Meningococcal Disease

Louise Elaine Vaz, MD, MPH*

*Division of Pediatric Infectious Diseases, Doernbecher Childrens Hospital, Oregon Health & Science University, Portland, OR

Practice Gap
Knowledge of the epidemiology of meningococcal disease and available
preventive measures, including prophylaxis and vaccines, is important to
ensure appropriate counseling for at-risk patients and families.

Objectives After completing this article, readers should be able to:

1. Understand the epidemiology of Neisseria meningitidis infections.

2. Understand which patients are at increased risk of invasive and
recurrent meningococcal disease.
3. Recognize the major clinical features associated with N meningitidis
infection.
4. Plan appropriate management for a patient with meningococcal
disease.
5. Plan appropriate prophylaxis for individuals exposed to N meningitidis.
6. Gain familiarity with meningococcal vaccines and their indications.

INTRODUCTION
AUTHOR DISCLOSURE Dr Vaz has disclosed
Neisseria meningitidis is the bacterium that causes meningococcal disease, one of no nancial relationships relevant to this
the leading sources of community-acquired sepsis and meningitis among chil- article. This commentary does not contain a
discussion of an unapproved/investigative
dren. Both sporadic and epidemic disease can occur, and a large number of
use of a commercial product/device.
individuals can become infected within a short period of time. The manner by
which meningococcal disease strikes previously healthy individuals, with a rapid ABBREVIATIONS
progressive illness and even death, has made this a disease of public health ACIP Advisory Committee on
Immunization Practices
concern. In this article, we review the basic microbiology, epidemiology, clinical
CDC Centers for Disease Control and
presentation, treatment, and prevention of meningococcal disease.
Prevention
CSF cerebrospinal uid
DIC disseminated intravascular
MICROBIOLOGY
coagulation
N meningitidis is an aerobic, nonmotile Gram-negative diplococcus bacterium. It FHbp factor H-binding protein
HIV human immunodeciency virus
is considered a fastidious organism, with specic temperature and carbon dioxide
LOS lipooligosaccharide
requirements, and grows best on chocolate or blood agar. All Neisseria species MIC minimum inhibitory concentration
(including Neisseria gonorrhoeae) are catalase- and oxidase-positive, although PCR polymerase chain reaction
individual species can be differentiated based on biochemical properties. For WBC white blood cell

