THERAPY IN PRACTICE Pediatr Drugs 2002; 4 (1): 9-19

1174-5878/02/0001-0009/$25.00/0

© Adis International Limited. All rights reserved.

Viral Diseases of the Skin

Diagnosis and Antiviral Treatment
Zoltan Trizna
Department of Dermatology, Texas Tech University, Health Sciences Center, Lubbock, Texas, USA

Contents
Abstract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9
1. Laboratory Diagnosis of Cutaneous Viral Infections . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10
2. Overview of the Antivirals Used in the Treatment of Cutaneous Infections . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11
3. Herpes Virus Infections . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11
3.1 Herpes Simplex Virus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11
3.2 Genital Herpes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13
3.3 Varicella (Chickenpox) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14
3.3.1 Varicella: Post-Exposure Prophylaxis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14
3.3.2 Varicella in Immunocompromised Patients . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15
3.3.3 Varicella in Pregnancy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15
3.4 Herpes Zoster (Shingles) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15
3.5 Other Herpes Virus Infections . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16
4. Human Papillomavirus Infections . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16
5. Molluscum Contagiosum . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17
6. Other Localized Poxvirus Infections of the Skin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17
7. Systemic Viral Infections with Mucocutaneous Manifestations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17
8. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18

Abstract Viral diseases in children can present with characteristic mucocutaneous manifestations. This article focuses,
from a practical clinical point of view, on the laboratory and clinical diagnoses, and treatment of pediatric
dermatological diseases that have specific antiviral therapies: herpes virus infections (including varicella),
papillomavirus infections and molluscum contagiosum.
Special issues, such as viral infections in pregnancy, therapy of viral infections in immunosuppressed chil-
dren, as well as special problems associated with the epidemiology of genital herpes and papillomavirus infec-
tions in adolescents are discussed.
The antivirals discussed in detail include: aciclovir, valaciclovir, famciclovir, penciclovir, cidofovir, foscar-
net and the immune response modulator, imiquimod. Since these antiviral drugs generally have not been eval-
uated in children, caution should be exercised with their usage.

Viral infections, both mucocutaneous and systemic, are com-
mon in children. Mucocutaneous manifestations of viral diseases
in children can reflect changes of virus-laden cells (e.g. verrucae),
with typical appearance and distribution. Systemic viral infec-
tions (e.g. measles) can show characteristic distribution, sequence
of appearance and other clinical correlations that are often helpful
in establishing the diagnosis. However, systemic viral infections
(e.g. hepatitis B) can also result in nonspecific viral exanthems in
children.
Historically, prevention in the form of immunization has been
very effective against certain viral infections (e.g. smallpox). The
live varicella vaccine has increasingly been used throughout North
America and in some European countries. There are promising trials
of active immunizations underway against herpes- and retro-virus
infections. In addition, there are successful animal models for
species-specific papillomavirus vaccinations. Selected immuni-
zations are reviewed in table I.
Recently developed antiviral agents have made it possible to
specifically target viral infections. This article focuses on pediat-
ric cutaneous diseases that have specific antiviral therapies. Cau-
10 Trizna

Table I. Vaccinations for viral diseases with cutaneous manifestations[1] fections (e.g. verrucae), whereas viral exanthems show only non-
Varicella Between 12 and 18 months of age or at age specific changes.
11-12 years if there is no reliable history of Detection of papillomaviruses is available in specialized lab-
immunization.
For those >13 years, two doses of the vaccine
oratories and research settings. Polymerase chain reaction (PCR)
(at least 1 month apart) are recommended can be applied to swabs from lesions. It has high sensitivity and
Measles-mumps-rubella First dose: between 12 and 15 months of age can be used to study nonviable biological materials. Commercial
Second dose: between 4 and 6 years or 11
papillomavirus typing is performed by using RNA probes for
and 12 years of age
Hepatitis B First dose: within 2 months of birth
viral DNA. Using this technique, one can differentiate between
Second dose: between 1 and 4 months of age the >80 human papillomavirus (HPV) types. Detection of onco-
Third dose: between 6 and 18 months of age genic HPV types may necessitate close follow-up of such patients
Those who have not been previously immunized
should be vaccinated at age 11-12 years
to allow early detection of cancers potentially developing in HPV-
infected areas. HPV typing can help in evaluating child abuse.[2]
However, the issue of child abuse should be approached with
tion should be exercised when using antiviral medications be-
caution since a significant number of genital HPV infections are
cause they have generally not been evaluated in children <18
thought to be either transmitted at birth or caused by transmitting
years of age. Therefore, because of the lack of data in children, it
the virus from the hand of a caretaker.
is difficult to provide appropriate dosages of these new therapies
The umbilicated papules of molluscum contagiosum are so
in this patient group.
clinically characteristic that usually no biopsies are performed. A
The therapy of viral infections in immunosuppressed patients
(e.g. children with AIDS, neonates, children treated with cortico- quick ascertainment of the diagnosis can be achieved by staining
steroids and antineoplastic agents) is a specialized field. For de- of the contents of the papules. The inclusion bodies are easily
tails of immunizations, use of corticosteroids, symptomatic relief, visualized in such cytological preparations.
and the continuously evolving field of antiretroviral therapy, we Detection of specific or nonspecific immunoglobulins in the
refer the reader to the current pediatric literature. sera can be a useful adjunct for confirming the diagnosis or for
following the activity of a viral infection. Even though such meth-
ods are not routinely used in dermatological practice, specific
1. Laboratory Diagnosis of Cutaneous immunoglobulin M antibody tests can be used for the diagnosis
Viral Infections of current or recent infections, e.g. rubella and parvovirus B19.
The Tzanck smear (figure 1) detects multinucleated giant Type-specific antibody tests are especially valuable for classify-
cells in cytological preparations obtained from the base of vesi- ing first episodes and for diagnosing subclinical, asymptomatic
cles. Whereas this simple, fast and inexpensive method of detect- or unrecognized genital HSV-infections.[3]
ing herpes virus infections is not specific (i.e. does not differen- Electron microscopy can also be used to demonstrate poxvi-
tiate herpes simplex from herpes zoster), the clinical correlation rus infections (malluscum contagiosum, orf and cowpox).
increases diagnostic accuracy. The Tzanck smear can be performed
in any office, but its evaluation requires some experience in path-
ology.
Specific immunological assays can differentiate between her-
pes simplex virus (HSV)-1, HSV-2 and varicella-zoster virus
(VZV). The specimen (a swab from the base of the lesion put into
an appropriate transport medium) can be collected by commer-
cially available kits and evaluated by expert laboratory services.
The results are usually obtained within a few hours.
Viral cultures have to be collected in special media and sent
to a specialized laboratory. The results can usually be obtained in
a few days.
Biopsies are infrequently used for the diagnosis of childhood
viral diseases. Characteristic giant cells can be seen in HSV/VZV
infections, and viral cytopathic changes can be seen in other in- Fig. 1. Tzanck preparation: note the multinucleated giant cells.

