Netter's Infectious Disease ( PDFDrive )

30 SECTION I╇ •â•‡ Vaccine-Preventable Diseases in Children and Adolescents

Hypothesis of pathogenesis Effects of live, attenuated poliovirus Paralytic poliomyelitis in USA,
vaccine orally administered (OPV) 1951 to 1976 (average number of
A. Virus is Extensive multiplication of vaccine cases per year) and effect of vaccine
ingested strains in alimentary tract with 22,208
by mouth. minimal or no viremia results in
B. Only if Vaccine virus resistance of alimentary tract to
amount of Antibody subsequent infection by naturally
ingested virus occurring polioviruses.
is very large D. Varying Development of antibodies
is there primary amounts of in blood that can neutralize
infection of virus enter naturally occurring polioviruses,
oropharyngeal bloodstream. which may escape barrier
mucosa. of resistant alimentary tract
C. In most
instances Medulla oblongata
virus is
swallowed Other 4594
and passes susceptible
through extraneural Spinal cord
stomach tissues F. From sites of multiplication in intestine,
into intestine, E. Other susceptible extraneural oropharynx, and other extraneural tissues,
where it multiplies tissues, including oropharynx, are virus reaches central nervous system,
rapidly and then frequently secondarily infected probably via regional afferent neural
invades via bloodstream, and virus also pathways, first into motor neurons of spinal
aggregated multiplies there. cord (primary spinal paralysis) or medulla
lymph nodules (primary bulbar paralysis). Further axonal
of intestinal spread of virus then occurs along insulated
wall (Peyer tracts to distal neurons elsewhere in central
patches). nervous system, and also by contiguity
to adjacent motor neurons.
468
9‡

1951- 1956- 1961-1965 1973-
1955 1960 IPV plus 1976
No IPV OPV† OPV
vaccine only antiepidemic only
plus plus later
G. Virus is excreted IPV* community
in feces, by which Properly vaccinated persons have intestinal resistance to 1955 programs
it is disseminated. subsequent infection by naturally occurring polioviruses.
Result is markedly decreased or no multiplication *IPV = inactivated poliovirus vaccine
of these viruses in alimentary tract, which breaks chain (Salk)
of dissemination. †OPV = oral poliovirus vaccine
(Salk)

‡Including
imported
and
question-
able
cases

Figure 7-1╇ Poliomyelitis.

meningitis clinically similar to other nonpolio enteroviral men- (corresponding to abortive poliomyelitis), then a few days of
ingitis. Although this illness is similar to abortive poliomyelitis, presumed recovery, followed by an abrupt onset of a major
generally the symptoms are more severe, with meningeal irrita- illness characterized by symptoms of meningitis, fever, head-
tion being the distinguishing feature. ache, neck stiffness, and cerebrospinal fluid (CSF) pleocytosis.
The hallmark of paralytic polio is asymmetric paresis or paraly-
Paralytic Poliomyelitis sis. The maximal loss of functions is typically seen within 3 to
Approximately 0.1% to 0.2% of infected, symptomatic individu- 5 days of onset but may progress for up to 1 week. Legs are
als develop paralytic polio characterized by severe back, neck, more often involved than arms, and proximal muscles of the
and muscle pain with the development of muscle weakness, loss extremities are more often involved than distal muscles (Figure
of reflexes, and paralysis. In children and rarely in adults, classic 7-2). Sensory loss with polio is very rare. Spastic paralysis sug-
paralytic polio is a biphasic course with an initial minor illness gesting upper motor neuron disease may be observed with
polioencephalitis, which may be seen in infants, but is rare.

CHAPTER 7╇ •â•‡ Poliomyelitis (Polio) and Polioviruses 31

Stages in
destruction of
a motor neuron
by poliovirus

A. Normal motor neuron B. Diffuse chromatolysis; C. Polymorphonuclear D. Complete
3 acidophilic nuclear cells invading necrotic neuronophagia
inclusions around neuron
nucleolus

Relative distribution Medullary
of neuronal lesions
in spinal and bulbar
poliomyelitis

Spinal Cervical Bulbar
Paralytic residua of Thoracic
spinal poliomyelitis Lumbar

Multiple crippling
deformities:
contractures,
atrophy, severe
scoliosis, and
equinovarus

Genu
recurvatum,
atrophy
of limb

Scoliosis

Figure 7-2╇ Poliomyelitis.

Bulbar Paralytic Poliomyelitis Acute Flaccid Paralysis
During epidemics, bulbar paralytic polio accounts for 5% to The World Health Organization (WHO) defines AFP as any
35% of cases. This entity results from paralysis of the muscle case of flaccid paralysis with acute onset in a child younger than
groups innervated by the cranial nerves, most commonly the 15 years of age or clinically suspected polio at any age. AFP is
ninth and tenth cranial nerves. The patient may have nasal the most common category of diagnoses that includes paralytic
speech, inability to swallow secretions, and dyspnea and often polio in the differential. Infectious agents are the leading identi-
appears anxious or distraught, attributable to difficulty breath- fied cause of AFP, though other causes must also be considered,
ing and the associated hypoxia. such as multiple sclerosis and spinal cord disorders (e.g., trans-
verse myelitis and cord compression). For infectious agents,
DIAGNOSTIC APPROACH viruses are most common, including non–polio enteroviruses
Clinical Findings (especially enterovirus 71 and coxsackievirus A7), West Nile
Suspicion for the diagnosis of polio is based on clinical virus, and less likely herpesviruses. Other infectious consider-
presentation. ations are Lyme disease, botulism, and diphtheria (especially for
bulbar poliomyelitis). Guillain-Barré syndrome (GBS) can easily
be confused with polio; however, it generally manifests as a

32 SECTION I╇ •â•‡ Vaccine-Preventable Diseases in Children and Adolescents

bilateral process with ascending paralysis with loss of sensory depression, and other disorders associated with a lower quality
functions, as well as motor neuron dysfunction. In addition, with of life.
GBS the spinal fluid generally has elevated protein with minimal
or no pleocytosis in the CSF. Identifying GBS is especially PREVENTION AND CONTROL
important, as management includes treatment with intravenous Availability of vaccination against polio was heralded as one of
immunoglobulin or plasmapheresis. the greatest successes of medical research in the twentieth
century. In 1955, the inactivated polio vaccine (IPV) was intro-
Laboratory Findings duced by Dr. Jonas Salk, followed by rapid decline in polio cases.
CSF findings with poliovirus infection are similar to those of In 1961 to 1962, the oral polio vaccine (OPV) was introduced
other forms of viral meningoencephalitis, in that generally the by Dr. Albert Sabin and quickly replaced IPV because of the
pleocytosis is mild (20 to 300 cells/mm3) with a lymphocyte ease of administration and potential benefits of herd immunity
predominance, though initially there may be a polymorphonu- through fecal shedding of the vaccine viruses. In most develop-
clear leukocyte predominance. The total protein may be normal ing nations, OPV is still in use and has led to a remarkable
or mildly elevated, and the CSF glucose is within the normal decline in the global burden of polio infections.
range. Other laboratory findings, such as the complete blood
count and serum chemistry values, are usually normal or have In the United States and other industrialized nations, newer
nonspecific mild abnormalities. enhanced-potency IPV (eIPV) with increased antigen content
has supplanted the use of OPV, in large part because of the
Cultures of the nasopharynx and stool usually yield the occurrence of vaccine-associated paralytic polio (VAPP) with
infecting poliovirus during the acute illness, though patients OPV. The risk of VAPP following OPV is approximately 1 in
may shed the virus for over 8 weeks after primary infection. In 2.5 to 4 million doses; in the latter half of the twentieth century,
addition, after receipt of oral polio vaccine, viral shedding may VAPP was observed more frequently than wild-type polio in the
persist for 6 weeks or longer. Isolation of polioviruses from the United States. This led to the switch of sequential vaccine
CSF is rare, including with paralytic polio. regimen with two doses of eIPV followed by two doses of OPV
from 1997 through 1999, and this was changed to an all-eIPV
In the absence of positive viral cultures, confirmation of polio dosage regimen in 2000. IPV is generally safe and well tolerated
infection may be obtained with serologic testing demonstrating by recipients, and it is contraindicated in individuals with previ-
a rise in antibody titers in paired acute and convalescent sera. ous adverse reaction to the vaccine or its components. Several
Serum neutralizing antibodies develop about 1 week after infec- combination vaccines for infants and children containing IPV
tion and are lifelong. Immunity is type specific; however, serol- are available and offer the benefit of fewer injections.
ogy cannot differentiate infection with wild-type or vaccine-type
viral strains. Currently, OPV is not routinely produced or used in the
United States; however, an emergency stockpile of OPV is
CLINICAL MANAGEMENT AND maintained in the event of a polio outbreak. OPV is recom-
DRUG TREATMENT mended as the vaccine of choice during a mass vaccination
Supportive care is the mainstay of treatment for poliomyelitis. campaign in the event of a polio outbreak. OPV should not be
This may include pain management and physical therapy, as well used in immunocompromised individuals, unvaccinated adults,
as ventilation for patients who progress to respiratory failure. or vaccinees with an immunocompromised household contact.
The role of antiviral therapy for polioviruses, as well as nonpo-
liovirus enterovirus infections, remains unclear. Pleconaril (an EVIDENCE
antiviral agent active against picornaviruses) has been evaluated
in a limited number of clinical studies, yielding mixed results. Centers for Disease Control and Prevention (CDC): Wild
At this time, no specific antiviral therapy is available. poliovirus type 1 and type 3 importations—15 countries,
Africa, 2008-2009, MMWR Morb Mortal Wkly Rep 58:357-362,
PROGNOSIS 2009. This reference provides data about polio strains involved in
During the time of polio epidemics, about 50% mortality was current outbreaks and strategies for control efforts.
observed in individuals with respiratory failure, with the overall World Health Organization (WHO): Conclusions and
mortality rate of around 5% to 10%. About two thirds of recommendations of the Advisory Committee on Poliomyelitis
patients with AFP do not regain full strength. Eradication, Geneva, 27-28 November 2007, Wkly Epidemiol
Rec 3:25-35, 2008. This reference provides information about the
In patients with a history of polio, new onset of functional most recent epidemiologic data, global control effort, and plans for
deterioration after a prolonged period of stability (post-polio eradication of polio.
syndrome) may occur weeks to years later in 25% to 35% of
survivors. Clinical presentation is characterized by muscle ADDITIONAL RESOURCES
weakness, atrophy, and fatigue in the same muscles as involved American Academy of Pediatrics (AAP): Poliovirus infections. In Pickering
in the original illness. Even without meeting criteria for post-
polio syndrome, many polio survivors have long-term sequelae LK, Baker CJ, Kimberlin DW, Long SS, eds: Red Book: 2009 Report of the
including muscle weakness, chronic pain, contractures, fatigue, Committee on Infectious Diseases, ed 28, Elk Grove Village, Ill, 2009, Ameri-
can Academy of Pediatrics, pp 541-545. This resource provides abbreviated
“standard of care” information about management and prevention.

CHAPTER 7╇ •â•‡ Poliomyelitis (Polio) and Polioviruses 33

Centers for Disease Control and Prevention (CDC): Poliomyelitis preven- 2009, Elsevier, pp 1176-1179. This resource provides a review of polio patho-
tion in the United States: updated recommendations of the Advisory genesis, clinical manifestations, and management.
Committee on Immunization Practices (AICP), MMWR Recomm Rep Simmons Z: Polio and infectious disease of the anterior horn. In Shefner
49:1-21, 2000. Available at: www.cdc.gov/mmwr/PDF/rr/rr4905.pdf. JM, Dashe JF, eds: 2009 UptoDate Version 17.2 (Revised), Wellesley, Mass,
This site provides guidelines and additional information about poliomyelitis 2009. Available at: www.uptodate.com. This site provides current summary
epidemiology and prevention. of polio pathogenesis, clinical manifestations, and management.

Moldanado YA: Polioviruses. In Long SS, Pickering LK, Prober C, eds:
Principles and practices of pediatric infectious diseases, ed 3, Philadelphia,

Influenza 8

Sylvia H. Yeh

ABSTRACT (antigenic drifts) wherein previous infections with influenza may
provide some protection against disease. Novel antigenic
Influenza is a viral infection characterized by abrupt onset of changes (antigenic shifts) typically involve reassortment of anti-
fever, chills, myalgias, and respiratory symptoms such as cough, gens between human and nonhuman influenza viruses. These
sore throat, and rhinitis. Influenza viruses, types A and B, cause antigenic shifts can lead to pandemics, in which individuals are
annual epidemics worldwide leading to a substantial morbidity immune naïve and thus susceptible to more severe disease and
and mortality. Vaccination is the most cost-effective means of widespread transmission. Humans may be infected with nonhu-
prevention. Antiviral therapy is available, but development of man influenza A strains, including swine and avian strains.
strain-specific resistance is becoming more common and
requires continued global monitoring and vigilance. RISK FACTORS FOR ENDEMIC DISEASE
With seasonal influenza epidemics, children have the highest
GEOGRAPHIC DISTRIBUTION AND rates of infections (accounting for 6 to 15 per 1000 pediatric
MAGNITUDE OF DISEASE BURDEN outpatient visits). In contrast, the highest risk for complications
Influenza infections occur in epidemics annually worldwide and and hospitalizations is seen in persons 65 years of age and older,
are estimated to cause 3 to 5 million cases of serious illnesses very young infants and children (younger than 2 years of age),
and 250,000 to 500,000 deaths annually. In the United States, and persons with chronic medical conditions. These conditions
seasonal influenza accounts for approximately 226,000 hospital- include congenital or acquired immunodeficiencies including
izations and 36,000 deaths each year. Pandemic influenza is human immunodeficiency virus (HIV) infection and receipt of
defined as the emergence and global spread of a new influenza immunosuppressive medications; chronic pulmonary, cardiac,
A subtype to which the population has little or no immunity and renal, hepatic, neurologic or neuromuscular, hematologic, and
that spreads rapidly from human to human. Pandemics may metabolic diseases (including diabetes); and receipt of long-term
cause greater numbers of hospitalizations and deaths. During aspirin therapy. Pregnant women and residents of long-term
the 1918-1919 pandemic, an estimated 21 million deaths care facilities are also at increased risk of complications.
occurred globally. Generally, lower rates for morbidity and mor-
tality were associated with 2009-2010 H1N1/09 pandemic, with With pandemic influenza the rate of infections and complica-
approximately 14,500 deaths reported globally from April 2009 tions may disproportionately affect healthy adults and others
through January 2010. with no known risk factors.

In temperate regions, the disease is prominent during the CLINICAL FEATURES
winter months, with the peak usually occurring in January and Influenza viruses are readily spread person to person by infected
February. In tropical areas, influenza viruses may circulate year respiratory droplets, and spread may also occur via fomites con-
round with one or two peaks of activity, usually associated with taminated with infected droplets. Viral shedding may occur for
the regional rainy season. During pandemic influenza, the 24 hours before onset of symptoms, continues for 5 to 10 days,
typical seasonality may not be observed because of sustained and correlates directly with the degree of fever. Shedding
transmission among immune-naïve populations. The most may be longer in young children and immunocompromised
recent pandemic started in spring 2009, spread globally, and had individuals.
a second observed peak of cases in late October 2009. A similar
pattern was observed in the 1918-1919 pandemic. After exposure to the virus, the incubation period is 1 to 4
days, with a mean of 2 days. Influenza in older children and
Three types of influenza viruses—A, B, and C—have been adults typically manifests with abrupt onset of fever, chills,
described; however, types A and B are the main causes of human myalgia, malaise, headache, and upper respiratory infection
disease. Influenza type C is associated with sporadic outbreaks (URI) symptoms such as rhinorrhea, cough, and pharyngitis.
of mild illnesses, primarily in children. Influenza viruses are Children may have only fever or may demonstrate URI symp-
single-stranded ribonucleic acid (RNA) viruses in the Ortho- toms indistinguishable from those of other viral respiratory
myxoviridae family, and are structurally similar but vary anti- infections. Conjunctival injection, abdominal pain, vomiting,
genically. Influenza A viruses are further classified based on and diarrhea are less commonly observed. Very young children
antigenic variations on their surface proteins, hemagglutinin and infants may have symptoms ranging in severity from non-
(HA) and neuraminidase (NA) (Figure 8-1). Recently the domi- specific URI, to moderate respiratory illness, to a sepsis-like
nant circulating A strains have been H1N1, H3N2, and H1N2. picture. Individuals who have preexisting immunity from
Both influenza A and B viruses undergo rapid antigenic changes. previous natural infections or vaccination may have milder
Minor changes account for the yearly seasonal epidemics symptoms.

CHAPTER 8╇ •â•‡ Influenza 35

Diagram of Hemagglutinin spikes Ribonucleic acid (RNA)
influenza virus Neuraminidase spike Polypeptides
budding from
plasma membrane Double lipid layer Cell membrane
of infected cell of virus capsule Cell cytoplasm
Protein layer

Pandemic Population antibody Pandemic Population antibody
Relationship level to virus level to antigenically
of influenza Epidemic different virus
incidence to Epidemic
population
antibody
levels*

*Modified Endemic
after
Kilbourne Incidence of influenza Incidence of influenza

1 2 34 5 6 78 9 10 11 12 13 14 15 16
Introduction of Time (years) New antigenically different
immunologically specific virus virus mutation appears

Figure 8-1╇ Influenza virus and epidemiology.

COMPLICATIONS Staphylococcus aureus (including methicillin-resistant S. aureus),
Although most influenza illnesses are self-limited, complications Streptococcus pneumoniae, Group A streptococci, and Haemophilus
are not infrequent. Influenza virus may cause infection in any influenzae. S. aureus is a prominent player for severe, progressive
part of the respiratory tract, including otitis media, croup, bron- pneumonia as well as bacterial tracheitis and toxic shock syn-
chiolitis, and pneumonia (see Figure 30-2). Approximately 10% drome in a setting of preceding influenza infection. Reye’s syn-
to 50% of children younger than 5 years of age develop viral drome (acute hepatic encephalopathy) and death may also occur.
bronchopneumonia with symptoms that are typically mild and
resolve without treatment. Other complications caused by direct In children, it is estimated that influenza accounts for 50 to
invasion of an organ by the influenza virus include myocarditis 85 per 1000 medical office visits and 6 to 27 per 1000 emergency
and encephalitis. Myositis is not an uncommon feature, more room visits each year in the United States. Also, a 10% to 30%
often seen after influenza B infection, at the time that respira- increase in the number of prescribed antimicrobial agents has
tory symptoms are resolving. Patients may exhibit calf tender- been reported. Hospitalization rates for young children rival
ness and refusal to walk. The myositis often self-resolves, though those for the elderly, with 108 compared with 190 hospitaliza-
rarely rhabdomyolysis and renal failure can occur. Complica- tions per 100,000 person-years in children younger than 5 years
tions involving the central nervous system (CNS) range from of age and persons older than 65 years of age, respectively.
febrile seizures to severe encephalopathy. Postinfluenza CNS
events, presumably caused by the host response to the virus, DIAGNOSTIC APPROACH
include encephalopathy, Guillain-Barré syndrome, postinflu- During an influenza epidemic the diagnosis of influenza may be
enza encephalitis, and transverse myelitis. made clinically. However, the clinical presentation may be dif-
ficult to distinguish from that of infections from other respira-
The most common complications are bacterial superinfec- tory pathogens, and laboratory identification of the causative
tion, which may occur anywhere along the respiratory tract, agent can be useful. In addition, specific viral testing and iden-
including otitis media, sinusitis, and secondary bacterial pneu- tification may be important for epidemiologic reasons (e.g.,
monia. Bacterial sepsis may also be seen in association with public health surveillance), for consideration of empiric antiviral
influenza. Secondary bacterial infections typically cause a recru- therapy, and for management of individuals at increased risk of
descence of fever with associated localizing symptoms (e.g., complications.
ear pain for otitis media, cough or shortness of breath for
pneumonia). The most common bacterial pathogens include Viral culture of nasopharyngeal secretions remains the
gold standard for identification of influenza viruses. Rapid

36 SECTION I╇ •â•‡ Vaccine-Preventable Diseases in Children and Adolescents

culture-based tests are available, including shell vial techniques, constitutional symptoms but does not necessarily shorten viral
in which small number of cells are inoculated and stained for shedding. Use of oseltamivir within 24 hours is associated with
detection of influenza antigens in a shorter period of time than reduced risk of asthma exacerbations with influenza. The most
traditional cell cultures. In addition, several rapid tests using common adverse effects from oseltamivir are nausea and vomit-
either antigen detection or polymerase chain reaction (PCR) to ing. Reports of self-injurious behavior and delirium associated
identify influenza A and/or B viruses have become available. Use with oseltamivir have been determined to be more likely caused
of these tests at the point of care may provide reassurance and by influenza disease itself, but advising parents to monitor for
limit the administration of unnecessary antibiotics and further abnormal behavior may be prudent. Bronchospasm has been
diagnostic testing. However, the positive predictive value of reported with zanamivir administration, and therefore this drug
these tests is highly dependent on the prevalence of influenza in should be used with caution in persons with asthma or pulmo-
the community; they are of limited value when the prevalence nary dysfunction.
is less than 10%. In addition, the rapid tests may not be able to
detect influenza viruses with significant antigenic changes, such PROGNOSIS
as in a pandemic setting. In most immunocompetent hosts, influenza is self-limited
illness. However, in very young children and the elderly, rates
CLINICAL MANAGEMENT of complications and death are higher than seen in other age
For most individuals with influenza, the care is supportive, groups. Hospitalization rates are much higher in very young
emphasizing patient comfort and fever control with antipyretics. children, with rates of 240 to 720 per 100,000 children per year
Acetaminophen is the preferred antipyretic for most infants and in infants younger than 6 months of age compared with 20 per
young children. For most individuals, ibuprofen is also accept- 100,000 children per year in children 2 to 5 years of age.
able, but with assurance of good hydration. Aspirin is contrain- Although death is rare, the rate is estimated at 0.4 per 100,000
dicated for children with influenza because of the association children younger than 5 years of age per year. Data from 2003
with Reye’s syndrome. to 2005 reveal that although children with underlying medical
conditions are at greater risk of death, most (51%) pediatric
Specific antiinfluenza medications, including adamantanes deaths resulting from laboratory-confirmed influenza occurred
and NA inhibitors, are available for treatment of influenza. in children with no known risk factors.
These antivirals, when used within 48 hours of illness onset, may
shorten the duration of symptoms. The NA inhibitors may Individuals older than 65 years of age with underlying
reduce the risk of morbidity from influenza in certain hosts. medical conditions have the highest rates of hospitalization,
Routine use for mild illnesses in immunocompetent hosts is not estimated at 560 per 100,000 persons per year (compared with
recommended but may be considered in persons at high risk 190 per 100,000 for persons older than 65 years of age who are
for complications from influenza. Antiviral resistances have healthy). Persons with immunodeficiency conditions, such as
emerged, and treatment recommendations should be based on HIV, and pregnant women also have demonstrable increased
susceptibility data of circulating strains, as discussed later. risk of hospitalization and death compared with persons in
similar age groups without these conditions.
Adamantanes
Available drugs in the adamantane class are amantadine and PREVENTION AND CONTROL
rimantadine, which are active only against influenza A. These Immunoprophylaxis
drugs target the M2 protein, which is present on influenza A Two types of influenza vaccines are available for the prevention
but not B. When the adamantanes are used within 48 hours of of influenza A and B: (1) inactivated vaccine (trivalent inacti-
symptom onset, the duration of fever, systemic symptoms, and vated influenza vaccine [TIV]), given intramuscularly, and (2)
viral shedding is shortened by 1 to 2 days. The most common live-attenuated influenza virus (LAIV), given intranasally. Each
adverse drug effects are insomnia, anxiety, nausea, and loss of year, these vaccines are formulated to contain two influenza A
appetite, and these are more commonly associated with aman- and one influenza B strains; the specific strains included are
tadine than rimantadine. CNS side effects are infrequent but based on the predicted likelihood of what strains will circulate
include agitation and an increase in seizure activity in persons in the hemisphere in the upcoming season. These predictions
with epilepsy; these are also more common with amantadine. are based on patterns of global circulation and are determined
This class of medications is not licensed for use in children by experts from the World Health Organization and from the
younger than 1 year of age. U.S. Food and Drug Administration and Centers for Disease
Control and Prevention (CDC) in the United States approxi-
Neuraminidase Inhibitors mately 9 months ahead of the influenza season.
NA inhibitors inhibit the NA protein present on both influenza
A and B, blocking the influenza virus from fusing with the host For both TIV and LAIV seasonal influenza vaccines, chil-
cell membrane. Two drugs in this class are available: oseltamivir, dren 8 years of age and younger require two doses of vaccine,
which is administered orally, and zanamivir, which is inhaled. separated by 4 weeks, the first time that they are immunized.
Use of these medications within 24 to 48 hours of symptoms Generally, other inactivated and live vaccines may be coadmin-
onset is associated with shortened duration of fever and istered with TIV and LAIV; however, no other live intranasal
vaccines may be simultaneously administered with LAIV.

