Pediatric Herpes Simplex Virus Infections: An Evidence

Transcription

Pediatric Herpes Simplex Virus
Infections: An Evidence-Based
Approach To Treatment
Abstract
Herpes simplex virus is a common virus that causes a variety of
clinical presentations ranging from mild to life-threatening. Orolabial
and genital herpes are common disorders that can often be managed in an outpatient setting; however, some patients do present to
the emergency department with those conditions, and emergency
clinicians should be aware of possible complications in the pediatric
population. Neonatal herpes is a rare disorder, but prompt recognition and initiation of antiviral therapy is imperative, as the morbidity and mortality of the disease is high. Herpes encephalitis is an
emergency that also requires a high index of suspicion to diagnose.
Herpes simplex virus is also responsible for a variety of other clinical
presentations, including herpes gladiatorum, herpetic whitlow, eczema herpeticum, and ocular herpes. This issue reviews the common
clinical presentations of the herpes simplex virus, the life-threatening
infections that require expedient identification and management, and
recommended treatment regimens.
Editor-in-Chief
Ilene Claudius, MD
Associate Professor of Emergency
Adam E. Vella, MD, FAAP
Medicine, Keck School of Medicine
of the University of Southern
Medicine, Pediatrics, and Medical
California, Los Angeles, CA
Education, Director Of Pediatric
Ari Cohen, MD
Emergency Medicine, Icahn
School of Medicine at Mount Sinai, Chief of Pediatric Emergency
Medicine Services, Massachusetts
New York, NY
General Hospital; Instructor in
Associate Editor-in-Chief
Pediatrics, Harvard Medical
School, Boston, MA
Vincent J. Wang, MD, MHA
Associate Professor of Pediatrics,
Keck School of Medicine of the
University of Southern California;
Associate Division Head,
Division of Emergency Medicine,
Children's Hospital Los Angeles,
Los Angeles, CA
AAP Sponsor
Martin I. Herman, MD, FAAP, FACEP
Professor of Pediatrics, Attending
Physician, Emergency Medicine
Department, Sacred Heart
Children’s Hospital, Pensacola, FL
Editorial Board
Jeffrey R. Avner, MD, FAAP
Professor of Clinical Pediatrics
and Chief of Pediatric Emergency
Medicine, Albert Einstein College
of Medicine, Children’s Hospital at
Montefiore, Bronx, NY
Richard M. Cantor, MD, FAAP,
FACEP
Professor of Emergency Medicine
and Pediatrics, Director, Pediatric
Emergency Department, Medical
Director, Central New York
Poison Control Center, Golisano
Children's Hospital, Syracuse, NY
T. Kent Denmark, MD, FAAP,
FACEP
Medical Director, Medical
Simulation Center, Professor,
Emergency Medicine, Pediatrics,
and Basic Science, Loma Linda
University School of Medicine,
Loma Linda, CA
Sandip Godambe, MD, PhD
Vice President, Quality & Patient
Safety, Professor of Pediatrics and
Emergency Medicine, Attending
Physician, Children's Hospital
of the King's Daughters Health
System, Norfolk, VA
January 2014
Authors
Volume 11, Number 1
Jennifer E. Sanders, MD
Pediatric Emergency Medicine Fellow, Department of Pediatric
Emergency Medicine, Icahn School of Medicine at Mount Sinai,
New York, NY
Sylvia E. Garcia, MD
Assistant Professor of Pediatrics and Pediatric Emergency
Medicine, Icahn School of Medicine at Mount Sinai, New York,
NY
Peer Reviewers
Ilene Claudius, MD
Associate Professor of Emergency Medicine, Keck School of
Medicine of the University of Southern California, Los Angeles,
CA
Beryl Greywoode, MD
Pediatrician with Special Interest in Infectious Diseases,
Imperial College Healthcare NHS Trust, London, United
Kingdom
CME Objectives
Upon completion of this article, you should be able to:
1.
Name the laboratory studies involved in the evaluation of
neonatal herpes infections.
2. List the appropriate dosage and length of treatment for
neonatal disseminated HSV disease; central nervous system
HSV disease; and skin, eyes, and mouth disease.
3. Name the type of therapy that can prevent transmission of
genital herpes.
Prior to beginning this activity, see “Physician CME
Information” on the back page.
Anupam Kharbanda, MD, MS
Research Director, Associate
Fellowship Director, Department
of Pediatric Emergency Medicine,
Children's Hospitals and Clinics of
Minnesota, Minneapolis, MN
Steven Rogers, MD
Clinical Professor, University of
Connecticut School of Medicine,
Attending Emergency Medicine
Physician, Connecticut Children's
Medical Center, Hartford, CT
Tommy Y. Kim, MD, FAAP, FACEP
Ran D. Goldman, MD
Assistant Professor of Emergency
Professor, Department of Pediatrics,
Medicine and Pediatrics, Loma
University of British Columbia;
Linda Medical Center and Children’s
Co-Lead, Division of Translational
Hospital, Loma Linda, CA
Therapeutics; Research Director,
Brent R. King, MD, FACEP, FAAP,
Pediatric Emergency Medicine, BC
FAAEM
Children's Hospital, Vancouver, BC, Professor of Emergency Medicine
Canada
and Pediatrics; Chairman,
Mark A. Hostetler, MD, MPH Department of Emergency
Clinical Professor of Pediatrics
Medicine, The University of
and Emergency Medicine,
Texas Houston Medical School,
University of Arizona Children’s
Houston, TX
Hospital Division of Emergency
Robert Luten, MD
Medicine, Phoenix, AZ
Professor, Pediatrics and
Ghazala Q. Sharieff, MD, FAAP,
FACEP, FAAEM
Clinical Professor, Children’s
Hospital and Health Center/
University of California; Director
of Pediatric Emergency Medicine,
California Emergency Physicians,
San Diego, CA
Marianne Gausche-Hill, MD,
FACEP, FAAP
Professor of Clinical Medicine,
Alson S. Inaba, MD, FAAP
Emergency Medicine, University of
David Geffen School of Medicine
Associate Professor of Pediatrics,
Florida, Jacksonville, FL
at the University of California at
University of Hawaii at Mãnoa
Garth Meckler, MD, MSHS
Los Angeles; Vice Chair and Chief,
John A. Burns School of Medicine, Associate Professor of Pediatrics,
Division of Pediatric Emergency
Division Head of Pediatric
University of British Columbia;
Medicine, Harbor-UCLA Medical
Emergency Medicine, Kapiolani
Division Head, Pediatric
Center, Los Angeles, CA
Medical Center for Women and
Emergency Medicine, BC
Children, Honolulu, HI
Michael J. Gerardi, MD, FAAP,
Children's Hospital, Vancouver,
FACEP
Madeline Matar Joseph, MD, FAAP,
BC, Canada
FACEP Joshua Nagler, MD
Medicine, Icahn School of
Professor of Emergency Medicine Assistant Professor of Pediatrics,
Medicine at Mount Sinai; Director,
and Pediatrics, Chief and Medical
Harvard Medical School;
Pediatric Emergency Medicine,
Director, Pediatric Emergency
Fellowship Director, Division of
Goryeb Children's Hospital,
Medicine Division, University
Emergency Medicine, Boston
Morristown Medical Center,
of Florida Medical SchoolChildren's Hospital, Boston, MA
Morristown, NJ
Jacksonville, Jacksonville, FL
Gary R. Strange, MD, MA, FACEP
Professor and Head, Department
of Emergency Medicine, University
of Illinois, Chicago, IL
Christopher Strother, MD
Assistant Professor, Director,
Undergraduate and Emergency
Simulation, Mount Sinai School of
Medicine, New York, NY
International Editor
Lara Zibners, MD, FAAP
Honorary Consultant, Paediatric
Emergency Medicine, St Mary's
Hospital, Imperial College Trust;
EM representative, Steering Group
ATLS®-UK, Royal College of
Surgeons, London, England
Pharmacology Editor
James Damilini, PharmD, MS,
BCPS
Clinical Pharmacy Specialist,
Emergency Medicine, St.
Joseph's Hospital and Medical
Center, Phoenix, AZ
Case Presentation
A 10-day-old full-term girl is brought to the ED with a
rectal temperature of 38.6°C. She has no cough, congestion, runny nose, vomiting, or diarrhea. She is formulafed and is tolerating her regular feeds. The mother
received prenatal care, and the prenatal labs, including
Group B Streptococcus, were negative for any pathology. The mother has no reported history of HSV, but she
has had a fever and throat pain for the past few days. The
infant is sleeping comfortably in her mother’s arms. On
examination, the anterior fontanel is soft and flat, and
the skin is negative for rash or lesions. Cardiac, respiratory, and abdominal examinations are within normal
limits. The infant’s temperature is now 38.7°C rectally.
