated, routine
Routine meningococcal vaccination is also recommended
vaccination is recommended for college freshmen living in
for persons in specific risk groups.1 These are microbiolo-
dormitories. Finally, other adolescents and college students
gists routinely exposed to isolates of N. meningitidis;
who wish to decrease their risk for meningococcal disease
military recruits; persons who travel to, or reside in
may elect to receive the vaccine.
countries in which N. meningitidis is hyperendemic or
epidemic; persons with terminal complement component
The ACIP recommends catch-up vaccination at approxi-
deficiencies; and those who have anatomic or functional
mately 15 years of age as an effective strategy to reduce
asplenia. HIV patients who wish to decrease their risk of
meningococcal disease incidence among adolescents and
meningococcal disease may elect to be vaccinated.
young adults. The routine vaccination recommendation
at 11-12 years of age might strengthen the role of the
Conjugate Versus Polysaccharide Vaccine
pre-adolescent visit and have a positive effect on vaccine
Vaccination with MCV4 is preferred for all persons in
Table 1:
Recommendations for Use of Meningococcal Conjugate Vaccine*
• At the pre-adolescent health care visit
(11-12 years old)
• At high-school entry (approximately 15 years old),
if not previously vaccinated with MCV4
• College freshmen living in dormitories
• Microbiologists routinely exposed to isolates
of N. meningitidis
• Military recruits
• International travelers and citizens residing in
endemic or hyperendemic areas
• Persons with anatomic or functional asplenia
• Persons with terminal complement component disorders
* Approved for use in persons aged 11 to 55 years
Source: CDC1
the age range for which it is approved, 11 to 55 years,
because of the benefits it should provide compared with
polysaccharide vaccine (Table 2).1 Immunogenicity data
show MCV4 induces antibody levels at least as good as the
polysaccharide vaccine. Both vaccines include protection
against four of the five strains (A, C, Y and W-135) that
cause the majority of cases worldwide. Neither includes
protection against serogroup B disease (see box, “About
Serogroup B Vaccines”).
Although the vaccines are equally immunogenic,
MCV4, which is administered intramuscularly (versus
subcutaneous injection of the polysaccharide vaccine) is
more reactogenic.1 MCV4 is expected to have a duration
of protection of at least 8 years compared with 3 to 5
years for the polysaccharide vaccine. Ongoing studies will
provide specific data about duration of protection in the
coming years.
8
Table 2:
Comparison: Conjugate and Polysaccharide Meningococcal Disease Vaccines
9
Conjugate (Menactra®)
Polysaccharide (Menomune®)
Strains included
A, C, Y, W-135
A, C, Y, W-135
Immunogenicity*
82% to 97%
80% to 95%
Duration of protection
> 8 years†
3-5 years
Administration
Intramuscular injection
Subcutaneous injection
Safety
Generally mild adverse reactions; mainly pain, redness
and induration at injection site, headache, fatigue and
malaise.
Generally mild adverse reactions; most
frequent is pain and redness at injection
site. Severe reaction uncommon.
Induction of immunologic memory‡
Expected
No
Booster responses‡
Expected
No
Reduction in nasopharyngeal
bacterial carriage‡
Expected
No
Herd immunity‡
Expected under some vaccination strategies
No
Cost§
$82
$86
* Measured as ≥four-fold rises in antibody titers in adolescents;
† Based on CDC model, ongoing evaluation is expected to provide direct data in three to five years;
‡ Assumptions based on demonstrated benefits of other conjugate vaccines
§ Retail cost to physicians.
Sources: CDC1, CDC unpublished data.
In fact, extensive post-licensure evaluation of MCV4 will
be ongoing. Data collected in the coming years will provide vaccine-specific information and will shape future
recommendations. The hope is that this conjugate vaccine
provides benefits similar to other conjugate vaccines.