© Adis International Limited. All rights reserved. Pediatr Drugs 2002; 4 (1)
Antivirals in Pediatric Dermatology
2. Overview of the Antivirals Used in the Treatment
of Cutaneous Infections
There are several antivirals of the ‘ciclovir’ group on the
market.
The guanine-analogues valaciclovir (the prodrug of aciclovir)
and famciclovir (the prodrug of penciclovir) have higher bio-
availability than their metabolites. These drugs are dependent on
the viral thymidine kinase for their first step of intracellular acti-
vation. Further steps of phosphorylation convert these drugs into
their triphosphate form and in these forms they act as: (i) inhibi-
tors of viral DNA synthesis; and (ii) alternative substrates of the
viral DNA polymerase. Thymidine kinase-deficient viral mutants
are aciclovir-resistant and a cross-resistance to these antiviral drugs
may be expected.[4]
Aciclovir has US Food and Drug Administration (FDA) ap-
proval for the following pediatric mucocutaneous viral diseases:
• initial and recurrent episodes of HSV infections in immuno-
compromised patients
• severe initial episodes of genital HSV infections in immuno-
competent patients
• varicella infections in immunocompromised or immunocom-
petent children
• acute herpes zoster in immunocompetent children.
It is important to remember that the dosage of the above
systemic antiviral agents generally has to be adjusted according
to renal function.
Cidofovir, an acyclic nucleoside phosphonate, is effective
against thymidine kinase–deficient VZV mutants because it is
converted by cellular enzymes (rather than by the viral thymidine
kinase) to the diphosphoryl derivatives that are responsible for
the selective inhibition of viral DNA synthesis. Cidofovir is ef-
fective against several DNA viruses, including HPV. In case re-
ports, the efficacy of topical and intralesional cidofovir has been
demonstrated, including the treatment of classical Kaposi’s sar-
coma in an HIV-negative patient[5] and in immunocompromised
patients with molloscum contagiosum.[6]
Other thymidine kinase–dependent nucleoside analogues in-
clude sorivudine, brivudine, fialuridine, fiacitabine and netivudine.
Oxetanocins represent another class of antivirals, with lobucavir
being currently evaluated clinically in the treatment of VZV infec-
tions.[4] Of these agents, only brivudine is available and approved
for clinical use in some countries.
Foscarnet blocks the pyrophosphate binding site on DNA
polymerases (and reverse transcriptases) without requiring any
metabolism. It is used for the treatment of cytomegalovirus (CMV)
retinitis and in the therapy of aciclovir-resistant VZV.[4]
Imiquimod is a new immune response modifier. Imiquimod
induces the production of cytokines (with interferon-α being the
© Adis International Limited. All rights reserved.
11
principal one for antiviral activity) and this leads to a reduction
of HPV load and regression of the verrucous lesions.[7]
These newer medications have not been tested in children.
FDA-approved indications are reviewed in table II.
3. Herpes Virus Infections
The herpes virus family includes HSV-1 and -2, Epstein-Barr
virus (EBV), CMV, human herpes virus (HHV)-6, -7 and -8, as
well as the VZV.
3.1 Herpes Simplex Virus
HSV-1 and -2 are large enveloped DNA viruses that can be
cultured and differentiated by laboratory techniques. In the past,
HSV-1 was mainly causing herpes labialis and nongenital herpes
virus infections, whereas HSV-2 was related to genital herpes.
Probably because of changing sexual habits and promiscuity,
there are more and more ‘crossovers’, i.e. HSV-1 causing genital
lesions and HSV-2 resulting in oral infections.
Primary HSV infections occur in patients without circulating
antibodies. The incubation period is usually 1 week. The infection
can result in: (i) an asymptomatic course, leading to the develop-
ment of antibodies; (ii) localized or general eruption; and (iii)
serious systemic disease, including encephalitis. After the pri-
mary infection, the virus persists in sensory nerve ganglia where
it may reactivate and cause recurrent disease.
Recurrent HSV infections, in general, are precipitated by an
event of stress, ranging from emotional stress, sunburn, menstru-
ation, localized trauma, to any febrile illness. These infections
tend to present in the same site as the primary infection, tend to
be less severe, and usually do not have constitutional symptoms.
Antiviral agents can shorten the duration of clinical illness
and viral shedding and reduce both morbidity and mortality.[8]
Generally, oral treatment is recommended in patients who have
significant symptoms but whose illness is not life-threatening.
Children with life- or sight-threatening infections should be hos-
pitalized and treated with intravenous antivirals.[9]
Herpes labialis (fever, blisters, cold sores) is the most com-
mon clinical form of herpes virus infections. The painful pro-
drome can be accompanied by general symptoms before the de-
velopment of the characteristic grouped vesicles on an
erythematous base (figure 2). The use of prophylactic topical or
oral aciclovir is usually ineffective.[8]
Herpetic gingivostomatitis presents with generalised symp-
toms and signs; a shallow grey ulcer surrounded by red halo, often
accompanied by halitosis and dysphagia. Whereas the fever usu-
ally subsides within 5 days, the oral lesions can persist for up to
2 weeks. Therapy is supportive, including symptomatic treatment
Pediatr Drugs 2002; 4 (1)
12 Trizna