CHAPTER 8╇ •â•‡ Influenza 37

The viruses for both types of vaccines are propagated in Box 8-1╇ Centers for Disease Control
chicken eggs and are contraindicated in persons with known and Prevention Advisory Committee
severe allergic reaction (i.e., anaphylaxis, angioedema, hives, and on Immunization Practices Specific Groups
allergic asthma) to chicken, egg proteins, or other components for Influenza Vaccination, 2010
of the vaccines. TIV can be used in any persons 6 months of
age and older. The efficacy of TIV is dependent on the age of Pediatric Recommendations
the host, underlying host factors, and the antigenic match All children aged 6 months to 18 years should be vaccinated
between the vaccine strain and the circulating strain. The effi- annually.
cacy of TIV varies from 60% to 95% against culture-confirmed
influenza when the vaccine strain matches the circulating strain. Children and adolescents at higher risk for influenza
LAIV is indicated for healthy persons 2 to 49 years of age. LAIV complications should be a focus of vaccination efforts when
should not be administered to persons with reactive airway vaccine supply is limited, including those who:
disease or asthma, known or suspected immunodeficiency, preg- • are aged 6 months to 4 years (59 months)
nant women, persons receiving salicylates, or persons with con- • have chronic pulmonary (including asthma), cardiovascular
ditions considered to be high risk for severe influenza (for whom
TIV is recommended). LAIV should be used with caution in (except hypertension), renal, hepatic, cognitive, neurologic
persons with a history of Guillain-Barré syndrome within 6 or neuromuscular, hematologic, or metabolic disorders
weeks after a previous dose of influenza vaccination. The effi- (including diabetes mellitus)
cacy of LAIV is approximately 90% against culture-confirmed • are immunosuppressed (including immunosuppression
influenza cases when the vaccine strain matches the epidemic caused by medications or by human immunodeficiency
strain. In addition, available data suggest that LAIV may provide virus)
cross-protection against mismatched strains owing to antigenic • are receiving long-term aspirin therapy and therefore might
drift. be at risk for experiencing Reye’s syndrome after influenza
virus infection
If influenza vaccination supply is sufficient, all persons 6 • are residents of long-term care facilities
months of age and older should be vaccinated each year. The • will be pregnant during the influenza season
specific groups designated by the CDC Advisory Committee for
Immunization Practices (ACIP) to be targeted when vaccine Adult Recommendations
supply is limited are listed in Box 8-1. Annual vaccination against influenza is recommended for any
adult who wants to reduce the risk of becoming ill with influ-
Chemoprophylaxis enza or of transmitting it to others.
In the event that annual influenza vaccination is not possible or
is contraindicated, chemoprophylaxis with antiviral medication Vaccination is recommended for all adults without contra-
is second-line protection. Studies of antiviral chemoprophylaxis indications in the following groups, because these persons
have demonstrated 20% to 40% reduction of secondary cases either are at higher risk for influenza complications, or who
within households. However, chemoprophylaxis has potential are close contacts of persons at higher risk:
drug toxicity as well as potential for development of antiviral • persons age 50 years and older
resistance and should not be considered equivalent to vaccina- • women who will be pregnant during the influenza season
tion. Chemoprophylaxis may be considered (1) for unimmu- • persons who have chronic pulmonary (including asthma),
nized individuals at high risk of complications from influenza or
those who were vaccinated less than 2 weeks before high-risk cardiovascular (except hypertension), renal, hepatic,
exposure to influenza virus, (2) for unimmunized close contacts cognitive, neurologic or neuromuscular, hematologic, or
of high-risk persons, (3) for immunized high-risk children when metabolic disorders (including diabetes mellitus)
the vaccine strain poorly matches the circulating strain, and (4) • persons who have immunosuppression (including
for control of an influenza outbreak in a close setting (such as immunosuppression caused by medications or by human
an institution). Because of the emergence of resistance to the immunodeficiency virus)
antivirals, recommendations regarding chemoprophylaxis need • residents of nursing homes and other long-term care
to be adjusted based on susceptibility of circulating strains. For facilities
the United States, these recommendations are available through • healthcare personnel
the CDC (www.cdc.gov/flu/professionals/antivirals/index.htm). • household contacts and caregivers of children age <5 years
and adults age 50 years or older, with particular emphasis
on vaccinating contacts of children age <6 months
• household contacts and caregivers of persons with medical
conditions that put them at higher risk for severe
complications from influenza

Adapted from Centers for Disease Control and Prevention (CDC):
Influenza prevention and control recommendations 2010-2011.
Available at: www.cdc.gov/flu/professionals/acip/
specificpopulations.htm.

38 SECTION I╇ •â•‡ Vaccine-Preventable Diseases in Children and Adolescents

EVIDENCE This reference provides a summary of disease, epidemiology, prevention, and
management.
Ambrose CS, Yi T, Walker RE, Conner EM: Duration of Centers for Disease Control and Prevention (CDC): Influenza. Available at:
protection provided by live attenuated influenza vaccine in www.cdc.gov/flu. This CDC site provide the most up-to-date data about epi-
children, Pediatr Infect Dis J 27:7444-7448, 2008. This reference demiology of circulating influenza strains.
provides a clinical trial of live attenuated influenza vaccine Derlet RW, Sandrock SE: Influenza. Available at: http://emedicine.
examining length of immunity and possible cross-protection from medscape.com/article/219557-overview. Accessed April 18, 2010. This
non-vaccine influenza strains. resource provides a summary for diagnosis and management of influenza.
Fiore AE, Shay DK, Broder K, et al: Prevention and control of
Finelli L, Fiore A, Dhara R, et al: Influenza-associated seasonal influenza with vaccines. Recommendations of the Advisory
pediatric mortality in the United States: increase of Committee on Immunization Practices (ACIP), 2009, MMWR Recomm
Staphylococcus aureus coinfection, Pediatrics 122:805-811, 2008. Rep 58:1-52. This provides the recent Centers for Disease Control and
This reference provides an epidemiologic study of influenza in Prevention (CDC) recommendations for prevention and control of seasonal
children and associated disease with S. aureus. influenza.
Long SS, Pickering LK, Prober C, eds: Principles and practices of pediatric
Walter ND, Taylor TH, Shay DK, et al: Influenza circulation infectious diseases, ed 3, St Louis, 2009, Elsevier, pp 1176-1179. This refer-
and the burden of invasive pneumococcal pneumonia during a ence provides a comprehensive review of the current clinical approach to influenza
non-pandemic period in the United States, Clin Infect Dis in pediatrics.
50:175-183, 2010. This reference provides an epidemiologic study of National Center for Immunization and Respiratory Diseases, Centers for
influenza in adults and risk of concomitant disease with pneumococcal Disease Control and Prevention (CDC): Use of influenza A (H1N1) 2009
pneumonia. monovalent vaccines. Recommendations of the Advisory Committee
on Immunization Practices (ACIP), 2009, MMWR Recomm Rep 58:1-8,
ADDITIONAL RESOURCES 2009. This provides the recent CDC recommendations for prevention and control
of 2009 pandemic influenza.
American Academy of Pediatrics (AAP): Influenza. In Pickering LK, Baker U.S. Department of Health and Human Services: Flu.gov. Available at:
CJ, Kimberlin DW, Long SS, eds: Red Book: 2009 Report of the Committee www.flu.gov. This site provides up-to-date information as monitored by the by
on Infectious Diseases, ed 28, Elk Grove Village, Ill, 2009, AAP, pp 541-545. the Health and Human Services Interagency Public Affairs Group on Influenza
Preparedness and Response.

Rotavirus Infection 9

S. Michael Marcy and Susan Partridge

ABSTRACT combination of intense viral shedding during clinical disease (up
to 1012 virions per gram of stool) together with a small oral
Rotavirus infections are the most common cause of severe dehy- infective dose (as few as 100 particles).
drating gastroenteritis worldwide. In developing countries, vir-
tually all children have been infected by age 2 to 3. Rotaviruses Risk factors for illness in infancy include use of formula
are double-stranded ribonucleic acid (RNA) viruses that belong rather than breastfeeding, low birth weight, residence in a
to the family Reoviridae. The viral capsid is composed of three household with one or more children younger than 2 years of
protein layers. Two structural proteins in the outer layer, VP4 age, attending a childcare facility, male gender, and young
and VP7, define the P (protease-sensitive) and G (glycoprotein) maternal age (Figure 9-1). Children and adults who are immu-
serotypes, respectively. Clinical presentation is characterized by nocompromised as a result of congenital or acquired immuno-
varying severity of vomiting, diarrhea, and fever, either alone or deficiency may also experience more severe or prolonged
in combination. Illness may be mild or asymptomatic, particu- gastroenteritis.
larly in older children and adults. Infection is self-limited and
treatment is supportive, directed at maintaining fluid and elec- CLINICAL FEATURES
trolyte balance and nutrition. Natural infection is generally pro- Occurrence of rotavirus infection has been highly seasonal in
tective against subsequent severe illness. Rotavirus immunization temperate climates. Prior to the availability of rotavirus immu-
available in most industrialized countries has markedly reduced nization, rotavirus activity in the United States, began in early
the rates of illness and death previously associated with rotavirus winter in the Southwest and progressed northward and east-
gastroenteritis. Two highly effective rotavirus vaccines are rec- ward, arriving in the New England states in the spring. Wide-
ommended for routine immunization in infancy. spread use of rotavirus vaccine in infancy has resulted in a
markedly diminished incidence of illness, although with little
GEOGRAPHIC DISTRIBUTION AND change in seasonality. The peak age of illness in developed
DISEASE BURDEN countries is from 6 to 24 months. In developing countries most
Rotavirus gastroenteritis is the most common cause of severe cases occur in the first year of life, which is probably a factor in
dehydrating diarrhea in infants and young children worldwide. the higher mortality in these areas.
Before the availability of rotavirus immunization almost all
children acquired infection by age 3 years, irrespective of their Illness begins from 1 to 2 days after infection, most often
geographic location or living conditions. In the United States, with the abrupt onset of vomiting and fever, followed shortly by
infection was responsible for a significant number of pediatric watery diarrhea (Figure 9-2). Any of these findings can occur
office and emergency department visits as well as hospitaliza- alone or in combination; however, 95% of children have vomit-
tions. Although approximately 3,000,000 cases of rotavirus ing, diarrhea, or both. Vomiting is usually brief in duration, and
disease occurred annually in the United State among children diarrhea resolves in most cases after 3 to 7 days. Although a third
younger than 5 years old, mortality rates were low, with 20 to of children manifest a fever of 39° C (102.2° F), most have a
60 deaths annually. In developing countries where infections low-grade fever and up to 25% are afebrile at the time of onset
occur earlier in infancy and access to medical care is often of clinical disease.
limited, rotavirus gastroenteritis has been and remains a leading
cause of mortality, with an estimated 600,000 childhood deaths Age is an important determinant of the clinical course. In the
per year, the majority in Asia and Africa. neonatal period, illness is usually asymptomatic or very mild,
although rotavirus infection has been associated with necrotiz-
RISK FACTORS ing enterocolitis, particularly in preterm infants. Older infants
Transmission of infection is primarily fecal-oral, not only and toddlers with their first infection manifest a broad spectrum
through person-to-person contact, but also via contact with of signs and symptoms, ranging from a single episode of watery
contaminated environmental surfaces. Contamination of water diarrhea or emesis to fulminant gastroenteritis leading rapidly
and food is an uncommon source; the role of respiratory droplet to electrolyte imbalance, hypovolemia, and shock. Although
transmission is uncertain. Rotavirus is shed in the stool of children with up to five rotavirus infections in the first 2 years
infected children not only during acute illness but also several of life have been described, illness occurring after the first infec-
days before and after. The high rate of transmission and preva- tion is almost always mild to moderate. With rare exceptions,
lence of early childhood infection is likely potentiated by a particularly among the elderly, adolescents and adults have
asymptomatic infection or mild disease, probably as a result of
protection derived from previous infection(s).

Rotavirus has been identified in the cerebrospinal fluid and
in up to 90% of sera during the course of acute illness. Infection
has been associated with seizures, encephalitis, meningitis, mild

40 SECTION I╇ •â•‡ Vaccine-Preventable Diseases in Children and Adolescents

Figure 9-1╇ Low birth rate and used of formula rather than breast feeding are risk factors for rotavirus infection in infants. The
bottle-fed boy shows signs of dehydration from rotavirus infection.

Infection Hospital Figure 9-2╇ Clinical course of rotavirus
admission infections. (Data from Marshall G,
Diarrhea Dennehy P, Matson DO, Staat MA:
Fever Rotavirus: prevention and vaccination
Vomiting strategies to address burden of
disease, Thorofare, NJ, 2008, Vindico
Viral shedding Medical Education.)

Ϫ5 Ϫ4 Ϫ3 Ϫ2 Ϫ1 0 1 2 3 4 5 6 7 8 9 10 11
Day from onset of symptoms

elevation of liver enzymes, pancreatitis, myocarditis, myositis, CLINICAL MANAGEMENT
and lower respiratory tract infection. Treatment of rotavirus gastroenteritis is supportive, directed at
restoration and maintenance of vascular volume, fluid, electro-
DIAGNOSIS lyte, and caloric balance. Illness is self-limited; there is no antivi-
No clinical features distinguish rotavirus disease from that ral therapy. In most cases, a few days of oral rehydration therapy
caused by many other gastrointestinal pathogens. Abrupt onset (ORT) with appropriate electrolyte-carbohydrate solutions are
of vomiting, profuse watery diarrhea, and mild fever occurring sufficient. Severe dehydration, persistent vomiting, intractable
in the winter or spring, depending on location, is highly sug- watery diarrhea, or refusal of oral fluids may necessitate paren-
gestive of a rotaviral cause. Prolonged high fever and dysenteric teral therapy. Breast-feeding should be continued or reinstituted
or grossly bloody stools would mitigate against rotavirus infec- as quickly as possible. In older infants and children, early refeed-
tion as the cause. ing with solids should be encouraged. Use of probiotics, specifi-
cally Lactobacillus GG (two capsules three times daily), has
Laboratory confirmation of rotavirus infection is not rou- provided some benefit in shortening the course of illness.
tinely necessary. When indicated, such as for a patient with a
prolonged or atypical course of gastroenteritis or for inpatient PREVENTION AND CONTROL
cohorting, a number of confirmatory laboratory tests can be Breastfeeding, hand washing, maintaining surface cleanliness
used. Enzyme-linked immunosorbent assay (ELISA) or latex (particularly in daycare centers), and diligently using contact
agglutination tests are available in most clinical laboratories. precautions with hospitalized children are helpful in preventing
Polymerase chain reaction (PCR) procedures may be available rotavirus infection.
in larger hospital laboratories or academic centers.

CHAPTER 9╇ •â•‡ Rotavirus Infection 41

In the United States, two rotavirus vaccines (RotaTeq, Merck; ADDITIONAL RESOURCES
Rotarix, Glaxo SmithKline) are recommended for routine infant American Academy of Pediatrics (AAP): Rotavirus. In Pickering LK, Baker
immunization in the first 8 months of life. They are comparably
effective and have resulted in an 80% reduction in rotavirus CJ, Kimberlin DW, Long SS, eds: Red Book: 2009 Report of the Committee
gastroenteritis of any severity and over 95% reduction against on Infectious Diseases, ed 28, Elk Grove Village, Ill, 2009, AAP, pp 576-579.
severe dehydrating gastroenteritis. In addition to providing This resource provides an abbreviated summary of the diagnosis, management,
direct protection in immunized infants, there is epidemiologic and prevention of rotavirus infections.
evidence that reduction in the community incidence of rotavirus Cortese MM, Parashar UD, Centers for Disease Control and Prevention
has occurred, likely related to development of herd immunity. (CDC): Prevention of rotavirus gastroenteritis among infants and chil-
dren: recommendations of the Advisory Committee on Immunization
EVIDENCE Practices (ACIP), MMWR Recomm Rep 58:1-37, 2009. This provides a
review of the preventative measures available for rotavirus.
Bernstein DI, ed: The changing epidemiology of rotavirus
gastroenteritis, Pediatr Infect Dis J 28:S49-S62, 2009. This
reference provides data about the changing epidemiology of rotavirus
in recent times.

World Health Organization (WHO): Oral rehydration salts
(ORS): a new reduced osmolarity formulation. Available at:
www.who.int/child-adolescent-health/New_Publications/
NEWS/Statement.htm. This reference provides information about
the preparation and use of ORS for diarrhea and dehydration in
infants and children.

Measles 10

Alison Margaret Kesson

ABSTRACT transmitted by direct contact with infected respiratory droplets
and less commonly by airborne spread. It is one of the most
Measles is a highly contagious, acute febrile illness caused by communicable of the infectious diseases, with an attack rate over
rubeola virus, most commonly seen in young children. Measles 80% for susceptible persons. Infected individuals are most con-
is characterized by a coryzal prodrome, with cough, conjuncti- tagious during the late prodromal phase, when cough and coryza
vitis, rhinorrhea, and fever, followed by an exanthem, a macu- are maximal.
lopapular rash. In addition, a pathognomonic enanthem, Koplik’s
spots (bluish spots on a red base), may be seen on the buccal The incubation period is 10 to 14 days from exposure to
mucosa. Most children recover completely, but serious compli- onset of symptoms. The virus invades endothelial and epithelial
cations involving the respiratory tract and central nervous cells. After invasion of the respiratory epithelium, local viral
system (CNS) may occur. In developing countries, measles con- multiplication and primary viremia with spread via leukocytes
tinues to be a significant cause of morbidity and mortality, but occurs. Next the prodromal phase begins, which generally lasts
these have been remarkably reduced in areas in which routine for 3 to 6 days and is thought to coincide with secondary viremia.
immunizations are used. Recently, however, growing antivac- About 2 to 3 days before the appearance of the rash, Koplik’s
cine sentiment has led to decreased acceptance of measles spots (bluish-grey specks, at times described as appearing like
vaccine by some, placing everyone at increased risk of natural coarse-size salt crystals, on an erythematous base) appear on
infection and its complications. the buccal mucosa, usually opposite the molars (Figure 10-1).
Koplik’s spots are pathognomonic of measles and may occur on
GEOGRAPHIC DISTRIBUTION AND any mucosal surface but may be overlooked without a careful
DISEASE BURDEN examination.
Measles occurs in every country in the world. In countries
without vaccine programs, epidemics of measles occur every 2 The prodrome resembles a severe upper respiratory tract
to 5 years. Globally, measles causes 20 to 30 million infections infection, with malaise, fever, and the classic “3 Cs” (conjuncti-
with at least 1 million deaths annually. Countries in which vitis, cough, and coryza) of measles. Profuse nasal discharge and
vaccine is widely used have experienced a marked decrease in a brassy cough are usually maximal at day 5. A transient scarla-
measles. However, in recent years purported risks associated tiniform or morbilliform rash lasting less than 24 hours may
with vaccination have led to decreased acceptance of measles occur in this early phase.
vaccine among some segments of the population. This has led
to an increase in unimmunized children and return of measles The characteristic morbilliform rash (fine, red maculopap-
infections in some countries, including the United States. Since ules) usually begins as blanching macules behind the ears and
2006, several outbreaks of measles have occurred in the United at the hairline (see Figure 10-1). It then spreads to involve the
States and European countries with high immunization rates, face and proceeds down the body to the extremities, and last
many of which can be linked to an outbreak in unimmunized to the palms and soles. The rash usually lasts 5 days, often
schoolchildren in Switzerland. becomes confluent, and then fades. A brownish discoloration of
the skin may remain for 10 days after the disappearance of
RISK FACTORS the rash. The skin may desquamate but this usually spares the
Humans are the only known hosts for rubeola virus, the caus- hands and feet. In uncomplicated illness, the duration from
ative agent of measles. In general, measles is a more severe late prodrome to resolution of fever and rash is 7 to 10 days.
illness in adults, infants, and children younger than 5 years of The rash may not develop in immunocompromised individuals,
age than in school-aged children. Individuals with compromised as the pathogenesis is thought to be hypersensitivity to the
cellular immunity (congenital or acquired), malnutrition, and virus.
vitamin A deficiency are at risk for more severe illness.
Other findings include generalized lymphadenopathy, sple-
CLINICAL FEATURES nomegaly, palpebral conjunctivitis, punctate keratitis, edema of
Rubeola virus is a single-stranded ribonucleic acid (RNA) the eyelids, and photophobia. Sore throat, myalgia, and head-
virus belonging to the family Paramyxoviridae. Infection is ache are also common. Nonsuppurative acute appendicitis may
also occur, which may be seen just before the rash.

