Tan-Goh2006 Article ViralInfectionsAffectingTheSki

Am J Clin Dermatol 2006; 7 (1): 13-29
THERAPY IN PRACTICE 1175-0561/06/0001-0013/$39.95/0
© 2006 Adis Data Information BV. All rights reserved.
Viral Infections Affecting the Skin in

Organ Transplant Recipients
Epidemiology and Current Management Strategies
Hiok-Hee Tan and Chee-Leok Goh

National Skin Centre, Singapore
Contents
Abstract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14
1. Background . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15
2. Herpes Simplex Virus (HSV) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15
2.1 Epidemiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15
2.2 Cutaneous Manifestations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15
2.3 Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16
2.3.1 Acyclovir . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16
2.3.2 Valaciclovir . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16
2.3.3 Famciclovir . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18
2.4 Treatment of Aciclovir-Resistant HSV . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18
2.4.1 Foscarnet . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18
2.4.2 Cidofovir . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18
2.4.3 Trifluridine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18
3. Varicella-Zoster Virus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18
3.1 Epidemiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18
3.3 Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19
3.3.1 General Measures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19
3.3.2 Specific Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19
3.3.3 Brivudine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19
3.3.4 Preventive Measures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20
4. Cytomegalovirus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20
4.1 Epidemiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20
4.3 Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20
4.3.1 Ganciclovir . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20
4.3.2 Valganciclovir . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20
4.3.3 Other Drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21
5. Epstein-Barr Virus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21
5.1 Epidemiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21
5.3 Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21
6. Human Herpesvirus (HHV) Types 6 and 7 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21
6.1 Epidemiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21
6.3 Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22
7. HHV-8 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22
14 Tan & Goh
7.1 Epidemiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22
7.3 Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22
8. Human Papillomavirus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23
8.1 Epidemiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23
8.3 Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24
8.3.1 Cryotherapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24
8.3.2 Electrodesiccation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24
8.3.3 Laser Surgery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24
8.3.4 Salicylic Acid . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24
8.3.5 Podophyllum and Podofilox . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24
8.3.6 Cantharidin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25
8.3.7 Trichloroacetic Acid . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25
8.3.8 Bleomycin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25
8.3.9 Retinoids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25
8.3.10 Imiquimod . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25
8.3.11 Other Medical Treatments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25
8.4 Strategies for Intervention and Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25
9. Molluscum Contagiosum . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26
9.1 Epidemiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26
9.2 Cutaneous Features . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26
9.3 Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26
10. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26
Abstract Viral skin infections are common findings in organ transplant recipients. The most important etiological
agents are the group of human herpesviruses (HHV), human papillomaviruses (HPV), and molluscum contagi-
osum virus. HHV that are important in this group of patients are herpes simplex virus (HSV) types 1 and 2,
varicella-zoster virus (VZV), cytomegalovirus (CMV), Epstein-Barr virus (EBV), HHV-6 and -7, and HHV-8,
which causes Kaposi sarcoma (KS). HSV infections are characterized by their ability to establish latency and
then reactivate at a later date. The most common manifestations of HSV infection in organ transplant recipients
are mucocutaneous lesions of the oropharynx or genital regions. Treatment is usually with acyclovir,
valaciclovir, or famciclovir. Acyclovir resistance may arise although the majority of acyclovir-resistant strains
have been isolated from AIDS patients and not organ transplant recipients. In such cases, alternatives such as
foscarnet, cidofovir, or trifluridine may have to be considered. VZV causes chickenpox as well as herpes zoster.
In organ transplant recipients, recurrent herpes zoster can occur. Acute chickenpox in organ transplant patients
should be treated with intravenous acyclovir. CMV infection occurs in 20–60% of all transplant recipients.
Cutaneous manifestations, which include nonspecific macular rashes, ulcers, purpuric eruptions, and
vesiculobullous lesions, are seen in 10–20% of patients with systemic infection and signify a poor prognosis. The
present gold standard for treatment is ganciclovir, but newer drugs such as valganciclovir appear promising.
EBV is responsible for some cases of post-transplant lymphoproliferative disorder, which represents the greatest
risk of serious EBV disease in transplant recipients. HHV-6 and HHV-7 are two relatively newly discovered
viruses and, at present, the body of information concerning these two agents is still fairly limited. KS is caused by
HHV-8, which is the most recently discovered lymphotrophic HHV. Iatrogenic KS is seen in solid-organ
transplant recipients, with a prevalence of 0.5–5% depending on the patient’s country of origin. HPV is
ubiquitous, and organ transplant recipients may never totally clear HPV infections, which are the most frequently
recurring infections in renal transplant recipients. HPV infection in transplant recipients is important because of
its link to the development of certain skin cancers, in particular, squamous cell carcinoma. Regular surveillance,
sun avoidance, and patient education are important aspects of the management strategy.
© 2006 Adis Data Information BV. All rights reserved. Am J Clin Dermatol 2006; 7 (1)
Viral Infections Affecting the Skin in Organ Transplant Recipients 15
1. Background reached 25% in White women, 20% in White men, 80% in African
American women, and 60% in African American men.
In the treatment of many end-stage organ diseases, transplanta- Prior to the onset of antiherpetic drug prophylaxis, recurrent
tion of solid organs is a successful and widely accepted mode of HSV-1 and HSV-2 infections accounted for as much as 70–80% of
treatment. Once the organ has been transplanted, the patient is severe mucocutaneous diseases in allogeneic bone marrow trans-
required to take potent immunosuppressive agents to prevent and plant recipients[6] and affected a significant but smaller number of
manage the problem of organ rejection. Organ transplant recipi- solid-organ transplant recipients.[7] HSV viral shedding can be
ents are therefore prone to developing a variety of skin lesions detected within 5–14 days after transplantation in 50–66% of
including cutaneous infections, neoplasms, and iatrogenic skin seropositive renal allograft recipients, although symptomatic vesi-
changes induced by the immunosuppressive drugs used to ensure cles or ulcers develop in only 15–45% of recipients.[8]
long-term graft survival. The diagnosis of viral skin infections in
organ transplant recipients is not often difficult, but management 2.2 Cutaneous Manifestations
of these infections is complicated by the need to maintain some
The most common manifestation of HSV infection in organ
degree of immunosuppression while infections are treated.
transplant recipients is mucocutaneous lesions of the oropharynx
2. Herpes Simplex Virus (HSV) or genital regions (figure 1). Typically, herpetic vesicles break
down to form shallow, grouped erosions and ulcers. In immu-
Herpes simplex virus (HSV) type 1 (human herpesvirus nosuppressed patients, however, these ulcers may become large,
[HHV]-1) and type 2 (HHV-2) are members of the genus Herpes- confluent, chronic, granulating, and slow-healing. HSV infections
virus. Approximately 100 herpesviruses have been identified,[1] of in the perioral region can also be associated with gingivitis,
which at least eight infect humans. stomatitis, and pharyngitis. In patients receiving sirolimus, it is
HHVs are an important cause of morbidity and mortality in important to be aware that this drug is associated with mucositis
transplant recipients. Herpesvirus infections are characterized by that can be difficult to distinguish from HSV infection.[9] Genital
their ability to establish latency, a phase during which they are not herpes infections may be associated with inguinal lymphade-
actively replicating but remain within the host. The virus can then nopathy, erythema of the penis or vulva, and perianal ulcers and
be reactivated later, resulting in recurrent infections and associated proctitis. Lesions may persist for months, and dissemination to
diseases.
2.1 Epidemiology
The development of type-specific serologic assays has allowed