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example, N meningitidis can produce acid from glucose
and maltose, but N gonorrhoeae is unable to utilize maltose.
(1)(2)
Humans are the only known reservoir for this bacterium.
The nasopharynx may be asymptomatically colonized via
aerosolized droplets containing meningococci. Coloniza-
tion provides the source by which organisms are spread.
Most of those who are colonized with meningococcus do not
get sick. Disease is caused when bacteria invade epithelia and
enter the bloodstream, resulting in systemic disease. (3)(4)
Bacterial virulence factors enable meningococci to sur-
vive and invade the human host. Those bacteria capable of
invasion are encapsulated. The capsule is characterized by a
specic serogroup that is antigenically and chemically dis-
tinct. The polysaccharide capsule serves as a defense barrier
by inhibiting host phagocytosis and complement-mediated
lysis. Twelve capsule serogroups have been identied: A, B,
C, H, I, K, L, W135, X, Y, Z, and 29E. (2)(5)(6) Those
commonly associated with disease are: A, B, C, Y, W135,
X, and occasionally L and Z. Within each group, subtypes
and genotypes vary in their virulence and the severity of
disease that they cause. (7)(8)
Other bacterial virulence factors play a role in attaching
to cells and eliciting the host response to infection. The pili
and opacity proteins on the outer membrane are instru-
mental in attachment, leading to colonization and invasion.
N meningitidis also contains lipooligosaccharide (LOS) mol-
ecules in the outer membrane wall of the cell envelope. LOS
is similar in function to the lipopolysaccharide endotoxin
in other Gram-negative bacteria but lacks the O-antigenic re-
peats. The release of the LOS endotoxin triggers a cascade of
inammation that produces the features of septic shock that
are seen in patients with meningococcemia. (9)(10) Higher
concentrations of meningococcal LOS are found in severe
meningococcal disease and correlate with mortality. (11)
EPIDEMIOLOGY
The annual incidence of meningococcal disease in the
United States has traditionally varied from 0.3 to 1.5 cases
per 100,000 persons. (12)(13) The United States is cur-
rently experiencing a historic low in meningococcal disease.
(14) In 2014, there were 426 total cases of meningococcal
disease reported, with an incidence rate of 0.14 cases per
100,000 persons. (15) This decrease preceded the introduc-
tion of meningococcal quadrivalent conjugate vaccines into
the immunization schedule and may be due to natural im-
munity within the population, changes in behavioral risk
factors (such as smoking), and decreased virulence of cir-
culating meningococcal strains. (16)(17)(18)(19)
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Peak incidence of disease occurs in the rst year after
birth, and 35% to 40% of cases occur in children younger
than age 5 years. The second peak occurs in adolescence. (13)
(20)(21) This correlates to what is observed for nasopharyn-
geal colonization rates. Colonization increases during child-
hood from 4% to 5% in infants to 23.7% in young adults,
only to decrease again in adults to 5% to 10% among
50-year-old adults. (22)(23) Colonization may be transient
or persistent, which may provide protection against in-
vasive disease by instigating the production of protective
antibodies. (12)(24)(25) Serogroup B causes the most disease
in those younger than age 5 years, whereas serogroups C, Y,
and W135 cause 75% of cases in adolescents and adults. (26)
Infections occur throughout the year but particularly in
the winter, which may reect an association with viral upper
respiratory tract infections. Infections occur globally, al-
though there is geographic variation in serogroup distribu-
tion. Serogroups B and C account for most of the disease in
Europe. In North America, serogroups B, C, and Y pre-
dominate. Epidemics of serogroup A can be found in Asia
and Africa, particularly in the area between Ethiopia and
Senegal called the meningitis belt. Serogroup W menin-
gococcal disease is reported in sub-Saharan Africa and is
also associated with the Hajj pilgrimage to Mecca in Saudi
Arabia. (27)
Although 98% of cases in the United States are sporadic,
outbreaks do occur. (13)(28)(29) Meningococcal disease is
a public healthreportable disease in all 50 states and the
District of Columbia and should be reported to public health
authorities within 24 hours of a conrmed or probable case.
(30) Recently, outbreaks in specic population groups have
received media attention. Between 2012 and 2014, multi-
ple outbreaks of meningococcal C infection were detected
among men who have sex with men in some of the larger US
cities, including New York, Los Angeles, and Chicago. (31)
Seven outbreaks of meningococcus serogroup B infection
have occurred on college campuses since 2009, most recently
in Ohio, New Jersey, California, and Oregon, resulting in 41
cases and 3 deaths. (32)(33)(34)(35)
Epidemic disease occurs in developing parts of the world
and is more commonly due to serogroups A, X, and W135.
(36) Risk factors for meningococcal epidemics include
conditions of overcrowding, poverty, and malnutrition. Trav-
elers to areas of endemic meningococcal disease are encour-
aged and may be required to undergo pretravel vaccination
in time for vaccine protection to take effect before actual
travel. (37)
Transmission occurs through respiratory droplets or
secretions from the nasopharynx of colonized persons and
requires close, direct contact. Asymptomatic carriers are the
Vol. 38 No. 4 APRIL 2017 159
 most common source of transmission, and disease is as-
sociated with new acquisition of an invasive strain. Risk
factors include age (younger than 1 year or between 15 and
24 years), crowded living conditions (military barracks,
dormitories), (21)(25)(38) cigarette smoking (active or pas-
sive), (39) prior viral respiratory infection (especially in-
uenza), family/household contact with meningococcal
disease, (40)(41) and immunodeciency (discussed later).
(29)(42)(43)(44)
Perhaps due to the bacteriums ability to infect healthy
young adults, attention has been paid to adolescent risk
factors in particular. Epidemiologic studies document that
carriage rates rise in the rst months of college arrival, and
risk of disease is highest among rst-year students living
in dormitories. (42) Despite this, there is not an increase in
the incidence of meningococcal infection among college
students compared with age-matched controls, although
among affected college students, the rates of illness were
higher among freshman and for students residing on
campus. (21)(41)(45)(46) Vaccination of college freshmen
with quadrivalent vaccine is recommended by the Advi-
sory Committee on Immunization Practices (ACIP) and has
been a focus for primary prevention of disease.
CLINICAL PRESENTATION
In the era of vaccination for Haemophilus inuenzae and
Streptococcus pneumoniae, meningococcal disease should be
considered for a child who presents with acute signs of
sepsis or meningitis. The incubation period is between 1
and 10 days (often <4 days) and believed to be within 48 to
72 hours of new colonization by an invasive strain. Clinical
presentation of N meningitidis infection can vary, ranging
from fever to meningitis or sepsis and fulminant disease
with death within hours. (19)
At the onset, patients can present with fever and signs
of an upper respiratory tract infection without toxicity. Myal-
gia may be intense and the presentation may be mistaken
for inuenza. (47) Median time from onset of symptoms to
hospital admission was estimated at less than 22 hours in
1 study. (47) Approximately 50% of cases result only in
meningitis, and the remainder are characterized by either
sepsis or both sepsis and meningitis. (15)(19)(29)
As the more common clinical presentation, meningo-
coccal meningitis itself is indistinguishable from acute
meningitis caused by other pathogens. In younger chil-
dren, meningeal signs may be less apparent, but irritabil-
ity is often present. Seizures may also occur but are less
common than seen with H inuenzae and S pneumoniae
infections. (48)
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Occult bacteremia is rare in meningococcal infection.
(49) Invasive disease is usually accompanied by systemic
signs of illness. Septicemia with meningococcus presents
with fever, followed by rash and rapid deterioration within
a few hours. Sepsis can precede nonspecic symptoms
such as limb pain or vomiting and abdominal pain. Pallor
or mottling, leg pain, or cold hands and feet are early sensi-
tive signs of meningococcal sepsis. (19)(47)(50) Vascular
collapse, instigated by LOS activating the release of inam-
matory mediators of shock, may lead to disseminated
intravascular coagulation (DIC). Increasing petechiae,
ecchymosis, or bleeding despite appropriate antibiotic ther-
apy is concerning for DIC. (51) Purpura fulminans may
lead to tissue necrosis and require aggressive debridement.
Adrenal insufciency may occur in a particular presenta-
tion known as the Waterhouse-Friderichsen syndrome. (52)
Shock can lead to decreased cerebral perfusion and multi-
organ failure.
The rash in meningococcal disease, a distinguishing
feature, begins as macules, papules, or urticaria but be-
comes petechial within hours after initial sick symptoms
begin. It is important to note that only 2% to 11% of children
who present with a petechial rash have meningococcal
disease. (53) Infection with other viruses, such as enterovi-
rus, Epstein-Barr virus, cytomegalovirus, and measles, may
demonstrate a similar-appearing rash. (19)(47)
Less common manifestations of meningococcal infec-
tion include pneumonia, septic arthritis, epiglottitis, osteo-
myelitis, urethritis, and pericarditis. (19)(54)(55)(56)(57)
Meningococcal conjunctivitis should be managed as inva-
sive disease because topical therapy does not prevent
invasion and secondary cases can occur. (58) Reactive com-
plications, such as arthritis, vasculitis, and pericarditis,
can occur a few days after treatment. These complications
can be associated with fever and resolve spontaneously
within 10 days. Symptomatic relief with nonsteroidal anti-
inammatory drugs may be benecial. (19)(59) Chronic
meningococcemia is a rare form of meningococcal infec-
tion characterized by recurrent episodes of fever, rash,
arthralgia, arthritis, and headache over weeks to months
in association with bacteremia that clears without treat-
ment. The patient is well between episodes. (60) Chronic
meningococcemia may be more common in patients with
immunodeciency. (61)
Predictors of poor outcome in meningococcal disease
include young age, hypotension, leukopenia, thrombocyto-
penia, and altered mental status. (19)(62)(63) Sequelae
associated with meningococcal disease occur in up to
20% of survivors, characterized by physical and neurologic
disabilities, such as loss of digits or limb(s), skin scarring,
deafness, or brain damage. (19)(29) Rates of severe neuro-
logic sequelae, however, are comparably lower after menin-
gitis due to N meningitidis than H inuenzae or S pneumoniae.
(50)(64) The current mortality rate from meningococcal dis-
ease is as high as 10% to 15% (50)(65)(66) but has been
reported to be as low as 5%. (16)(67) A major determinant
of a favorable outcome is the timing of antibiotic delivery
and early correction of shock.
DIAGNOSIS
Because N meningitidis can be a component of normal na-
sopharyngeal ora, isolation of the pathogen from throat
cultures alone is not helpful for diagnosis of clinical disease.
Diagnosis is made through positive blood, cerebrospinal
uid (CSF), or skin lesion cultures or a culture from another
sterile site. Culture is the gold standard for diagnosis and
may be helpful in identifying drug resistance. (2)(68) For
public health purposes, positive cultures are useful to clas-
sify cases, identify serogroup, and monitor for vaccine ef-
fectiveness. Blood cultures may be positive in 40% to 75%
and CSF cultures in 90% of those not pretreated with
antibiotics. Gram-stains of CSF are positive in 75% to
80% of untreated cases of meningitis and often demon-
strate the classic-appearing Gram-negative diplococci. (69)
(70) Antibiotics sterilize CSF within hours. (71) Use of other
parameters, such as elevated CSF white blood cell (WBC)
count (>22 CSF WBCs if younger than age 28 days and >15
CSF WBCs if older than age 28 days), elevated CSF pro-
tein (>120 g/dL), or low CSF glucose (<20 mg/dL) may
be helpful to assess central nervous system involvement if
cultures are pretreated or if there is a traumatic lumbar
puncture. (72)(73) Skin biopsy and culture of the rash seen
in meningococcemia shows endothelial necrosis, with men-
ingococci present within the endothelium and thrombi. (74)
Specic agglutination rapid diagnostic systems have been
used in parts of the world in which the ability to obtain
cultures is limited. (75) Real-time polymerase chain reaction
(PCR) detection systems may be available for blood or CSF
and help in pretreated cases, although the Centers for Disease
Control and Prevention (CDC) continues to recommend culture
as the gold standard for diagnosis. Molecular typing may also
aid in tracking and linking cases in an outbreak. (76)(77)(78)(79)
Based on the 2015 CDC case denitions, a conrmed
case is a clinically compatible case in which N meningitidis is
isolated by culture or PCR from a normally sterile site or
purpuric lesions. Probable cases are those in which the
presence of N meningitidis antigen by immunohistochem-
istry or latex agglutination of CSF is detected. Suspected
cases are those in which a Gram-stain shows Gram-negative
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diplococci that are not yet identied obtained from a sterile
site or there is clinical purpura fulminans but a negative
blood culture. (30)
TREATMENT
Early diagnosis and optimal medical care are associated with
improved outcomes. With antibiotics, mortality has been
substantially reduced from a range of 70% to 85% to a range
of 10% to 15%. (15)(25) Antibiotics should be immediately
administered after blood specimens are obtained for cul-
ture in suspected meningococcal cases. The drug of choice
for empirical treatment of meningococcal disease is a third-
generation cephalosporin, such as ceftriaxone or cefotaxime
(Table 1). (19)(42)
Once susceptibilities are known, antibiotics can be
changed to penicillin if the isolate has a minimum inhib-
itory concentration (MIC) of less than 0.1 mg/mL. (80) If the
MIC is greater than this, a third-generation cephalosporin
is preferred. (68)(81) Even if the bacterium is penicillin-
susceptible, ceftriaxone is often used due to ease of admin-
istration, cost, and efcacy. Although ceftriaxone resistance
may be seen with other Neisseria species, this is considered
unlikely for N meningitidis. (82) If cultures were not obtained
and treatment is presumptive based on clinical ndings,
treatment with ceftriaxone is continued. Care must be taken
to dose antibiotics for the compartments that are infected.
For patients with a history of anaphylaxis with penicillin or
cephalosporin use, chloramphenicol can be used if available.
Adverse effects of chloramphenicol include bone marrow
suppression and in infants, gray syndrome. Meropenem is
also an option, although the rate of cross-reactivity with peni-
cillin is between 2% and 3%. (19)(80)
Treatment duration is typically 5 to 7 days, and shorter
treatment durations have been used in epidemic situations.
(83)(84) Duration of therapy for infection in other sites
(eg, bone, joints) may need to be longer and customized
to clinical and inammatory marker response. Droplet
precautions should be continued for the rst 24 hours of
appropriate antibiotic therapy. (40)(42)
In addition to antibiotics, patients who have signs of
shock should be treated with appropriate uid and vaso-
pressors. (85) Surgical debridement may be needed for
any signs of tissue breakdown. Deep-tissue necrosis may
require amputation. (86) Dexamethasone has not been
shown to be of benet in meningococcal meningitis. (87)
Several recent small clinical trials have demonstrated the
benet of protein C concentrate in addressing coagulopathy,
but this is not readily available or widely used at this time.
(88)(89)
Vol. 38 No. 4 APRIL 2017 161
 TABLE 1. Treatment and Prophylaxis Options for Neisseria meningitidis:
Summary of Recommendations*
DRUG DOSE COMMENTS