COMPLICATIONS
The most common complications are respiratory tract infec-
tions, diarrhea, and CNS involvement. In infants, respiratory
complications are more common; in older children, CNS com-
plications are more common.

CHAPTER 10╇ •â•‡ Measles 43
Measles rash

Koplik spots

Figure 10-1╇ Clinical features of measles.

Respiratory Tract Infections consciousness. The incidence of measles encephalitis is 1 in
Invasion of any part of the respiratory tract is part of the measles 1000 to 2000 cases; the condition ranges from mild to severe,
virus infection. In addition, bacterial superinfection can occur and neurologic sequelae are common in survivors.
in any area of the respiratory tract, including the middle ear.
Otitis media, sometimes with spontaneous perforation of the Acute postinfectious measles encephalomyelitis or acute dis-
tympanic membrane, can occur, as can laryngotracheobronchitis seminated encephalomyelitis (ADEM) may also be seen after
(croup) and bronchiolitis. measles. It is rare in children younger than 2 years of age but
has an incidence of approximately 1 in 1000 in older children.
Pneumonia may be caused by direct viral invasion of the It generally develops after the first week of rash and manifests
lungs or by bacterial superinfection. Radiographic evidence of with an abrupt onset of fever, headache, and seizures proceeding
pneumonia is common even with uncomplicated measles. Sec- to obtundation and coma. The CSF may show a mild lympho-
ondary bacterial pneumonia cannot be differentiated from cyte pleocytosis and elevated protein. Antibodies to myelin basic
measles pneumonia based on the pattern of x-ray changes. Bac- protein are present in the CSF. There is no evidence of measles
terial pneumonia is commonly caused by Streptococcus pneu- virus antigens or RNA or intrathecal synthesis of measles
moniae, Haemophilus influenzae, or Staphylococcus aureus and antibodies, supporting an immunologic and not a virologic
usually occurs 5 to 10 days after the onset of the rash. The pathogenesis.
patient usually has high fevers, purulent sputum, and leukocy-
tosis at the time that the rash is resolving. Pneumonia is the Subacute Sclerosing Panencephalitis
most common cause of measles-associated deaths in infants. In Subacute sclerosing panencephalitis (SSPE) is a chronic, degen-
developing countries the mortality rate with measles may erative CNS disorder attributed to persistent infection with a
approach 80%. Although pneumonia is less frequent in indus- defective measles virus despite robust host immune responses.
trialized countries, it is still responsible for the majority of SSPE is a rare complication (approximately 1 in 300,000 cases)
deaths in infants with measles. of measles, occurring predominantly in children in their first
decade of life. The findings are of subtle deterioration in intel-
In adults, measles virus pneumonia is more common than lectual function and personality changes. Later manifestations
secondary bacterial pneumonia and manifests clinically as include myoclonic jerks with characteristic EEG slow wave
increasing respiratory distress and hypoxia in parallel with the changes. Affected patients develop progressive intellectual dete-
rash. There may be evidence of prolonged viral replication with rioration, extrapyramidal dyskinesia with dystonic posturing,
persistent high fever, prolonged Koplik’s spots and rash, bio- and often progressive visual loss. Onset is usually several years
chemical myositis, and hepatitis. This is a severe illness, but after the initial infection and progression is variable, with remis-
fatalities are rare. sions, but it is usually fatal within 3 years. Patients with SSPE
can be diagnosed by the very high titers of measles antibody in
Encephalitis their serum and CSF.
Cerebrospinal fluid (CSF) pleocytosis and electroencephalo-
graphic (EEG) abnormalities may occur in up to 50% of indi- Modified Measles
viduals with measles who have no overt CNS symptoms. Acute A mild form of measles has been observed in persons with
measles encephalitis occurs during the convalescent phase and some degree of passive immunity, such as infants who have
is characterized by a resurgence of fever, headaches, and altered

44 SECTION I╇ •â•‡ Vaccine-Preventable Diseases in Children and Adolescents

passively acquired maternal antibodies and some individuals mothers have measles antibodies (from immunization or natural
who have received immune globulin (IG). The symptoms infection). In the absence of maternal antibodies neonatal
of modified measles are variable, and many classic features measles is often severe.
may be absent. The illness is usually mild and abbreviated,
though the incubation period may be prolonged up to 21 days. Other Abnormalities
Complications of measles and transmission to others are Tuberculosis may be exacerbated or reactivated by measles
extremely rare. infection but not measles vaccine; however, measles vaccine does
suppress tuberculin skin sensitivity. This effect lasts approxi-
Atypical Measles mately 4 to 6 weeks and is presumed to be secondary to sup-
Atypical measles has been described in persons who received pressed cell-mediated immunity.
formalin-inactivated measles vaccine and who years later devel-
oped wild measles infection. A prodrome of fever, cough, and Transient biochemical hepatitis has been reported during
dyspnea is followed by appearance of the rash, which, unlike in acute measles in approximately 30% of cases and is more
classical measles, begins peripherally and spreads centrally while common in adults than children. Myositis with myalgia, elevated
sparing the face. The rash may be urticarial, maculopapular, creatine phosphokinase, and hypocalcemia is observed in
hemorrhagic, vesicular, or a combination of these. The rash is approximately a third of adults and adolescents.
accompanied by high fevers and edema of the extremities, and
complications may occur. Despite the severity, the illness is Disseminated intravascular coagulation with measles virus
often self-limited. Measles virus has not been isolated from infection of endothelium resulting in bleeding from epithelial
these patients. The pathogenesis is thought to be related to and mucosal surfaces (“black measles”) occurs rarely in countries
hypersensitivity to the measles virus in a partially immune host. with high vaccine coverage. Hemorrhagic measles is often
The killed measles virus vaccine was removed from the market severe and has a high mortality rate.
in 1967.
DIAGNOSTIC APPROACH
Measles in Immunocompromised Hosts Clinical Findings
Severe measles infection may occur in persons with deficient Classic measles with cough, coryza, conjunctivitis, Koplik’s
cellular immunity, such as those being treated for malignancy spots, and a maculopapular rash may be readily diagnosed clini-
and those with acquired immunodeficiency syndrome (AIDS) or cally. Laboratory diagnosis may be useful for possible atypical
congenital immunodeficiencies. Often these individuals do not measles, for unexplained pneumonia or encephalitis in immu-
have a rash; however, there is a significant incidence of pneu- nocompromised patients, and in areas where clinicians may be
monitis and encephalitis. A chronic form of encephalitis resem- unfamiliar with the clinical constellation of measles.
bling SSPE often with concomitant pneumonia has also been
reported. Diagnostic considerations for measles may vary with the
geographic location of the patient and include dengue fever,
Malnutrition leading to impaired cellular immunity, as well Rocky Mountain spotted fever, and other Rickettsia infections;
as intense exposure resulting from overcrowding appear to parvovirus B19; scarlet fever; Mycoplasma pneumoniae; Stevens-
be factors contributing to severe measles infection in develop- Johnson syndrome; adverse drug reactions; and rheumatologic
ing countries. In addition, vitamin A deficiency, which may disorders.
occur with malnutrition, is also associated with more severe
illness. Laboratory Testing
Laboratory confirmation can be obtained by virus isolation,
Measles during Pregnancy detection of measles antigen, RNA, or antibody measurement.
Measles during pregnancy may be severe, mainly related to Measles virus isolation is technically difficult and is not usually
primary measles pneumonitis. During pregnancy, measles is available in clinical laboratories. Viral culture is useful in patients
associated with higher risk of miscarriage and premature deliv- with unexplained pneumonia or encephalitis and in immunode-
ery; however, is not known to cause congenital anomalies of the ficient patients in whom antibody responses may be minimal;
fetus. however, culture may take 2 to 3 weeks. Measles antigen on cells
from nasal exudates or urinary sediment may be detected using
Measles in Neonates immunofluorescent antibodies, which can be done in a few
Congenital measles, in which the rash is present at birth or hours. A sensitive reverse transcription–polymerase chain reac-
appears in the first 10 days of life, varies from mild to severe tion (RT-PCR) method demonstrating viral RNA is available
with mortality approaching 30%. Mortality is higher in prema- but primarily in reference laboratories.
ture infants and in infants who do not develop a rash. Postnatally
acquired neonatal measles is rare, because generally infants are Serology is the most commonly used laboratory method.
protected by transplacentally acquired antibodies as most Detection of measles IgM antibodies by enzyme-linked immu-
nosorbent assay (ELISA) is diagnostic of acute infection;
however, these antibodies are often not detectable until the rash
appears. A fourfold rise in titers between acute and convalescent

CHAPTER 10╇ •â•‡ Measles 45

sera can be measured using, neutralization, complement fixation considered to be less than the risk of natural disease. Measles
(CF), or hemagglutination inhibition (HAI). Neutralization vaccine virus is grown in chick embryo tissue cultures and con-
assays are technically difficult and generally not available; tains a negligible amount of egg protein. Persons with a history
ELISA, CF, and HAI are more widely available. These tests are of anaphylactic reaction to eggs can safely be given measles
not overly sensitive but are specific. An individual’s immune vaccine, but it should be administered in a setting where any
status can be determined by measuring measles IgG antibodies adverse reactions can be dealt with appropriately.
using an ELISA or HAI.
In 1998, Wakefield published a study of autistic children that
Diagnosis of SSPE is performed by demonstration of high raised the question of a connection between the MMR vaccine
measles HAI titers in serum and CSF in the presence of a com- and autism. This study has subsequently been withdrawn by The
patible illness. More commonly, measles IgG demonstrated by Lancet and Dr. Wakefield reprimanded for falsification of data.
ELISA in CSF is used to confirm this diagnosis. In addition, no subsequent studies have identified a link between
MMR vaccine and autism or other chronic illnesses.
TREATMENT
There is no recognized specific treatment for measles. The After Exposure
World Health Organization recommends treatment with IG can be given intramuscularly to prevent or ameliorate
vitamin A for all children with acute measles, regardless of their measles in susceptible individuals, when given within 6 days of
nutritional status or country of residence, to help decrease the exposure. IG is indicated for susceptible individuals with house-
severity of illness. Supportive therapy such as antipyretics and hold or close contacts at high risk of complications (such as
fluids is important. infants younger than 12 months of age, pregnant women, or
immunocompromised persons) or for whom measles vaccine is
Secondary bacterial infections need prompt treatment contraindicated. Individuals who routinely receive intravenous
with appropriate antimicrobials; however, prophylactic antibiot- IG (IVIG) do not need IG prophylaxis for measles if they
ics are of no known value. The measles virus is susceptible in received a dose of at least 400╯mg/kg of IVIG within 3 weeks
vitro to ribavirin; however, ribavirin administered intravenously of exposure. After receipt of IG or IVIG, adjustment of the
or by aerosol for treatment of measles is of unproven efficacy timing of subsequent active measles vaccination must be made
and has not been approved by the U.S. Food and Drug (guidelines are published in the AAP Red Book).
Administration.

PREVENTION EVIDENCE
Before Exposure
Prevention is carried out by the administration of live-attenuated Aaby P: Malnutrition and overcrowding/intensive exposure in
measles virus vaccine. Both killed and live virus vaccines have severe measles infection: review of community studies, Rev
been developed; however, the killed vaccine was withdrawn in Infect Dis 10:478-491, 1988. This review investigated the
1967 after the recognition of atypical measles (as described community factors associated with measles morbidity and mortality.
earlier). The vaccine routinely used currently is combined
measles, mumps, rubella vaccine (MMR), which is given to Clements CJ, Cutts FT: The epidemiology of measles: thirty
healthy children 12 to 15 months of age, with a second dose of years of vaccination, Curr Top Microbiol Immunol 191:13-33,
vaccine given later in childhood (generally at 4 to 6 years of age 1995. This article provides a discussion of the epidemiology of measles
in the United States). The vaccine is not routinely given to to help inform vaccination strategies.
infants younger than 12 months of age because the induction of
immunity may be suppressed by residual maternal antibodies. Johnson RT, Griffin DE, Hirsch RL, et al: Measles
Measles vaccine can be given to infants 6 to 12 months of age encephalomyelitis—clinical and immunological studies, N Engl
residing in or planning travel to areas with a high incidence of J Med 310:137-141, 1984. This is a study of 19 patients with
natural measles but should be routinely followed by additional postinfectious encephalomyelitis complicating natural measles
doses after 12 months of age. Fever and a mild maculopapular infection.
rash can develop about 1 week after vaccination in 5% to 15%
of children. The vaccine is usually not effective if the recipient Kaplan LJ, Daum RS, Smaron M, McCarthy CA: Severe
has measles antibodies present, such as infants younger than 12 measles in an immunocompromised patient, JAMA 267:1237-
months of age or recent recipients of blood products. No delete- 1241, 1992. This article provides case studies and a review of the
rious side effects have been associated with recurrent measles literature describing clinical features and outcome of measles infection
vaccination. In the general population, 95% of properly immu- in immunocompromised individuals.
nized children respond serologically to the vaccine with persis-
tent immunity for many years. ADDITIONAL RESOURCES

Live-attenuated measles vaccine is contraindicated in indi- American Academy of Pediatrics (AAP): Measles. In Pickering LK, Baker
viduals with cell-mediated immunodeficiency; however, it is CJ, Kimberlin DW, Long SS, eds: Red Book: 2009 Report of the Committee
recommended for children with asymptomatic human immuno- on Infectious Diseases, ed 28, Elk Grove Village, Il, 2009, AAP, pp 444-455.
deficiency virus (HIV) infection, as the risk of vaccination is This resource provides abbreviated “standard of care” information about man-
agement and prevention of measles.

Bellini WJ, Sever JL: Measles, mumps and rubella. In Specter S, Hodinka
RL, Young SA, eds: Clinical virology manual, ed 3, Washington DC, 2000,

46 SECTION I╇ •â•‡ Vaccine-Preventable Diseases in Children and Adolescents

ASM Press, pp 501-512. This resource provides a review of the virology and Gershon A: Measles. In Mandell G, Bennett J, Dolin R, eds: Principles and
pathogenesis of rubeola. practice of infectious diseases, Philadelphia, 2005, Elsevier, pp 2031-2037.
Chen SP, Fennelly GJ: Measles. Available at: http://emedicine.medscape.com/ This resource provides a summary of the diagnosis, management, and prevention
article/966220-overview. Accessed March 25, 2010. This is a review article of measles.
about the features of measles infection and prevention.
Cherry JD: Measles. In Feigin R, Cherry J, Demmler G, Kaplan S, eds: World Health Organization (WHO): MMR and autism. Available
Textbook of pediatric infectious diseases, ed 6, Philadelphia, 2009, WB Saun- at: www.who.int/vaccine_safety/topics/mmr/mmr_autism/en/. Accessed
ders, pp 2283-2304. This resource provides an overview of pathogenesis, epi- August 2009. The statement by WHO on measles vaccine, autism, and inflam-
demiology, and diagnosis of measles. matory bowel disease.

Mumps 11

Alison Margaret Kesson

ABSTRACT days. Mumps virus can be isolated from saliva 5 days before the
onset of parotitis to 5 days after. Mumps is highly contagious,
Mumps virus is the only known cause of epidemic parotitis. and peak infectivity occurs just before the onset of parotitis.
Mumps is an acute systemic viral infection, and the most sig-
nificant clinical finding is a nonsuppurative inflammation of the In symptomatic individuals, the prodrome includes low-
salivary glands, most notably one or both parotid glands. In grade fever, anorexia, malaise, and headaches. In primary infec-
prepubertal children and most adults the illness is benign, and tions, approximately 25% of patients initially have involvement
approximately one third of infections are subclinical. After of only one parotid gland; however, the second parotid gland
puberty the disease is more likely to be severe, with more fre- usually enlarges within a few days. Patients commonly complain
quent occurrence of extrasalivary gland involvement, including of earache, and parotid gland tenderness is noted on palpation.
orchitis, meningitis, encephalitis, and pancreatitis. Although a The parotid gland(s) may be painful and visibly enlarged. The
feared complication of orchitis, sterility is rarely observed. ear of the affected side may be pushed upwards and outwards.
Treatment is supportive, and the primary means of prevention The enlarged parotid gland may obscure the angle of the man-
is with use of a live-attenuated mumps vaccine, which elicits an dible and should not be confused with cervical adenopathy,
immune response in over 90% of recipients. In countries with which does not usually obscure this anatomic landmark. After
widespread use of mumps vaccine, the occurrence of infection the parotid swelling has peaked (at 3 to 5 days), the fever and
has decreased by nearly 99%. tenderness rapidly resolve, and the parotid gland(s) return to
normal size, usually within a week. Involvement of other salivary
GEOGRAPHIC DISTRIBUTION glands may occur, and involvement of submandibular glands
Mumps virus is a member of the Paramyxoviridae family in the may be confused with anterior cervical lymphadenitis. Involve-
genus Rubulavirus and naturally infects only humans. Mumps is ment of sublingual glands is less common but may be associated
endemic throughout the world, with an estimated annual global with tongue swelling. The orifices of Stensen’s and Wharton’s
incidence of 100 to 1000 per 100,000 of the population. In the ducts are often erythematous and edematous (Figure 11-1).
prevaccine era, epidemics occurred every 2 to 5 years, the peak Patients may complain of trismus and difficulty speaking and
incidence was in late winter and early spring in temperate cli- drinking. Acidic foods may induce parotid pain.
mates, and it occurred throughout the year in tropical climates.
In areas with widespread use of mumps vaccine, this epidemiol- Natural infection was once considered to provide lifelong
ogy is no longer seen. immunity, but more recent evidence suggests that reinfections
can occur; these are usually milder and often lack the typical
RISK FACTORS parotitis.
Absence of mumps-specific antibody is the primary risk factor
for susceptibility to infection. Mumps is uncommon in infants Central Nervous System Involvement
younger than 1 year of age, presumably because of passive Central nervous system (CNS) involvement is the most common
immunity from transplacentally acquired maternal antibodies. extrasalivary gland manifestation of mumps and is caused by the
In the prevaccine era, mumps occurred most commonly in chil- neurotropism of the mumps virus. This is significantly more
dren 5 to 9 years of age, and more than 90% of children younger prevalent in males than females for unexplained reasons. CNS
than 15 years of age had mumps. More recently in countries manifestations range from asymptomatic cerebrospinal fluid
with universal immunization, outbreaks of mumps have been (CSF) pleocytosis (seen in 50% of patients) to a very rare ful-
reported in closed populations of older children, adolescents, minant and potentially fatal encephalitis. Clinical meningitis
and young adults, such as secondary schools, colleges, universi- occurs in 10% to 30% of cases and may occur before, during,
ties, and military groups. These outbreaks have been attributed after, or in the absence of parotitis. Typical clinical features
to waning vaccine-induced immunity. include headache, vomiting, fever, and nuchal rigidity. The CSF
may contain up to 2000 cells/mm3, predominately lymphocytes,
CLINICAL FEATURES though a predominance of neutrophils may occur early in the
The mumps virus is transmitted through infected respiratory disease. Protein levels are normal to mildly elevated, and glucose
secretions via direct contact, droplets, or fomites. The incuba- concentration may be low in up to 30% of patients (more com-
tion period ranges from 12 to 25 days with a mean of 16 to 18 monly than in other viral meningitides). The CSF abnormalities
may lead clinicians to consider bacterial meningitis in the dif-
ferential diagnosis. Generally, mumps meningitis is benign, with
complete recovery and an absence of any sequelae.

Encephalitis is a very rare and much more serious CNS
manifestation of mumps. Signs of encephalitis include alteration

48 SECTION I╇ •â•‡ Vaccine-Preventable Diseases in Children and Adolescents

Figure 11-1╇ Mumps parotitis.