About Serogroup B Vaccines
In clinical trials, most candidate vaccines against
serogroup B polysaccharide have not stimulated
Conjugate technology changes the nature of the immune
protective immunity in humans.42 Research has
response from T-cell independent to T-cell dependent. This
focused on noncapsular antigens as vaccine
leads to benefits not seen with polysaccharide vaccines,
including induction of immunologic memory, booster
responses and reduction in nasopharyngeal bacterial
carriage. Reduction in asymptomatic carriage rates, if wide-
candidates. For example, an outer-membrane
protein serogroup B vaccine, licensed for use in
New Zealand in 2004, was designed to match
spread, leads to protection of unvaccinated individuals
and combat an outbreak of serogroup B disease
through a herd immunity effect. These benefits have been
ongoing throughout the 1990s. However, this
demonstrated with use of a monovalent meningococcal
approach does not address the diversity of outer-
conjugate C vaccine in the U.K. and widespread Hib and
membrane proteins that cause sporadic serogroup
B disease or geographic variations.43,44
pneumococcal conjugate vaccination in the U.S. (discussed
below). Data on similar benefits are not yet available on MCV4.
pneumococcal vaccination also appears to have a
substantial herd immunity effect. While the vaccine is
used only in children, disease rates have declined among
adults. For the serotypes included in the vaccine, disease
incidence decreased in those aged 20 to 39 years, 40 to
64 years and 65 years and older by 46%, 20% and 29%,
respectively (CDC. Unpublished data).
The U.K. Experience: Monovalent
Meningococcal Conjugate C Vaccine
Additional evidence comes from the U.K., where a
comprehensive monovalent meningococcal conjugate C
vaccine immunization program was implemented in 1999.9
Disease epidemiology in the U.K. differs from that in the
U.S.; the U.K. sees very little serogroup Y disease and has
a higher incidence of serogroup C infection. Widespread
use of the monovalent conjugate C vaccine would be
The quadrivalent meningococcal polysaccharide vaccine
(Menomune®, sanofi
expected to have a greater relative impact in the U.K.
pasteur) continues to be recom-
mended in children aged 2 to 10 years and adults older
The U.K. program includes a routine 3-dose infant
than 55 years who are at increased risk of infection. The
vaccination course (at 2, 3 and 4 months) with a single
polysaccharide vaccine is also an acceptable alternative for
dose for children aged 12 months to 17 years (with a
persons aged 11 to 55 years if MCV4 is unavailable.
subsequent extension to 25 years of age).9 Immunization
rates of about 85% in target groups resulted in an 81%
Both vaccines are recommended for control of menin-
reduction in serogroup C disease incidence within 18
gococcal disease outbreaks, with the conjugate vaccine
months. While the vaccine was immunogenic in young
preferred for those aged 11 to 55 years. Revaccination may
infants, their immunity waned at about 1 year.46
be indicated for those who previously received the polysaccharide vaccine if they remain at high risk for infection
Despite this, control of disease in all age groups has been
and are aged 11 to 55 years.
excellent with disease incidence declining 67% in the
unvaccinated population.10 This is attributable to the herd
Benefits of Other Conjugate Vaccines
immunity arising from the marked reduction in nasopha-
Non-meningococcal conjugate vaccines, including Hib
ryngeal carriage (a key feature of conjugate vaccines).
and a 7-valent pneumococcal, are routinely used in the
Nasopharyngeal carriage rates decreased 66% among
U.S. Before introduction of the vaccine, Hib disease was
students aged 15 to 17 years.47 Surveillance has shown
the leading cause of bacterial meningitis in children
no evidence of serogroup replacement or development
younger than 5 years. Incidence of invasive Hib disease
of capsular switching in the first 18 months in the U.K.48
has declined more than 99% since vaccine licensure.45
MCV4 will be used much differently in the U.S. than the
Similarly, rates of invasive pneumococcal disease
monovalent vaccine is used in the U.K. It is unclear if the
in children younger than 2 years have declined 70% to
current U.S. immunization strategy will yield a herd
80% since vaccine licensure in
2000.2,12
Conjugate
immunity benefit.
10
PRESENTATIONS, PROGRESSION AND SEQUELAE
Meningitis and
Meningococcemia
Meningococcal disease
manifests most commonly
A 12-year-old African-American boy was rushed to the
as meningitis and/or meningococcal bacteremia.7,8 It is
emergency room by his parents at 5 p.m. on a Saturday
meningococcemia, however,
Otherwise healthy, he had had two days of a non-productive
a less common but more
cough accompanied by malaise, headache and intermittent
after they found him unresponsive in the bathroom.
severe presentation (5% to 20% of cases) that is associated
nausea. He had been seen that morning by his physician
with the highest mortality rates and long-term sequelae.
who prescribed azithromycin for bronchitis. It had taken
Meningococcemia often begins with a sudden onset of
some time to fill the prescription and the boy received only
fever, malaise, myalgia and headache; seizures occur in
one dose of the medication, which he promptly vomited just
20% of cases. About half of
dren and young
11
CASE REVIEW: 12-year-old male
adults)50
patients49
(even more chil-
develop a prominent petechial
or purpuric rash, primarily on the extremities. When
present, a meningococcal rash can change and spread
very rapidly. Meningococcemia may occur either with
or without meningitis.