Table II. Food and Drug Administration-approved applications and recommended adult doses of aciclovir, valaciclovir and famciclovir (current as of 2001)
Drug Indication and route of treatment Dosage
Aciclovira Herpes simplex (mucocutaneous) – intravenous 750 mg/m2/day divided into 3 doses, or 5 mg/kg every 8 hours for 5-10 days
Herpes simplex (herpes genitalis, initial episode 200mg every 4 hours, 5 times daily for 7-10 days
and mucocutaneous herpes) – oral
Herpes genitalis, recurrent (current suppressive 400mg twice daily for up to 12 months, followed by re-evaluation in 1 year
therapy)
Herpes genitalis, recurrent (episodic therapy) 200mg every 4 hours, 5 times daily for 5 days, initiated at the earliest sign of
symptoms and recurrence
Chickenpox (in children ≥2 years of age) 20 mg/kg doses orally 4 times daily for 5 days (children >40kg should receive the
adult dosage for chickenpox, i.e. 800mg 4 times daily for 5 days)
Shingles (zoster) – intravenous The maximum dose is 20 mg/kg every 8 hours. The length of therapy and dosage
should be selected according to the clinical situation
Shingles (zoster) – oral 800mg every 4 hours orally 5 times daily for 7 to 10 days
Valaciclovirb Genital herpes (initial episode) 1g twice daily for 10 days
Genital herpes, recurrent (suppressive therapy) 500mg daily for 5 days if no more than nine episodes per year; 500mg twice daily if
– oral 10 or more episodes per year
Genital herpes, recurrent (episodic therapy) 500mg twice daily for 5 days
Herpes zoster 1g orally 3 times daily for 7 days (therapy should be initiated at the earliest sign or
symptoms of herpes zoster and is most effective when started within 48 hours of,
but no later than 72 hours after, the onset of eruption)
Famciclovirc Genital herpes, recurrent (suppressive therapy) 250 mg orally, twice daily for up to one year
Genital herpes, recurrent (episodic therapy) 125mg twice daily for 5 days, initiated at the first sign or symptom
Herpes zoster 500mg every 8 hours for 7 days (therapy should be initiated upon diagnosis of zoster,
preferably within the first 48-72 hours)
a Therapy with aciclovir should begin immediately after the first symptoms are noticed, but no later than 72 hours thereafter. Intravenous aciclovir is indicated for the treatment
of varicella-zoster infections in immunocompromised patients. Orally administered aciclovir in children <2 years of age has not been fully studied. Dosages should be modi-
fied in the case of renal impairment.
b Valaciclovir therapy of genital herpes should begin at the first sign or symptom of an episode, but no later than 24 hours thereafter. Dosages should be modified in the case of
renal impairment. Tolerability and effectiveness of valaciclovir in pediatric patients have not been established.
c The pharmacokinetics, tolerability, or effectiveness of famciclovir (or penciclovir) have not been evaluated in patients <18 years of age.