Pouting of orifice
of Stensen’s duct

Parotitis
(obstruction or
ascending infection)

in the level of consciousness, convulsions, paresis, aphasia, and epididymo-orchitis months to years after the infection. In men
involuntary movements. Mumps encephalitis has a bimodal dis- with unilateral epididymo-orchitis, a slight cosmetic imbalance
tribution of onset. There is an early group in which onset coin- in testicular size may occur.
cides with the presence of parotitis and a larger later group in
which the condition develops 7 to 10 days after the onset of Oophoritis develops in about 5% of postpubertal women
parotitis. Early-onset encephalitis represents direct damage to with mumps. Symptoms of fever, nausea, and lower abdominal
neurons as a result of viral invasion, whereas late-onset disease pain are frequent. Rarely, reduced fertility and premature meno-
is considered to be a postinfectious process related to the host pause have been reported as a consequence. Some postpubertal
immune response. The CSF findings are similar to those of women with mumps complain of swelling and pain in their
mumps meningitis. The neurologic manifestations usually breasts consistent with mastitis.
resolve over a period of 1 to 2 weeks; however, a small minority
of patients have significant neurologic sequelae, and death can Pancreatitis
occur. In countries without vaccination, mumps can be a signifi- Pancreatitis is an uncommon and severe complication of mumps
cant cause of viral meningitis and encephalitis. that causes fever, nausea, vomiting, and severe epigastric pain.
There is considerable controversy surrounding the relationship
Cerebella ataxia, facial palsy, transverse myelitis, Guillain- of mumps with juvenile diabetes mellitus. Although mumps
Barré syndrome, and a poliomyelitis-like syndrome have rarely virus has been shown to infect beta cells from pancreatic islets
been associated with mumps. Aqueductal stenosis resulting in in vitro, no evidence of infection has been demonstrated in vivo.
hydrocephalus has developed after CNS infection caused by Many reports of temporal association of diabetes mellitus after
mumps. mumps have been described, albeit occurring months to years
after mumps infections.
Epididymo-orchitis and Oophoritis
Epididymo-orchitis is the most common extrasalivary gland Other Associated Conditions
manifestation of mumps in adults but is rare before puberty. It Along with arthritis and arthralgia, myocarditis, and deafness,
develops in 20% to 30% of postpubertal males with mumps and other rare associations with mumps infection include nephritis,
is bilateral in about 15%. Most cases occur during the first week hepatitis, thyroiditis, thrombocytopenia, and ocular complica-
of parotitis, but it may precede parotitis or be the only manifes- tions (e.g., iritis, keratitis, and central retinal vein thrombosis).
tation of mumps. Physical examination reveals a warm, swollen,
tender testicle and erythema of the scrotum accompanied by ARTHRITIS AND ARTHRALGIA
fever, headache, nausea, and vomiting. The testicular swelling Mumps may be associated with arthritis or arthralgia infre-
usually resolves in 7 to 10 days, but residual tenderness may quently in adults and very rarely in children. Migratory polyar-
persist for several weeks. Mumps orchitis is often associated thritis is the most common manifestation, but monarticular
with significant anxiety and fear of sexual impotence or sterility; arthritis and arthralgia have been reported. Both large and small
however, these complications rarely occur. Some degree of
testicular atrophy occurs in about half of the patients with

CHAPTER 11╇ •â•‡ Mumps 49

joints may be involved. Symptoms usually appear 10 to 14 days amylase can be determined by isoenzyme analysis or by deter-
after the onset of parotitis and may last several weeks. Mumps mining pancreatic lipase. Amylase in the presence of parotitis
virus has not been isolated from joint fluid, and no evidence of may remain elevated for 2 to 3 weeks after resolution of
immune complex deposits has been detected, so the cause of the symptoms.
arthritis is uncertain. The process usually resolves spontane-
ously without any joint damage. The peripheral white blood cell and differential counts are
usually normal; however, mild leukopenia with a relative lym-
MYOCARDITIS phocytosis may be seen. In patients with evidence of meningitis,
Electrocardiographic changes occur in up to 15% of patients epididymo-orchitis, or pancreatitis, a leukocytosis with poly-
with mumps, these being depressed ST segments, flattened or morphonuclear predominance may be noted.
inverted T waves, and prolonged PR intervals. Clinical myocar-
ditis is rare; however, deaths have been reported. SEROLOGY
Laboratory confirmation of a typical case of mumps is often
DEAFNESS unnecessary but may be useful in some settings. In areas with
Sensorineural hearing loss caused by cochlear damage from the high vaccine coverage, the disease is uncommon, and clinicians
mumps virus can occur infrequently, with an incidence of 0.5 may be less familiar with the manifestations. The diagnosis of
to 5 cases per 100,000 cases of mumps. Deafness may have mumps is confirmed with serology by detection of mumps
an abrupt or gradual onset, is often unilateral, and may be tran- immunoglobulin M (IgM) antibodies using enzyme-linked
sient or more commonly permanent. Vertigo is a common immunosorbent assay (ELISA). Alternatively, seroconversion
accompaniment. from negative to positive or a fourfold rise in mumps IgG anti-
body titers between acute and convalescent sera, measured using
Congenital Infection complement fixation, hemagglutination inhibition, or neutral-
An increase in fetal death and spontaneous abortion has been ization assays, can confirm the diagnosis. Of note, hemaggluti-
documented in pregnant women with mumps in the first trimes- nation inhibition tests can have significant cross-reactivity with
ter of pregnancy, but no significant increase in fetal loss has been other infectious agents, particularly with parainfluenza viruses.
noted with infections in the second or third trimesters. Mumps
infection during pregnancy does not result in congenital abnor- VIROLOGY
malities of the fetus. Mumps virus is excreted in breast milk. The Virus isolation is the definitive method to diagnose mumps. It
incidence of perinatal mumps in infants of mothers with mumps is advisable to discuss viral cultures with the laboratory, espe-
is extremely rare, and the low incidence is thought to be a result cially in regions where mumps is rare, as cell cultures may not
of the protective effect of transplacental maternal antibodies. be readily available. The virus can be isolated from saliva and
urine, as well as from CSF in patients with clinical meningitis.
DIAGNOSIS Mumps viral ribonucleic acid (RNA) can also be detected by
Clinical Findings reverse transcription–polymerase chain reaction (RT-PCR)
Diagnosis of mumps is usually based on the history of exposure from throat or CSF specimens.
and physical examination findings of parotid swelling and ten-
derness accompanied by fever and malaise. However, a variety CLINICAL MANAGEMENT
of other infectious and noninfectious causes of acute parotid The treatment for mumps parotitis or orchitis is symptomatic
swelling can be confused with mumps. Parainfluenza 3, cox- and supportive. There is no specific antiviral therapy available.
sackieviruses, cytomegalovirus, and influenza A have all been
associated with parotid swelling. Bilateral parotid swelling can PREVENTION AND CONTROL
also occur in human immunodeficiency virus (HIV) infection. Infection Control Precautions
Noninfectious causes of bilateral parotid swelling include medi- Infected individuals should be considered contagious for 5 days
cations, diabetes mellitus, malnutrition, uremia, and metabolic after the onset of parotid swelling. Hospitalized patients with
disorders. Acute bacterial infection of the parotid, as well as mumps should be maintained with droplet precautions for 5
noninfectious causes such as tumors, cysts, and ductal obstruc- days after onset of parotid swelling to prevent spread to suscep-
tion, are usually associated with unilateral parotid swelling. tible individuals.

Laboratory Diagnosis Vaccination
BLOOD ABNORMALITIES Active immunization with a live-attenuated mumps vaccine,
Serum amylase is often elevated in mumps, indicating inflam- usually administered as measles, mumps, and rubella (MMR)
mation of the salivary glands or pancreas. The origin of the vaccine, elicits protective levels of mumps neutralizing antibod-
ies in more than 90% of recipients after one dose. Significant
adverse reactions to vaccination are rare, but parotitis, orchitis,

50 SECTION I╇ •â•‡ Vaccine-Preventable Diseases in Children and Adolescents

and fever have been reported. Aseptic meningitis occurs in EVIDENCE
less than 0.3% of vaccine recipients. Individuals with known
anaphylactic reactions to neomycin or gelatin should receive Dayan GH, Quinlisk P, Parker AA, et al: Recent resurgence of
mumps-containing vaccines in a setting that can manage such mumps in the United States, N Engl J Med 358:1580-1589,
reactions and only after consultation with an allergist. A desen- 2008. This reference provides a description of the epidemiology and
sitization protocol may be used before vaccination if required. role of vaccine failure in a recent mumps outbreak.
Individuals with egg allergies are at very low risk of anaphylactic Forsberg P, Fryden A, Link H, Orvell C: Viral IgM and IgG
reactions, as mumps vaccines are produced in chicken embryo antibody synthesis within the central nervous system in mumps
cells, which contain little ovalbumin. meningitis, Acta Neurol Scand 73:372-380, 1986. This reference
provides data about the diagnostic tests for mumps meningitis.
Routine vaccination is recommended for children at 12 to 15 Poggio GP, Rodrieguez C, Cisterna D, et al: Nested PCR for
months of age, after loss of transplacentally acquired maternal rapid detection of mumps virus in cerebrospinal fluid from
antibodies. Most Western countries also recommend a second patients with neurological diseases, J Clin Microbiol 38:274-278,
vaccination with MMR vaccine at 4 to 12 years of age, primarily 2000. This resource provides data about the diagnostic tests for
to prevent measles. This has also resulted in decreasing the risk mumps meningitis.
of mumps vaccination failure. From 2002 to 2007, mumps
outbreaks were reported in both the United States and United ADDITIONAL RESOURCES
Kingdom, predominantly involving young adults. A significant American Academy of Pediatrics (AAP): Mumps. In Pickering LK, Baker
minority of affected individuals had received two MMR vaccina-
tions, indicating that vaccine-induced immunity to mumps may CJ, Kimberlin DW, Long SS, eds: Red Book: 2009 Report of the Committee
wane with time, leaving populations susceptible to outbreaks. on Infectious Diseases, ed 28, Elk Grove Village, Ill, 2009, AAP, pp 468-472.
This resource provides an abbreviated summary of the diagnosis, management,
Because it is a live-attenuated viral vaccine, mumps vaccine and prevention of mumps.
should not be administered to pregnant women, individuals who Bellini WJ, Sever JL: Measles, mumps and rubella. In Specter S, Hodinka
have received immunoglobulin or a blood product in the pre- RL, Young SA, eds: Clinical virology manual, ed 3, Washington DC, 2000,
ceding 3 months, patients receiving immunosuppressive therapy ASM Press, pp 501-512. This resource provides a review of the virology and
or who have congenital or acquired immunodeficiency, patients pathogenesis of rubella.
with advanced malignancy, or individuals with an intercurrent Cherry JD: Mumps. In Feigin R, Cherry J, Demmler G, Kaplan S, eds:
febrile illness. Individuals with HIV infection who are not Textbook of pediatric infectious diseases, ed 6, Philadelphia, 2009, WB Saun-
severely immunocompromised may be immunized with mumps ders, pp 2451-2461. This resource provides an overview of pathogenesis, epi-
or combined MMR vaccines. demiology, and diagnosis of mumps.
Litman N, Baum S: Mumps. In Mandell G, Bennett J, Dolin R, eds: Prin-
Mumps vaccine given to an immune-susceptible individual ciples and practice of infectious diseases, Philadelphia, 2005, Elsevier, pp
postexposure has not been shown to be protective but will 2003-2006. This resource provides a summary of the diagnosis, management,
provide protection for subsequent exposures. Passive protection and prevention of mumps.
for exposed susceptible persons has been provided using mumps
immunoglobulin, but this is no longer commercially available
in the United States.

Rubella 12

Alison Margaret Kesson

ABSTRACT birth, and they may transmit infection to susceptible contacts.
Persons who are vaccinated against rubella may transiently
Rubella virus is a positive single-stranded ribonucleic acid excrete rubella virus from the pharynx, but they do not transmit
(RNA) virus belonging to the family Togaviridae and is the only the rubella to others, likely because the quantity of virus shed
member of the genus Rubivirus. Rubella (German measles) is an is small.
acute viral infection that can affect people in all age groups.
When acquired postnatally, it is characterized by a generalized Rubella infection confers lifelong protection in most people.
maculopapular rash, low-grade fever, and lymphadenopathy and However, despite persistence of specific immunity to rubella
resembles a mild case of rubeola (measles). Many infections with virus, reinfection can occur. The majority of reinfections are
rubella are very mild or even subclinical; however, it may cause asymptomatic. Rubella reinfection months to years after rubella
arthritis, especially in adolescent and adult females. When infec- vaccination has been observed and is more common among
tion occurs in the developing fetus, it has the potential to cause vaccinees than individuals who have experienced natural infec-
severe infection with resultant birth defects (congenital rubella tion. This may be because of lower concentrations of antibodies
syndrome [CRS]). No specific antiviral treatment is available in persons with vaccine-induced immunity than in those with
for rubella, and control is primarily through use of a live-viral natural immunity. Rubella reinfection during pregnancy has
vaccine administered during childhood. been documented to cause CRS in the fetus; however, this is an
extremely rare event.
GEOGRAPHIC DISTRIBUTION
In the prevaccine era, rubella occurred globally, with minor RISK FACTORS
epidemics every 6 to 9 years. Large-scale epidemics occurred at The age of an infected individual is an important determinant of
intervals of up to 30 years; the most recent major pandemic in severity of rubella, with children being more likely to have milder
the western world occurred in 1964. Since 1969, with availabil- disease than adults. In contrast, the fetus is at high risk of develop-
ity of rubella vaccine, no major epidemics have occurred in ment of serious sequelae if infected early in pregnancy.
countries with widespread use of the vaccine. The World Health
Organization (WHO) estimates that there are over 100,000 Rubella is only moderately contagious when compared with
cases of CRS annually, with most cases occurring in developing measles. Before the introduction of the rubella vaccine, only
nations in which rubella vaccination is not routinely used. 80% to 90% of adults were immune to rubella compared with
98% who were immune to measles. This allowed for a signifi-
PATHOGENESIS cant number of susceptible adults and thus the frequent occur-
Transmission of rubella virus is by droplets that are shed from rence of CRS. After introduction of the rubella vaccine, a
respiratory secretions of infected persons. Incubation for rubella significant decrease in the population of susceptible adults and
appears to be related to the size of the inoculum and ranges from the number of CRS cases has been observed.
12 to 23 days with an average of 18 days. Initial infection of the
nasopharyngeal epithelium is followed by lymphatic spread to CLINICAL FEATURES
the regional lymph nodes and transient viremia. Maximal Postnatal Rubella
viremia and viruria occur 10 to 17 days after infection. The rash Generally, postnatal rubella is a mild illness and the major clini-
usually appears 16 to 18 days after infection, with antibody cal manifestations are lymphadenopathy, which may last several
production being detected at the time of clearance of the weeks, and rash. The lymph nodes most commonly involved
viremia. Maximal viral transmission occurs from 5 days before include the posterior auricular, posterior cervical, and suboc-
through 6 days after the onset of the rash. cipital chains. Splenomegaly can occur rarely. Sometimes called
“3-day measles,” clinically the disease may resemble a mild case
Few data assessing the pathologic findings in postnatal of measles (rubeola). The rash of rubella begins on the face and
rubella are available. In contrast, extensive pathologic studies moves down the body and is maculopapular, but unlike measles
have been performed for CRS, though most were completed is not confluent and may desquamate during convalescence
before the availability of contemporary molecular techniques. (Figure 12-1). The rash may be absent in some cases, but the
Defects caused by CRS result from both specific cell damage presence and distribution of lymphadenopathy may suggest
and a decrease in the number of cells. the diagnosis. An enanthem consisting of petechial lesions of the
soft palate (Forschheimer spots) has been described with rubella,
Infants with congenital rubella infection shed large quantities but this is not diagnostic. The rash may be accompanied by mild
of the virus from body secretions for many months or years after coryza and conjunctivitis and usually lasts 3 to 5 days. Fever is

52 SECTION I╇ •â•‡ Vaccine-Preventable Diseases in Children and Adolescents

present but rarely lasts beyond the first day of rash. Arthritis survivors have no sequelae. The neurologic symptoms appear
and arthralgia have been reported in as many as one third of abruptly from day 1 to 6 after the rash and include headache,
adult women with rubella but is much less common in children vomiting, lethargy, nuchal rigidity, and generalized seizures
and in men. The arthritis tends to involve fingers, wrists, and often accompanied by encephalographic abnormalities. Cere-
knees and may be slow to resolve, lasting up to 1 month, but brospinal fluid is characterized by pleocytosis, mildly elevated
rarely becomes chronic. protein, and normal glucose concentrations.

In addition to measles, other diagnostic considerations Congenital Rubella Syndrome
include scarlet fever, roseola, parvovirus B19 infection, infec- The connection between maternal rubella infection and some
tious mononucleosis, toxoplasmosis, some enteroviral infec- birth defects was first described in 1941 by Gregg. Congenital
tions, Kawasaki disease, rheumatologic disorders, and allergic rubella infection can cause fetal death, premature delivery, and
reactions. an array of congenital defects. In general, the younger the fetus
when infected, the more severe the injuries observed. Infection
The majority of postnatal rubella cases resolve without prob- during the first 2 months of gestation has a 65% to 85% chance
lems. Hemorrhagic manifestations are an uncommon complica- of affecting the fetus with an outcome of multiple congenital
tion of rubella and may be secondary to thrombocytopenia and defects, spontaneous abortion, or both. Rubella during the third
vascular damage. Thrombocytopenia, which is more common month of gestation has been associated with a 30% to 35%
in children than in adults, may last from weeks to months and chance of developing a single defect, such as deafness or con-
may cause serious problems if bleeding occurs in vital areas (e.g., genital heart disease. Infection in the fourth month carries a
brain, kidney, or eye). Thrombocytopenic purpura has also been 10% risk of a single congenital defect, and this risk continues
reported. until 20 weeks of gestation.

Encephalitis and postinfectious encephalopathy are extremely Specific signs and symptoms of CRS can be classified as either
rare complications of rubella. Central nervous system involve- temporary (e.g., low birth weight), permanent (e.g., deafness), or
ment is more frequent in adults than in children, and most developmental (e.g., myopia) (Table 12-1). The most common
manifestations are growth retardation, deafness, cataracts or
glaucoma, congenital heart disease, and intellectual handicap.
The characteristic rash occurs in about 5% of cases and results
from dermal erythropoiesis; this has been called “blueberry
muffin syndrome” (Figure 12-2). CRS should not be considered
a static disease. Delayed manifestations include progressive
encephalopathy (which resembles subacute sclerosing panen-
cephalitis of measles), deafness, and endocrinopathies. The
development of insulin-dependent diabetes mellitus in late child-
hood has been observed in approximately 20% of individuals with
CRS. Autoimmune thyroid dysfunction has also been described.

Figure 12-1╇ Child with rubella rash. (Courtesy Centers for Disease DIAGNOSIS
Control and Prevention Public Health Image Library.) Because of the features and nonspecific nature of the illness,
both congenital and postnatal rubella infection can often be
difficult to diagnose clinically. Virus isolation from the throat,

Table 12-1╇ Features of Congenital Rubella TRANSIENT DEVELOPMENTAL

PERMANENT Low birth weight Hearing loss
Thrombocytopenic purpura Myopia
Hearing loss Hepatosplenomegaly Intellectual handicap
Cataract and microphthalmia Jaundice Pulmonary stenosis
Retinopathy Hepatitis Central language disorders
Patent ductus arteriosus Pneumonitis Diabetes mellitus
Pulmonary stenosis Lymphadenopathy Thyroid disorders
Intellectual handicap Seizures
Behavioral disorders Behavioral disorders
Central language disorders
Cryptorchidism
Inguinal hernia
Diabetes mellitus
Thyroid disorders

CHAPTER 12╇ •â•‡ Rubella 53

Figure 12-2╇ Congenital rubella syndrome and “blueberry TREATMENT
muffin” rash. No specific therapy for rubella is available, and because postna-
tal rubella is a mild illness, treatment is usually not indicated.
urine, synovial fluid, or other secretions is diagnostic. In utero Individuals with arthralgia or arthritis may need symptomatic
diagnosis of congenital rubella infection has been made by isola- treatment with rest and nonsteroidal antiinflammatory agents.
tion of the virus from amniotic fluid. However, viral culture may No treatment is available for infants with CRS.
take several weeks, making diagnosis retrospective. If viral
culture is considered, it is advisable to discuss this with the labo- PREVENTION AND CONTROL
ratory before obtaining the samples, as tissue culture cells may Infection Control
not routinely be available. More recently, molecular methods Hospitalized patients with rubella should be maintained with
such as reverse transcription–polymerase chain reaction (RT- procedures for droplet precautions to prevent the spread of
PCR) are preferred to virus isolation, as they are rapid and more infection to susceptible individuals. Individuals with postnatal
sensitive. rubella should be excluded from activities until 7 days after the
onset of rash. Infants with CRS should be considered infectious
Laboratory diagnosis of postnatal rubella is usually made until they are at least 1 year of age or have demonstrated two
serologically by detection of antibodies using hemagglutination negative viral cultures after 3 months of age.
inhibition (HAI) assay, which is considered to be the assay stan-
dard. More recently, latex agglutination or enzyme-linked Vaccination
immunosorbent assay (ELISA) techniques, which detect either Active immunization for rubella is with a live-attenuated vaccine
rubella immunoglobulin G (IgG) or IgM antibodies, have either as the trivalent measles, mumps, and rubella (MMR)
become available and are technically easier to perform. Acute vaccine or, in some countries, as a monovalent rubella vaccine.
postnatal infection may be diagnosed by demonstration of The rationale for the use of the vaccine is to prevent congenital
rubella IgM or a fourfold or greater increase in rubella IgG rubella by control of postnatal rubella. This approach has been
antibody titer between acute and convalescent serum specimens. very successful, and universal immunization of populations
Positive rubella IgM antibody tests are diagnostic of recent against rubella has led to a significant decrease in the incidence
primary postnatal infection, but they can also rarely have posi- of CRS. Immunization with rubella vaccine may cause a mild
tive results in patients who have reinfection with rubella virus. transient viremia. Although uncommon, the main complications
of vaccination are fever, lymphadenopathy, arthritis, and arthral-
A demonstration of rubella IgG is evidence of immunity to gia. Seroconversion after rubella vaccination is approximately
rubella. The true protective level of rubella IgG antibodies 95%, and booster injections of rubella vaccine are not routinely
against reinfection has not been determined. Thus revaccination indicated but may be advised for women of childbearing age
before pregnancy for women of childbearing age with low who have less than 40 international units per milliliter of IgG
rubella IgG titers (less than 40 international units per milliliter) antibodies. No cases of CRS have been attributed to rubella
is commonly recommended. vaccination; however, vaccination during pregnancy is contrain-
dicated. If a pregnant woman is inadvertently vaccinated with
For CRS in a newborn infant, serologic diagnosis can be rubella vaccine, termination of pregnancy is usually not recom-
made with serial testing showing a rise in the titer of rubella mended because of the very low theoretical risk of CRS.
IgG rather than the expected fall with passively acquired mater-
nal antibodies. The detection of rubella IgM antibodies in Administration of immunoglobulin after a known rubella
newborn infant serum is diagnostic of congenital infection, as contact is not advocated for prevention or modification of
this antibody does not cross the placenta. Congenital rubella rubella in susceptible pregnant women, as there is no evidence
infection can also be diagnosed by placental biopsy at 12 weeks that it protects the fetus against congenital infection.
with demonstration of rubella antigen or detection of RNA by
in situ hybridization or PCR. It may also be diagnosed by the EVIDENCE
presence of specific IgM in fetal blood, but this is usually not
detectable until at least 22 weeks of gestation. Gregg NM: Congenital cataract after German measles in the
mother, Trans Ophthalmol Soc Aust 3:35-46, 1941. This reference
provides the initial description of congenital rubella syndrome.
Horstmann DM: Rubella—the challenge of its control, J Infect
Dis 123:640-654, 1971. This reference contains a discussion of the
epidemiology data of rubella.
Horstmann DM, Liebhaber H, LeBouvier GL, et al: Rubella
reinfection of vaccinated and naturally immune persons
exposed in an epidemic, N Engl J Med 283:771-778, 1970. This
reference provides data about rubella reinfection observed during an
epidemic.