You explain to the medical student working with you on
the case that because the baby is < 28 days old and there
are no symptoms other than fever, she will require a full
sepsis workup, including a lumbar puncture. You inform
the medical student that this is standard of care for neonates who present with a fever, and the diagnostics will
aid in determining the cause of the fever. Even though
the mother has no history of HSV, you have a high index
of suspicion for this. The medical student asks you if the
baby should be started on acyclovir.
Introduction
Herpes simplex virus (HSV) is a common virus
that affects up to 90% of the population by adulthood.1 Approximately one-third of children contract a
primary HSV1 infection by the age of 5 years.2 In the
United States, neonatal HSV disease occurs in approximately 1 in 3200 deliveries, or 1500 new cases
annually.3 Because HSV has many clinical presentations, the emergency clinician must maintain a
high index of suspicion for HSV infections and be
prepared to offer the appropriate management. The
emergency clinician must also be aware of possible
complications in the pediatric population as well as
the recommended treatments.
Critical Appraisal Of The Literature
A search was performed in PubMed for articles published since 1960 pertaining to children aged
< 18 years using multiple combinations of the search
terms herpes simplex virus, neonatal herpes, acyclovir,
treatment, herpes encephalitis, and genital herpes. The
Cochrane Database of Systematic Reviews was also
consulted. Articles relevant to pediatric HSV infections were selected and reviewed. Over 300 articles
were reviewed, 122 of which were chosen for inclusion in this review, including a number of randomized controlled trials, meta-analyses, and clinical
practice guidelines.
Pediatric Emergency Medicine Practice © 20142
Etiology And Pathophysiology
Herpes viruses are enveloped, double-stranded
DNA viruses, and their types number > 80. Those
that affect humans include herpes simplex virus
type 1 (HSV1), herpes simplex virus type 2 (HSV2),
human herpesviruses 6 and 7 (HHV6, HHV7),
Kaposi sarcoma-associated herpes virus (HHV8),
cytomegalovirus, varicella-zoster virus, and EpsteinBarr virus. HSV is transmitted primarily through
exposure to skin or mucous membranes that have
active lesions. Additionally, transmission may occur
through direct contact with saliva or respiratory
droplets, or from exposure to mucocutaneous secretions from an individual who is shedding the virus.
It should be noted that HSV can be transmitted even
if there are no visible sores.
The incubation period for primary or initial
HSV1 or HSV2 infection ranges from 2 to 12 days
with an average period of 4 days.4 Following
primary infection, there is a period of viral shedding that lasts from 1 to several weeks. Shedding
is the process in which the virus may be found on
the surface of the skin of patients with no clinical
signs. Following the initial or primary infection, the
virus typically remains latent within the autonomic
ganglia of the host. HSV1 tends to reside within the
trigeminal ganglion, while HSV2 commonly resides
in the sacral ganglia. While in the ganglia, the virus
may replicate without being detected by the host’s
immune system.
Clinical symptoms occur when the virus is reactivated. Both internal and external stimuli (eg, stress,
fever, menstruation, extremes in temperature, and
sunlight exposure) may trigger reactivation. When
activated, the virus travels along the sensory nerve
and affects the mucocutaneous region that was
primarily infected, which is typically the oral area
for HSV1 and the genital area for HSV2. Lifelong latency and periodic recurrences are hallmarks of HSV
infections.
Disseminated disease may occur when the host
is unable to control viral replication. This is usually
seen in neonates and immunocompromised hosts.
In patients with disseminated disease, the virus invades the lungs, liver, and adrenal glands, and may
or may not affect the central nervous system (CNS).
In herpes encephalitis, neurons are destroyed
via lytic and hemorrhagic processes that have a predilection for the temporal lobes. In approximately
one-third of cases, herpes encephalitis is the result of
a primary HSV infection, while the other two-thirds
of cases are due to reactivation of the virus.5
Epidemiology
Infections with HSV1 are common worldwide. At
the time of the most recent National Health and Nutrition Examination Survey (NHANES) completed
www.ebmedicine.net • January 2014
in 2004, two-thirds of the United States population
aged > 12 years had an antibody to HSV1, with the
seroprevalence higher among females (70.9%) compared to males (64.2%).6
Both in the United States and globally, the
prevalence of HSV1 infections has been shown to
increase consistently with age, reaching approximately 40% by the teenage years and 60% to 90%
by older adulthood.7,8 Worldwide, the prevalence
of HSV1 infection is greater than HSV2 infection.
HSV2 is primarily transmitted through sexual
contact, so it is not as prevalent in young children.
The seroprevalence of HSV2 in patients aged > 12
years is estimated at 21.9%.9,10 However, despite efforts to promote safer sex practices, the prevalence
of this infection in this population has increased by
30% since the 1970s.10 Predictors of positive HSV2
status include female gender, black race, greater
lifetime number of sexual partners, older age, and
low socioeconomic status.9,11,12 Along with the rise
of genital HSV2 infection, there has been a rise in
the number of genital HSV1 infections,13-18 which is
most likely secondary to oral-genital contact with a
person infected with HSV1.
In the United States, herpes encephalitis is the
most common of the lethal encephalitides, with an incidence of 2 cases per million people per year.5,19 The
disease has a bimodal distribution with the first peak
occurring in those aged < 20 years and the second
peak occurring in those aged > 50 years. Both sexes
are affected equally, and there is no racial predilection.19 Almost all cases are the result of HSV1 infection, but there have been reports of the occurrence of
HSV2 herpes encephalitis.5,20 The mortality rate of untreated herpes encephalitis exceeds 70%, and the survivors almost always have neurologic sequelae.21,22
partum period, and it is estimated that 10% of infants
are infected postnatally when they come into contact
with someone shedding the virus.25-27 HSV infections
that are acquired in the peripartum or postpartum period are classified into 3 categories: (1) disseminated
disease; (2) CNS disease with or without skin lesions;
and (3) disease limited to the skin, eyes, and mouth.
Morbidity and mortality differ with each category,
but disseminated disease has the highest morbidity
and mortality.25-27
A small retrospective review indicated that
disseminated HSV infections accounted for approximately 85% of neonatal cases;28 however, a
later retrospective review of 291 patients showed
a decrease in the number of neonates with disseminated disease and an increase in patients with
skin, eyes, and mouth disease.29 The mortality rate
for untreated disseminated HSV is approximately
85%, and even with treatment, it remains high.30
Death is usually the result of disseminated intravascular coagulopathy, liver failure, and pulmonary involvement.
Approximately 33% of neonates with HSV
infection are classified as having CNS disease.29 The
1-year mortality rate for untreated CNS disease is
approximately 50%; however, long-term neurological sequelae of survivors have been noted in 67% of
patients, even with high-dose antiviral therapy.30,31
Infection limited to the skin, eyes, and mouth
accounts for approximately 45% of neonate HSV
cases.29 While mortality in patients with skin, eyes,
and mouth disease is essentially zero, because of
the possibility of subclinical CNS infection, infants
may still develop neurologic impairments if they
are not treated.32 In fact, approximately 75% of
infants with skin, eye, and mouth infection will
progress to have CNS or disseminated disease if
they are left untreated.29
Neonatal Epidemiology
Seventy percent of neonatal HSV cases are due to
HSV2 infection, with the remaining 30% due to
HSV1.23 With the prevalence of HSV2 and the increase in genital HSV1 cases, it is possible that there
will be more cases of neonatal HSV in the future.
Neonatal HSV infection can be acquired either during intrauterine exposure or during the peripartum
and postpartum periods. The estimated incidence
of intrauterine HSV infection is 1 in 100,000 deliveries,24 and HSV2 is thought to account for 90% of
these cases.24 While this is considered to be a rare
disorder, intrauterine HSV can lead to significant
morbidity and mortality.
Exposure during the peripartum and postpartum
periods can be due to maternal infection or an alternative external source; however, as with intrauterine
acquisition, mother-to-infant contact transmission
remains the highest-risk source for both peripartum
and postpartum neonatal infection. Eighty-five percent of infected infants acquire infection in the periJanuary 2014 • www.ebmedicine.net
Differential Diagnosis
The differential diagnosis for herpes infections varies greatly depending upon presentation of the infection. Table 1 (see page 4) summarizes the differential
diagnosis when evaluating for HSV infections.
Neonates
The differential diagnosis for neonatal herpes includes serious infections (such as bacterial sepsis,
viral pneumonia, and hepatitis) as well as benign
rashes (such as erythema toxicum and pustular
melanosis). The age of the patient and the appearance
of the lesions, along with other clinical symptoms,
may aid in narrowing the differential diagnosis. Both
erythema toxicum and pustular melanosis usually appear within the first days of life, as opposed to HSV,
which typically appears approximately 10 to 20 days
after birth.