of pain (e.g. lidocaine in viscous base). In the immunosuppressed
or severely affected patient, antivirals are indicated. Oral aciclo-
vir (15 mg/kg 5 times daily for 7 days), started within the first 3
days of onset of symptoms, shortens the duration of all clinical
manifestations and the infectivity of affected children.[10]
Herpetic keratoconjunctivitis and keratitis are primary her-
pes virus-infections of the eyes. Herpetic keratitis (and its poten-
tial sequelae, secondary infection or ulceration) is one of the lead-
ing causes of unilateral blindness. Severe purulent conjunctivitis
may be seen with vesiculation, erythema and edema, leading to
corneal erosions or ulcerations. Pain, photophobia and lacrima-
tion are the rule. Visual impairment can result from persistent
secondary infection or ulceration. Systemic or topical corticoste-
roids may enhance the dissemination of the virus and can, there-
fore, lead to a more serious disease. Current guidelines state that
topical and systemic corticosteroids are absolutely contraindi-
cated in herpetic keratoconjunctivitis. Specific therapy includes
ophthalmic formulations of idoxuridine, trifluridine, aciclovir and
vidarabine. In cases of severe involvement of the eyes, systemic
antiviral therapy is indicated. Oral aciclovir has recently been
reported to be useful in treating HSV keratitis in pediatric pa-
tients.[11]
Neonatal herpes usually results from the transmission of
HSV from the infected mother to the infant. This usually occurs
during childbirth when the infant comes in contact with an active
lesion. However, caregivers who are HSV carriers can also trans-
mit HSV to the neonate. There were approximately 11 cases of
neonatal HSV per 100 000 live births from 1985 to 1995 in Cali-
fornia.[12] Neonatal herpes is potentially life-threatening to an
infant with disseminated infection. Early diagnosis and antiviral
treatment are indicated.[8]
Herpes gladiatorum is a special type of herpes infection, re-
sulting from transmission of the virus between exposed surfaces
of the head and neck, limbs and trunk during contact sport activ-
ities (e.g. wrestling and rugby football). The clinical manifesta-
tions are the same as in other herpes virus infections. Prevention
is important; the athletes, their parents and coaches should be
educated that any herpetic lesion is a potential source of risk to
others by direct contact. This should be treated as a primary her-
pes virus infection.

© Adis International Limited. All rights reserved. Pediatr Drugs 2002; 4 (1)
Antivirals in Pediatric Dermatology
Herpetic whitlow is the result of primary cutaneous inocula-
tion of HSV. It is not uncommon in children and can be prevented
by avoiding contact with the active herpetic lesions of another
individual. Superficial vesicles and/or pustules can be seen. Deeper
lesions can be extremely painful. There is usually a characteristic
white-blue swelling, sometimes characterized as having a ‘honey-
combed’ appearance. Treatment with oral aciclovir was shown to
accelerate healing in adults.[8]
Kaposi’s varicelliform eruption (eczema herpeticum) is a
rare form of herpes virus infection in patients with atopic derma-
titis, Darier’s disease, or other syndromes affecting the epithelial
barrier. The skin usually shows umbilicated vesicles in the areas
affected by the underlying disease. In addition to oral antiviral
agents in milder cases, symptomatic measures and prevention of
secondary infections are important. Severe cases should be
treated with intravenous antivirals.
HSV-associated erythema multiforme is a recurrent disease.
It can be precipitated by sun exposure or other stressful events. It
does not usually progress to Stevens-Johnson syndrome. HSV-
associated erythema multiforme may be unresponsive to treat-
ment; however, oral aciclovir (20 mg/kg/day) can be beneficial
in its prophylaxis.[13]
Herpetic geometric glossitis is a recently described form of
HSV-1 infection of the tongue in immunosuppressed patients. It
usually completely resolves after oral aciclovir (1000 mg/day, in
Fig. 2. Herpes simplex on the buttocks of a child.
© Adis International Limited. All rights reserved.
13
5 divided doses in children); however, in some cases higher doses
may be required.[14]
HSV infection in pediatric burn patients is most likely to
occur in the areas of healing partial thickness wounds, and donor
sites. Treatment includes intravenous aciclovir, wound care and
the prevention of nosocomial spread.[15]
Folliculitis attributable to HSV may be a sign of immunosup-
pression.[16] Folliculitis or folliculitis-like dermatoses, refractory
to anti-infective and anti-inflammatory treatment, should be biop-
sied. Finding HSV (or molluscum contagiosum) should raise the
possibility of an underlying immunosuppression and more exten-
sive workup of these patients is indicated. Specific antiviral ther-
apy should be considered.
3.2 Genital Herpes
The incidence of genital herpes has shown an alarming in-
crease in the US and Europe, especially in adolescents and young
adults. Genital HSV- or HPV-infections of children can occur as
a result of sexual abuse; however, it is not clear what proportion
of the cases could have resulted from sexual abuse or transmission
by other means,[17] e.g. by transmission from an infected caregiver’s
hand.
With the changing epidemiology of genital HSV-infections,
not only is there a rising rate of HSV-2 infection but there is an
increasing incidence of first episodes caused by HSV-1.[18] It should
be noted that these data are different in every country. Whereas
symptoms of primary HSV-1 and -2 genital infections are similar,
recurrence of the infection is less frequent in patients with HSV-1
infection.[19] 60 to 90% of patients with HSV infection are not
aware (or deny) that they have genital herpes, even though at least
half have a history of recurrent typical genital lesions.[20]
The prodrome is characterized by general symptoms, regional
lymphadenopathy, and burning pain of the genitalia. Vesicles are
usually grouped on an erythematous base. They tend to lead to
erosions and by coalescing they can form ulcers, accompanied by
edema and pain. It is important to remember that the lesions of
herpes genitalis can be found inside the vagina and on the cervix.
This is especially important at the time of childbirth.
In adults, treatment of the first episode of genital herpes re-
duces the severity and duration of symptoms, time to lesion heal-
ing and cessation of viral shedding. Aciclovir (200mg orally, 5
times daily) and valaciclovir (1g orally, twice daily) were found
to be beneficial in adults. Episodic treatment of recurrences may
be of benefit to some patients. Daily suppressive therapy reduces
the frequency of recurrences and asymptomatic viral shedding. It
is reasonable to suggest that early institution of similar strategies
in adolescents with genital herpes will have important implica-
Pediatr Drugs 2002; 4 (1)
14 Trizna