Treatment Ceftriaxone 75-100 mg/kg per day divided every Although ceftriaxone resistance is seen with other Neisseria
12 or 24 hours species, it is considered unlikely for meningococcal
disease. (79)
Cefotaxime 200-300 mg/kg per day divided every
6-8 hours
Penicillin G 300,000 U/kg per day divided every 4-6 hours May be used if the isolate has an MIC of <0.1 mg/mL. (77)
Meropenem 120 mg/kg per day Approximately 2%-3% of penicillin- or cephalosporin-
allergic patients may cross-react.
Chloramphenicol 75-100 mg/kg per day PO or IV divided May need to monitor serum concentrations.
every 6 hours Used in penicillin- or cephalosporin-allergic patients.
Prophylaxis Rifampin Age <1 month: 10 mg/kg PO divided every Not recommended in pregnancy.
12 hours x 2 days
Age 1 month: 20 mg/kg PO divided every
12 hours x 2 days, maximum 600 mg/dose
Ciprooxacin Age >1 month: 20 mg/kg PO ONCE, Not recommended in pregnancy.
maximum 500 mg In areas of ciprooxacin resistance, this agent should
not be used.
Ceftriaxone <15 years: 125 mg IM ONCE
15 years: 250 mg IM ONCE
Azithromycin 10 mg/kg PO ONCE, maximum 500 mg Considered second-line. Used in areas with
ciprooxacin resistance if no other alternative.