3
Oral Lesions
Herpes infections in and around the mouth have
many mimickers, including aphthous ulcers, herpangina, and impetigo. Herpes lesions typically lack the
honey-colored crust and often follow a dermatomal
distribution, which can help distinguish this from impetigo. However, superinfection with Staphylococcus
or Streptococcus is possible and can result in impetiginization of the primary herpetic lesion. Aphthous
ulcers are similar in appearance to herpetic ulcers, but
they can be distinguished by the lack of a vesicular
stage and they do not tend to appear on the outside of
the lip.33 Herpangina, which is caused by coxsackieviruses, manifests with yellowish ulcers with a red halo
that are found on the buccal surface, gingivae, soft
palate, and tonsillar pillars.33
Table 1. Differential Diagnosis Of Herpes
Simplex Virus Infections
Classification
Differential Diagnosis
Congenital herpes
•
•
•
•
Toxoplasmosis
Cytomegalovirus
Syphilis
Rubella
Neonatal herpes
•
•
•
•
•
•
Neonatal sepsis
Erythema toxicum
Pustular melanosis
Varicella-zoster virus
Viral pneumonia
Viral hepatitis
Herpes labialis and
gingivostomatitis
•
•
•
•
•
•
Impetigo
Aphthous ulcers
Herpangina
Hand, foot, and mouth disease
Acute necrotizing ulcerative gingivitis
Behcet syndrome
Genital herpes
• Sexually transmitted viral infections
Condyloma acuminata
• Sexually transmitted bacterial infections
l
l
Syphilis
l
Chancroid
Lymphogranuloma venereum
• Non-sexually transmitted infections
l
l
Trauma
l
Lichen planus
l
Lichen sclerosis
l
Behcet syndrome
Herpes zoster
• Other
l
l
Herpes encephalitis
•
•
•
•
•
•
•
•
•
Scabies
Abscess/subdural empyema
Tumor
Subdural hematoma
Systemic lupus erythematosus
Adrenal leukodystrophy
Vascular disease
Toxic encephalopathy
Reye syndrome
Viral encephalitides
Genital Lesions
The differential diagnosis of genital herpes is broad.
Primary syphilis, caused by Treponema pallidum,
presents with painless ulcers, in contrast to the
painful lesions of HSV. Chancroid ulcers are painful lesions with a serpiginous border and central
exudates caused by Haemophilus ducreyi.2 Ulcerations
in Behcet syndrome resemble large aphthous ulcers
with irregular borders.
Encephalitis
Herpes encephalitis has a broad differential diagnosis, including other viral encephalitides, structural
lesions, and vascular disease.
Prehospital Care
Emergency medical services (EMS) providers may
transport well-appearing patients to the emergency
department (ED), but they should be prepared to
provide basic and advanced life support for the sick
patient with disseminated HSV or HSV encephalitis. Support of the patient’s airway, breathing, and
circulation is critical. Intravenous access should be obtained, if needed, and patients should receive isotonic
fluid boluses if hemodynamic instability occurs.
Emergency Department Evaluation
HSV can cause relatively benign as well as lifethreatening diseases. Emergency clinicians must
have a high index of suspicion in cases where HSV
disease may not be clinically apparent. A thorough
history and physical examination is paramount.
History
A focused approach to the history may vary based
on the patient’s age and presentation. For example,
in neonates, maternal history is important, as elements of this may influence suspicion for the risk of
HSV transmission.
Neonates
When evaluating an ill-appearing or febrile neonate, there are several elements of the history that
should be investigated. Documentation should
include the height of the fever and the method
by which it was obtained (rectal, axillary, or tympanic). The family should be questioned regarding
how the infant is feeding, as poor feeding can be a
sign of illness. Additionally, increased irritability or
lethargy should be assessed. The family should be
asked if they have noted any rashes on the infant,
though these are not always present. The age of the
infant is also important, as disseminated disease
typically presents at 10 to 12 days after birth, while
disease presentation for CNS HSV infection is usually around 16 to 19 days after birth.34
The factors that influence the risk of transmission of HSV from mother to baby should be explored. The 5 known risk factors that influence transmission of HSV from mother to baby include: (1) the
type of maternal infection (primary vs recurrent); (2)
maternal HSV antibody status; (3) duration of time
after rupture of amniotic sac membranes; (4) mode
of delivery (cesarean section vs vaginal delivery);
and (5) integrity of mucocutaneous barriers (use of
fetal scalp monitors).3,35-41
During pregnancy, recurrent genital herpes is
the most common form of genital HSV infection.35
However, women with primary genital herpes are at
the highest risk of transmitting HSV to their infant.
In a prospective study of over 58,000 pregnant
women, Brown et al found that the risk of neonatal
transmission was 57% for those with first-episode
primary HSV infection versus 25% for first-episode
nonprimary HSV infection, and 2% for recurrent
genital HSV infections.3 This effect is most likely
explained by the lower concentrations of maternal
HSV antibodies in women with primary infection
versus a higher antibody concentration in women
who have recurrent outbreaks.35,38,39 However, 60%
to 80% of women who acquire genital HSV during pregnancy are asymptomatic, have no clinical
findings to suggest genital HSV infection, and are
unaware that they have genital HSV.28,29,39
The duration of the rupture of membranes in the
mother may have an effect on the risk of acquiring
neonatal infection. The emergency clinician should
ask if the mode of delivery was cesarean versus vaginal, as cesarean delivery has been proven effective
at preventing transmission of HSV to the neonate.3
The American College of Obstetricians and Gynecologists updated its guidelines for management
of genital herpes in pregnancy in 1999.42 The recommendations state that cesarean delivery should
be performed if genital HSV lesions or prodromal
symptoms are present at the time of delivery in
order to reduce the risk of neonatal HSV disease. In
the Brown et al study, cesarean delivery significantly
reduced HSV transmission rate among women from
whom HSV was isolated.3 However, there have been
reports of neonatal HSV infection despite cesarean
delivery performed before membrane rupture.29,42
Randolph and colleagues found that 386 cesarean deliveries had to be performed on women
with recurrent herpes in order to prevent 1 neonatal
infection, which places the cost at more than $1.3
million per neonatal infection prevented.43 In an
effort to reduce the number of cesarean deliveries,
several studies have evaluated the use of suppressive acyclovir (Zovirax®) therapy to decrease the occurrence of transmission of genital HSV at the time
of delivery.44-51 The use of this suppressive therapy
has reduced the number of cesarean sections;44,49-51
however, even with acyclovir prophylaxis, transmission of HSV to neonates can still occur.52
January 2014 • www.ebmedicine.net
The use of fetal scalp monitors has been found
to be a risk factor for transmission of HSV due to
interruption of the infant’s mucocutaneous barriers.40,41 Therefore, on presentation to the ED, parents
should be asked about the use of fetal scalp monitors
at the time of delivery, as they may not recall recurrent crusting or blistering over the scalp.
Oral Lesions
Acute herpetic gingivostomatitis and herpes labialis
are common presentations of primary HSV infection
in children. Usually, the onset is quite abrupt and
symptoms may persist for 10 to 14 days. A history of
eczema, impetigo, or other skin breakdown should
be determined, as the oral lesions may be the result
of infection secondary to skin breakdown. The
presence or absence of fever, irritability, or fatigue
should be ascertained, as well as the child’s ability
to eat or drink. Due to pain, children may become
dehydrated during a herpetic outbreak and they
may require fluid resuscitation or admission for
hydration. Special attention should be paid to the
presence or absence of visual or ocular symptoms, as
perioral HSV infection can be a risk factor for ocular
infections due to the potential for spread through
the trigeminal ganglion.
Genital Lesions
The diagnosis of genital HSV is most often made by
physical examination. The first episode of a genital
outbreak is often accompanied by severe constitutional symptoms, including fever, fatigue, and
myalgias. The patient may experience pain, itching, or tingling sensations in the genital region for
24 to 48 hours prior to the development of physical
lesions. The emergency clinician should ascertain
whether the patient has had an outbreak before, as
approximately 90% of patients will have had at least
1 recurrence.4 Attention should be given to the level
of pain that the patient is experiencing. Genital lesions are very painful, and this may cause difficulty
with ambulation and urination. Urinary retention
may be a complication of genital herpes and should
be addressed when taking the history.
Herpes Encephalitis
The clinical presentation of herpes encephalitis is
varied and ranges from mild febrile illness with
minimal cognitive impairment to seizures and
death. The typical presentation is a flu-like illness
with fever and headache, altered mental status,
and focal neurologic symptoms. When evaluating a
patient with possible herpes encephalitis, the emergency clinician should inquire about the presence
of headache, fever, and alterations in consciousness. Focal neurological symptoms may be present, including focal weakness, memory loss, and
psychiatric symptoms.