tions for public health and may help in reducing the psychological
and psychosocial impact of genital herpes on individual patients.[21]
Recurrent genital herpes is becoming an issue of greater im-
portance with the increasing incidence and prevalence of genital
HSV infections. This emphasizes the importance of early diagno-
sis and treatment of genital herpes in the sexually active popula-
tion. Education regarding risks of sexually transmitted diseases
cannot be neglected in the adolescent population. Frequent recur-
rences can have a significant impact on the well-being of the
young patients. Suppressive therapy with oral aciclovir, valaci-
clovir, or famciclovir have been reported to be beneficial in pa-
tients with recurrent genital herpes. Not only were both the fre-
quency and severity of symptomatic outbreaks decreased but the
frequency of asymptomatic virus shedding was also reduced.[8]

3.3 Varicella (Chickenpox)

VZV is a member of the herpes virus family. It causes pri-

mary infections (varicella, chickenpox) as well as reactivation in-
fections (herpes zoster, shingles). Varicella is generally benign in
immunocompetent patients.
Chickenpox is a highly contagious disease of childhood and
is transmitted by close contact and droplets from the respiratory
tract. A 2-week incubation period is followed by general symp-
toms. Characteristic is the simultaneous presence of lesions of all
stages and sizes (figure 3) with a centripetal distribution; the maculo-
papular eruption initially appears on the head and neck, spreads
rapidly to the trunk, while the extremities are relatively spared.
The vesicles are on an erythematous base and are referred to as
‘teardrops’ or ‘dewdrops on a rose petal’. Typically, the vesicles
rapidly progress to crusted pustules. Scarring is rare in uncompli-
cated varicella.
Active immunization can be achieved with a live attenuated
virus (of the Oka strain). Vaccination is recommended for healthy
children, and patients with chronic diseases, leukaemia in remis-
sion and those receiving immunosuppressive therapy. The vac-
cine may also prevent herpes zoster and the associated neural-
gia.[4] Passive prophylaxis with varicella zoster immune globulin
(VZIG) is indicated in high risk susceptible patients (i.e. immuno-
compromised children and pregnant women) exposed to varicella.
Aciclovir treatment results in significant suppression of vire-
mia in varicella.[22] Aciclovir alone may be valuable for the treat-
ment of immunologically healthy children.[23] Aciclovir (see table
I) has been recommended for the treatment of varicella in other-
wise healthy adults and adolescents, but not for routine use in
children <13 years of age unless they had sibling contacts or other
medical conditions.[24]
Fig. 3. Varicella: initial lesions on the head
In an open multicenter study of oral aciclovir in the treatment
of varicella in immunocompetent patients in the first 2 years of
life, 53 children received aciclovir (80 mg/kg/day in 4 divided
doses for 4 to 6 days). There was a rapid resolution of fever,
itching and other constitutional symptoms, with interruption of
vesicle formation and acceleration of cutaneous healing processes.
No statistically significant differences have been demonstrated as
to disease progression between patients whose treatment was started
within the first 24 hours of symptom onset, when compared with
participants receiving aciclovir in the following 24 hours.[25]
Aciclovir therapy is recommended for children with altered
cell-mediated immunity, newborns during the first 2 weeks of
life, preterm infants and any patient with severe varicella or shin-
gles (including ocular zoster), as well as during pregnancy. Intra-
venous administration of aciclovir is suggested for those with
severe disease, including those at risk of dissemination and in
children <2 years of age. Varicella may exacerbate the underlying
disease or increase the risk of secondary bacterial sepsis in chil-
dren with serious cardiopulmonary disease or chronic skin disor-
ders; in these clinical situations aciclovir may also be beneficial.[26]
3.3.1 Varicella: Post-Exposure Prophylaxis
Prophylaxis with VZIG early in the incubation period can
prevent or attenuate the disease manifestations of varicella in sus-