*Data from American Academy of Pediatrics Red Book. 30th ed. 2015.

Ampicillin can also be used: 200-400 mg/kg per day divided every 6 hours.
IMintramuscularly, IVintravenously, MICminimum inhibitory concentration, POorally.

IMMUNITY asplenia (which are associated with impaired antibody pro-

Most individuals develop natural immunity to meningo-
coccus in the rst 2 decades of life from exposure through
nasopharyngeal colonization or cross-reactivity with other
bacteria that have similar antigenic structures. (90) Suscep-
tibility to invasion by a newly acquired strain of N menin-
gitidis is associated with the absence of bactericidal antibody.
Antibody titers in infants are similar to maternal serum
concentrations but decrease by age 6 months, correlating to
the noted rst peak incidence of meningococcal disease. In
the absence of protective bactericidal titers, invasive disease
is more likely. Developing sporadic meningococcal disease
more than once is rare but possible due to infection with
other serogroups; however, this would be highly suspicious
for an underlying host immune defect. (91)
Certain individuals may be at increased risk for menin-
gococcal disease. These include children with human immu-
nodeciency virus (HIV), some children with partial T-cell
defects (eg, DiGeorge syndrome, Wiskott-Aldrich syndrome,
ataxia telangiectasia), those who have anatomic and functional
duction), and those who have complement deciencies. (29)
(92) Complement deciency involving both the late (C5-C9)
and early components (including C3, properdin, or factor
H and D) of the complement system has been associated
with increased susceptibility to meningococcal infection.
The importance of complement-mediated killing in pro-
tection against meningococcal disease is highlighted by the
high incidence of invasive meningococcal disease in per-
sons with terminal complement deciencies, which dem-
onstrates that the membrane attack complex appears to be
unique for killing meningococcus. Approximately 0.3% of
those with meningococcal disease may have complement
deciency. (91) Recurrent attacks have been observed in
those with terminal complement deciency. (93)(94)
Acquired complement deciencies can result from in-
adequate production of complement components due to
liver dysfunction, increased consumption of complement by
autoimmune disease such as lupus, or increased excretion
by protein-losing diseases. Patients receiving eculizumab
therapy for atypical hemolytic-uremic syndrome are also at