The more common clinical presentation, meningococcal
meningitis, is often nonspecific. Early symptoms may mimic
those of other more common but less serious diseases.5,8
Patients may present with sudden onset of fever, headache,
meningismus and signs of cerebral dysfunction. However,
before he was discovered in the bathroom.
In the emergency department, the boy had no detectable
blood pressure and required immediate intubation. A few
petechial lesions were evident on the palms and soles
of the feet, at the belt line and in the conjunctivae. The
peripheral white blood cell count was 25,900/cumm with
a profound left shift and a platelet count of 35,500/cumm.
Antimicrobials and pressor agents were started immediately.
A lumbar puncture revealed a white cell count of 19,340
with 85% neutrophils and a glucose concentration of 16
mg/dl. Both blood and CSF culture grew N. meningitidis.
the classic triad of headache, confusion and nuchal rigidity
The patient had a prolonged, stormy course. He never
is not always evident. Wide variations in presentation can
regained consciousness, developed purpura fulminans and
occur at all ages, and symptoms can progress and change
peripheral gangrene that required bilateral below-the-knee
rapidly during the course of the disease.
amputation. He died of pulmonary complications after 33
days in the hospital.
Infants and the elderly may not present with the classic
symptoms and signs of meningococcal meningitis.51
Meningismus is absent in neonates and often in infants.52
One of the most important clues to a meningitis diagnosis
in neonates is a change in affect or level of alertness.
Clinical suspicion should also be raised by temperature
instability, listlessness, high-pitched crying, lethargy, weak
suck, refusal to eat, irritability, jaundice, vomiting, diarrhea
Teaching Points: Symptoms of meningococcemia can
appear suddenly and progress rapidly. Even with rapid
diagnosis and appropriate treatment, serious sequelae are
possible; deafness being the most common one in children.
Meningococcal rashes may appear at areas where pressure
occurs from stockings, elastic or belts.
or respiratory distress. Elderly patients, especially those
with multiple co-morbid diseases, may be afebrile or
hypothermic, lethargic or exhibit reduced alertness and
Figure 3:
Clinical Manifestations of Meningococcal Disease
have variable signs of meningeal inflammation. Confusion
is common,53 as is a prior or concurrent respiratory tract
Bacteremia 43.3%
infection. A definitive diagnosis of meningococcal disease
is based on isolation of N. meningitidis from a normally
Pneumonia 6.0%
sterile site (e.g., blood; CSF; joint, pleural or pericardial fluid).
Arthritis 2.0%
Otitis media 1.0%
Meningococcal meningitis is fatal in approximately 10%
Epiglottitis 0.3%
of cases among the general population; the case fatality
Pericarditis 0.1%
rate is as high as 53% in patients with meningococcemia.7
Meningitis 47.3%
Factors associated with an increased mortality rate include
recovery of an isolate from the bloodstream and serogroup
C infection.6
Source: Rosenstein6
Other Presentations
Up to 15% of patients with meningococcal disease have
pneumonia.6,54,55 Meningococcal pneumonia occurs
primarily in older adults and is most commonly associated
with serogroup Y or W-135
infection.6
Less common mani-
festations of disease (<2% of cases) include pericarditis,
otitis media, epiglottitis and arthritis (Figure 3).6
Sequelae
Even with appropriate therapy, systemic meningococcal
infection can progress rapidly — often within hours of the
first symptoms. Despite the susceptibility of N. meningitidis
to penicillin and advances in medical care, 11% to 19% of
patients who survive invasive meningococcal disease suffer
from permanent sequelae, including hearing loss, neurologic
or brain damage, renal failure and limb amputation.7,8
Prevention of Secondary Disease
The primary method of preventing secondary meningococcal disease is antimicrobial prophylaxis of persons in
close contact with an infected person (Table 3). Those
Table 3:
Meningococcal Disease Prophylaxis Recommendations:
High-Risk Contacts
• Household contact (especially young children)
• Child care or nursery school contact*
• Direct exposure to secretions of index patient
through kissing, sharing toothbrushes or eating
utensils (markers of close social contact)*
• Mouth-to-mouth resuscitation, unprotected contact
during endotracheal intubation*
• Frequently slept or ate in same dwelling as
index patient*
* During 7 days before onset of illness
Source: AAP60
12
CASE REVIEW: 18-year-old female
An 18-year-old white female attending a state univer-
12,500/cumm with a marked left shift. Although the blood
sity (freshman dormitory resident) began to experience
culture was negative, the CSF culture was positive for
aches and chills while at class during the third week of
N. meningitidis, Group C. The patient was hospitalized
the semester. The patient assumed she had a mild viral
for 8 days and was discharged to the care of her parents
illness and returned to the dorm to sleep. Shortly after
at home. She re-started her college studies during the
dinner, she went to the infirmary complaining of aches
second semester. Subsequent testing determined that the
and nausea. The patient reported that she came to the
patient had sustained a moderate high and mid-range
infirmary at the urging of her roommate. The patient was
bilateral hearing loss.