54 SECTION I╇ •â•‡ Vaccine-Preventable Diseases in Children and Adolescents

ADDITIONAL RESOURCES ders, pp 2271-2300. This resource provides an overview of the pathogenesis,
American Academy of Pediatrics: Rubella. In Pickering LK, Baker CJ, epidemiology, and diagnosis of rubella.
Cooper LZ, Alford CA Jr: Rubella. In Remington JS, Klein JO, Wilson CB,
Kimberlin DW, Long SS, eds: Red Book: 2009 Report of the Committee on Baker CJ, eds: Infectious diseases of the fetus and newborn infant, ed 6, Phila-
Infectious Diseases, ed 28, Elk Grove Village, Ill, 2009, AAP, pp 579-584. delphia, 2006, Elsevier, pp 893-926. This resource provides a review of the
This resource provides a brief overview of the diagnosis and prevention of rubella. diagnosis and management of congenital rubella.
Bellini WJ, Sever JL: Measles, mumps and rubella. In Specter S, Hodinka Gershon A: Rubella. In Mandell G, Bennett J, Dolin R, eds: Principles and
RL, Young SA, eds: Clinical virology manual, ed 3, Washington DC, 2000, practice of infectious diseases, Philadelphia, 2005, Elsevier, pp 2003-2006.
ASM Press, pp 501-512. This resource provides a review of the virology and This resource provides a summary of the diagnosis, management, and prevention
pathogenesis of rubella. of congenital and postnatal rubella.
Cherry JD: Rubella. In Feigin R, Cherry J, Demmler G, Kaplan S, eds:
Textbook of pediatric infectious diseases, ed 6, Philadelphia, 2009, WB Saun-

Varicella-Zoster Virus Infections 13

Sylvia H. Yeh

ABSTRACT respiratory droplets and direct contact) for 1 to 2 days before
the onset of rash until all lesions have crusted (usually 5 to 7
Varicella-zoster virus (VZV) causes primary varicella, a common days). For 24 to 48 hours before the rash, constitutional symp-
childhood illness called chickenpox. This virus establishes latency toms such as fever, malaise, anorexia, headache, and mild
and may reactivate later in life causing herpes zoster, commonly abdominal pain may be present. Cutaneous lesions develop first
called shingles. Although both varicella and zoster usually resolve on the scalp, face, or trunk and then spread to the lower portions
without event, significant complications may develop, even in of the body. Lesions start as erythematous macules, which then
healthy individuals. In the United States, widespread use of a develop into clear fluid–filled vesicles, often described as resem-
VZV vaccine in children has diminished the burden of disease; bling “dewdrops on a rose petal” (Figure 13-1). These lesions
however, worldwide VZV infections remain a significant cause are usually pruritic. After 24 to 48 hours the fluid becomes
of morbidity and mortality. cloudy, and eventually the lesions crust over. Lesions develop at
different intervals such that at any one time, lesions at multiple
GEOGRAPHIC DISTRIBUTION AND stages are present. In unimmunized children, primary infection
DISEASE BURDEN produces fewer than 300 lesions.
VZV is a member of the Herpesviridae family, and initial infec-
tion (varicella) is commonly called chickenpox. Varicella is present Primary varicella infection tends to be more severe in chil-
worldwide and is common in areas without routine vaccination. dren infected from a household contact (likely because of more
Seasonal epidemics occur with peaks in late winter and spring. intense exposure), as well as in adolescents and adults. Individu-
In the United States, before the introduction of routine vaccina- als with underlying skin conditions such as eczema, trauma, and
tion in 1996, approximately 4 million cases of chickenpox sunburn may have higher concentration of lesions at the afflicted
occurred each year. Most individuals were infected by adoles- sites.
cence, and the peak age of onset was 4 to 5 years of age. Attack
rates are lower in tropical areas, where a greater proportion of Although primary varicella usually resolves without event,
adolescents and adults are susceptible. healthy children rarely develop complications. Bacterial super-
infection (commonly with Staphylococcus aureus or Streptococcus
After chickenpox the virus remains latent in the dorsal root pyogenes) is the most common cause of morbidity in healthy
ganglia and can reactivate, causing herpes zoster, commonly children. These children may have impetigo-like lesions, cel-
referred to as shingles. Herpes zoster is infrequent in children, lulitis, lymphadenitis, subcutaneous abscesses, bacteremia,
but persons older than 60 years of age have an incidence of 7.2 osteomyelitis, or necrotizing fasciitis. Neurologic complications
to 11.8 cases per 1000 population per year, increasing with such as meningoencephalitis or cerebellar ataxia are typically
advancing age. immune mediated, and generally resolve without treatment.
Meningoencephalitis is associated with rapid recovery, whereas
RISK FACTORS cerebellar ataxia may take weeks to resolve. Other rare compli-
VZV is highly transmissible, with attack rates of nearly 90% cations include hepatitis, Reye’s syndrome, thrombocytopenia,
among susceptible household contacts but only 10% to 30% nephritis, and arthritis.
among susceptible persons with casual contact (e.g., classroom
or hospitals). Individuals with impaired immunity are at increased Herpes Zoster (Shingles)
risk for severe disseminated disease caused by VZV, including Herpes zoster manifests with an eruption of vesicular lesions in
complications of pneumonitis and hepatitis, which rarely may a sensory dermatomal distribution (Figure 13-2). Lesions may
lead to hepatic failure. Adolescents and adults, pregnant women, erupt over a course of 3 to 7 days, with complete resolution of
and neonates born within 2 days before or 4 days after onset of the rash usually within 2 weeks. The rash is pruritic and may be
maternal varicella are also at risk for progressive disease. associated with local pain and hyperesthesia. Zoster is unusual
in childhood, but when present the extent of the lesions is
CLINICAL FEATURES limited, with minimal neuropathic symptoms. Risks for develop-
Varicella (Chickenpox) ing zoster during childhood include having primary varicella
The incubation period for primary VZV infection ranges infection in the first year of life and immunocompromising
from 10 to 21 days. Once infected, persons are contagious (via conditions, especially those affecting cellular immunity (e.g.,
acquired immunodeficiency syndrome, chemotherapy, or pro-
longed high-dose steroids). In compromised hosts, zoster may
disseminate, with lesions occurring outside of the dermatome
and involvement of internal organs. Other complications of
zoster depend on the dermatome affected.

56 SECTION I╇ •â•‡ Vaccine-Preventable Diseases in Children and Adolescents

Approximately 80% to 85% of persons over 50 years of age with
zoster will develop postherpetic neuralgia. The pain can be quite
debilitating and may last for weeks to months. Early antiviral
treatment can ameliorate the severity and duration.

Figure 13-1╇ Child with chickenpox. Disease in High-Risk Hosts
In children with underlying immunodeficiency (congenital or
Figure 13-2╇ Zoster in ophthalamic branch. acquired), with hematologic malignancy, or receiving chemo-
therapy, primary varicella without antiviral therapy is often pro-
Some unique manifestations of herpes zoster occur when the gressive, manifesting with an extended period of new lesion
reactivated virus involves nerves of the head and neck. Ramsay- eruptions, pneumonitis, hepatitis, encephalitis, and/or dissemi-
Hunt syndrome occurs when VZV reactivates in the geniculate nated intravascular coagulation (DIC) (Figure 13-3). The mor-
ganglion and consists of unilateral facial palsy, pain and vesicles tality rate of untreated primary varicella in these hosts ranges
in the auditory canal, and lost of taste in the anterior two thirds from 7% to 17%. Presentations of potentially life-threatening
of the tongue. When zoster involves the ophthalmologic branch varicella include respiratory symptoms, hemorrhage into a
of the facial nerve (herpes zoster ophthalmicus) sight-threatening vesicular lesion (indicative of potential DIC), or severe abdomi-
keratitis may develop, necessitating emergent ophthalmologic nal or back pain.
consultation. Zoster involving the maxillary or mandibular
branch of the trigeminal nerve may cause intraoral lesions Adolescents and adults are at increased risk for having com-
affecting the palate, tonsillar fossa, tongue, and floor of the plicated primary varicella despite being otherwise healthy. In
mouth. this population the most common complication is varicella
pneumonia, which may manifest with cough, pleuritic chest
Pain preceding the rash, acute neuritis, and postherpetic neu- pain, and hemoptysis, with or without cyanosis. This occurs on
ralgia are more common with zoster in adults than in children. average 3 days (range of 1 to 6 days) after the onset of the rash.
Resolution usually occurs within 24 to 72 hours without antivi-
ral treatment, but varicella pneumonia can progress to respira-
tory failure.

Nonimmune pregnant women are at high risk for adverse
outcomes with primary varicella, with pneumonia being the
major cause of morbidity and mortality. In addition, severe
sequelae to the fetus including spontaneous abortion, fetal
demise, or premature delivery can occur. Rarely (less than 2%
of cases), maternal varicella can lead to congenital varicella syn-
drome, the severity of which is dependent on the gestational age
at the time of infection. Infection during the first 20 weeks
of gestation carries the highest risk of severe embryopathy.
Congenital varicella can affect the skin (cutaneous defects,
cicatricial scars, hypopigmentation, bullous lesions), the
extremities (hypoplastic limb, muscular atrophy and denerva-
tion, joint abnormality, absent or malformed digits), eye (cho-
rioretinitis, microphthalmia, anisocoria), the central nervous
system (CNS) (intrauterine encephalitis with cortical atrophy,
seizures, mental retardation), or other organs (e.g., hydrone-
phrosis or hydroureter and esophageal dilatation or reflux).

Varicella may also be severe for the neonate born within 2
days before or 4 days after the onset of maternal varicella, with
a mortality rate of 30% if untreated. This is a result of the lack
of transfer of maternal antibodies with the primary viremia.
Neonates born 5 days after the onset of maternal varicella are
not at increased risk for severe disease, as maternal antibodies
have had the opportunity to cross the placenta.

Herpes zoster in immunocompromised hosts can lead to
severe dermatomal infection, extension beyond the dermatome,
and dissemination. Pneumonia, hepatitis, encephalitis, and DIC
may result from hematogenous spread of reactivated virus.
Severely immunocompromised hosts such as those with human
immunodeficiency virus infection may have chronic or relapsing
cutaneous disease, retinitis, and CNS infections with or without
skin findings.

CHAPTER 13╇ •â•‡ Varicella-Zoster Virus Infections 57
Hemorrhagic chickenpox

Varicella pneumonia. Nodular
infiltrates in both lower lobes

Pleural hemorrhagic pocks

Pulmonary histology, low power. Alveoli filled
with fibrin, fluid, and cellular exudate.

High power: Mononuclear infiltrate in interstitium Multinucleated giant cell
and fibrin lining alveoli. with much fluid in alveolus.
Figure 13-3╇ Varicella pneumonia.

DIAGNOSTIC APPROACH Complete blood count and liver function tests may be indi-
In healthy individuals, primary varicella and zoster are clinical cated when disseminated disease is suspected; however, lympho-
diagnoses. In atypical presentations or in patients with other cytosis and mild hepatic enzymatic elevations are common in
possible causes of vesicular lesions, laboratory confirmation may uncomplicated disease. When neurologic complications exist,
be necessary to facilitate initiating appropriate therapy. Vesicu- mild cerebrospinal pleocytosis (<100 cells/mm3) with moderate
lar fluid or lesions can be tested for VZV by polymerase chain protein elevation (<200╯mg/mL) may be present. Patients with
reaction, direct fluorescent antibody (DFA), or tissue culture. uncomplicated zoster may also have cerebrospinal fluid
DFA is the most commonly available test and offers better sen- pleocytosis.
sitivity than a Tzanck smear. Serologic tests for VZV-specific
antibodies are often not useful in the acute phase, because CLINICAL MANAGEMENT
immune globulin M (IgM) anti-VZV antibodies are inconsis- For most healthy children, symptomatic therapy for chickenpox
tently present. If present, IgM anti-VZV antibodies indicate and herpes zoster is all that is required. Antiviral therapy is
current or recent infection. Acute and convalescent serum speci- recommended for adolescents, adults, immunocompromised
mens may demonstrate a rise in IgG VZV antibodies and may hosts, and individuals with disseminated disease but is not
improve sensitivity.

58 SECTION I╇ •â•‡ Vaccine-Preventable Diseases in Children and Adolescents

routinely recommended for healthy children. The optimal PREVENTION AND CONTROL
timing of therapy is within the first 72 hours of the onset of the Individuals with varicella should be considered contagious until
rash. Acyclovir is the most commonly used medication, and the all lesions are crusted. Hospitalized patients should be main-
prodrug valacyclovir may be used when oral administration is tained with airborne precautions. Children should be excluded
an option (Table 13-1). from school or daycare. Persons with zoster do not need to be
isolated if the lesions can be covered. Healthcare workers
Aspirin should not be used during varicella infections owing without evidence of immunity who have been exposed to vari-
to the risk of Reye’s syndrome. Symptomatic relief of fever with cella should not be in the hospital setting from days 8 to 21 after
acetaminophen may be undertaken with careful attention to exposure or for 28 days if they received VariZIG.
dosage. Ibuprofen use has been associated with increased rates
of necrotizing fasciitis in isolated reports, and therefore this Active Immunoprophylaxis: Vaccination
drug should be used cautiously. After weighing risks and bene- Currently in the United States a live-attenuated varicella vaccine
fits, antihistamines and topical calamine lotion may be used for (Varivax, Merck & Co., Inc.) is recommended for use in all
pruritus treatment. Should bacterial superinfection develop, children; a two-dose regimen is used, with vaccine given at 12
antibiotics that include coverage for group A Streptococcus and S. to 15 months and 4 to 6 years of age. After licensure in 1995,
aureus (including methicillin-resistant S. aureus) based on local widespread vaccination at 12 to 15 months of age led to a dra-
epidemiology and sensitivity patterns should be instituted. matic decline in primary varicella. However, from 2001 to 2005,
breakthrough cases of chickenpox began to occur, peaking in
For zoster in all age groups, acyclovir reduces the develop- children aged 7 to 10 years. Although most of these cases were
ment of new lesions from over 1 week to less than 3 days. In mild, typically with fewer than 50 lesions, they posed a risk to
adults, acyclovir treatment may also reduce the likelihood of the children and their susceptible contacts. Therefore in 2007
developing acute neuritis. the addition of the second dose of vaccine at 4 to 6 years of age
was recommended, after postlicensure data suggested a reduc-
PROGNOSIS tion of breakthrough disease in this preadolescent age group.
For healthy children with primary varicella, the prognosis is
good with complete recovery. Although most lesions heal Because it is a live virus, VZV vaccine is contraindicated in
without scarring, many children have one or two scars, typically persons with altered immunity and in pregnant women. Vari-
on the face, as these earlier lesions may involve deeper layers of cella vaccines should not be given to persons on high-dose
the skin. For adolescents, adults, pregnant women, and immu- immunosuppressive therapy including systemic steroids (≥2╯mg
nocompromised hosts, there is greater risk of morbidity and of prednisone per kilogram or total ≥20╯mg of prednisone
mortality, but this may be reduced with prompt antiviral therapy. per day or equivalent for ≥2 weeks). In 2009, no combination
varicella-containing vaccines were available in the United States.
After herpes zoster, most children do not incur long-term A combination varicella with measles, mumps, and rubella
sequelae. Adults, however, may experience postherpetic neural-
gia, which may be debilitating and may require treatment tar-
geting pain control.

Table 13-1╇ Recommendations and Doses of Acyclovir for Varicella

RECOMMENDATION DOSAGE TIMING
Intravenous acyclovir: Initiate as soon as possible after
Indicated: • <1 year old: 30╯mg/kg/day divided
• Malignancy, bone marrow, or organ transplant, initial lesions
q8h, infusion to run over 1 hour Treat for 7 days or until 48 hours
high-dose steroid therapy • ≥1 year old: 1.5╯g/m2/day divided
• Congenital T-lymphocyte immunodeficiency after no new lesions
• HIV infection q8h, infusion to run over 1 hour
• Neonatal varicella (maternal varicella within 5 Initiate within 24 hours after initial
Oral acyclovir†: lesions appear
days after or 2 days before delivery) • 80╯mg/kg/day divided into four
• Associated pneumonia or encephalitis Treat for 5 days
Optional: doses (max 800╯mg/dose)
• Chronic mucocutaneous disorders
• Chronic diseases that may be exacerbated by

acute VZV infection*
• Healthy persons >12 years of age or secondary

household contacts

HIV, Human immunodeficiency virus.
*These conditions may include cystic fibrosis, other pulmonary disorders, diabetes mellitus, disorders requiring chronic salicylate therapy or
intermittent corticosteroid therapy.
†Valacyclovir may be used.

CHAPTER 13╇ •â•‡ Varicella-Zoster Virus Infections 59

Box 13-1╇ Situations for Consideration of should be considered are listed in Box 13-1. VariZIG should be
Postexposure Antibody Prophylaxis administered within 96 hours of the exposure. If VariZIG is not
available, intravenous immune globulin (IVIG) may be given to
Candidates for VariZIG with Significant Exposure high-risk individuals postexposure, though the amount of
• Susceptible immunocompromised children varicella-specific antibody in different preparations of IVIG
• Susceptible pregnant women varies. Although no longer available, varicella-zoster immune
• Newborn infant whose mother had onset of chicken pox globulin protected against development of primary varicella or
attenuated the course, when given within 48 hours of exposure.
within 5 days before delivery or within 48 hours after
delivery CHEMOPROPHYLAXIS
• Hospitalized preterm infant (≥28 weeks gestation) of Prophylactic use of acyclovir given within 7 days after exposure
mother without evidence of varicella immunity may help prevent or attenuate varicella disease for susceptible
• Hospitalized preterm infant (<28 weeks gestation or immunocompromised individuals when active or passive immu-
≤1000╯g birth weight), regardless of maternal immunity nization is not possible.
status
EVIDENCE
Situations Qualifying for Significant Exposure
• Residing in the same household Coffin SE, Hodinka RL: Utility of direct immunofluorescence
• Face-to-face indoor play lasting at minimum 5 minutes and virus culture for detection of varicella-zoster virus in skin
lesions, J Clin Microbiol 33:2792-2795, 1995. This reference
(some experts use 1 hour) provides comparative data for the DFA and culture of VZV.
• Hospital varicella exposure: same 2- to 4-person bedroom Kuter B, Matthews H, Shinefield H, et╯al: Ten-year follow-up
of healthy children who received one or two dose injections of
or adjacent beds in a large ward varicella vaccine, Pediatr Infect Dis J 23:132-137, 2004. This
• Hospital zoster exposure: intimate contact (e.g., touching reference provides data about the postlicensure follow-up of clinical
trial participants for varicella vaccine and incidence of breakthrough
or hugging) a person considered to be contagious varicella.

vaccine is available in the European Union and is being evalu- ADDITIONAL RESOURCES
ated for licensure in the United States. American Academy of Pediatrics (AAP): Varicella-zoster infections. In Pick-

In 2006, Zostavax (Merck & Co., Inc.) was licensed for adults ering LK, Baker CJ, Kimberlin DW, Long SS, eds: Red Book: 2009 Report
60 years of age and older to reduce the risk of zoster and of the Committee on Infectious Diseases, ed 28, Elk Grove Village, Ill, 2009,
expressly to prevent postherpetic neuralgia (67% efficacy in AAP, pp 714-727. This resource provides an overview of the diagnosis, treat-
preventing postherpetic neuralgia and 73% efficacy in prevent- ment, and prevention of VZV infections.
ing postherpetic pain lasting more than 6 months). Zostavax Arvin A: Varicella-zoster virus. In Long SS, Pickering LK, Prober CG, eds:
differs from Varivax in that it contains up to a 14 times greater Principles and practice of pediatric infectious diseases, ed 3, Philadelphia, 2008,
amount of live-attenuated VZV. Zostavax is contraindicated in Churchill Livingstone, pp 1021-1029. This resource provides a review of the
persons with primary or acquired immunodeficiency. virology, diagnosis, and treatment of VZV infections.
Harpaz R, Ortega-Sanchez IR, Seward JF; Advisory Committee on Immu-
Postexposure Prophylaxis nization Practices (ACIP) Centers for Disease Control and Prevention
(CDC): Prevention of herpes zoster: recommendations of the Advisory
VACCINATION Committee on Immunization Practices (ACIP), MMWR Recomm Rep
VZV vaccine can be given to susceptible individuals after expo- 57:1-29, 2008. This resource provides recommendations for the prevention of
sure to varicella, if not otherwise contraindicated. Postexposure herpes zoster.
vaccination should be given within 3 days but can be given up Marin M, Güris D, Chaves SS, et al; Advisory Committee on Immunization
to 5 days after exposure and may reduce the likelihood of disease Practices, Centers for Disease Control and Prevention (CDC): Preven-
or its severity. tion of varicella: recommendations of the Advisory Committee on Immu-
nization Practices (ACIP), MMWR Recomm Rep 56:1-39, 2007. This
PASSIVE IMMUNOPROPHYLAXIS resource provides recommendations for the prevention of varicella infections.
VariZIG, an investigational high-titer VZV immune globulin, is
available in the United States through a new drug expanded
access program. High-risk individuals for whom VariZIG

Hepatitis A Infection 14
and Prevention

Dean A. Blumberg

ABSTRACT hepatitis A have occurred in the western United States, but this
geographic variation is no longer present.
Hepatitis A infection is one of the most commonly reported
vaccine-preventable diseases in the United States. Clinical RISK FACTORS FOR INFECTION
illness, characterized by fever, malaise, jaundice, and nausea, HAV is most commonly contracted via ingestion. After a brief
caused by hepatitis A virus (HAV) is similar to hepatitis caused viremia, the primary site of replication is the liver, and the virus
by other viral pathogens. Although most cases of hepatitis A are is shed into the bile with subsequent passage to the intestines
self-limited, fulminant hepatitis resulting in death may occur. and feces. The highest concentration of virus in the stool, and
Widespread routine childhood vaccination against hepatitis A thus the period of greatest infectivity, occurs during the 2 weeks
has resulted in an impressive decrease in hepatitis A infections, before onset of symptoms. Infected stools result in transmission
with a notable diminishment of previous racial or ethnic and to others, through either ingestion of contaminated water or
geographic disparities. food or person-to-person contact. An outbreak of hepatitis A
infection can be caused by a combination of these factors—for
ETIOLOGY example, contaminated food may infect restaurant patrons and
Hepatitis A infection is caused by HAV, a ribonucleic acid employees, who then are the source for further transmission
(RNA) virus in the genus Hepatovirus within the family Picor- into their larger communities.
naviridae. HAV is an icosahedral-shaped nonenveloped virus
that replicates in the cytoplasm. The genome consists of single- Children are most at risk for infection. They are at increased
stranded RNA that encodes information for 11 individual pro- risk for acquiring infection from fecal oral pathogens, including
teins. There are four closely related genotypes of human HAV HAV, because they have limited proficiency with personal
strains but only one major serotype. hygiene and toileting habits and because of their propensity to
explore the environment with their mouths. Because most
GEOGRAPHIC DISTRIBUTION AND infected children have asymptomatic or unrecognized infection,
MAGNITUDE OF DISEASE BURDEN they can play a major role in community outbreaks.
Approximately 1.5 million clinical cases of hepatitis A occur
each year worldwide, and the prevalence of antibodies (indicat- Epidemics may occur locally or nationwide, often related to
ing previous infection) in the population can vary from 15% to food-borne outbreaks. With more frequent international travel
almost 100% in some countries. Nordic countries show the and global food production, hepatitis A can readily spread
lowest prevalence of infection, approximately 15%. In other beyond the regions of known high endemicity to any area of the
parts of Europe, Australia, Japan, and the United States, the world. In communities with high rates of hepatitis A, most
seroprevalence of antibodies to HAV is 30% to 70% in adults. people are infected before reaching young adulthood. In the
In developing areas of the world, most adults show serologic United States, communities with high rates of infection include
evidence of past infection (see Figure 67-1). Alaskan Native, American Indian, and selected Hispanic,
migrant, and religious communities, although in recent times
In the United States the incidence of hepatitis A has reached these elevated rates are less pronounced, likely because of wide-
historic lows since the late 1990s, when hepatitis A vaccines spread vaccination (Figure 14-2). In communities with low rates
became more widely used. However, hepatitis A remains one of of hepatitis A, most infections occur in school-age children,
the most frequently reported vaccine-preventable diseases in the adolescents, and young adults.
United States, with about 22,700 cases representing 38% of all
hepatitis cases (5-year average from all routes of transmission) HAV may also be transmitted through sexual contact and in
reported annually. In general, the incidence of hepatitis A in the rare instances through transfusion of blood products collected
United States has been cyclic, with nationwide increases occur- from donors during the viremic period. Adults most at risk
ring every 10 to 15 years. The last peak occurred in 1995, with for infection with hepatitis A include household and sexual
the decline in rates likely attributable to wider routine use of contacts of infected individuals, men who have sex with men,
hepatitis A vaccines (Figure 14-1). Historically, higher rates of individuals in personal contact with a child who attends a
daycare center, illicit drug users, and individuals traveling to
countries where hepatitis A is common. In the United States,

CHAPTER 14╇ •â•‡ Hepatitis A Infection and Prevention 61

180,000 Reported acute cases clay-colored stools, and/or dark-colored urine. Pruritus is less
160,000 Estimated acute cases common. Diarrhea is common in young children (60%) but
140,000 infrequent in adults. Physical findings can include jaundice,
Number of cases 120,000 abdominal tenderness, hepatomegaly, or splenomegaly (Figure
100,000 14-3).