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increased risk for meningococcal disease. Eculizumab is a
monoclonal antibody that binds complement protein C5,
inhibiting the terminal complement cascade. (91)
Reasons to consider screening for complement de-
ciency include recurrence of meningococcal disease; disease
due to serogroups other than A, B, and C; or other family
relatives with meningococcal disease. (95)(96) Screening
can be accomplished with the total hemolytic complement
activity assay. If this test yields abnormal results, patients
can be evaluated further by assessing individual comple-
ment factor concentrations and enzymatic function to deter-
mine the precise defect.
PREVENTION
Chemoprophylaxis
Clinicians must notify public health authorities at the onset
of an index case to aid in the initiation of chemoprophylaxis
and observation for secondary cases and outbreak preven-
tion. (12) Chemoprophylaxis is indicated for close contacts
irrespective of immunization status and should be admin-
istered as soon as possible after an exposure. The attack rate
for close contacts of patients with sporadic disease is 4 in
1,000 exposed. (42) High-risk contacts who qualify for
prophylaxis include household members (500-1,000 times
the risk compared to general population). (29) In addition,
for the 7 days before the onset of illness, high-risk contacts
include those who slept in the same dwelling, those with
prolonged contact (>8 hours) in close proximity (3 feet) to
the index case, those exposed to the patients oral secretions
(eg, kissing, sharing of food or glasses), and child care
contacts or preschool contacts. Chemoprophylaxis is also
recommended for health care workers exposed directly to
patients oral secretions who did not wear a surgical mask in
the rst 2 days of therapy. (40)(41)(42)(97)
Chemoprophylaxis ideally should be administered within
24 hours of identication of the index patient. (98) Close
follow-up evaluation is necessary due to the rapid onset of
disease in linked cases. Secondary cases usually occur with-
in 10 days of infection of the index case. Chemoprophylaxis
administered greater than 14 days after exposure to the index
case is of limited value and not recommended by the CDC.
Mass chemoprophylaxis is generally not recommended, but
this decision is directed by local public health authorities. (12)
(78)(97)
Untreated contacts can reinfect treated contacts, so it is
important that all close contacts receive timely prophylaxis.
Options for prophylaxis include rifampin, ceftriaxone, or
ciprooxacin (Table 1). Rifampin is the only agent that has
been studied widely, but there may be drug-drug interactions
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to consider. Adverse effects such as nausea and diarrhea can
occur, and 4 doses are required for effective prophylaxis.
Ceftriaxone in a single dose has been shown to be more than
97% effective in eradicating carriage after 1 to 2 weeks of
follow-up assessment and is safe in pregnancy. (19) Cipro-
oxacin also eradicates carriage in a single dose, although
it cannot be used in pregnant women, and there may be
concerns for resistance in parts of the United States. (99)
Other adverse effects that should be discussed between the
clinician and patient are rash, diarrhea, joint or tendon pain,
confusion, or numbness or tingling of extremities. (100)
Azithromycin may be used but is generally not recommended
as a rst-line agent. (42)(97)(101) Oral third-generation ceph-
alosporin antibiotics are not recommended. (101) If a patient
with meningococcal disease received therapy with an agent
other than a parenteral third-generation cephalosporin, ad-
ditional chemoprophylaxis with 1 of the antibiotics listed in
Table 1 is required to reliably eradicate nasopharyngeal car-
riage before hospital discharge, thereby preventing transmis-
sion to close contacts. (19)(42)
Vaccines
Primary prevention through vaccination may reduce risk
among certain groups and may be recommended by public
health authorities during ongoing outbreaks. (12) Second-
ary prevention, when directed by public health, can be an
adjunct to chemoprophylaxis when there is an outbreak
caused by a serogroup contained in a vaccine. Some coun-
tries have implemented vaccine programs among high-risk
groups based on the prevalent serogroups circulating. Spe-
cic vaccines are available with indications for administra-
tion that vary based on national guidelines. (102) In the
United States, there are 3 vaccines for the A, C, Y, and W135
serogroups; 1 for serogroups C and Y that is combined with
H inuenzae type b vaccine; and 2 new vaccines for sero-
group B. Vaccine development for serogroup B has lagged
behind vaccine development for other serogroups due to
poor immunogenicity of the B capsule, which contains a
structure similar to human intracellular adhesion mole-
cules. (103) In addition, the B serogroups are genetically di-
verse, making it challenging to create a vaccine that covers all
circulating serogroup B strains.
Meningitis A, C, W135, and Y Vaccines
Vaccines have been developed for serogroups A, C, W135,
and Y. They include a currently available polysaccharide vac-
cine rst licensed in 1981 and the newer quadrivalent (ACWY)
conjugated vaccines. (29) The polysaccharide vaccine has a
shorter duration of protection based on antibody persistence,
there are concerns for hyporesponsiveness with repeated
Vol. 38 No. 4 APRIL 2017 163
 doses, and the vaccine lacks efcacy in eradicating nasopha-
ryngeal carriage. In contrast to the polysaccharide vaccine,
the conjugated vaccines elicit a T-cell-dependent memory
response that results in a more robust immune response.
ACIP recommends universal vaccination for adoles-
cents with 1 of the 2 quadrivalent meningococcal vaccines
licensed for protection against serogroups A, C, W135, and Y:
MenACWY-D (Menactra, Sano Pasteur, Swiftwater, PA)
or MenACWY-CRM (Menveo, Novartis Vaccines and Diag-
nostics, Inc, Cambridge, MA), (Table 2). Antibody persis-
tence studies indicate that circulating antibody declines 3 to
5 years after a single dose of MCV-4. The effectiveness, or the
estimate of how well the vaccine works based on observa-
tional data, of quadrivalent vaccines is estimated at 80% to
85%. This range came from a 2005 through 2008 study
among adolescents who received 1 dose of MenACWY-D,
in whom there were 14 cases of breakthrough disease. (104)
A booster at age 16 years is now recommended to ensure
persistence of protective levels. (29)(105)106) No booster is
required if the patient receives the vaccine at age 15 years or
older. Vaccination coverage was estimated at 79% in 2014
among 13- to 17-year-old adolescents, but it lags behind
tetanus toxoid, reduced diphtheria toxoid, and acellular
pertussis, adsorbed vaccination in this age group, which
nationally is approximately 87%. (107) Common adverse
effects of the MCV-4 quadrivalent vaccines include fe-
ver (16.8%), headache (16.0%), injection site erythema
(14.6%), and dizziness (13.4%), followed by syncope (10%).
(29)(93)
Meningitis A, C, W135, and Y Vaccines in
High-risk Individuals
Vaccination is additionally recommended for high-risk indi-
viduals such as patients with persistent complement de-
ciencies; functional or anatomic asplenia, including sickle
cell, HIV infection, or recent eculizumab administration;
with outbreak control; for travel to an epidemic area; and for
those in high-risk occupational settings such as in micro-
biology laboratories and military recruit housing. (29)(108)
For infants falling into 1 of these high-risk categories, vaccine
options include HibMenCY-TT (MenHibrix, GlaxoSmithKline,
Research Triangle Park, NC) or MenACWY-CRM (Menveo,
Novartis Vaccines and Diagnostics, Inc, Cambridge, MA).
HibMenCY-TTwas licensed in 2012 for ages 6 weeks through
18 months as a 4-dose series at 2, 4, and 6 months of age and
once from age 12 to 15 months of age. This vaccine contains
coverage for only meningococcal serogroups C and Y and is
combined with vaccination for H inuenzae type b. The child
who received 1 of these vaccines still needs 1 of the quadri-
valent (ACWY) vaccines when older. HibMenCY-TT is not
164 Pediatrics in Review
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sufcient for children living in or traveling to endemic re-
gions because it does not contain serogroup A or W, which are
signicant serogroups in worldwide meningococcal disease.
MenACWY-D is licensed for use in ages 9 months
through 55 years and is administered as a 2-dose primary
series, 3 months apart. In young children at high risk of
pneumococcal disease, such as the presence of asplenia,
coadministration of MenACWY-D with pneumococcal
13-valent vaccine is not recommended due to concerns
for pneumococcal hyporesponsiveness. Pneumococcal anti-
body responses to some serotypes in pneumococcal 13-valent
vaccine were decreased when the vaccine was given at the
same time as MenACWY-D. Because of this, if MenACWY-D
is used in patients with anatomic or functional asplenia, ad-
ministration is recommended after age 2 years and at least
4 weeks after the last pneumococcal dose. (93) Because the
risk of pneumococcal disease in asplenic patients is higher
than that for meningococcal disease, pneumococcal vaccina-
tion should be completed rst in this particular group. (42)
MenACWY-CRM is licensed for infants as a 4-dose series
at 2, 4, 6, and 12 months of age and can be given through age
55 years. MenACWY-CRM can be given simultaneously with
pneumococcal 13-valent vaccine or at any interval after receipt
of pneumococcal 13-valent vaccines. (29)(109)
For those older than 2 years who have completed pneu-
mococcal vaccination, either MenACWY-D or MenACWY-CRM
can be used for primary vaccination. The rst booster dose
for the ACWY vaccines in high-risk groups is every 5 years.
The exception is for those who received the vaccine before
age 6 years, when the rst booster is given 3 years after the
last meningococcal vaccine and every 5 years thereafter. (29)
(94)(110)
Meningococcal B Vaccines
The new serogroup B meningitis vaccines underwent ac-
celerated approval and were licensed in the United States
in 2014 and 2015. They include MenB-FHbp (Trumenba,
Wyeth, Philadelphia, PA) and MenB-4C (Bexsero, Novar-
tis Vaccines and Diagnostics, Inc, Cambridge, MA). Both
are approved for ages 10 through 55 years. MenB-4C is
licensed in Europe, Canada, and Australia in addition to the
United States; MenB-FHbp is only licensed in the United
States. Both are recombinant protein vaccines. The primary
differences between the 2 vaccines are the different sub-
capsular antigens and dosing regimens. MenB-FHbp is
composed of 2 recombinant lipidated factor H-binding
protein (FHbp) variants from N meningitidis serogroup B.
MenB-FHbp is currently administered as a 3-dose series,
with second and third doses given 2 and 6 months after the
rst, but it has recently gained approval for a 2-dose series.
TABLE 2. Immunocompetent Host Vaccine Options for Meningococcal
Disease: Summary of Recommendations from the 2016
Advisory Committee on Immunization Practices (ACIP)
SEROGROUP AGE GROUP ADMINISTRATION FOR
NAME BRAND NAME LICENSED TARGETED TYPE APPROVAL IMMUNOCOMPETENT HOST