5
Physical Examination
After obtaining a complete history, the physical
examination should be conducted with the patient
undressed and in a hospital gown. A complete
neurological examination should be performed on
all patients, including evaluating for irritability, focal
neurological deficits, and assessment of the anterior
fontanel. The skin should be evaluated for vesicles,
ulcers, or other lesions.
Neonates
Infants with congenital HSV are usually diagnosed
shortly after birth. CNS, cutaneous, and ophthalmologic involvement is noted in 30% to 50% of
intrauterine cases.24,53,54 Other complications include
limb abnormalities, hydrops fetalis, visceral involvement, and intrauterine demise.24
Neonates with peripartum and postpartum HSV
may have a wide variety of clinical presentations,
from a well-appearing febrile neonate to a floridly
ill-appearing patient. Close attention should be paid
to the skin examination, including the former site
of a scalp probe. The skin examination may or may
not reveal vesicles or other skin changes; however,
when present, lesions are characteristically grouped
vesicles on an erythematous base. (See Figure 1.)
They may occur anywhere on the body, but are usually noted on the scalp, nose, mouth, and eyes. It is
important to note that the absence of vesicles does
not exclude HSV disease.28,29
Disseminated HSV, HSV with CNS involvement, and HSV skin, eye, and mouth disease have
varied presentations. Patients with disseminated
disease often present with signs of sepsis, including respiratory collapse, liver failure, disseminated
intravascular coagulopathy, and pneumonitis.
Figure 1. Neonatal Herpes Simplex Virus
Pustules
While the presence of vesicular lesions can aid in
the diagnosis, approximately 20% of patients never
develop cutaneous lesions during the course of the
illness.29,30,55 Clinical manifestations of CNS involvement include seizures, irritability, a bulging fontanel,
and temperature instability. In contrast to patients
with disseminated disease, 60% to 70% of neonates
with CNS disease have skin vesicles at some point in
the disease course,30 and vesicular lesions are present in 80% to 85% of cases of neonatal skin, eye, and
mouth disease.30
Oral Lesions
Herpes labialis will often present with a painful
crusted lesion over the outer vermilion border of the
lip. Herpetic gingivostomatitis presents with multiple round ulcers or erosions that are commonly seen
on the palate, tongue, and gingivae. (See Figure 2.)
Diffuse redness and swelling of the gingiva may be
seen, along with drooling, halitosis, and anorexia.
The lesions may be preceded by a prodrome of generalized malaise and fatigue.
Genital Lesions
Genital herpes classically presents as macules and
papules that progress into vesicles, pustules, and
ulcers. The ulcers overlying the skin crust over,
while those on the mucous membranes heal without
crusting.56 The lesions are painful to the touch. Most
patients with genital herpes will also have inguinal lymphadenopathy. Females may have cervical
involvement, without any external lesions, especially with first-episode disease. Symptoms are often
preceded by a prodrome of fever, headache, malaise,
and myalgias.
Herpes Encephalitis
Herpes encephalitis may have subtle physical findings or the findings may be more overt. Typical
Figure 2. Herpetic Gingivostomatitis
Pustules on an erythematous base scattered on the trunk of a neonate. An annular lesion with pustules and skin peeling are noted.
Reprinted with permission of Paul Hamilton, MD.
Ulcerations with crusting noted on the lower lip.
presentations include altered mental status, fever,
and headache. A thorough neurological examination
may reveal focal deficits including unilateral weakness, ataxia, and cognitive problems (eg, memory
impairment). Cutaneous findings are uncommon.
testing is of little clinical value in neonatal HSV,
since distinguishing between HSV1 and HSV2 does
not change the medical management.
Polymerase Chain Reaction Testing
Polymerase chain reaction (PCR) testing has revolutionized the diagnosis of HSV and can reliably
test cerebrospinal fluid (CSF) and blood for the
presence of infection. The sensitivity and specificity of the CSF PCR is > 95%.65 PCR testing is one of
the modalities recommended by the United States
Centers for Disease Control and Prevention (CDC)
for diagnosing genital HSV.
Kimberlin et al compared PCR results to cultureproven HSV disease in 77 neonates and discussed
PCR use in neonatal herpes.66 In that study, PCR
detected HSV in approximately 25% of infants who
were believed to have isolated skin, eye, and mouth
disease,66 which suggests that neonatal HSV may
represent a disease spectrum rather than 3 distinct
categories (CNS disease; disseminated infection;
and skin, eye, and mouth disease). Overall sensitivities of CSF PCR testing in neonatal HSV range from
75% to 100%, and specificities range from 71% to
100%.30,67,68 In a study of older patients with biopsyproven herpes encephalitis, PCR analysis of CSF had
a sensitivity of 98% and a specificity of 94%.69
The broad range of sensitivities in these studies
can be explained, in part, by the different methods
used in the studies, but false positives and false
negatives can occur, so PCR results must be correlated with the patient’s clinical course.70 The presence of high protein levels or blood in the CSF can
interfere with PCR assays and cause false-negative
results. The detection of HSV in the CSF also decreases markedly after 1 week of antiviral therapy.69
When using the PCR tests on cutaneous lesions, the
sensitivity drops to 80% to 90%, but this may vary
among laboratories.57
Diagnostic Studies
Viral Culture
Viral culture remains the definitive test for the
detection of HSV infection outside of the CNS. It
has a reported sensitivity of 50% and specificity of
nearly 100%.57 The laboratory turn-around time for
viral culture is approximately 3 to 7 days.57 When
evaluating a neonate for HSV disease, surface viral
cultures should be obtained from the mouth, conjunctivae, nasopharynx, and rectum before starting
antiviral therapy. Skin lesions and vesicles should
also be cultured. However, treatment should be initiated based on clinical suspicion rather than awaiting
culture results. Treatment can be tailored, if necessary, based on the results.
Skin or mucous membrane lesions should be
unroofed using a sterile needle or scalpel. The base
of the vesicle should be swabbed using a Dacron® or
rayon swab, and the swab should be firmly rotated
over the base of the vesicle. The swab should then be
transferred to viral media.58,59 No alcohol or cleansing
solutions should be used to clean the lesion prior to
swabbing, and calcium alginate swabs should not be
used, as they are toxic to HSV.59 With recurrent genital and mucocutaneous lesions, the sensitivity of viral
culture is low and declines further as lesions heal.
Serologic Testing
Serologic testing can detect HSV1 or HSV2 in people
with active disease or with a history of prior infection. Of the numerous tests available, the Western
blot is the gold standard. There are also type-specific
serologic tests now available that can distinguish
between HSV1 and HSV2 antibodies.60-63 For these
type-specific tests, the sensitivity has been reported
at 90% to 100% and the specificity between 91% and
100%,60,61,63 which is similar to the Western blot. The
estimated time to results is 1 to 2 weeks.57
Type-specific testing can be used as a supplement to antigen testing or viral culture and may be
used as a point-of-care test to distinguish patients
with HSV-like lesions from patients with HSV. In
patients with genital herpes, the patient’s prognosis
and counseling needs depend on the herpes serotype (HSV1 or HSV2) causing the infection.64 These
tests also allow for the identification of serodiscordant couples (couples in which one partner is HSV2
negative, and the other partner is seropositive).
Uninfected females in serodiscordant couples are at
risk of acquiring HSV2 during pregnancy and transmitting the virus to the neonate at birth. Serologic
Tzanck Smear
The Tzanck smear is one of the oldest and cheapest tests that can assist in the diagnosis of cutaneous HSV infections, but it is rarely used alone for
diagnosis. This testing cannot distinguish between
HSV1 and HSV2 and it cannot differentiate between
HSV and varicella-zoster virus. PCR testing has been
found to be superior to the Tzanck smear; however,
the Tzanck smear remains reliable, with a sensitivity of 76.9% and specificity of 100%.71 Due the low
sensitivity, the Tzanck smear should not be used in
the workup of neonatal HSV, but it may be a quick
and useful test in the diagnosis of cutaneous herpes
infections.71 In order to collect a Tzanck preparation,
the floor of an ulcer is scraped and the obtained material is spread on a glass microscope slide. The slide
is then stained with Giemsa stain. If multinucleated
giant cells are noted, then the test is positive.