80,000 Symptoms and severity of illness correlate inversely with age.
60,000 In children younger than 6 years of age, 70% of infections are
40,000 asymptomatic, and less than 10% of patients will have jaundice.
20,000 Older children and adults usually develop symptoms. Generally,
more than 75% of infected adults are symptomatic, with 50%
0 to 85% exhibiting jaundice.

12221211111111909999990099909890909088988060024220448686 COMPLICATIONS
No chronic or long-term infection is associated with hepatitis
Year A; however, prolonged or relapsing symptoms for up to 9
months occur in approximately 10% of infected individuals.
Figure 14-1╇ Incidence of hepatitis A by year, United States, Infrequent complications of hepatitis A include pancreatitis,
1980 to 2007. (Data from Centers for Disease Control triggering autoimmune hepatitis, and cholestatic hepatitis,
and Prevention. Available at: www.cdc.gov/hepatitis/HAV/ which is characterized by fever, pruritus, and prolonged elevated
StatisticsHAV.htm#section3. Accessed February 6, 2010.) bilirubin that can persist for months.

60 HAV is a rare but important cause of fulminant hepatitis,
manifested by increasingly severe jaundice, and deterioration in
55 American Indian/ liver function. This may result in hepatic encephalopathy and
50 Alaska Native coagulopathy, particularly in older adults and individuals with
45 Asian/Pacific Islander chronic liver disease.
Hispanic
Incidence* 40 Black, non-Hispanic DIAGNOSTIC APPROACH
35 White, non-Hispanic Clinically, infection with HAV may be indistinguishable from
30 other causes of hepatitis. Hepatitis A can be differentiated from
other types of viral hepatitis only through laboratory testing.
25 Serologic testing detects immunoglobulin M antibody to HAV
(IgM anti-HAV) starting 5 to 10 days before symptom onset,
20 and these antibodies may be detectable for up to 6 months after
infection. Immunoglobulin G antibody to HAV (IgG anti-HAV)
15 also appears early in the course of infection and is detectable for
life, denoting immunity to hepatitis A infection.
10
Other laboratory abnormalities include elevated liver
5 enzymes. Serum alanine aminotransferase (ALT), aspartate ami-
notransferase (AST), and γ-glutamyltranspeptidase (GGT) con-
0 1990 1992 1994 1996 1998 2000 2002 2004 2006 centrations are elevated before symptom onset, and bilirubin
elevation follows. ALT and AST elevations usually range from
*Per 100,000 population. Year 200 to 5000 international units per liter and peak at 3 to 10 days
after onset of symptoms, though these findings are not specific
Figure 14-2╇ Incidence of acute hepatitis A by race or ethnicity for HAV infection. Generally with HAV infection, elevated liver
and year, United States, 1990 to 2007. (Data from function test findings return to normal by 2 to 3 months after
Centers for Disease Control and Prevention. Available at: the onset of illness. Patients with acute HAV infection usually
www.cdc.gov/mmwr/preview/mmwrhtml/ss5803a1.htm. have a mild lymphocytosis, and occasional atypical mononuclear
Accessed February 6, 2010.) cells may be seen.

85% of travel-related cases are associated with travel to Central Although polymerase chain reaction (PCR) testing of serum
and South America. Of note, a specific risk factor cannot be and stool for HAV is a promising diagnostic tool, such tests are
determined for more than half of all individuals who acquire not standardized and are not widely available. Liver biopsy is
hepatitis A infection. generally not indicated for HAV infection. However, when per-
formed, typical pathology of viral hepatitis is observed, includ-
CLINICAL FEATURES ing hepatocellular necrosis, inflammatory cell infiltration, and
HAV can cause symptomatic or asymptomatic infection. The regeneration of hepatocytes.
necessary infectious dose is not known but presumably is 10 to
100 viral particles. Clinical features usually appear after an Other diagnostic considerations for HAV infection include
average incubation period of 28 days, with a range of 15 to 50 other viral agents, most commonly hepatitis B and C, but also
days. Symptomatic infection is characterized by a relatively
acute onset of symptoms that may include jaundice, weakness,
fatigue, myalgia, anorexia, nausea, abdominal pain, fever,

62 SECTION I╇ •â•‡ Vaccine-Preventable Diseases in Children and Adolescents

Infectious Fever
hepatitis (A)
incubation period Abdominal tenderness
15–50 days Anorexia,
Portal of entry nausea, vomiting
mainly oral but
also parenteral

Preicteric Icteric phase
phase Children—usually 10–12 days
4–7 days Adults—usually 15–30 days or more

Figure 14-3╇ Clinical course of hepatitis A.

Epstein-Barr virus (EBV), cytomegalovirus (CMV) and other years of age and older. In the United States, more than 70% of
enteroviruses, and bacterial infections (e.g., leptospirosis). Toxic deaths from hepatitis A occur in individuals 50 years of age and
hepatitis caused by prescribed medications that are metabolized older.
by the liver (e.g., isoniazid, acetaminophen), alcohol, illicit drugs
or poisons (e.g., carbon tetrachloride), and nonspecific injury PREVENTION AND CONTROL
(e.g., ischemia or shock) may also be considered. Hepatitis A vaccine provides the best protection against hepati-
tis A infection, but other important preventative measures
CLINICAL MANAGEMENT include improved sanitation and meticulous personal hygiene
There is no specific antiviral treatment for patients with hepa- practices, such as good hand washing and proper food-handling
titis A. Supportive care is the mainstay of treatment. Alcohol techniques.
avoidance is recommended during the acute stage. No other
dietary restrictions are recommended. Patients are encouraged Hepatitis A Vaccines
to monitor their energy level and increase activities judiciously. The first hepatitis A vaccine was licensed in the United States
Medications that might cause liver damage or are metabolized in 1995. Vaccine guidelines have evolved over the years from
hepatically should be used with caution (Figure 14-4). Patients target-group recommendations (i.e., vaccine for specific ages,
with prolonged jaundice and cholestatic hepatitis may benefit communities, and groups with risk factors) to the current rec-
from a short course of rapidly tapered corticosteroids, resulting ommendations for routine childhood vaccination.
in improved symptoms and resolution of disease.
The hepatitis A vaccines currently available in the United
In general, most individuals infected with HAV can be States are prepared from purified, cell culture–grown HAV that
managed as outpatients. Because nausea and vomiting may lead is formalin-inactivated and are licensed for intramuscular use
to inadequate fluid intake, patients should be monitored for in persons 1 year of age and older. HAV vaccines are highly
dehydration. If dehydration occurs, intravenous fluid adminis- immunogenic, resulting in excellent efficacy (≥94% efficacy
tration and hospitalization may be necessary. Infected individuals starting 2 weeks after one dose and >99% 1 month after the
with signs or symptoms of acute liver failure require manage- second dose). There are two monovalent formulations, one for
ment in an intensive care setting for appropriate monitoring of children 18 years of age or younger and one for adults, available
liver function, as well as supportive care. Liver transplantation from two manufacturers (Havrix from GlaxoSmithKline and
may be considered for patients with fulminant hepatic failure. Vaqta from Merck & Co.). These vaccines are given in a two-
dose series consisting of an initial dose with a second dose 6 to
PROGNOSIS 18 months later. The duration of protection after vaccination is
Most infected individuals recover within 2 months. Hepatitis A not known but, based on surveillance data, is predicted to be at
does not cause chronic infection. Relapsing hepatitis, in which least 10 years. Adverse events after immunization are generally
exacerbations may occur weeks or months after apparent recov- mild local reactions and self-limited. Hepatitis A vaccines are
ery, occur in 10% to 15% of cases. Fulminant hepatitis is rare contraindicated in those with a severe allergic reaction to a
but may result in death. The overall case fatality rate of hepatitis previous dose of hepatitis A vaccine or known allergy to any of
A is 0.8% in the United States, and it rises to 2.6% in adults 60 the vaccine components.

CHAPTER 14╇ •â•‡ Hepatitis A Infection and Prevention 63

Hepatitis A is a liver infection caused by No specific treatment exists. Most people
hepatitis A virus. The most common source can be cared for at home. Proper rest
is infected food handlers who don’t wash for several days after diagnosis is
their hands well after using the bathroom. important. Eat a well-balanced diet.
Often, people don’t know how they got
infected.

Liver with The main symptom
hepatitis is jaundice (yellow skin
and whites of the eyes).

Others symptoms Abdominal pain
Pale or clay-colored
stools, dark urine

Flu-like Make sure you wash your
symptoms hands if you have hepatitis
or care for someone who
Itching does, if you’re a restaurant
worker, or if you work in a
daycare center and change
diapers.

Your doctor will examine Don’t drink alcohol or anything
you and do a blood test to that may harm the liver.
find antibody to the virus.

Figure 14-4╇ Management of hepatitis A.

Hepatitis A vaccine is also available in combination with factor concentrates, those with chronic liver disease, and anyone
hepatitis B vaccine. The combined hepatitis A–hepatitis B wishing to be immunized.
vaccine is licensed in the United States for those 18 years of age
and older and is administered as either a three- or four-dose Hepatitis A vaccine is preferred for preexposure protection
series. in all populations unless contraindicated and for postexposure
prophylaxis for most individuals aged 1 through 40 years.

Hepatitis A Vaccine Recommendations Preexposure Prophylaxis with
Since 2005 in the United States, routine childhood vaccination Immune Globulin
has been recommended beginning at 1 year (12 to 23 months) Intramuscular immune globulin (IG) confers >85% protection
of age. Vaccination is also recommended for unvaccinated indi- against HAV infection if administered before or within 2 weeks
viduals 1 year of age and older who are traveling to a hepatitis of HAV exposure. Preexposure prophylaxis with IG should be
A–endemic area, all individuals 1 year of age and older during provided to susceptible individuals traveling to an area with an
an outbreak, men who have sex with men, illicit drug users, increased rate of hepatitis A and in whom use of HAV vaccine
those with occupational exposure, individuals receiving clotting is not permissible. Administration of hepatitis A vaccine is

64 SECTION I╇ •â•‡ Vaccine-Preventable Diseases in Children and Adolescents

generally recommended; however, there are situations in which Postexposure Prophylaxis
prophylaxis with IG instead of, or in addition to, the hepatitis Postexposure prophylaxis should be given to persons who have
A vaccine is appropriate. Older adults, immunocompromised recently been exposed to hepatitis A if they have not been previ-
persons, and persons with chronic liver disease or another ously vaccinated. They should receive either hepatitis A vaccine
chronic medical condition may not have a brisk immune or IG (0.02╯mL/kg) as soon as possible, within 2 weeks of expo-
response to hepatitis A vaccine. If these individuals are planning sure. Hepatitis A vaccine is preferred if they are healthy and 12
to depart in less than 2 weeks, they should receive IG in addition months to 40 years of age. For persons over 40 years of age, IG
to hepatitis A vaccine (simultaneously, at separate anatomic is preferred because of the lack of hepatitis A vaccine efficacy
sites). In addition, travelers with a contraindication to hepatitis data for older age groups in this situation and the possibility of
A vaccine should receive a single dose of IG. The dose depends a more severe clinical course of hepatitis A in older adults. For
on the anticipated length of exposure: 0.02╯mL/kg provides children younger than 12 months old, immunocompromised
protection for up to 3 months; if the travel period exceeds 2 persons, persons with chronic liver disease, and those with a
months, 0.06╯mL/kg should be administered (this dose must be vaccine contraindication, IG should be used.
repeated if the travel period exceeds 5 months). Because hepa-
titis A vaccine is not licensed for children younger than 12 ADDITIONAL RESOURCES
months of age, an appropriate dose of IG is recommended for American Academy of Pediatrics (AAP): Hepatitis A. In Pickering LK, Baker
this age group.
CJ, Long SS, McMillan JA, eds: Red Book: 2009 Report of the Committee
EVIDENCE on Infectious Diseases, ed 28, Elk Grove Village, Ill, 2006, AAP, pp 329-336.
This resource provides an overview of the diagnosis, treatment, and prevention
Advisory Committee on Immunization Practices (ACIP), Fiore of HAV infections.
AE, Wasley A, Bell BP: Prevention of hepatitis A through Centers for Disease Control and Prevention (CDC): Hepatitis A information
active or passive immunization: recommendations of the for health professionals. Available at: www.cdc.gov/hepatitis/HAV/
Advisory Committee on Immunization Practices (ACIP), index.htm. Accessed December 22, 2009. This resource provides an overview
MMWR Recomm Rep 55:1-23, 2006. This reference provides of hepatitis A for medical professionals.
information about the efficacy of hepatitis A vaccine and Centers for Disease Control and Prevention (CDC): Update: prevention of
immunoglobulin for preventing hepatitis A infections. hepatitis A after exposure to hepatitis A virus and in international travel-
ers. Updated recommendations of the Advisory Committee on Immuni-
Daniels D, Grytdal S, Wasley A; Centers for Disease Control zation Practices (ACIP), MMWR Morb Mortal Wkly Rep 56:1080-1084,
and Prevention (CDC): Surveillance for acute viral hepatitis— 2007. This resource provides the recommendations for prevention of HAV
United States, 2007, MMWR Surveill Summ 58:1-27, 2009. infections.
This reference provides the most recent data about viral hepatitis, Gilroy RK, Mukherjee S: Hepatitis A. Available at: http://
including hepatitis A in the United States. emedicine.medscape.com/article/177484-overview. Accessed February 6,
2010. This resource provides an update about HAV infection and prevention.
Fiore AE: Hepatitis A transmitted by food, Clin Infect Dis U.S. Food and Drug Administration (FDA): Hepatitis A virus. In: Bad
38:705-715, 2004. This reference provides data about food-borne bug book: foodborne pathogenic microorganisms and natural toxins
hepatitis A infections. handbook. Available at: www.fda.gov/Food/FoodSafety/FoodborneIllness/
FoodborneIllnessFoodbornePathogensNaturalToxins/BadBugBook/
ucm071294.htm. This resource provides an overview of food-related hepatitis
A infections.

Hepatitis B Infection 15

Dean A. Blumberg

ABSTRACT horizontally. The virus is present in all body fluids, except stool,
but only salvia, semen, and serum have been proven infectious.
Globally, hepatitis B infection is one of the most common com- Infants are most often infected from exposure to blood during
municable diseases. Acute hepatitis B may be asymptomatic or the birth process to an infected mother. Horizontal transmission
cause clinical illness similar to infections caused by other hepa- is less well defined but appears to occur rarely in households
totropic viruses (hepatitis A to E). Most acute infections resolve where one or more members have chronic infection. Other risk
without sequelae; however, progression to chronic infection factors for infection include high-risk sexual activity (e.g., mul-
may occur. The risk for developing chronic infection is inversely tiple partners or traumatic contact), injection drug use (IDU),
related to age at the time of acquisition of infection. The main and men who have sex with men. In adolescents 12 to 21 years
morbidity and mortality from hepatitis B occur secondary to of age, high-risk sexual activity and IDU are the most commonly
chronic hepatitis B infection, which may result in cirrhosis or identified risk factors; additional factors are homelessness and
hepatocellular carcinoma. Treatment of acute hepatitis B infec- being a runaway. Even after intensive investigation, up to 40%
tion is primarily supportive. Children and adolescents with of patients with acute hepatitis B infection have no identifiable
chronic hepatitis B infection should undergo routine monitor- risk factors.
ing for disease progression and to determine appropriate treat-
ment initiation. Treatment includes antiviral agents and Many international adoptees are from geographic areas with
interferon and is usually managed by pediatric liver specialists. high prevalence of hepatitis B infection. Because children may
Hepatitis B is preventable with vaccination, which is universally have few or no symptoms with hepatitis B infection, all inter-
recommended for infants in most industrialized nations as well nationally adopted children should be screened.
as in many developing areas.
CLINICAL FEATURES
ETIOLOGY Acute Infection
Hepatitis B virus is a member of the Hepadnaviridae family. The The incubation period is generally 3 months but ranges from
virus contains partially double-stranded deoxyribonucleic acid 6 weeks to 6 months. The clinical features of acute hepatitis
(DNA) and hepatitis B core antigen (HBcAg), surrounded B infection depend partly on age. The manifestations of
by hepatitis B surface antigen (HBsAg). Humans are the only infection range from asymptomatic, mild nonspecific symptoms
known host, and people with chronic hepatitis B infection are (i.e., flulike illness), clinical hepatitis with jaundice, to fulminant
the primary reservoir. hepatitis, which may lead to hepatic failure and death.
Acquisition of horizontal infection at a younger age usually
GEOGRAPHIC DISTRIBUTION AND results in milder illness or may even be asymptomatic, whereas
MAGNITUDE OF DISEASE BURDEN older children and adults are more likely to be symptomatic.
Worldwide, more than 350 million individuals are infected with Acute hepatitis B is usually asymptomatic in children
hepatitis B virus, and 5% of the world’s population has chronic younger than 1 year of age (<1% develop symptoms).
hepatitis B infection. The highest prevalence of hepatitis B About 10% of children 1 to 4 years of age will be symptomatic,
occurs in Asia (particularly in China and Taiwan), Africa, the and this increases to about 40% for older children and
Amazon basin, Greenland, and North America among Native adults.
North Americans in Canada and Alaska. The Centers for
Disease Control and Prevention (CDC) estimate that over 1 Clinical illness from hepatitis B is similar to hepatic infection
million U.S. residents have chronic hepatitis B infection, with caused by other hepatotropic viral pathogens. Onset is generally
2000 to 4000 deaths annually. Since 1990 the incidence of hepa- insidious with nonspecific signs and symptoms such as nausea,
titis B infection has declined in all age groups in the United vomiting, abdominal pain, fever, malaise, headache, and
States, with the largest decline (approximately 98%) occurring decreased appetite (Figure 15-1). Dark urine appears before
in children younger than 15 years of age, largely attributable to the onset of jaundice. Jaundice is generally present for 1 to 3
use of hepatitis B vaccination. weeks and is associated with abdominal pain and hepatomegaly.
Light or gray stools may be present. Recovery is gradual,
RISK FACTORS FOR INFECTION and fatigue and malaise usually resolve within a few weeks or
Hepatitis B is transmitted parenterally (e.g., by needlestick or months.
sharing of needles), perinatally, sexually, and less commonly
In pediatric age groups, extrahepatic manifestations may
include glomerular nephritis, serum sickness, arthralgias and
arthritis, and rashes such as urticaria and papular acrodermatitis
(Gianotti-Crosti).

66 SECTION I╇ •â•‡ Vaccine-Preventable Diseases in Children and Adolescents

Acute form

Serum hepatitis (B) Infectious Fever
incubation period hepatitis (A)
incubation period
40–180 days 15–50 days Leukopenia
Portal of entry Portal of entry
mainly oral but Abdominal tenderness
parenteral also parenteral Anorexia,
or sexual
nausea, vomiting

Preicteric phase Icteric phase
4–7 days Children—usually 10–12 days
Adults—usually 15–30 days or more

Subacute fatal form

Visceral surface of liver Cut surface of liver
in subacute (nodular)
fatal viral hepatitis
Figure 15-1╇ Hepatitis B clinical presentation.