MPSV4 Menomune 1981 A, C, W, Y Polysaccharide 2 years and Subcutaneous

(Sano Pasteur, older Not routinely recommended
Swiftwater, PA )
MenACWY-D Menactra (Sano 2005 A, C, W, Y Quadrivalent 9 months Single dose between ages 11
Pasteur) Conjugated through and 12 years (preferred) or
55 years ages 13 and 15 years, with
booster age of 16-18 years
Single dose with no booster if
given between ages 16 and 18
years; may be given as a catch-
up immunization between
ages 19 and 21 years
Not routinely recommended
after age 21 years
MenACWY-CRM Menveo (Novartis 2010 A, C, W, Y Quadrivalent 2 months Single dose between ages 11
Vaccines and Conjugated through and 12 years (preferred) or
Diagnostics, Inc, 55 years ages 13 and 15 years, with
Cambridge, MA) booster age of 16-18 years
Single dose with no booster if
given between ages 16 and 18
years; may be given as a catch-
up immunization between
ages 19 and 21 years
Not routinely recommended
after age 21 years
Hib-MenCY-TT MenHibrix (Glaxo- 2012 C, Y Bivalent 6 weeks Not routinely recommended
SmithKline, Conjugated through unless high risk
Research Triangle Combination 18 months
Park, NC) Vaccine
MenB-FHbp Trumenba 2014 B Recombinant 10-55 years Not routinely recommended;
(Wyeth, Protein consider for those ages 16 to
Philadelphia, PA) 23 years for short-term
protection
3-dose series: second dose 2
months after the rst and last
dose 6 months after rst dose;
a 2-dose regimen is also
available
MenB-4C Bexsero 2015 B Recombinant 10-55 years Not routinely recommended;
(Novartis) Protein consider for those ages 16 to
23 years for short-term
protection
2-dose series 1 month apart