7
Direct Fluorescent Antibody Testing
Direct fluorescent antibody (DFA) testing uses an
antibody tagged with a fluorescent agent that forms
an antigen-antibody complex when exposed to an
antigen. Slides can be prepared at the bedside for
DFA testing using the same technique described for
obtaining a viral culture. (See page 7.) Instead of
placing the swab in viral culture media, the swab
is rolled onto the microscope slide. The cutaneous
lesion may also be unroofed and scraped with a
spatula and the material collected can then be spread
onto a slide. The slide should air dry prior to being
sent to the lab. Results can be available in as little as
60 to 90 minutes.72 The sensitivity of DFA is reported
to be 61%, while speciﬁcity is 99%.72
Lumbar Puncture
A lumbar puncture should be performed on neonates and all patients with suspected CNS involvement. CSF should be sent to the lab for cell count
and differential, routine studies to rule out bacterial infection, HSV PCR, and any other diseasescreening studies the emergency clinician feels are
relevant. Red blood cells and xanthochromia may
be seen on CSF studies in patients with CNS HSV
infections, but in 5% to 10% of patients, initial CSF
studies may be normal.73 The presence of red blood
cells in the CSF is not a feature of neonatal infection, even with CNS involvement.27 In most cases
of herpes with CNS involvement, patients have
either an elevated CSF white blood cell count or
elevated CSF protein level.74
The evaluation of neonates with suspected HSV
infection, regardless of category (disseminated; CNS;
or skin, eye, and mouth), should include a lumbar
puncture with CSF studies in order to rule out CNS
involvement. Suspicion for HSV may be heightened
based on the results of this testing. In a retrospective study of 5817 neonates, Caviness et al found
that CSF pleocytosis was more often seen in bacterial meningitis (5.4%) than in HSV infection (1%).75
However, in patients with mononuclear CSF pleocytosis, the presence of HSV was twice as likely (1.6%)
than it was in bacterial meningitis (0.8%).75
Liver Function Tests
In neonates, liver function tests (LFTs) may be
helpful in determining possible HSV infection.
Elevation of serum aspartate transaminase (AST)
levels > 10 times normal have been associated with
increased mortality in neonates with disseminated
herpes.27,32,76 Elevation of LFTs has also been noted
in neonates with disseminated HSV,75,77 and LFT results may serve as a screening tool for disseminated
disease in infants undergoing a sepsis rule-out. Currently, there is no set value for LFTs that correlates
with an increased risk of disease.
Imaging Studies
The use of brain imaging may assist in the diagnosis
of HSV encephalitis, and magnetic resonance imaging (MRI) is the preferred imaging study. Abnormalities on MRI are found in approximately 90% of
patients, with temporal lobe involvement being the
most common. In neonates, involvement may be
seen in the periventricular white matter. However,
early in the illness, the MRI may be normal.78 Computed tomography (CT) scans are less sensitive than
MRI, but they may show changes (such as edema
and hemorrhage). These changes often do not appear until 3 to 5 days into the illness when patients
are often comatose.79 In a study of 12 patients, the
sensitivity of CT for the detection of herpes encephalitis was 75%.80 Imaging studies are not routinely
performed in neonatal HSV, but when brain imaging
is performed, any part of the brain can be involved,
and, often, multiple parts of the brain are involved.
Other Studies
In neonates with CNS herpes infection, and in patients
with herpes encephalitis, electroencephalography
(EEG) is diffusely abnormal. Herpes encephalitis
causes characteristic (though not pathognomonic)
findings on EEG, including focal slowing, spiking, and
lateralizing epileptiform discharges.81 Similar findings
are also noted in neonatal patients with HSV.82
Treatment
Neonates
Prior to the use of antiviral therapy, 85% of neonates
with disseminated HSV disease and 50% of neonates
with CNS disease died within 12 months of diagnosis.31 Vidarabine (Vira-A®) was the first antiviral
medication licensed for use in neonatal HSV. A randomized controlled trial published in 1991 comparing vidarabine with acyclovir found no difference
in morbidity or mortality between patients treated
with either drug.26 Despite the lack of evidence of
therapeutic superiority, acyclovir became the drug
of choice for neonatal HSV due to its more desirable safety profile over vidarabine. Known adverse
events of acyclovir use are nephrotoxicity and
neutropenia. Acyclovir crystals and precipitate in
the renal tubules can cause renal tubular damage
and possible renal failure. It is important to ensure
that the patient is properly hydrated prior to starting
the drug to aid in avoiding nephrotoxicity. Approximately 20% of infants receiving intravenous acyclovir have been noted to develop neutropenia.30
The initial studies of acyclovir used a dosage of
10 mg/kg every 8 hours for 10 days.26,83 The current
recommendation is that neonates with HSV should
be treated with intravenous acyclovir at 20 mg/kg/
dose every 8 hours.30,58 A prospective study of 72
infants with HSV by Kimberlin et al demonstrated
Clinical Pathway For Management Of Herpes Simplex Virus
Infection In Neonates
Neonate presents with any of the following:
• Fever
• History of seizures
• Hypothermia
• More ill than expected
• Irritability
• Vesicles
• Lethargy
• Seizures
• Known exposure to HSV
• Crusting on the scalp
Perform laboratory tests:
• CBC with differential
• Blood culture
• Urinalysis
• Urine culture
• Liver function tests
• Lumbar puncture
Elevated LFTs
or
CSF mononuclear pleocytosis?
YES
NO
Antibiotics only
(Consider acyclovir if suspicion remains high)
Perform surface cultures and HSV CSF and blood PCR testing
(Class I)
Antibiotics AND acyclovir (Class II)
Abbreviations: CBC, complete blood count; CSF, cerebrospinal fluid; HSV, herpes simplex virus; LFT, liver function test; PCR, polymerase chain reaction.
Class Of Evidence Definitions
Each action in the clinical pathway section of Pediatric Emergency Medicine Practice receives a score based on the following definitions.
Class I
Class II
• Always acceptable, safe
• Safe, acceptable
• Definitely useful
• Probably useful
• Proven in both efficacy and effectiveness
Level of Evidence:
Level of Evidence:
• Generally higher levels of evidence
• One or more large prospective studies
• Non-randomized or retrospective studare present (with rare exceptions)
ies: historic, cohort, or case control
• High-quality meta-analyses
studies
• Study results consistently positive and
• Less robust randomized controlled trials
compelling
• Results consistently positive
Class III
• May be acceptable
• Possibly useful
• Considered optional or alternative treatments
Level of Evidence:
• Generally lower or intermediate levels
of evidence
• Case series, animal studies, consensus panels
• Occasionally positive results
Indeterminate
• Continuing area of research
• No recommendations until further
research
Level of Evidence:
• Evidence not available
• Higher studies in progress
• Results inconsistent, contradictory
• Results not compelling
This clinical pathway is intended to supplement, rather than substitute for, professional judgment and may be changed depending upon a patient’s individual needs. Failure
to comply with this pathway does not represent a breach of the standard of care.
Copyright © 2014 EB Medicine. 1-800-249-5770. No part of this publication may be reproduced in any format without written consent of EB Medicine.
9
a statistically significant higher survival rate in
patients treated with the higher dose of acyclovir.30
Premature infants may require increased dosing intervals, based on their creatinine clearance abilities.84
The duration of therapy is 21 days for patients with
disseminated disease or CNS disease and 14 days for
skin, eye, and mouth disease.58
The use of empiric therapy in neonates is debated among experts in the field,58,85 and the practice
of starting empiric antiviral therapy differs among
hospitals. There are several considerations when
choosing to treat for HSV in this manner. Empirically treating all febrile neonates with acyclovir is
costly and not without risks, as infants may experience adverse drug reactions and nephrotoxicity.86
Identifying infants at higher risk for disease is difficult, given that most infants with HSV are born to
mothers who have no history of herpetic infection.35
However, untreated neonatal HSV carries high morbidity and mortality rates, and delaying initiation
of acyclovir has been shown to be associated with
inhospital death.87
Currently, there are no guideline recommendations regarding when to start antiviral medications
in febrile neonates. Caviness et al found that the
prevalence of HSV infection was similar to that of
bacterial meningitis,75 which prompted considerable
debate regarding whether all infants undergoing
sepsis rule-out should receive empiric acyclovir,
since all febrile neonates are empirically covered
with antibiotics. One study found that empiric
acyclovir use in all infants < 21 days of age captured
90% of neonatal HSV cases.88 Kimberlin et al recommend initiating acyclovir therapy for HSV in neonates undergoing a sepsis rule-out if the following
are present: (1) high index of suspicion (presence of
vesicles, seizures, elevation of hepatic transaminases); (2) sepsis-like picture, including hypothermia;
(3) the infant is more ill than expected; and (4) CSF
mononuclear cell pleocytosis is present outside of
enterovirus season (May through October).58 Long
et al concurred with Kimberlin, but limited the age
to < 21 days, added CSF mononuclear pleocytosis
regardless of season, fever ≥ 38ºC without other clear
diagnosis, and purulence or crusting at a former
scalp electrode site.85
With the use of high-dose acyclovir (60 mg/
kg/day), the 24-month mortality for patients with
disseminated neonatal HSV and CNS HSV disease
has decreased to 31% and 6%, respectively.27 However, survivors of neonatal HSV still may have poor
outcomes. Kimberlin et al found that approximately
20% of survivors of disseminated disease and approximately 70% of those with CNS disease had
neurological sequelae 12 months after completion of
treatment with acyclovir. Recent trials have supported the use of suppressive therapy with oral acyclovir
for 6 months after the completion of standard initial
therapy.89,90 The current recommendation for antiviral suppressive therapy after completion of standard
initial therapy is to treat with 300 mg/m2/dose of
oral acyclovir 3 times daily for 6 months. The absolute neutrophil count should be checked at 2 weeks,
at 4 weeks, and then monthly during the 6-month
period to monitor for neutropenia.58 Another widely
used treatment regimen is 1500 mg/m2/dose divided every 12 hours for 12 months.91 Please refer to the
Pediatric Emergency Medicine Practice February 2013
article entitled, "Evaluation Of The Febrile Young
Infant: An Update" for additional information.