© Adis International Limited. All rights reserved. Pediatr Drugs 2002; 4 (1)
Antivirals in Pediatric Dermatology 15

ceptible high risk contact persons. Live attenuated varicella vac- pediatric patients who had undergone renal transplant, all of whom
cine can be successfully used after exposure.[24] had immunity to varicella virus before transplantation.[33] These
In 9-month-old to 9-year-old children with household expo- children were treated with oral aciclovir and had an uncompli-
sure to patients with varicella, oral aciclovir (5 to 80 mg/kg daily cated recovery. In another group of 109 children, the cumulative
in 4 divided doses) during the latter half of the incubation period incidences of pediatric VZV infections after bone marrow trans-
of varicella led to dose-dependent decreases in the number of plantation at 1 and 5 years of age were 26 and 45%, respectively.
cutaneous lesions.[27] All patients responded to aciclovir.[34]
As children with household exposure to varicella may have
3.3.3 Varicella in Pregnancy
more severe disease than children with community-acquired in-
Embryopathy attributable to maternal infection with vari-
fection, they may particularly benefit from aciclovir treatment.[28]
cella (particularly in the first half of pregnancy) has an incidence
Oral aciclovir (40 mg/kg/day in 4 divided doses), administered to
of 1 to 2%. Varicella of the newborn is a life-threatening illness
healthy susceptible infants and children 9 to 11 days post-expo-
that may occur: (i) when a newborn is delivered within 5 days of
sure, led to the prevention or modification of varicella.[29] In a
the onset of maternal illness; or (ii) after postdelivery exposure
study of 15 children who had household exposure to varicella and
to varicella. Susceptible neonates should receive VZIG. Intrave-
received post-exposure prophylaxis with aciclovir (40 mg/kg/day
nous or oral aciclovir should be considered for the therapy of
for 7 to 14 days), aciclovir was very effective clinically and did
pregnant women as well as of neonates.[35]
not appear to attenuate the immune response; however, it is still
In the framework of family planning and prenatal care, women
unclear whether, in the absence of clinically apparent varicella,
should be questioned about their past exposure and immunity to
such patients will acquire specific immunity.[30]
varicella. Serological testing and VZV vaccine should be offered,
if indicated. Susceptible patients should avoid contact with indi-
3.3.2 Varicella in Immunocompromised Patients viduals who have chickenpox or herpes zoster. If exposure occurs,
Chickenpox in childhood should not be considered trivial VZIG (administered within 96 hours) may prevent maternal in-
because serious and/or fatal complications may occur, especially in fection.[35]
the immunosuppressed. The most common complication is sec-
ondary staphylococcal or streptococcal infection.
3.4 Herpes Zoster (Shingles)
In immunocompromised patients (especially patients with
AIDS), recipients of transplants, as well as in patients with can- Varicella in early childhood is a risk factor for herpes zoster
cer, VZV infections may be life-threatening. In these clinical sit- in otherwise healthy children. Exposure of a child to varicella
uations, the current treatment of choice is an antiviral agent. In may cause reactivation of the latent virus.[36] VZV persisting in
addition, VZIG can be used. the dorsal root ganglia can replicate because of stress or other
Children who are immunocompromised have a high risk for causes still poorly understood. The virus migrates along sensory
disseminated varicella infections. Intravenous aciclovir for 7 to nerves, causing severe pain and vesiculation in a characteristic
10 days is frequently recommended. Oral aciclovir is only effec- dermatomal distribution (figure 4). Whereas herpes zoster is rare
tive if it is initiated within 24 hours of the onset of rash.[24] in children it should be considered in the differential diagnosis of
In a study of 26 immunocompromised children exposed to any pain, as misdiagnosis can lead to severe sequelae (e.g. unnec-
chickenpox, intravenous aciclovir (1500 mg/m2/day in 3 divided
doses) was used. The patients were switched to oral aciclovir after
48 hours of intravenous treatment if they were afebrile, had no
new lesions for 24 hours and had no involvement of internal or-
gans. Such sequential use of intravenous and oral aciclovir re-
sulted in the reduction of intravenous treatment and hospitaliza-
tion, with 25 out of 26 patients having resolution of their disease
without further need for intravenous therapy.[31]
Aciclovir prophylaxis was administered as an adjunctive mea-
sure to VZIG for the prevention of potentially serious varicella
infection in children receiving corticosteroids for renal disease.[32]
Immunosuppression achieved with mycophenolate mofetil was
associated with increased susceptibility to varicella infection in Fig. 4. Herpes zoster on the leg of a child.