Chronic Infection recent acute infection, although false-positive assay results may
Chronic hepatitis is defined as persistence of HBsAg in occur. The presence of hepatitis E antigen (HBeAg) is a marker
serum for at least 6 months or the presence of HBsAg in a of increased infectivity in those with acute or chronic infection;
person negative for immunoglobulin M (IgM) antibodies to antibody to HBeAg (anti-HBe) may be detected after acute or
HBcAg. chronic infection. Hepatitis B vaccination elicits only anti-HBs
antibodies.
Chronic infection may cause no symptoms or may result in
chronic active hepatitis and cirrhosis (Figure 15-2). Individuals Polymerase chain reaction (PCR) assays are available to
with chronic active hepatitis often have fever, abdominal pain, detect and quantify hepatitis B DNA, which may be useful for
and malaise. Advanced disease may lead to spider nevi, ascites, monitoring disease progression.
coagulopathy, and esophageal varices. About 25% of patients
with chronic infection eventually die from complications related DIFFERENTIAL DIAGNOSIS
to hepatitis B infection. Hepatitis B also causes up to 80% of The diagnostic considerations vary with age, vaccination history,
hepatocellular carcinomas. and exposures, such as travel, sexual activity, and known infec-
tious contacts. The most common diagnostic considerations
DIAGNOSTIC APPROACH include hepatitis caused by other viral agents, especially hepati-
Patients with acute hepatitis B infection have elevated transami- tis A and C, and D and E (if there is a history of travel to
nases and bilirubin. Definitive diagnosis of hepatitis B infection endemic regions) (see Chapter 67). Other viral considerations
is most commonly confirmed by use of several serologic assays. include cytomegalovirus, herpes simplex virus, Epstein-Barr
HBsAg may be detected during acute or chronic infection. Anti- virus, and yellow fever. Bacterial causes for hepatitis are less
body to HBsAg (anti-HBs) is detected during the recovery common but may include sepsis, leptospirosis, Lyme disease,
period of acute infection, but may also be seen in those chroni- and syphilis. Noninfectious considerations include Wilson’s
cally infected. Antibody to hepatitis core antigen (anti-HBcAg) disease, malignancies, toxins, illicit drugs, and ingestions (acci-
may denote past infection; anti-HBcAg IgM usually represents dental or intentional).

CHAPTER 15╇ •â•‡ Hepatitis B Infection 67

Normal healing Sequelae of Viral Hepatitis Cholangiolitis
Recurrent (Chronic nonfatal hepatitis)

Granuloma formation

Fibrosis Nonspecific changes

Figure 15-2╇ Chronic hepatitis B sequelae.

Nodule
formation

CLINICAL MANAGEMENT elevated ALT or alpha fetoprotein or positive family history of
Acute Infection liver disease should have consultation with a pediatric liver
Treatment is primarily supportive for acute infection, with par- specialist.
ticular attention to hydration, nutrition, and patient comfort.
Antiviral therapy (lamivudine or telbivudine) may be considered In patients in all age groups, co-infection should be assessed
for fulminant hepatitis B and with entecavir for protracted and by checking human immunodeficiency virus (HIV) serology,
severe acute hepatitis B (Figure 15-3). antibodies to hepatitis A, and hepatitis C virus and hepatitis D
virus antibody (if the patient is from an endemic area or has a
Chronic Infection history of IDU). To prevent further hepatic injury, patients
For children identified to have chronic hepatitis B infection, should be vaccinated against hepatitis A if they are nonimmune.
obtaining baseline alanine aminotransferase (ALT), alpha feto- Heavy alcohol use, as well as use of medications that are metab-
protein, HBeAg, anti-HBe, and viral load; performing liver olized by the hepatic system, should be avoided.
ultrasound; and assessing the family history for liver disease
are recommended. If the ALT is normal, alpha fetoprotein Indications for treatment are based on disease progression,
is <10╯ng/mL, and family history is negative, then periodic viral load, and liver biopsy results. Treatment is generally initi-
follow-up blood tests are recommended (ALT and alpha feto- ated and monitored by specialists in the field. For chronic hepa-
protein every 6 months; HBeAg and anti-HBe every 12 months). titis B infection, immunomodulators and antiviral therapy may be
The development of anti-HBe antibody is a good prognostic administered. Medications approved by the U.S. Food and Drug
sign and may occur before resolution of HBsAg. Hepatic ultra- Administration (FDA) for use in adults include interferons (inter-
sound should be considered for those at high risk, and liver feron α-2b and pegylated interferon α-2a) and antiviral agents,
biopsy considered to assess the disease stage. Patients with including lamivudine, adefovir, entecavir, telbivudine, and teno-
fovir. Both interferon preparations and lamivudine are approved
for treatment of chronic hepatitis B infection in children; however,
interferon therapy results in significant adverse effects. The anti-
viral agents specifically inhibit hepatitis B viral DNA polymerase,

68 SECTION I╇ •â•‡ Vaccine-Preventable Diseases in Children and Adolescents Cut surface:
Gross appearance acutely congested,
of liver “spleenlike”

Cut surface:
more common
“nutmeg” liver

Low magnification: High magnifi- Reticulum stain: reticular
massive necrosis, cation: cellular network intact
infiltration of lobules exudate consists
and portal areas, bile chiefly of mono-
duct proliferation nuclear cells
and plasma cells;
complete loss of
parenchymal cells

Figure 15-3╇ Pathology of fulminant hepatitis B infection.

but antiviral resistance has been described. Combination therapy and 5% to 7% for older children and adults. Chronic infection
is often used to improve responses and minimize resistance issues. may lead to cirrhosis and hepatocellular carcinoma, both of
Treatment is generally for prolonged time periods (months to which occur more commonly in those infected as infants com-
years). The optimal regimen for children remains unknown, and pared with adults. Serious complications occur in 15% to 40%
investigational trials are underway. of individuals with chronic hepatitis B infection. Patients with
chronic hepatitis B infection are susceptible to superinfection
PROGNOSIS with hepatitis D virus, which increases the risks of development
Acute Infection of cirrhosis and of mortality.
Hospitalization rates for acute hepatitis B infection range from
25% to 35%, with the higher rate occurring among older PREVENTION AND CONTROL
patients. Case fatality rates are generally <2%. Recovery without Nonvaccine Measures
sequelae occurs in 90% to 95% of infants with horizontal trans- Blood and body fluids from patients with acute or chronic hepa-
mission, and 80% to 85% of adults. Fulminant hepatitis may titis B infection are infectious, and appropriate measures should
occur in 1% to 2% of infants and 1% of adults. Co-infection be implemented to prevent transmission to other people. Stan-
with hepatitis D may result in a more severe clinical course of dard precautions should be followed for hospitalized patients.
acute hepatitis B. Hepatitis B–infected individuals should not share items that may
be contaminated with blood, such as toothbrushes or razors, or
Chronic Infection donate blood, sperm, or organs.
Age of infection is inversely correlated with the risk of chronic
infection. The risk of developing chronic infection is 90% Screening for Hepatitis B Infection
among newborns infected perinatally, 50% for children infected Foreign-born individuals, including international adoptees,
at 1 year of age, 20% for children infected at 1 to 4 years of age, immigrants, and refugees from areas with high prevalence

CHAPTER 15╇ •â•‡ Hepatitis B Infection 69

of hepatitis B infection (>2%), should be screened for infec- anti-HBs. HBIG may be used to provide short-term protection
tion. Serologic testing may also be considered for other high- in specific postexposure settings. Indications include perinatal
risk groups, but testing should not delay initiation of exposure of infants to mother with unknown status or known
immunizations. hepatitis B infection, travelers with inadequate time to receive
the vaccine series, and specific, discrete exposures to HBsAg-
To prevent perinatal hepatitis B transmission, all pregnant positive or unknown-status individuals.
women should be tested for HBsAg at an early prenatal visit.
Testing should be repeated in late pregnancy if clinical hepatitis Active Vaccination to Prevent Infection
develops, an exposure occurs, or other risk factors are present Hepatitis B vaccination is available for preexposure and postex-
(e.g., IDU). If no prenatal testing is performed or the results are posure prophylaxis and provides long-term protection. Hepati-
not available, the mother should be tested at the time of delivery. tis B vaccines are produced recombinantly in yeast cell systems.
Management of infants based on the mother’s hepatitis B status The vaccines contain noninfectious HBsAg (10 to 40╯mcg of
is shown in Table 15-1. HBsAg protein per milliliter), a small amount of yeast protein,
and aluminum hydroxide as an adjuvant. Pediatric formulations
Passive Immunoprophylaxis contain trace or no thimerosal. Administration is via the intra-
Hepatitis B immune globulin (HBIG) is prepared from hyper- muscular route. Adverse effects are generally mild and mainly
immunized donors whose plasma has high concentrations of

Table 15-1╇ Hepatitis B Immunoprophylaxis Administration Based on Infant Birth Weight
and Mother’s Hepatitis B Status

MATERNAL HBSAG INFANT BIRTH WEIGHT ≥2000╯g INFANT BIRTH WEIGHT <2000╯g
STATUS Hepatitis B vaccine + HBIG (within 12 hours of birth)
Hepatitis B vaccine + HBIG (within 12 hours of
HBsAg positive Continue vaccine series beginning at 1-2╯mo of age birth)

Check anti-HBs and HBsAg after completion of Continue vaccine series beginning at 1-2╯mo of
vaccine series age

HBsAg-negative infants with anti-HBs levels Immunize with four doses of vaccine; do not
≥10╯mIU/mL are protected and need no further count the birth dose as part of the series
interventions
Check anti-HBs and HBsAg after completion of
HBsAg-negative infants with anti-HBs levels vaccine series
≤10╯mIU/mL should be reimmunized with three
doses at 2-mo intervals and then retested HBsAg-negative infants with anti-HBs levels
≥10╯mIU/mL are protected and need no further
HBsAg-positive infants need follow-up and interventions
monitoring for chronic liver disease
HBsAg-negative infants with anti-HBs levels
≤10╯mIU/mL should be reimmunized with three
doses at 2-mo intervals and then retested

HBsAg-positive infants need follow-up and
monitoring for chronic liver disease

HBsAg unknown Test the mother for HBsAg immediately on Test the mother for HBsAg immediately on
admission for delivery admission for delivery

Hepatitis B vaccine within 12 hours of birth Hepatitis B vaccine within 12 hours of birth
HBIG within 7 days if mother tests positive for HBIG within 7 days if mother tests positive for

HBsAg; if mother’s status remains unknown, some HBsAg; if mother’s status remains unknown,
experts recommend HBIG within 7 days some experts recommend HBIG within 7 days
Continue vaccine series beginning at 1-2╯mo of age, Continue vaccine series beginning at 1-2╯mo of
based on mother’s HBsAg status age, based on mother’s HBsAg status
Immunize with four doses of vaccine; do not
count the birth dose as part of the series

HBsAg negative Hepatitis B vaccine at birth, before hospital Hepatitis B vaccine dose 1 at 30 days of
discharge chronologic age if medically stable, or at
hospital discharge if <30 days
Continue vaccine series beginning at 1-2╯mo of age
Continue vaccine series beginning at 1-2╯mo of
Follow-up HBsAg and anti-HBs not needed age

Follow-up HBsAg and anti-HBs not needed

Adapted from Pickering LK, Baker CJ, Kimberlin DW, Long SS, eds: Red Book: 2009 Report of the Committee on Infectious Diseases, ed 28, Elk Grove
Village, Ill, 2009, AAP.
HBsAg, Hepatitis B surface antigen; HBIG, hepatitis B immune globulin; anti-HBs, antibody to HBsAg.

70 SECTION I╇ •â•‡ Vaccine-Preventable Diseases in Children and Adolescents

consist of local tenderness and low-grade fever. After a vaccine Booster doses of hepatitis B vaccine beyond the initial series
series, more than 95% seroconversion is achieved, which results are generally not recommended. The long incubation period of
in >90% efficacy. Studies are ongoing to determine length of hepatitis B theoretically allows for the development of a protec-
immunity, but it is at least 20 years. tive anamnestic immune response after exposure.

Two hepatitis B single antigen vaccines are available in the Postexposure Prophylaxis
United States: Recombivax from Merck & Co. and Engerix-B Postexposure prophylaxis may be administered to unvaccinated
from GlaxoSmithKline. Both vaccines come in doses for pedi- individuals after an identified percutaneous or sexual exposure
atric (5 to 10╯mcg/0.5╯mL) and adult (10 to 40╯mcg/1.0╯mL) to hepatitis B virus. The regimen includes prompt initiation and
populations. High-dose vaccines are available for adult hemodi- completion of the appropriate doses of the hepatitis B vaccine
alysis and immunocompromised patients. Both vaccines are series for those previously unimmunized, as well as prompt
given in a three-dose series (at 0, 1 to 2, and 6 months) and are (ideally within 24 hours) administration of HBIG.
generally interchangeable. A fourth dose may be given if a birth
dose was administered. The birth dose must be a single antigen EVIDENCE
formulation. Dienstag JL: Hepatitis B virus infection, N Engl J Med
359:1486-1500, 2008. This reference provides information about
In the United States and most industrialized nations, as well hepatitis B infection, complications, and management.
as many developing countries, routine immunizations are started Herck KV, Van Damme P: Benefits of early hepatitis B
at birth and completed during infancy. Hepatitis B vaccines are immunization programs for newborns and infants, Pediatr Infect
also recommended for all unvaccinated individuals, especially Dis J 27:861-869, 2008. This reference provides data about the
those at increased risk of exposure to hepatitis B, including impact on infection of hepatitis B immunization of newborns and
travelers to countries where hepatitis B infection is endemic. infants.
Healthcare workers should have documented hepatitis B immu-
nization because of the increased risk of percutaneous exposure ADDITIONAL RESOURCES
in healthcare settings. All close contacts of individuals with Daniels D, Grytdal S, Wasley A; Centers for Disease Control and Preven-
chronic hepatitis B infection should receive hepatitis B
vaccinations. tion (CDC): Surveillance for acute viral hepatitis—United States, 2007,
MMWR Surveill Summ 58:1-27, 2009. This resource provides a review of the
Hepatitis B vaccine is also available as a component of com- epidemiology of viral hepatitis in the United States.
bination vaccines. For the vaccination of infants and children, a Haber BA, Block JM, Jonas MM, et al: Recommendations for screening,
diphtheria-tetanus–acellular pertussis–hepatitis B–inactivated monitoring, and referral of pediatric chronic hepatitis B. Pediatrics
polio vaccine (DTaP-HBV-IPV, Pediarix, GlaxoSmithKline) is 134:e1007-e1013, 2009. This resource provides a current review for the man-
available and may be administered for the first three doses of agement of children with chronic hepatitis B infection.
the infant vaccine series. Hepatitis B vaccine combined with Lok ASF, McMahon BJ: Chronic hepatitis B: update 2009. Hepatology 50:1-
Haemophilus influenzae type B conjugate vaccine (Hib-HBV, 36, 2009. This resource provides a review of the diagnosis and treatment of
ComVax, Merck & Co.) may be administered at 2, 4, and 12 chronic hepatitis B infection.
months of age. For adults (18 years of age and older), a combi- Mast EE, Margolis HS, Fiore AE, et al: A comprehensive immunization
nation hepatitis B–hepatitis A vaccine (HBV-HAV, TwinRix, strategy to eliminate transmission of hepatitis B virus infection in the
GlaxoSmithKline) is available. The primary schedule for United States, MMWR Recomm Rep 54:1-23, 2005. This resource provides
HBV-HAV vaccine is administration at 0, 1, and 6 months; a review of the strategies in place to progress toward elimination of hepatitis B
alternatively, a four-dose schedule, given on days 0, 7, and 21 to in the United States.
30, followed by a booster dose at 12 months, may be used. Pickering LK, Baker CJ, Kimberlin DW, Long SS, eds: Red Book: 2009
Report of the Committee on Infectious Diseases, ed 28, Elk Grove Village, Ill,
“Catch-up” immunization for hepatitis B may be performed 2009, American Academy of Pediatrics. This resource provides abbreviated
at any age for unimmunized individuals. At their routinely information about the diagnosis, management, and prevention of hepatitis B
scheduled health maintenance visit, previously unvaccinated 11- infections in infants, children, and adolescents.
to 12-year-old children should receive hepatitis B vaccine
administered in a three-dose series at 0, 1, and 6 months if
pediatric formulations are used. Alternatively, use of two 10 mcg
doses of Recombivax, administered at 0 and 4 to 6 months, is
FDA approved for those 11 to 15 years of age.

Human Papillomavirus Infections 16
and Prevention

Dean A. Blumberg

ABSTRACT deaths, every year. Invasive cervical cancer incidence and mor-
tality rates are higher in black women compared with white
Human papillomavirus (HPV) is the most common sexually women (approximately a 6â•:› â•1› ratio). Direct medical costs related
transmitted infection worldwide, causing warts and also ano- to HPV disease, detection, and management are nearly $4
genital cancers, most notably cervical cancer. Worldwide, it is billion annually, second in cost only to human immunodefi-
the second most common cause of cancer mortality in women. ciency virus (HIV) among sexually transmitted infections.
In the United States and several other industrialized nations,
vaccination to prevent HPV infection is now routinely recom- RISK FACTORS FOR INFECTION
mended for girls and young women to prevent morbidity and HPV causes cutaneous and mucosal epithelial infection. Primary
mortality from cervical and other cancers. HPV vaccination may HPV infection occurs in the basal layer of the epidermis. Minor
also be performed to prevent genital warts in males, as well as trauma of the epidermis allows HPV to access the basal layer,
females, 9 to 26 years of age. where replication initially occurs. Viral replication leads to
virion production. Virions are released from the epidermis,
ETIOLOGY which leads to further infections.
Papillomaviruses affect a wide variety of animals, though they
are highly species specific. HPV is a deoxyribonucleic acid Naturally thin mucosal layers, such as occur in the cervix or
(DNA) virus that infects only humans. There are over 100 types anus, are particularly susceptible to infection (Figure 16-1).
of HPV, of which approximately 40 have been identified to cause Infection may result from an infectious contact or autoinocula-
clinical infections. HPV types may be grouped according to tion. Minor trauma is often not clinically apparent and may
clinical site and consequences of infection: cutaneous (mostly result from normal sexual intercourse or other skin-to-skin
asymptomatic), plantar warts, common and flat warts, external contact activities.
genital warts, and genital mucosal cancer–associated types.
There are several factors that increase risk for HPV infec-
Low-risk types usually cause warts. HPV types 6 and 11 are tion. Sexual behavior influences infection, with increasing risk
the low-risk types that cause more than 90% of genital warts. for HPV infection noted for individuals with young age at sexual
Other low-risk types that cause genital warts include types 40, initiation, increasing number of sex partners, increasing number
42, 43, 44, 54, 61, 70, 72, 81, and CP6108. Types classified as of partner’s sex partners, and young age (less than 25 years).
high risk cause low-grade and high-grade genital lesions and Sexual activity leads to anogenital HPV transmission. In the
may progress to cause cervical and other anogenital cancers, as United States, more than 50% of men and women acquire HPV
well as head and neck cancers. High-risk types 16 and 18 cause infection within 5 years of initiation of sexual activity. Men who
the majority of cervical and other cancers. Other high risk types have sex with men are at increased risk for infection and for
include types 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 68, 73, and developing anogenital cancer. Other factors that have been less
82. consistently found to be associated with increased risk for HPV
infection include smoking, diet, hormonal contraceptives,
GEOGRAPHIC DISTRIBUTION AND inconsistent condom use, uncircumcised male partner, and
MAGNITUDE OF DISEASE BURDEN history of genital herpes simplex virus infection.
HPV infections occur worldwide and are the most common
sexually transmitted infection. Globally, approximately 500,000 CLINICAL FEATURES
cases of cervical cancer are caused by HPV every year, repre- HPV infections may be classified as asymptomatic (generally
senting about 10% of all cancers of women. Cervical cancer is mucosal), subclinical, or clinical (apparent, usually seen on the
the leading cause of cancer mortality in women in many devel- skin). Clinically apparent infections usually result in warts rather
oping countries, and it is the second most common cause of than malignancies. Most HPV infections are asymptomatic, and
cancer mortality in women worldwide. many associated lesions are self-limited. However, the concerns
with HPV infections, most notably anogenital and head and
In the United States approximately 20 million people are neck lesions, are the risks to progress to cancer. Of note, it
infected with HPV, with more than 6 million new infections appears that HPV infection alone does not cause malignant
occurring every year. HPV affects >1% of the general popula- transformation of the infected tissue, but cofactors (e.g. tobacco
tion and causes nearly all anogenital warts. HPV causes approxi- use, ultraviolet radiation, pregnancy, folate deficiency, and
mately 10,000 cases of cervical cancer, resulting in about 4000 immune suppression) are important contributors for developing
malignancy.

72 SECTION I╇ •â•‡ Vaccine-Preventable Diseases in Children and Adolescents

Uterine cervical canal Vaginal lumen Figure 16-1╇ Human papillomavirus cervical
Uterine cervix infection. The area that is circled on
Vagina the uterine cervix is depicted by the
enlarged cross-section of the cervical
Stratified cervical epithelium epithelium where the virus proliferates.
Basal layer of the cervical epithelium
Lamina propria
Virus

Warts CLINICAL MANAGEMENT
Almost all genital warts are caused by HPV (see Figure 57-1). There is no specific antiviral therapy available for HPV infec-
Plantar warts and common and flat warts are also caused by tions. Generally, treatment is directed toward HPV-associated
HPV. conditions such as warts or cervical dysplasia.
Management of Warts
If mothers have genital warts or asymptomatic genital HPV For treatment of warts, reduction of symptoms is usually the
infection, newborns may be exposed to the virus during the birth primary goal. No single therapeutic approach has proven ben-
process. Aspiration of genital secretions may result in respira- eficial for all warts. Medications used for HPV cutaneous infec-
tory tract infection and subsequent recurrent respiratory papil- tions are applied topically and may be associated with pain or
lomatosis. Approximately 3000 cases of recurrent respiratory adverse local reactions of the skin and should not be used on
papillomatosis occur every year in the United States. Because mucosal surfaces. Treatment of anogenital warts may be painful;
extensive warts may result in airway obstruction, aggressive sur- often multiple treatments are required. Recurrence is common
gical therapy may be needed, sometimes necessitating several (75% recur within 6 months).
procedures every year.
Two broad categories of medications are effective in treating
Cancers HPV disease. The first category is the immune response modi-
All cervical cancers are caused by HPV. HPV also causes fiers (i.e., imiquimod and interferon-α), and the second category
approximately 50% of vaginal, vulvar, and penile cancers; 90% is the cytotoxic agents (e.g., podofilox, podophyllin, 5-fluorouracil,
of anal cancers; and 20% to 30% of oropharyngeal cancers. salicylic acid, trichloroacetic acid [TCA], and bichloroacetic
acid [BCA]). Surgical treatment may also be considered for
DIAGNOSTIC APPROACH some lesions, especially those that are extensive. Recurrence
Please see discussion in Chapter 57. after complete surgical removal is less common than after
medical treatment.