articulate and mildly febrile (101ºF); she expressed a
desire to go back to her room. Infirmary staff agreed and
Teaching Points: Early symptoms of meningococcal
ordered Tylenol and rest.
infection can mimic other mild to generally moderate
illnesses (e.g., cold and flu). The onset of symptoms in
13
In the morning, when she did not join her friends at
this patient was insidious and, upon her first presentation
breakfast, they went to the patient’s room to check on
to the infirmary, non-specific. The cognitive dysfunction
her. She was in bed, and friends described her as “inco-
was not evident until her second visit to the infirmary.
herent” and “confused.” The friends brought the patient
Meningococcal disease was not immediately evident
back to the infirmary where staff noticed a rash on her
(e.g., she had no rash or high fever) upon her initial pre-
torso. Transport to a local hospital took approximately 35
sentation in the university infirmary. Therapy should be
minutes.
started upon suspicion of meningococcal infection and
not withheld pending results of cultures.
Antibiotics were started within 15 minutes of arrival in the
emergency department. The white blood cell count was
most in need of chemoprophylaxis against meningococcal
meningococcal disease (Table 4).11,60 One study showed
infection include household members, daycare center
azithromycin is also effective in eradicating nasopharyngeal
contacts and persons directly exposed to the oral
carriage.61 Persons with invasive meningococcal disease
secretions of a patient with invasive meningococcal
treated with agents other than ceftriaxone or other third-
infection. Antimicrobial prophylaxis of at-risk persons
generation cephalosporins should also receive one of the
should be initiated within 24 hours after the index
chemoprophylactic antibiotics before hospital discharge.62
infection is identified, if possible.11
Outbreak Control
Oral rifampin and ciprofloxacin and parenteral ceftriaxone
Given the devastating nature of meningococcal disease,
substantially reduce (by 90% to 95%) nasopharyngeal
sporadic cases often become the topic of front-page and
carriage of
TV news. Such cases elicit community fear and increased
N. meningitidis56-59
and are therefore
recommended by the ACIP and the AAP for prophylaxis of
telephone calls and visits to treatment centers. Public
health departments are faced with assessing potential
associated with this intervention are high compared with
outbreaks, determining the need for and designing
many other recommended preventive measures.63 A similar
appropriate control procedures and fielding public
analysis examining routine vaccination in college freshmen
inquiries. Requests for chemoprophylaxis and vaccination
also highlighted the high cost of a widespread meningo-
are common, even among those without close contact
coccal vaccination program.64 Both analyses included a
with infected persons.
wide range of costs associated with each meningococcal
disease case. The high end of these ranges demonstrates
The decision to implement mass vaccination is
the potential for serious disease sequelae and even death
complicated.11
that accompany each infection.
Such vaccination campaigns are expensive,
require considerable public health effort and can create
unwarranted public concern. Still, mass vaccination may
Although data about the economic impact of meningococcal
be necessary to prevent the substantial morbidity and
disease are imperfect, older CDC data estimated the direct
mortality associated with meningococcal disease. The
cost of meningococcal disease at $13,431 per case (1995
CDC has issued guidelines, including criteria for deciding
dollars).65 The estimated lifetime costs of sequelae ranged
whether use of meningococcal vaccine is warranted
from $44,187 per case (hearing loss) to $864,980 (severe
(available at: www.cdc.gov/mmwr/pdf/rr/rr4605.pdf).
retardation). Indirect costs (lost productivity) were estimated
to be $1 million per case. Preventing disease would avert
Economic Impact and Cost Effectiveness
these costs for the individual, families, health care providers,
An economic cost and benefit analysis of routine menin-
employers, health care payers and society.