© Adis International Limited. All rights reserved. Pediatr Drugs 2002; 4 (1)
16
essary laparotomy). A particularly important location is the face;
if the tip of the nose is affected by herpes zoster, immediate sys-
temic antiviral therapy (see table II) should be initiated to avoid
meningitis or ophthalmological sequelae.
In children and adolescents, followed for a period of 75 750
person years, 121 episodes of acute zoster developed (incidence
1.6/1000/year) in 118 patients. Even though systemic aciclovir
was not used, none of the patients developed postherpetic neuralgia,
moderate or severe pain or any pain lasting longer than 1 month
from start of the rash.[37] Thus, the probability of postherpetic
neuralgia in children and adolescents was considered to be ex-
tremely low.
In immunocompromised children with herpes zoster, aciclo-
vir therapy initiated within 3 days of the onset of the exanthem
prevented significant morbidity and death.[36]
The rare Ramsay-Hunt syndrome (facial paralysis and herpes
zoster oticus) is attributable to the involvement of the geniculate
ganglion: severe earache is followed by vesicular eruption of the
tympanic membrane and external auditory canal, often involving
the concha. In addition to the lower motor neuron palsy, vertigo
is common. Intravenous aciclovir (combined with methylprednis-
olone) was effective in the treatment of a case of Ramsay-Hunt
syndrome.[38]
3.5 Other Herpes Virus Infections
EBV infections (infectious mononucleosis), roseola in-
fantum (‘sixth disease’, exanthema subitum; caused by HHV-6),
and pityriasis rosea (with HHV-7 as a putative causative agent)
should be treated symptomatically. HHV-8 infection (presenting
as Kaposi’s sarcoma) is rare in children, and in selected cases
intralesional cidofovir may be beneficial. Severe hairy leucoplakia
of the tongue (an EBV-related disease) in the case of a 9-year-old
boy with AIDS showed complete resolution after treatment with
aciclovir 600 mg/day.[39]
Symptomatic CMV infection during pregnancy can lead to
spontaneous abortion or serious fetal malformations. CMV infec-
tions are rarely associated with cutaneous manifestations. Ganci-
clovir, foscarnet and cidofovir are used for the treatment of CMV
infections that threaten life or loss of sight in immunocompro-
mised patients. Prophylactic aciclovir plus CMV immune globu-
lin, followed by early therapy with intravenous ganciclovir de-
creased the morbidity in pediatric patients who had undergone
renal transplantation.[40]
4. Human Papillomavirus Infections
HPVs are double-stranded, circular DNA viruses with spe-
cific affinity to epithelial tissues. Several of the >80 types of HPV
© Adis International Limited. All rights reserved.
Trizna
preferentially infect certain sites, primarily causing benign muco-
cutaneous tumours (including verruca vulgaris, verruca plana,
deep palmoplantar warts, epidermodysplasia verruciformis and
anogenital warts).
Visible skin lesions often cause embarrassment or discom-
fort.[41] The prevalence of common warts in school-age children
is between 2 and 20%.[42] Verrucae can also occur in the oral
cavity, especially in the immunocompromised. Epidermodyspla-
sia verruciformis (EDV) presents with widespread, long-lasting,
pityriasis versicolor–like macules and flat, wart-like papules.
EDV usually occurs in early childhood and there is a risk of de-
veloping multiple skin cancers in the third decade.[43] Skin can-
cers in these patients were associated with HPV-5, -8 or -14.
Genital HPV infections are transmitted by sexual contact.[41]
The prevalence of genital HPV infection among sexually active
asymptomatic women is between 20 and 40%. However, subclin-
ical infection accounts for up to 70% of HPV infections.[44] Vis-
ible genital warts are present in approximately 1% of sexually
active adults in the US and HPV DNA assays suggest that at least
15% have subclinical infection.[45] The highest rates of genital HPV
infection are found in adults aged between 18 and 28 years.[46]
Young girls with external anogenital warts are also frequently
infected with HPV at internal mucosal sites.[47] These data are
important because certain HPV types (HPV-16, -18, -31, -33 and
-51) may lead to cervical cancer and other anogenital malignan-
cies.[46] The issue of treating latent HPV infections remains prob-
lematic and is generally considered futile. Unfortunately, such
lesions can be infectious.
Whereas in sexually active adults the primary means of trans-
mission of genital warts is through sexual contact, the epidemi-
ology and social significance of anogenital warts in prepubertal
children is controversial.[17] It is probable that HPV was transmit-
ted during the routine care of the child or through nonsexual in-
timate contact with an adult, e.g. bathing with the infant. Sexual
abuse should be considered under certain circumstances and it is
important to note that the probability of acquiring anogenital warts
because of sexual abuse increases with the age of the child.[2] HPV
typing may be helpful in such situations.
Most localized HPV infections are treated with destructive
methods, such as cryotherapy, electrosurgery, laser vaporization
and excision. Topical agents such as salicylic acid, acetic acid,
podophyllin, podophyllotoxin, canthadrin and fluorouracil, as well
as drugs administered intralesionally such as bleomycin or fluo-
rouracil can be used. Although these methods (alone or in com-
bination) usually remove the visible lesion, they may not com-
pletely eliminate the viral burden. Therefore, recurrence rates may
be high.
Pediatr Drugs 2002; 4 (1)
Antivirals in Pediatric Dermatology
Antiviral or immunomodulatory treatment of HPV infections
not only targets the elimination of the lesion but also intends to