(111) MenB-4C is composed of 4 distinct antigens, includ-
ing a recombinant FHbp and other antigens. MenB-4C is
a 2-dose series, with doses given 1 month apart. (94)(110)
The tip cap of the syringe of MenB-4C may contain natural
rubber latex. Although the risk of allergy is believed to be
extremely low, precautions for possible allergic reactions
should be taken when administering MenB-4C to latex-
allergic patients. (112)
Meningococcal B vaccines have been approved for use in
high-risk patients age 10 years and older (Table 3). (94)(110)
ACIP has specically detailed high-risk patients as those
with asplenia, persistent complement deciency, or eculi-
zumab administration; those involved in outbreak settings;
and microbiologists working with meningococcus in the
laboratory. Under clinical discretion, teens and young adults
(ages 16 through 23 years and preferably between ages 16

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 and 18 years) may also be vaccinated with a serogroup
B meningococcal vaccine to provide short-term protection
and maximize the likelihood for protection to last through
the highest age-related risk period. Antibody persistence is
estimated to be at least 48 months. (110)(113) Meningococcal
B vaccines are not expected to provide protection against
disease caused by all serogroup B strains circulating in the
United States, but there may be cross-protection against simi-
lar meningococcal B strains. (110) In a recent study, 34% of
vaccinated adolescents in a college outbreak did not mount
an immune response to the outbreak strain after 2 doses of
MenB-4C. In this case, the outbreak strain was not included
in the vaccine, although 2 of the vaccine antigenic components
were on the outbreak strain. No cases of meningococcal dis-
ease were reported among vaccinated students. (114)
Changes to meningococcal B guidelines may occur in
the near future. ACIP does not currently recommend any
booster doses of meningococcal B vaccine, although it is still
being determined how long protective antibodies per-
sist. (110) For the meningitis B vaccines, the same vaccine
product should be used for all doses due to differences in the
antigenic components. (29)(94)(110) They may be given
concomitantly with either MenACWY meningococcal con-
jugate vaccines but at different anatomic sites. Although
safety and immunogenicity for the meningitis B vac-
cines have been evaluated, effectiveness of the vaccines

TABLE 3. High-risk Host Vaccine Options for Meningococcal Disease:

Summary of Recommendations from the 2016 Advisory
Committee on Immunization Practices (ACIP)
AGE AT FIRST FUNCTIONAL OR ANATOMIC PERSISTENT COMPLEMENT OTHER (OUTBREAK,d TRAVEL,e
VACCINE ASPLENIAb DEFICIENCYc OCCUPATIONAL,f HIV)

8 weeks-18 monthsa MenACWY-CRM: 4 doses at 2, 4, 6, and MenACWY-CRM: 4 doses at 2, 4, 6, and MenACWY-CRM: 4 doses at 2, 4, 6,
12-15 months 12-15 months and 12-15 months
OR OR OR
Hib-MenCY-TT: 4-dose series for Hib-MenCY-TT: 4-dose series for Hib-MenCY-TT: 4-dose series for
children at 2, 4, 6, and 12-15 months children at 2, 4, 6, and 12-15 months children at 2, 4, 6, and 12-15 months
OR OR
MenACWY-D 2 doses at 9 months of MenACWY-D: 2 doses at 9 months of
age, minimum 8 weeks apart age, minimum 8 weeks apart
19-23 monthsa MenACWY-CRM: 2 doses minimum MenACWY-CRM: 2 doses minimum MenACWY-CRM: 2 doses minimum
8 weeks apart 8 weeks apart 8 weeks apart
OR OR
MenACWY-D: 2 doses minimum MenACWY-D: 2 doses minimum
8 weeks apart 8 weeks apart
24 months-10 yearsa MenACWY-CRM: 2 doses minimum MenACWY-CRM: 2 doses minimum MenACWY-CRM: 2 doses minimum
8 weeks apart 8 weeks apart 8 weeks apart
MenACWY-D: at least 4 weeks after MenACWY-D: 2 doses minimum MenACWY-D: 2 doses minimum
completion of all PCV13 doses; can 8 weeks apart 8 weeks apart
administer 2 doses minimum
8 weeks apart
10 years and older MenACWY-CRM: 2 doses minimum MenACWY-CRM: 2 doses minimum MenACWY-CRM: 2 doses minimum
8 weeks apart 8 weeks apart 8 weeks apart
MenACWY-D: 2 doses minimum MenACWY-D: 2 doses minimum MenACWY-D: 2 doses minimum
8 weeks apart 8 weeks apart 8 weeks apart
MenB-FHbp: 2-dose series 1 month MenB-FHbp: 2-dose series 1 month MenB-FHbp: 2-dose series 1 month
apart apart apart
MenB-4C: 3-dose series, with second MenB-4C: 3-dose series with second MenB-4C: 3-dose series with second
dose 2 months after the rst and last dose 2 months after the rst and last dose 2 months after the rst and
dose 6 months after rst dose dose 6 months after rst dose last dose 6 months after rst dose
a
All high-risk children who receive MenACWY vaccines before age 7 years require a booster in 3 years and every 5 years after that. For high-risk children
who receive their rst meningococcal vaccines after age 7 years, boosters are every 5 years.
b
Avoid coadministration of MenACWY-D with pneumococcal 13-valent vaccine due to concerns for pneumococcal hyporesponsiveness.
c
Includes eculizumab.
d
In outbreak situations with serogroup C or Y for infants, Hib-MenCY-TT may be used.
e
MenACWY-CRM is certied halal for those who are traveling to Mecca.
f
Occupation exposure includes military recruits, laboratory workers.
MenACWY vaccines are interchangeable; MenB vaccines are not. HIVhuman immunodeciency virus.