gococcal vaccination at 11 years of age showed that costs
Table 4:
Schedule for Antibiotic Prophylaxis of Meningococcal Disease
Drug
Age Group
Dosage and Route of Administration
Duration
Ciprofloxacin
Adults
500 mg po
Single dose
Ceftriaxone
Children < 15 yrs
Adults
125 mg IM
250 mg IM
Single dose
Single dose
Rifampin
Children < 1 mo
Children > 1 mo
Adults
5 mg/kg po q12h
10 mg/kg po q12h
600 mg po q12h
2 days
2 days
2 days
Sources: CDC1, AAP60
14
CONCLUSION
meningococcal disease is a serious illness that can
Health care providers must also be aware of the variable
progress rapidly, resulting in substantial morbidity
and potentially fulminant clinical presentation of menin-
and mortality, even with appropriate treatment. U.S.
gococcal disease. The difficulty of a quick and accurate
immunization policy shifted with the availability of
diagnosis and the occurrence of substantial morbidity
a quadrivalent conjugate meningococcal vaccine.
and mortality even with appropriate and rapid treatment
The conjugate vaccine is approved for use in persons
are compelling reasons for a conjugate vaccine-based
aged 11 to 55 years and recommended for routine
approach to the prevention of meningococcal disease.
vaccination of adolescents and college freshmen living
in dormitories. Others at high risk and therefore
recommended for vaccination include microbiologists
routinely exposed to isolates of N. meningitidis,
international travelers or U.S. citizens living in areas where
N. meningitidis is endemic or hyperendemic, those with
anatomic or functional asplenia or terminal complement
15
component disorders and military recruits.
The constantly changing epidemiology, coupled with
the ease and frequency of travel of U.S. citizens, suggests
broad coverage against meningococcal serogroups is
warranted. Although no vaccine against serogroup B is
available currently, the quadrivalent meningococcal
conjugate and polysaccharide vaccines both provide protection against the other four clinically relevant strains
of N. meningitidis (A, C, Y, W-135). The conjugate vaccine
is available for persons aged 11 to 55 years while the
polysaccharide vaccine is approved for use in anyone
aged 2 years or older and recommended for those aged
2 to 10 and 55 years and older.
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65. Levine OS, Shaffer P, Haddix A, Perkins BA. Cost-effectiveness
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International Pathogenic Neisseria Conference, Baltimore, MD,
September 1996.
SELF-ASSESSMENT EXAMINATION
Please circle the correct answer. (At least seven of the ten answers must be correct to obtain a CME certificate.)
See mailing instructions on next page.
1. What percent of meningococcal disease cases in the
U.S. are fatal?
a) <4
b) 4 to 6
c) 6 to 10
d) 10 to 14
6. Which factors affect whether N. meningitidis crosses
the mucosal barrier and gains access to the
bloodstream, CNS and other organs?
a) Bacterial virulence
b) Host defense mechanisms
c) Neither A nor B
d) Both A and B
2. What percent of meningococcal disease survivors
experience permanent sequelae (e.g., hearing loss,
brain damage, renal failure or limb amputation)?
7. Which symptom is absent in neonates with
meningococcal meningitis?
a) 4 to 7
a) Change in affect or alertness level
b) 8 to 10
b) Fever
c) 11 to 19
c) Headache
d) ≥20
d) Meningismus
3. What is the most common cause of bacterial
meningitis in the U.S.?
a) Haemophilus influenzae type b
b) Neisseria meningitidis
c) Staphylococcus aureus
d) Streptococcus pneumoniae
8. Incidence of invasive Hib disease has fallen by what
percent following widespread uptake of the conjugate
Hib vaccine?
a) 50
b) 70
c) 90
d) >99
4. Which serogroup, commonly responsible for U.S.
epidemics a century ago, now rarely causes infection
in this country?
9. Which benefit is not associated with use of the
polysaccharide meningococcal vaccine?
a) A
a) Highly effective in older children and adults
b) C
b) Favorable safety profile
c) Y
c) Lifelong immunity
d) W-135
d) Protection against serogroups A, C, Y and W-135
5. Which serogroup caused 2% of cases in the early
1990s, but nearly 40% by the end of the decade?
10. Conjugate vaccines are associated with which
benefit(s) versus polysaccharide vaccines?
a) A
a) Herd effect
b) C
b) Improved duration of activity
c) Y
c) Induction of immunologic memory
d) W-135
d) All of the above
18
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