reduce the latent viral infection. Interferon-α has been used for
the treatment of condylomata acuminata in adults. It is relatively
difficult to use (requiring frequent injections), slow acting, asso-
ciated with systemic adverse effects and expensive.[8] The immuno-
modulatory agent, imiquimod, can be topically applied by the
patient to the affected genital areas. This agent induces endoge-
nous production of cytokines (interferons-α and -γ and interleukin-
12). Imiquimod 5% cream has been used for the treatment of
external genital and perianal warts in adults with a good response
rate.[7] There are no data in children.
Intralesional cidofovir injections were promising in the treat-
ment of respiratory papillomatosis in children.[48] Such observa-
tions suggest that cutaneous papillomavirus infections may ben-
efit from a similar approach.[49]
5. Molluscum Contagiosum
Molluscum contagiosum is a self-limiting papular eruption
caused by a poxvirus. Young children are infected either by direct
contact or through fomites. Lesions on the genitalia and on the
surrounding skin can occur after sexual contact, sometimes rais-
ing concerns about sexual abuse.
The characteristic lesions develop following an incubation
period that can vary from 2 to 7 days to quite prolonged periods.
The individual papules are usually smaller than 0.5cm, shiny,
pearly and smooth with an umbilicated centre (figure 5). These
lesions tend to involute within 2 months. Several lesions may
sometimes be seen at different stages of development. Molluscum
contagiosum can present over a period of several years in the
same patient. Pruritus and tenderness are uncommon; however,
some lesions can become secondarily infected. There are patients
Fig. 5. Molluscum contagiosum: pearly papules, some of them with umbilication.
© Adis International Limited. All rights reserved.
17
who develop an eczematoid reaction around the papules. In the
immunocompromised host the lesions are more generalised, exten-
sive and persistent. Unusual presentations, (e.g. folliculitis owing
to molluscum contagiosum) are rare and might be considered a
sign of immunosuppression.[16]
One therapeutic approach is reassurance of the patients and
their parents. Destructive methods (e.g. liquid nitrogen or curet-
tage) can be beneficial if the patient does not have too many
lesions. In a double-blind, placebo-controlled study of 100 males
between 9 and 27 years of age with histologically confirmed mol-
luscum contagiosum, patients self-administered a topical 1% an-
alogue of imiquimod 3 times daily for 5 consecutive days per
week for 4 weeks.[50] This analogue of imiquimod cream cured
82% of the patients as opposed to 16% in the placebo-treated
group. Antiviral therapy includes topical cidofovir. Cidofovir cream
(3%) has been tried in a few cases of molluscum contagiosum in
children[51,52] and in immunocompromised adults, with clearing
of the treated areas in 2 to 6 weeks..[6]
6. Other Localized Poxvirus Infections of the Skin
Orf (figure 6) and milker’s nodules have no specific thera-
peutic modalities. Both have a benign self-limited course and
affected patients often do not even seek medical care. In rare
cases, cowpox and catpox infections can occur, presenting with
painful (occasionally haemorrhagic) vesicles or black crusting on
the face, neck and hands.[53]
7. Systemic Viral Infections with
Mucocutaneous Manifestations
Systemic viral infections that have mucocutaneous manifes-
tations include rubeola (measles), rubella (German measles), ery-
thema infectiosum (parvovirus B19), roseola infantum (HHV-6),
enterovirus, coxsackie virus, echovirus and reovirus infections,
infectious mononucleosis (EBV), and the now eradicated small-
pox. Some of these viral infections may have devastating conse-
quences affecting the fetus or a newborn. These entities have no
specific antiviral therapies. Prevention and supportive care are
available for the care of these patients. It should be kept in mind
that other viral infections, such as hepatitis B and HIV, may also
have mucocutaneous manifestations.
Enterovirus infections (e.g. hand, foot and mouth disease
caused by coxsackie A virus) and echovirus infections may pres-
ent with vesicular eruptions and should, therefore, be considered
in the differential diagnosis.
Pediatr Drugs 2002; 4 (1)
18
Fig. 6. Orf on the lateral aspect of a finger
8. Conclusions
Pediatric dermatological diseases having specific antiviral ther-
apies include herpes simplex virus infections, varicella, papillo-
mavirus infections, and molluscum contagiosum. The treatment
of these diseases is based on extensive clinical experience and on
extrapolations from adult studies. Viral infections in pregnancy
and the therapy of viral infections in immunosuppressed children
require individual assessment and treatment planning. Special prob-
lems of the epidemiology of genital herpes and papillomavirus
infections in adolescents are also reviewed. The antivirals dis-
cussed include aciclovir, valaciclovir, famciclovir, penciclovir,
cidofovir, foscarnet, and the immune response modulator, imi-
quimod. Caution should be exercised with their usage because
these antiviral agents have generally not been evaluated in chil-
dren.
Acknowledgements
The authors would like to thank the Department of Dermatology, Texas
Tech University, Lubbock, Texas, USA, for the use of slides in preparing the
illustrations.
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Correspondence and offprints: Dr Zoltan Trizna, Department of Dermatol-
ogy, Texas Tech University, Health Sciences Center, Mail Drop #9400, 3601
4th Street, Lubbock, TX 79416, USA.
E-mail: zoltan.trizna@ttmc.ttuhsc.edu
Pediatr Drugs 2002; 4 (1)