Oral Lesions
Antiviral therapy is not routinely used in uncomplicated primary herpetic gingivostomatitis,
as weak evidence exists that acyclovir may be
effective in reducing the number of oral lesions
and/or the development of new lesions.92 Oral
acyclovir, 15 mg/kg, 5 times daily for 7 days may
reduce the severity of disease if it is administered
within the first 72 hours of the onset of symptoms.93 Oral nonsteroidal anti-inflammatory drugs
(NSAIDs) should be used to reduce pain. "Magic
mouthwash," which consists of diphenhydramine,
magnesium hydroxide, and/or viscous lidocaine,
may be used to reduce pain; however, the use of
mouthwashes does not speed recovery.
The treatment of recurrent herpes labialis should
be evaluated on an individual basis, with consideration given to the frequency of recurrences, the
cost of treatment, and the impairment of quality of
life. Treatment options are varied and include topical and oral antiviral therapies. Topical treatment
with penciclovir (Denavir®) and docosanol (Abreva®) have been shown to be of some benefit when
introduced during the prodromal phase. However,
penciclovir has not been approved by the United
States Food and Drug Administration (FDA) for
use in children aged < 18 years, and docosanol has
not been approved for children aged < 12 years.5,93
Episodic systemic therapy has also been shown to be
effective at reducing the severity and frequency of
outbreaks when it is started at the earliest signs of an
outbreak94 or within 24 hours. Long-term suppressive therapy may also be used to reduce the number
of recurrences.93 Table 2 outlines the recommended
therapies for herpes labialis.
Genital Lesions
Antiviral therapy is the mainstay of treatment for
symptomatic genital herpes. However, topical
analgesia, sitz baths, and counseling on methods to
reduce transmission are also important in the clinical
management of these patients. Antiviral drugs can
aid in controlling the signs and symptoms of herpes
outbreaks, but they cannot eliminate the latent virus.
This is essential to remember when treating females
of child-bearing age. The 3 medications proven
to have clinical benefit are acyclovir, valacyclovir
(Valtrex®), and famciclovir (Famvir®). Management
differs, depending on whether the patient has a first
outbreak or a recurrent infection. Table 3 outlines
the recommended treatments for genital HSV.
and valacyclovir are equally effective for suppressive treatment of genital herpes.4 Concerns about
transmission to a partner may also play a role when
choosing a drug regimen for patients. Corey et al
demonstrated that once-daily suppressive therapy
with valacyclovir significantly reduced the risk of
transmission of genital herpes among HSV2-discordant couples. Safety monitoring of the long-term use
of acyclovir, valacyclovir, and famciclovir has been
performed and has confirmed that the drugs are safe
for long-term use.97,98 Drug regimens for suppressive therapy are listed in Table 3.
Another option for treatment is episodic therapy,
in which an antiviral medication is administered
during or just preceding an outbreak. Patients
First-Episode
The first outbreak of genital HSV may cause a prolonged illness with severe genital ulcerations. All
patients with first-episode outbreaks should receive
antiviral therapy within 72 hours of the appearance of lesions.95 Treatment may be extended for
> 10 days if healing is incomplete or if new lesions
continue to form. Patients should be counseled to remain abstinent from sexual activity when prodromal
symptoms or lesions are present. All persons with
genital HSV should be encouraged to inform their
current sexual partner that they have genital HSV,
and should be educated on ways to reduce HSV
transmission to a sexual partner, including proper
condom use and suppressive drug therapy.
Table 3. Recommended Therapy For Genital
Herpes Simplex Infections20,58,95
Recurrent Episodes
The majority of patients with genital HSV2 infections will have recurrent episodes, while those with
genital HSV1 infections have fewer recurrences.4
Recurrences may be symptomatic or asymptomatic, but viral shedding occurs during a recurrence,
regardless of symptoms. Patients may receive suppressive therapy to prevent outbreaks or episodic
therapy to shorten the duration of illness.
Suppressive therapy can reduce the frequency of
recurrences by 70% to 80%.96 Acyclovir, famciclovir,
Classification
Recommended Treatment
Primary genital
herpes
Acyclovir*
• 400 mg PO tid for 10 days
or
• 200 mg PO 5 times/day for 10 days
• Children aged < 12 y: 40-80 mg/kg/day
divided over 3-4 doses for 5-10 days
• Max daily dose: 1000 mg
Famciclovir†
• 250 mg PO tid for 10 days
Valacyclovir
• 1 g PO bid for 10 days
Recurrent genital
herpes (episodic
therapy)
Table 2. Recommended Therapy For Herpes
Labialis Infections In Immunocompetent
Patients20,58,93,95
Classification
Recommended Treatment
Primary herpes labialis
Acyclovir
• 15 mg/kg PO 5 times/day for
5-10 days
Recurrent herpes labialis (episodic therapy)
Recurrent herpes labialis (suppressive therapy)
Famciclovir†
• 125 mg PO bid for 5 days
Valacyclovir
• 500 mg PO bid for 3 or 5 days
or
• 1000 mg PO qd for 5 days
Recurrent genital
herpes (suppressive therapy)
• Acyclovir* 400 mg 5 times/day
for 5 days
• Valacyclovir* 2 g bid for 1 day
• Famciclovir† 125 mg bid for 5
days or 1500 mg qd for 1 day
Acyclovir*
• 400 mg bid
• Children aged < 12 y: 300 mg/m2/dose tid
Famciclovir†
• 250 mg bid
Valacyclovir
• 500 mg qd
or
• 1000 mg qd
Acyclovir
• 400 mg bid or 40-80 mg/kg/day
divided tid
Abbreviations: bid, 2 times per day; q, every; qd, 1 time per day; PO,
by mouth; tid, 3 times per day.
Abbreviations: bid, 2 times per day; q, every; qd, 1 time per day; PO,
by mouth; tid, 3 times per day.
*Non-weight-based dosing recommendations for patients aged ≥ 12
years.
†
Dosing recommendations for patients aged ≥ 18 years.
*Dosing recommendations for patients aged ≥ 12 years.
†
Dosing recommendations for patients aged ≥ 18 years.
Acyclovir*
• 200 mg PO 5 times/day for 5 days
or
• 800 mg PO bid for 5 days
• Max daily dose: 80 mg/kg divided q6-8h
11
should be provided a prescription for a drug regimen to initiate on their own. In order for episodic
treatment to be effective, patients must initiate therapy within 1 day of the onset of lesions or during the
prodrome that some patients experience. Episodic
therapy does not reduce the risk of viral transmission. If transmission is a concern, patients should be
placed on suppressive therapy.
Encephalitis
The drug regimen for the treatment of herpes encephalitis has changed over the years, with acyclovir now being the treatment of choice. Whitley et
al published a randomized controlled trial of 208
patients with brain-biopsy-proven herpes encephalitis and found that acyclovir was more effective
than vidarabine in decreasing mortality rates.83 The
recommended dose of acyclovir is 10 mg/kg every 8
hours for 21 days.58
Vaccine
Presently, there is no effective vaccine to prevent
HSV1 or HSV2 acquisition. There have been several
attempts to develop a vaccine for genital herpes,
and some appear promising. An HSV2 glycoproteinD-subunit vaccine with alum and 3-O-deacylatedmonophosphoryl lipid A was found to be effective in
women who were seronegative for HSV1 and HSV2
prior to receiving the vaccine.99 In another randomized double-blind trial testing the same vaccine in
seronegative women, an efficacy of 58% against
HSV1 genital disease was found, but the vaccine
lacked efficacy against HSV2.100 With continued
research, an effective vaccine may be possible in the
coming years.