CHAPTER 16╇ •â•‡ Human Papillomavirus Infections and Prevention 73

Further discussion of the specific treatment of warts is heterologous system (yeast), and the recombinant proteins
included in Chapter 57. self-assemble into viruslike particles that mimic the structure
of natural virions. Immunity to HPV is predominantly type-
Prevention of Progression to specific, and L1 proteins host the virion immunodominant neu-
Cervical Cancer tralization epitopes. The vaccines induce neutralizing antibodies
Periodic Papanicolaou tests (Pap tests or smears) are recom- that prevent HPV cell entry.
mended for women to detect low-grade and high-grade lesions
that are associated with HPV infection, which may progress to HPV vaccines are administered prophylactically. The aim
cervical cancers. With the initiation of routine screening with is to reduce HPV infection and subsequently reduce HPV-
Pap smears in the 1940s, detection and removal of these lesions associated morbidity and mortality. Timing of vaccination is
has resulted in a 70% reduction in cervical cancer mortality in important. Ideally individuals should be vaccinated before sexual
the United States, though the rate of new infections has remained debut, suggesting that younger age at vaccination should result
fairly constant. in the greatest benefit. Current HPV vaccines are not intended
for treatment of established HPV infection.
PROGNOSIS
More than 95% of HPV infections are transient. High-risk HPV type 16 accounts for 53% of cervical cancers, and HPV
HPV types that cause persistent infection (detectable for more type 18 accounts for an additional 17% of cervical cancers.
than 6 to 12 months) are the most important predictor of high- Therefore vaccines contain HPV types 16 and 18 viruslike par-
grade cervical cancer precursors. Persistent active infection ticles in order to address 70% of cervical cancers in the United
causes continued cellular proliferation leading to inhibition of States. Worldwide, the proportion of cervical cancers caused by
cellular differentiation and the development of premalignant high-risk HPV types varies; however, HPV types 16 and 18
and malignant lesions. cause a majority of cervical cancers in every geographic region.

The risk of persistent HPV infection is increased by smokÂ

74 SECTION I╇ •â•‡ Vaccine-Preventable Diseases in Children and Adolescents

immunization is recommended for all girls at 11 to 12 years of EVIDENCE
age, with catch-up immunization at 13 to 26 years of age. Ideally
for maximal benefit, vaccination should occur before onset of Dunne EF, Datta SD, Markowitz LE: A review of prophylactic
sexual activity. However, sexually active girls and women are human papillomavirus vaccines: recommendations and
likely to benefit from vaccination, as they are not likely infected monitoring in the US, Cancer 113:2995-3003, 2008. In this
with all HPV types included in the vaccines. report the authors provide a brief review of the epidemiology of HPV
infection and an overview of prophylactic HPV vaccines and
In 2009, the ACIP made a recommendation for permissive postvaccine licensure monitoring in the United States.
use of HPV4 vaccine for males aged 9 through 26 years to Kahn JA: HPV vaccination for the prevention of cervical
reduce their likelihood of acquiring genital warts. Similar to use intraepithelial neoplasia, N Engl J Med 361:271-278, 2009. This
in females, HPV4 would be most effective when administered reference provides a discussion of the clinical trials for therapy and
to males before exposure to HPV through sexual contact. A prevention of HPV infections.
stronger recommendation for vaccination of males was not
made because it was not considered to be cost beneficial in this ADDITIONAL RESOURCES
group. American Academy of Pediatrics Committee on Infectious Diseases: Pre-

HPV vaccination is recommended for individuals with an vention of human papillomavirus infection: provisional recommendations
equivocal or abnormal Pap test result, positive HPV test result, for immunization of girls and women with quadrivalent human papillo-
or genital warts, as past infection is not likely with all HPV types mavirus vaccine, Pediatrics 120:666-668, 2007. This resource provides recom-
included in the vaccines; therefore vaccination should provide mendations for prevention of HPV infections, including the use of HPV vaccines,
protection against some HPV types. Individuals who are immu- in the recommended age group of girls and women.
nosuppressed may not have as robust of an immune response as Committee on Adolescent Health Care, ACOG Working Group on Immu-
immunocompetent subjects but may still benefit from vaccina- nization: ACOG Committee Opinion No. 344: human papillomavirus
tion. Lactating women may be vaccinated, as the HPV vaccines vaccination, Obstet Gynecol 108:699-705, 2006. This resource provides recom-
are inactivated with no known or theoretical adverse events mendations for introduction and use of HPV vaccinations, primarily in gyneco-
expected. HPV vaccines can be administered at the same visit logic practices.
with other inactivated and live-viral vaccines, including tetanus- Gearhart PS, Randall TC, Buckley RM: Human papillomavirus. Updated
diphtheria–acellular pertussis vaccine (Tdap), tetanus-diphtheria March 2010. Available at: http://emedicine.medscape.com/article/219110-
vaccine (Td), and meningococcal conjugate vaccine (MCV), overview. Accessed June 28, 2010. This resource provides an updated review
which are also recommended at the 11- to 12-year-old health of the diagnosis, management, and prevention of HPV infections.
maintenance visit. Markowitz LE, Dunne EF, Saraiya M, et al: Quadrivalent human papillo-
mavirus vaccine: recommendations of the Advisory Committee on Immu-
HPV vaccines should not be administered during pregnancy. nization Practices (ACIP), MMWR Recomm Rep 56:1-24, 2007. This
The vaccine series should be delayed until after pregnancy. If a resource provides recommendations for the prevention of HPV infections.
vaccine dose is administered during pregnancy, there is no indi- Saslow D, Castle PE, Cox JT, et al: American Cancer Society guideline for
cation for intervention. human papillomavirus (HPV) vaccine use to prevent cervical cancer and
its precursors, Cancer 57:7-28, 2007. This resource provides recommendations
Precautions and contraindications for HPV vaccine admin- from the American Cancer Society for prevention of HPV-associated infections
istration include moderate or severe illness (defer until clinical and cervical cancer.
improvement) and a history of immediate hypersensitivity or
severe allergic reaction to yeast or to any vaccine component.

Currently studies are underway to assess possible therapeutic
use of HPV vaccines alone or adjunctly with medications.

Edited by Dennis L. Stevens II

Skin and Soft-
Tissue Infections

17 Introduction to Skin and Soft-Tissue Infections
18 Impetigo
19 Erysipelas and Cellulitis
20 Folliculitis, Furuncles, and Carbuncles
21 Life-Threatening Skin and Soft-Tissue Infections
22 Superficial Dermatophyte Infections of the Skin
23 Herpes Simplex Virus Infection
24 Nontuberculous Mycobacterial Skin Infections

Introduction to Skin and 17
Soft-Tissue Infections

Dennis L. Stevens

ABSTRACT exploration may be necessary to obtain specimens for appropri-
ate staining and culture. This is extremely important in those
Skin and soft-tissue infections are among the most common patients with systemic signs of infection or those with historical
human afflictions, and descriptions from the last few centuries or observational evidence of rapid progression. With the emer-
suggest that many of these have the same clinical presentations gence of antimicrobial resistance among many of these microbes,
today as historically described. Regardless of the cause, location, treatment (particularly for severe infections) should be based on
or chronicity, the cardinal manifestations of inflammation (heat, the results of Gram stain and cultures and antimicrobial
swelling, erythema, and tenderness or pain) are invariably susceptibility.
present. Infections of the skin and/or subcutaneous tissues are
highly diverse in respect to cause, location, incidence, systemic EPIDEMIOLOGY
manifestations, severity, and complications. They may occur as Although the exact incidence of these infections in the general
single or recurrent episodes. Many cases are mild or self-limited, population is unknown, they are among the most common
but some progress to cause scarring, loss of digits or limbs, or infections occurring in all age groups. Some skin and soft-tissue
even death. Though skin and soft-tissue infections are common, infections are age related—for example, impetigo is more
the causes are diverse, and therefore the clinician faces an common in children, and erysipelas is more common in older
immense challenge in establishing a specific diagnosis and pre- adults. Infections of the skin and soft tissues can be caused by
scribing definitive treatment. Important considerations in evalu- bacteria (including rickettsiae), fungi, viruses, parasites, and spi-
ating patients are the following: rochetes. There are hundreds of possible causative agents, with
two common species of gram-positive cocci being the predomi-
• The patient’s symptoms nant causes of skin and soft-tissue infections—S. aureus and
• The general appearance of the infected site Streptococcus pyogenes—although other streptococci, such as
• Historical clues such as contact with insects or animals, groups B, C, and G streptococci, are being recognized more
commonly. Staphylococcal skin infections are most commonly
especially involving bites, travel to specific geographic associated with infections that begin in hair follicles and cause
areas, occupation, use of a hot tub, or having a home a variety of infections ranging from folliculitis, furuncles, car-
aquarium buncles, and subcutaneous abscesses. Staphylococcal infections
• The immune status of the host usually have a focal central collection of pus with surrounding
• Chronicity erythema. Some practitioners have advocated referring to these
• Anatomic distribution types of infections as purulent cellulitis. It is unclear if the sur-
Anatomic considerations are paramount to the correct diag- rounding erythema is indeed cellulitis (infection in the skin) or
nosis. In general, vesicular lesions (herpes simplex) and crusted merely sympathetic inflammation. In contrast, streptococci
lesions are the most superficial and may be either impetigo more commonly cause erysipelas or cellulitis. Both cause a
(Staphylococcus aureus or group A Streptococcus) or dermatomyco- diffuse erythematous infection not associated with purulent
sis caused by a variety of fungi. Erysipelas is also superficial, drainage. Thus, streptococcal infections should be called nonpu-
caused by group A Streptococcus and characterized by brilliant red rulent cellulitis. It should be noted that staphylococcus and group
color, well-demarcated edges, and pain. None of these superfi- A Streptococcus can both cause impetigo, which is superficial
cial infections is associated with scarring. Localized soft-tissue infection of the keratin layer of the skin associated with crusting
infections (folliculitis, furuncles, carbuncles, and abscesses) lesions that occasionally weep golden brown fluid. In the past,
involve the epidermis and dermis and are usually purulent in many terms have been used to describe rapidly destructive
nature and caused by S. aureus, including methicillin-resistant lesions of the skin and soft tissues, and such nomenclature has
S. aureus (MRSA). Cellulitis is caused by a variety of streptococci not been helpful to the clinician. Gas gangrene and necrotizing
and affects the subcutaneous tissues and is characteristically a fasciitis are examples of such devastating infection. Whereas gas
pinkish erythema with less distinct borders than erysipelas. Nec- gangrene is generally also referred to as clostridial myonecrosis, in
rotizing infections invariably involve the fascia (necrotizing fas- fact most cases involve all the layers of the soft tissue including
ciitis) or muscle (gas gangrene and clostridial myonecrosis). In muscle, fascia, subcutaneous tissue, and skin. Similarly, necrotiz-
general, these necrotizing infections may ultimately involve all ing fasciitis can be caused by mixed aerobic and anaerobic bac-
the layers of the soft tissue, particularly if there is a delay in teria (polymicrobial) or monomicrobial. The latter type is most
recognition and treatment. commonly caused by group A Streptococcus, but cases involving
If the diagnosis cannot be established based on the history, Aeromonas hydrophila and Vibrio vulnificus have also been
symptoms, and signs, then needle aspiration, biopsy, or surgical

CHAPTER 17╇ •â•‡ Introduction to Skin and Soft-Tissue Infections 77

described. As with gas gangrene, necrotizing fasciitis commonly Necrosis of the skin and deeper tissue may occur if there is
destroys not only fascia but also muscle, subcutaneous tissue, severe hypoxia. The following are two examples:
and skin. Thus rightfully these should both be reclassified as
simply necrotizing soft-tissue infections. Because these necro- • Pressure necrosis resulting in decubitus ulcers
tizing soft-tissue infections are rapidly progressive and cause • Compartment syndromes resulting in hypoxia and then
extensive mortality and morbidity, an aggressive approach to
diagnosis and treatment is mandatory. necrosis in muscles confined within tight fascial bundles
When the host is physiologically, structurally, and immuno-
Skin and soft-tissue infections caused by newly recognized or logically normal, only certain pathogens such as S. aureus and
previously rarely encountered microbes are continually being group A streptococci are able to cause disease by virtue of their
described in immunocompromised patients, especially those potent virulence factors, such as toxins, capsules, or dermone-
with acquired immunodeficiency syndrome (AIDS). crotic enzymes. This statement is supported by the observation
that normal skin, although constantly exposed to many indige-
Several noninfectious diseases can mimic infection of the soft nous and exogenous microbes, rarely becomes infected. In con-
tissues—for example, contact dermatitis, pyoderma gangreno- trast, patients who have compromised skin integrity (e.g.,
sum, gout, psoriatic arthritis with distal dactylitis, Reiter’s syn- patients with burns), vascular defects (e.g., those who have dia-
drome, relapsing polychondritis, or mixed cryoglobulinemia betes mellitus or pressure ulceration), or immunologic deficits
secondary to immune complex disease from chronic hepatitis C may become infected with either virulent organisms (e.g.,
or B virus infection. All may manifest with erythematous rashes, staphylococci or streptococci) or microbes that are usually sap-
with or without fever. rophytic, such as Pseudomonas aeruginosa, Escherichia coli, entero-
cocci, or Fusarium species.
PATHOGENESIS
The integument is an organ that reacts to noxious, infectious, PREVENTION
external and internal stimuli in a limited number of ways. It is Avoidance of cuts, scratches, and other forms of trauma that
therefore not surprising that infection can be mimicked by the disrupt the natural barrier function of the skin helps to prevent
noninfectious inflammatory conditions listed previously. The skin and soft-tissue infections. For example, stopping shaving
rich plexus of capillaries beneath the dermal papillae provides may prevent recurrent folliculitis in the beard area (sycosis
nutrition to the stratum germinativum and the dermatocytes, barbae). Prompt cleansing, debridement, and disinfection of
which are bound together by tight junctions and form the such lesions are important for preventing infection, particularly
barrier to microbial invasion. Once microbes have penetrated in the case of bite wounds. Treatment of eczema reduces the
this barrier through a hair follicle, cut, or bite, the dermal plexus risk of secondary bacterial infection.
of capillaries delivers the components of the host’s defense—
oxygen, complement, immunoglobulins, macrophages, lympho- Prevention of recurrent folliculitis or furunculosis is difficult
cytes, and granulocytes—to the site of infection. At some to achieve, but there has been some success using intranasal
locations, factors such as pressure, thrombosis, or drugs may applications of bacitracin or mupirocin ointment. Hexachloro-
reduce or stop blood flow, resulting in inadequate oxygenation. phene or chlorhexidine soaps may be tried to eliminate or
If tissue perfusion is moderately attenuated, tissues may remain reduce staphylococcal carriage in adults. Prophylaxis with sys-
viable, but the threshold for progression of infection may be temic antibiotics is of doubtful efficacy and can result in the
lowered. Predisposing conditions in this category include the emergence of resistant strains; it should be tried only for severe
following: cases. Finally, recurrent bacterial cellulitis of the lower extremi-
ties can often be prevented by topical antifungal treatment for
• Peripheral vascular disease affecting large arteries dermatophyte infections such as tinea pedis because even minor
• Diabetes mellitus causing microvascular disease or inapparent superficial fungal infection can serve as a portal
• Chronic venous stasis causing postcapillary obstruction of entry for gram-positive cocci.

Impetigo 18

Dennis L. Stevens

ABSTRACT be either bullous or nonbullous in appearance. The former
appear initially as superficial vesicles that rapidly enlarge to form
Impetigo is a common crusted and superficial infection of the flaccid bullae filled with clear yellow fluid, which later becomes
skin that occurs in individuals throughout the world. From the darker, more turbid, and often purulent. Bullae may rupture,
historical perspective, impetigo has occurred most frequently leaving a thin brown crust resembling lacquer. The lesions of
among economically disadvantaged children in tropical or sub- nonbullous impetigo begin as papules that rapidly evolve into
tropical regions, but it is also prevalent in northern climates vesicles surrounded by an area of erythema and then into pus-
during the summer months. Its peak incidence is in children tules that gradually enlarge and then break down over a period
aged 2 to 5 years, though older children and adults, including of 4 to 6 days to form characteristic thick-crusted cutaneous
the homeless and migrant farm workers, may also be affected. lesions. Impetiginous lesions heal slowly and leave depigmented
There is no sex predilection, all races are susceptible, and impe- areas but do not form scars. A deeply ulcerated form of impetigo
tigo is nearly always caused by beta-hemolytic streptococci and/ is known as ecthyma. Regional lymphadenitis may occur, but
or Staphylococcus aureus. In recent times impetigo caused by S. systemic symptoms are usually absent.
aureus, including methicillin-resistant S. aureus (MRSA), have
become problematic. The appearance of impetiginous lesions provides some clues
regarding the etiology. For example, bullous impetigo is usually
GEOGRAPHIC DISTRIBUTION caused by strains of S. aureus that produce a toxin causing cleav-
Impetigo occurs in all regions of the world but is most common age in the superficial skin layer. In the past, nonbullous lesions
in children in the tropics. In temperate areas, impetigo has been were usually caused by streptococci. Now, 50% of cases are
described in Native American children living on Indian reserva- caused by staphylococci alone or in combination with strepto-
tions and in children in poor economic conditions in cities. In cocci. Streptococci isolated from lesions are primarily group
adults, impetigo has recently been described in the homeless, A, but occasionally other serogroups such as C and G are
migrant farm workers, and travelers returning from tropical responsible.
vacations.
DIAGNOSTIC APPROACH
RISK FACTORS Impetigo is most commonly diagnosed based on the character-
Studies of streptococcal impetigo performed at the Red Lake istic dry, crusted skin lesions that weep golden-colored fluid.
Indian Reservation in the 1960s demonstrated that personal Gram stain of vesicular fluid or exudates beneath the crusts
hygiene, humidity, and geographic location influence the inci- reveals gram-positive cocci resembling S. aureus or group A
dence of disease. Predisposing factors also include minor trauma, Streptococcus (GAS). Cultures are invariably positive for one or
abrasions, and insect bites. Skin colonization of unbroken skin the other or both. Cultures are more important than ever based
with particular streptococcal strains such as M-type 49 precedes on the evolving resistance of S. aureus (MRSA) and high-level
the development of impetiginous lesions by an average of 10 resistance in specific geographic areas of GAS to erythromycin.
days. Inoculation or colonization of surface organisms into the The anti–streptolysin O response is weak in patients with strep-
skin by abrasions, minor trauma, or insect bites then ensues. tococcal impetigo, presumably because skin lipids suppress
Over the course of 2 to 3 weeks, proliferation of streptococcal streptolysin O response but anti-DNase B levels are consistently
strains results in the classic crusted lesions with yellow serosan- elevated.
guineous drainage. At this stage streptococci may be transferred
from the skin and/or impetigo lesions to the upper respiratory Although assays of streptococcal antibodies are of limited
tract. In contrast, in patients with staphylococcal impetigo, nasal value in diagnosis and management of impetigo, they provide
colonization usually precedes cutaneous disease. helpful supporting evidence of recent streptococcal infection in
patients suspected of having poststreptococcal glomerulone-
CLINICAL FEATURES phritis. It must be emphasized that the greatest consequence of
The cutaneous distribution of impetigo is largely on exposed impetigo caused by GAS is not the impetiginous lesion, but the
areas of the body, most often the face and extremities (Figure postinfection sequela, poststreptococcal glomerulonephritis. In
18-1). Interiginous areas are spared. Individual lesions are well times past, there was a strong association between specific
localized, but multiple cutaneous lesions may develop and may strains of GAS that caused impetigo and the development of
poststreptococcal glomerulonephritis. In the last 20 years, the
incidence of this complication has markedly declined to less
than 1 case per 100,000 population. This is likely related to the
rarity of the classic M-49 strain (Red Lake strain) in modern
times compared with the 1950s era.

CHAPTER 18╇ •â•‡ Impetigo 79

Blister Crust

Outer Impetigo starts with
skin layer painless blisters,
(epidermis) usually on the face,
especially near the
Staphylococcus nose and mouth.
Blisters fill with
Muscle Streptococcus clear or yellow fluid
and crust over.
Bacteria called Staphylococcus (staph) and Streptococcus Your doctor makes a diagnosis from the look of the blisters and sores.
(strep) cause impetigo. They normally live on the skin surface
but can go deeper and cause infection.
Figure 18-1╇ Managing impetigo.

CLINICAL MANAGEMENT All these agents have been approved by the FDA for compli-
In the past, therapy directed primarily at group A streptococci cated skin and soft-tissue infections; however, no clinical trials
(e.g., penicillin) was successful, both in healing the lesions and have been performed with these agents for impetigo per se.
decreasing recurrences of nonbullous impetigo for at least
several weeks. Because S. aureus currently accounts for most PROGNOSIS
cases of bullous impetigo as well as a substantial portion of Impetiginous lesions resolve spontaneously with or without
nonbullous infection, penicillinase-resistant penicillins or first- antibiotics and do not leave a scar because the infection occurs
generation cephalosporins are preferred, although impetigo in the outer keratin layer of skin. Antibiotic treatment topically
caused by MRSA is increasing in frequency. Erythromycin has or orally speeds the rate of resolution. Suppurative complica-
been a mainstay of pyoderma therapy, but its utility may be tions of streptococcal impetigo are uncommon, and for as yet
lessened in areas where erythromycin-resistant strains of S. unexplained reasons, rheumatic fever has never occurred after
aureus, or more recently Streptococcus pyogenes, are prevalent. streptococcal impetigo. On the other hand, cutaneous infections
Topical therapy with mupirocin is equivalent to oral systemic with nephritogenic strains of GAS are the major antecedent of
antimicrobials and may be used when lesions are limited in poststreptococcal glomerulonephritis in many areas of the
number. It is expensive, however, and resistance not only has world. No conclusive data indicate that treatment of streptococ-
developed but is in part related to the general usage of mupiro- cal pyoderma prevents nephritis.
cin in the community. Recently, retapamulin ointment was
approved by the Food and Drug Administration (FDA) for PREVENTION AND CONTROL
treatment of impetigo caused by both GAS and S. aureus. General body hygiene is important in preventing impetigo. In
Bullous impetigo caused by MRSA poses a difficult problem for addition, minor skin trauma and abrasions in children should be
clinicians. Although empiric treatment with dicloxacillin, quickly cleansed with soap and water and appropriately covered
amoxicillin-clavulanate, or an oral cephalosporin may be the with sterile dressings. Antibiotic ointment probably aids in pre-
easiest choice, patients should be observed carefully for evidence vention of impetigo because it is useful in shortening the course
of clinical failure as a result of MRSA. If this occurs, of established impetigo, yet such studies have not been per-
trimethoprim-sulfamethoxazole or clindamycin may be effec- formed. Topical or oral antibiotics are also important as an
tive, though resistance to both agents has been described. Occa- epidemiologic intervention to eradicating nephritogenic strains
sionally in patients with extensive impetigo caused by MRSA, from the community and for reducing transmission within fami-
parenteral antibiotics such as vancomycin, daptomycin, or line- lies and daycare settings.
zolid would be reasonable choices based on susceptibility testing.