166 Pediatrics in Review

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and duration of protection are still being determined in
the postmarketing period. Both vaccines appear to be well
tolerated, with similar adverse effects as other vaccines.
(113,114)
Indications for meningococcal vaccinations are evolv-
ing, particularly as new information is gathered on vaccine
effectiveness and duration of protection as well as the
evolving epidemiology of meningococcal disease. Parents
should be advised of the recommendations set forth by
the ACIP and the American Academy of Pediatrics, includ-
ing for infants and adolescents. (94)(110)(113) Clinicians
should counsel families on the unknown efcacy of these
vaccines and review the risk in certain population groups,
with vigilance to local community outbreaks. Clinicians
should review the latest ACIP guidelines for the latest
developments, changes to the vaccine schedule, and indi-
cations for administration.
CONCLUSION
Despite antibiotics and advances in the understanding and
management of sepsis, N meningitis remains among the
worlds most feared infectious diseases. Prompt attention to
particular risk groups, including those younger than age 1
year and adolescents, is important. Early initiation of anti-
biotics and supportive care is needed to mitigate the mor-
bidity and mortality seen with this disease. Public health
concerns due to the contagiousness of the disease and the
ability to cause epidemic disease demonstrate the need for
early identication of index patients and their contacts. The
effect of new vaccines on disease distribution and incidence
needs to be studied through postlicensure studies.
Summary
On the basis of observational and epidemiologic studies, in the
era of Streptococcus pneumoniae and Haemophilus inuenzae
vaccination, Neisseria meningitidis infections remain a common
cause of sepsis and meningitis, particularly in young children and
adolescents. (14)(15)(16)(17)
On the basis of expert opinion, antibiotic administration should
not be delayed if there is clinical concern for meningococcal
disease. The initial preferred agent is a third-generation
cephalosporin. (19)(80)(85)
On the basis of a systematic review and expert opinion,
prompt involvement of public health can help mitigate
spread of disease through prophylaxis of close contacts.
(42)(101)
On the basis of observational studies and expert opinion, all
adolescents and children in high-risk groups should receive
MenACWY vaccine. (42)(93)
On the basis of expert opinion, new meningitis B vaccines are
recommended for high-risk children age 10 years or older and
may be considered for adolescents for short-term
immunogenicity. (94)(110)(113)
References for this article are at http://pedsinreview.aappubli-
cations.org/content/38/4/158.

Additional Pediatrician Resources

AAP Textbook of Pediatric Care, 2nd Edition
Chapter 366: Meningococcemia - https://pediatriccare.solutions.aap.org/chapter.aspx?sectionId137951682&bookId1626
Point-of-Care Quick Reference
Meningococcemia - https://pediatriccare.solutions.aap.org/content.aspx?gbosid165600

Parent Resources from the AAP at HealthyChildren.org

Meningococcal Disease: Information for Teens and College Students: https://www.healthychildren.org/English/ages-stages/teen/
Pages/Meningococcal-Disease-Information-for-Teens-and-College-Students-.aspx
Meningococcal ACWY Vaccines: What You Need to Know (VIS): https://www.healthychildren.org/English/safety-prevention/
immunizations/Pages/Meningococcal-Vaccines-What-You-Need-to-Know.aspx
Serogroup B Meningococcal (MenB) Vaccines: What You Need to Know (VIS): https://www.healthychildren.org/English/safety-
prevention/immunizations/Pages/MenB-Vaccines-What-You-Need-to-Know-VIS.aspx

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1. A 9-month-old girl is brought to the emergency department by her parents with an 8- REQUIREMENTS: Learners
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2017 Pediatrics in Review
Two days after admission, her blood and CSF cultures grow Neisseria meningitidis. Her
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2. A 3-year-old child presents with a 1-day history of a temperature to 103.3F (39.6C) and an activity. If you score less than
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 A. Atypical hemolytic-uremic syndrome.
B. DiGeorge syndrome.
C. Human immunodeciency virus infection.
D. Terminal complement deciency.
E. Protein-losing enteropathy.
5. A 17-year-old girl is seen for her yearly physical examination before attending college. She
is up-to-date on her vaccines. The last vaccines she received were the MenACWY-D and the
tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis, adsorbed vaccines at her
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appropriate to administer?
A. No immunization is needed today.
B. One dose of MenACWY-D and 2 doses of MenB-4C 1 month apart.
C. Two doses of both MenACWY-D and MenB-4C 1 month apart.
D. Two doses of MenACWY-D 1 month apart.
E. Two doses of MenB-4C 1 month apart.

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 Meningococcal Disease
Louise Elaine Vaz
Pediatrics in Review 2017;38;158
DOI: 10.1542/pir.2016-0131

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 Meningococcal Disease
Louise Elaine Vaz
Pediatrics in Review 2017;38;158
DOI: 10.1542/pir.2016-0131

The online version of this article, along with updated information and services, is
located on the World Wide Web at:
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