Special Circumstances
Eczema Herpeticum
Eczema herpeticum, also known as Kaposi-Juliusberg
varicelliform eruption, is a dermatologic emergency
presenting as a diffuse HSV skin infection, typically
in children or young adults with eczema.101,102 It
is characterized by a diffuse eruption that quickly
develops from vesicles and pustules that become
crusted over.101 (See Figure 3.) Fever, malaise, and
regional lymphadenopathy are often present.93,101-103
The severity is variable, ranging from a mild transient
disease to a fulminant fatal disorder.101,102 Mortality
rates prior to the advent of antiviral medications were
estimated to be between 10% and 50%,101 but today,
mortality rates are < 10%.104 Early identification and
treatment of eczema herpeticum is important, as it
may progress to disseminated disease if untreated.105
Diagnosis is often made clinically and verified with
PCR, viral culture, and/or DFA.103 Acyclovir is the
treatment of choice, and either oral or intravenous
acyclovir can be used, depending on the severity of
the illness. The recommended intravenous dosage is
15 to 30 mg/kg/day divided into 3 doses for 7 to 10
days.103 The recommended oral dose is 30-60 mg/kg/
day divided into 3 doses for 5 to 10 days.106 Antibiotics should be provided to patients in whom bacterial
superinfection is suspected.107 Topical steroids have
not been shown to be associated with worse outcomes
or increased length of stay in children with eczema
herpeticum, and they may be used for treatment,108
especially as combination therapy for control of eczema flare-ups. Ophthalmology should be consulted
emergently if any lesions are near the eye or along the
trigeminal nerve, as keratoconjunctivitis can occur,
which can lead to blindness.
Herpes Gladiatorum
Figure 3. Eczema Herpeticum
Pustules and crusted lesions are noted over the knee.
First reported in the 1960s,109 herpes gladiatorum is
an HSV1 infection that typically occurs in athletes
who participate in contact sports. It is also known as
“wrestler’s herpes,” “mat pox,” or “scrum pox.” Athletes are inoculated with HSV1 through abraded skin
and typically develop cutaneous eruptions on the face,
neck, ears, and upper extremities within 2 weeks of the
contact with the virus.2,110,111 Other symptoms include
facial pain, fever, and lymphadenopathy.111 Treatment
includes oral antiviral medications and restriction from
sports until resolution of the outbreak. Primary outbreaks should be treated with 10 to 14 days of antiviral
medications, while recurrent outbreaks require 5 days
of therapy.112 Any person in contact with an infected
individual during the 3 days prior to the outbreak
should be isolated from contact sports for 8 days and
should be examined prior to return to play.112 Some
evidence suggests that the prophylactic use of valacyclovir during sports camps or a competitive season
may minimize the risk of transmission.113
may have dendritic lesions noted on fluorescein
testing. Index of suspicion for ocular herpes should
be high if any lesion is noted along the trigeminal
nerve. Urgent referral to an ophthalmologist for
diagnosis and treatment is optimal. Treatment varies
with presentation and should be dictated by ophthalmology specialists, when available. Dendritic
or epithelial keratitis can be managed with topical
antiviral agents, such as vidarabine and trifluridine
(Viroptic®) for 10 to 14 days, or with oral acyclovir
400 mg 5 times daily for 10 days.117
Herpetic Whitlow
Herpetic whitlow is a self-limited cutaneous infection that typically occurs on the distal phalanx of
the fingers, and it often affects healthcare workers,
children with primary oral herpes, and adolescents
and adults with genital herpes. The estimated
incidence is 2.4 cases per 100,000 people per year.114
Herpetic whitlow is most commonly transmitted via
direct contact with a herpetic lesion, autoinfection
from nail biting, or contact with HSV-infected bodily
fluids.2,93,94,114 The most common clinical presentation is pain at the affected fingertip. With primary
infection, fever and malaise may also occur. Within 1
to 2 days after the onset of pain, small vesicles may
coalesce to form bullae. (See Figure 4.) After 10 to
14 days, the skin lesions become crusted and peel,
revealing normal skin. Scarring rarely occurs with
herpetic whitlow. Diagnosis is often made clinically,
but can be confirmed with a Tzanck smear measurement of antibody titers to HSV, viral culture, or DFA.
Incision and drainage of the lesion should be avoided, as this may cause increased duration of infection
and increased risk of further infection.115 The area
should remain covered with a dressing to prevent
transmission, and patients should be provided with
analgesics. Data regarding the efficacy of topical or
oral antiviral medications are limited, but in patients
with severe disease, treatment may be beneficial.114
Controversies And Cutting Edge
Although the vast majority of neonatal HSV cases
are acquired in the peripartum period from contact
with secretions from the maternal genital tract, occasionally, neonatal infection is acquired postnatally.
There have been multiple case reports of neonatal
HSV in male infants following out-of-hospital Jewish ritual circumcision.118-120 In Jewish tradition,
male infants are circumcised 8 days after birth by
a mohel in a ritual known as a bris. Mohels receive
specific training on the procedure. In a small subset
of the Orthodox Jewish community, the Mohel orally
sucks the blood after cutting the foreskin, an act
known at mezizah.
In New York City between 2000 and 2011, 11
male newborns were found to have HSV infection
following an out-of-hospital Jewish ritual circumcision. Ten of the 11 newborns were hospitalized, and
Ocular Herpes
Ocular herpes is one of the most common causes
of corneal blindness in the United States.2,94 Infection may cause unilateral or bilateral conjunctivitis.
There are various types of clinical expression of this
disease, each with specific examination findings and
treatment. Epithelial keratitis is the most common
form of ocular HSV infection and accounts for 50%
to 80% of cases.116 Patients with epithelial keratitis
Time- And Cost-Effective
Strategies
• Do not initiate empiric antiviral therapy on all
infants. There are several considerations when
choosing whether or not to empirically treat for
HSV. Empirically treating all febrile neonates
with acyclovir is costly and is not without risks,
as infants may experience adverse drugs reactions and nephrotoxicity.86 Identifying infants
at higher risk for disease is difficult, given that
most infants with HSV are born to mothers who
have no history of herpetic infection.35 When
evaluating an infant for a sepsis rule-out, there
are many opinions regarding when to start empiric acyclovir. A suggested algorithm for starting acyclovir in neonates is included on page 9.
• Combine viral surface cultures for neonatal herpes. Viral swabs from the conjunctiva,
mouth, nasopharynx, and anus (anal swab
should be performed last) may be collected
with single swab and placed in a viral transport
media tube. The presence or absence of viral
replication is the key indicator of HSV.
Figure 4. Herpetic Whitlow
Small vesicles and bullae on a red base are noted on the fingertip.
13
Risk Management Pitfalls For Herpes Simplex Virus Infections
1. “The mother of the ill-appearing 15-day-old
infant did not have a history of herpes, so the
infant most likely has a bacterial infection rather
than neonatal herpes.”
Almost two-thirds of women who acquire genital
herpes during pregnancy are asymptomatic
and have no clinical findings to suggest genital
HSV infection, as they have never had an
HSV outbreak, nor have their partners had an
outbreak.28,29,39,122
2. “The lumbar puncture was not bloody, so the
patient probably does not have HSV.”
While the presence of red blood cells and
xanthochromia on a lumbar puncture may be seen
on CSF studies in patients with HSV encephalitis
or CNS involvement, 5% to 10% of patients have
normal CSF studies. Red blood cells in the CSF
is not a feature of neonatal infection, even with
CNS involvement.27 PCR should be completed on
the CSF of all patients suspected of having HSV
encephalitis or CNS involvement.73 In most cases
of herpes with CNS involvement, patients have
either an elevated CSF white blood cell count or
elevated CSF protein level, which may heighten
the emergency clinician’s suspicion for CNS
herpes infection.74
3. “The 3-day-old infant had pustules on the skin,
so he probably has neonatal herpes.”
The presence of pustules on an infant does not
necessarily mean the patient has HSV. Pustular
melanosis and erythema toxicum are both benign
pustular eruptions that can mimic HSV.
4. “The baby was born via cesarean delivery, so
herpes does not need to be ruled out.”
While cesarean delivery has successfully reduced
the number of neonatal herpes cases, HSV may be
transmitted to an infant despite cesarean delivery.
5. “I did not see any dendrites on the fluorescein
examination, so the patient does not have ocular
herpes.”
All patients who are suspected of having
ocular herpes should be evaluated by an
ophthalmologist. Findings may be subtle, and
those with expertise in the evaluation of the
cornea should be involved when there is any
clinical concern for ocular HSV infection.
6. “The child had swelling and pain near the fingertip, so I performed an incision and drainage.”
Routine incision and drainage is not recommended
in patients with herpetic whitlow. Herpetic whitlow
is a self-limited disease. Vesicles may be unroofed
to help relieve symptoms, but deep incisions should
be avoided.
7. “No lesions are visible on the external genital
examination, so the patient does not have a herpes
outbreak.”
Patients with herpes outbreaks may not have
lesions visualized on external examination. If
lesions are not noted, a pelvic examination should
be performed to evaluate for the presence of
cervical lesions.
8. “The Tzanck prep was negative on the skin lesion
of the 15-day-old infant, so HSV was ruled out.”
While the Tzanck prep may be a relatively reliable
test for cutaneous lesions, it does not definitively
rule out neonatal herpes. If suspicion is high for
neonatal herpes infection, infants require the
following testing: (1) CSF for indices; (2) HSV PCR
and bacterial culture; (3) viral culture swabs from
the base of any vesicles as well as swabs from the
mouth, conjunctiva, nasopharynx, and rectum; (4)
HSV PCR on whole blood; and (5) LFTs.
9. “The CT scan on the febrile teenager with altered
mental status was negative, so HSV PCR does not
need to be sent on the CSF.”
CT scans are less sensitive than MRI, but they may
show changes (such as edema and hemorrhage) in
patients with herpes encephalitis. However, early in
the illness, CT and MRI may be normal, so clinical
suspicion should guide management and workup.
10. “LFTs are not part of the routine sepsis rule-out.
They play no role in the evaluation of febrile
infants.”
Elevation of serum aspartate transaminase levels
> 10 times normal have been associated with
increased mortality in neonates with disseminated
herpes.27,32,76 Elevation of LFTs have been noted
in neonates with disseminated HSV75,77 and
LFT levels may serve as a screening tool for
disseminated disease in those infants undergoing
a sepsis rule-out.
2 died. Analysis of the cases of neonatal HSV that
were reported to the New York City Department
of Health and Mental Hygiene from April 2006 to
December 2011 demonstrated that the risk of contracting HSV following ritual Jewish circumcision
involving direct orogenital suction was 3.4 times
greater than in infants who did not receive direct
orogenital suction.121 Many Orthodox ritual circumcisers have modified the practice to avoid direct oral
suction, but a minority of mohelim continue this
practice today.
have greatly improved the efficacy and tolerability of treatment of HSV infections, prevention of
disease, either by reducing transmission rates or by
the development of a vaccine, should remain the
primary goal.
Case Conclusion
A full sepsis workup was completed on the patient. Her
CSF differential was notable for a mononuclear cell
pleocytosis, and her LFTs were elevated. You started her
on empiric antibiotics, and you explained to the medical
student that the elevated LFT results and mononuclear
cell pleocytosis increased your suspicion for neonatal
HSV, so you also started empiric acyclovir. Blood and
urine cultures were negative at 48 hours, but her CSF
HSV PCR was positive. She was admitted to the hospital and continued on intravenous acyclovir for 21 days.
After that point, she was discharged home on suppressive oral acyclovir.
Disposition
The disposition of a patient with HSV infection
depends upon the age of the patient, the location of
the infection, and any comorbid illnesses that the
patient may have. The neonate with presumed or
confirmed HSV infection and the patient with presumed or confirmed herpes encephalitis should be
hospitalized for monitoring and parenteral acyclovir. The majority of patients who present with oral
HSV lesions can be discharged home. The exception is the dehydrated or immunocompromised
child. Emergency clinicians should ensure that
patients with oral lesions can tolerate liquids prior
to discharge. Most immunocompromised patients
should be hospitalized for intravenous antiviral
medications to prevent overwhelming spread of
infection. Patients with genital lesions should be
evaluated for urinary retention and efficacy of pain
control. Any patient who is exhibiting or endorsing
urinary retention due to HSV infection or patients
with poor pain control on oral analgesics should
be hospitalized for supportive care. Additionally,
partner treatments should be arranged prior to
discharge. Mothers of infants with neonatal herpes
should follow up with a primary care physician or
gynecologist for further management.
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and outcomes of children hospitalized with eczema herpeticum. Pediatr Dermatol. 2013;30(2):207-214. (Retrospective;
1150 patients)
108. Aronson PL, Shah SS, Mohamad Z, et al. Topical corticosteroids and hospital length of stay in children with eczema
herpeticum. Pediatr Dermatol. 2013;30(2):215-221. (Retrospective; 1331 patients)
109. Selling B, Kibrick S. An outbreak of herpes simplex among
wrestlers (herpes gladiatorum). N Engl J Med. 1964;270:979982. (Retrospective; 6 patients)
110. Likness LP. Common dermatologic infections in athletes and
return-to-play guidelines. J Am Osteo Ass. 2011;111(6):373379. (Review)
111. Anderson BJ. Managing herpes gladiatorum outbreaks in
competitive wrestling: the 2007 Minnesota experience. Curr
Sports Med Rep. 2008;7(6):323-327. (Review)
112. National Federation of State High School Associations
SMAC. Sports-related skin infections position statement and
guidelines. 2013. Available at: http://www.mshsaa.org/
resources/ pdf/2013%2020Skin.pdf. Accessed July 20, 2013.
(Clinical practice guidelines)
113. Anderson BJ. Prophylactic valacyclovir to prevent outbreaks
of primary herpes gladiatorum at a 28-day wrestling camp.
Jpn J Infect Dis. 2006;59(1):6-9. (Prospective; 94 patients)
114. Gill MJ, Arlette J, Buchan K. Herpes simplex virus infection
of the hand. A profile of 79 cases. Am J Med. 1988;84(1):89-93.
115. Feder HM Jr, Long SS. Herpetic whitlow. Epidemiology,
clinical characteristics, diagnosis, and treatment. Am J Dis
Child. 1983;137(9):861-863. (Case series; 8 patients)
116. Wilhelmus KR. Antiviral treatment and other therapeutic
interventions for herpes simplex virus epithelial keratitis.
Cochrane Database Syst Rev. 2010(12): CD002898. (Meta-analysis; 106 trials, 5872 eyes)
117. Collum LM, McGettrick P, Akhtar J, et al. Oral acyclovir
(Zovirax) in herpes simplex dendritic corneal ulceration. Br J
Ophthalmol. 1986;70(6):435-438. (Prospective; 60 patients)
118. Distel R, Hofer V, Bogger-Goren S, et al. Primary genital
herpes simplex infection associated with Jewish ritual circumcision. Isr Med Assoc J. 2003;5(12):893-894. (Case study; 1
patient)
4. Which of the following statements regarding
genital herpes is TRUE?
a. The majority of cases are caused by HSV1.
b. External lesions may not be noted during an outbreak.
c. Episodic treatment can prevent transmission to sexual partners.
d. There is no indication for hospitalization for genital herpes.
119. Rubin LG, Lanzkowsky P. Cutaneous neonatal herpes
simplex infection associated with ritual circumcision. Pediatr
Infect Dis J. 2000;19(3):266-268. (Case studies; 2 patients)
120. Gesundheit B, Grisaru-Soen G, Greenberg D, et al. Neonatal
genital herpes simplex virus type 1 infection after Jewish
ritual circumcision: modern medicine and religious tradition.
Pediatrics. 2004;114(2):e259-e263. (Retrospective; 8 patients)
121. Neonatal herpes simplex virus infection following Jewish
ritual circumcisions that included direct orogenital suction
- New York City, 2000-2011. MMWR Morb Mortal Wkly Rep.
122. Brown ZA, Selke S, Zeh J, et al. The acquisition of herpes simplex virus during pregnancy. N Engl J Med.
5. Which of the following tests is important for
the evaluation of neonatal HSV?
a. CSF PCR
b. Surface cultures
c. Liver function tests
d. All of the above
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for the diagnosis of neonatal HSV involving
the CNS?
a. Type-specific serology
b. Viral culture
c. Tzanck smear
d. PCR assay
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7. What is the recommended initial standard therapy dose of acyclovir to treat neonatal herpes?
a. 10 mg/kg/dose every 8 hours
b. 20 mg/kg/dose every 8 hours
c. 60 mg/kg/dose every 8 hours
d. 30 mg/kg/dose every 8 hours
8. The recommended duration of standard initial
treatment for neonatal CNS HSV infection is:
a. 10 days
b. 14 days
c. 21 days
d. 30 days
1. Which of the following statements is most accurate?
a. HSV1 is usually acquired in adulthood.
b. The majority of people in the United States have a history of genital herpes.
c. The majority of people in the United States have antibodies to HSV1.
d. The main cause of genital herpes is HSV1.
9. In herpes encephalitis patients, there is no
difference in outcome for patients treated with
vidarabine versus patients treated with acyclovir.
a. True
b. False
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transmission of HSV to a neonate?
a. Prolonged rupture of membranes
b. Use of fetal scalp monitors
c. Primary maternal HSV infection
d. All of the above
10. A lesion noted along the distribution of the trigeminal nerve should raise concern for ocular
herpes infection.
a. True
b. False
3. What percentage of mothers who have an
infant with neonatal HSV did not know they
were infected with the virus?
a. < 10%
b. 10% to 20%
c. 30% to 50%
d. 60% to 80%
19
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Pediatric Herpes Simplex Virus Infections: An Evidence

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