more accurate evaluation of the seroprevalence of HSV-1 and
HSV-2. The prevalence of antibodies to HSV increases with age
and correlates with socioeconomic status.[2]
HSV-1 is responsible for most herpesvirus infections above the
waist, e.g. herpes labialis and keratitis. HSV-1 establishes a latent
infection in the trigeminal ganglion. It often infects individuals
early in life, leading to a seroprevalence of 50–80% among adults
in Western countries.[3]
HSV-2 is responsible for most herpesvirus infections below the
waist, principally genital herpes (figure 1). It establishes a latent
infection in the sacral ganglion. Antibodies to HSV-2 are not
routinely detected in sera until puberty, and antibody prevalence
rates correlate with past sexual activity.[4] In the US, a ser-
oprevalence study showed an HSV-2 seroprevalence of 21.7% in
adults, with an increase being noted over the years 1976–1994.[5] Fig. 1. Severe genital erosions caused by herpes simplex virus type 2
In that same study, the cumulative lifetime incidence of HSV-2 (courtesy of National Skin Centre, Singapore).
16 Tan & Goh
other organs such as the liver and bladder or the eye (resulting in advances center on the management of viral infections caused by
corneal and retinal infection) may occur. Widespread disseminat- the herpesvirus family. Most of the antiviral drugs used are dis-
ed HSV infection of the skin is not common (figure 2) but is cussed in greater detail in this section, as the same drug may be
associated with high mortality rates.[8] HSV infections can also used for several herpesvirus infections.
trigger erythema multiforme, characterized by lesions with con-
2.3.1 Acyclovir
centric color change (target lesions) that are symmetrically distrib-
Acyclovir is a synthetic purine analog derived from guanine.
uted predominantly over the extremities and acral areas.[10]
Acyclovir was the first oral antiherpesvirus agent and is still used
Diagnosis of HSV infection is still achieved mainly by cul-
extensively to treat herpesvirus infections. Acyclovir is phospho-
ture of the virus from mucosal surfaces or vesicles. Direct immu-
rylated to acyclovir monophosphate by viral thymidine kinases
nostaining of cells from these specimens with fluorescent-dye-
(TK) but not by cellular kinases. Subsequent phosphorylations to
conjugated monoclonal antibodies specific for HSV-1 and HSV-2
diphosphate and triphosphate can be mediated by viral and cellular
antigens can be used as a supplementary test.[11] Another rapid test
kinases. Acyclovir triphosphate then inhibits herpesvirus DNA
that may be useful is the Tzanck smear, which is performed on
polymerases.[13] Acyclovir has potent in vitro activity against
scrapings from the base of the vesicle. A positive Tzanck smear
HSV-1 and HSV-2.[14] Although active against HSV, acyclovir
would show ballooned keratinocytes or giant cells. Although this
does not eradicate the virus. One limitation of acyclovir is its poor
is not specific to HSV, it can be used to aid the diagnosis.
oral availability as only 20% of the orally administered drug is
Molecular-based techniques such as polymerase chain reaction
absorbed through the gastrointestinal tract.[15] As elimination of
(PCR) have been used to detect HSV in herpes encephalitis,
acyclovir takes place primarily by glomerular filtration with a
corneal infections, and skin lesions, including HSV-associated
smaller component of tubular secretion, patients with renal impair-
erythema multiforme.[12]
ment (creatinine clearance rate <10 mL/min) require dosage ad-
justment.[16] The serum half-life of acyclovir is 2.5–3 hours.[16]
2.3 Treatment
Acyclovir markedly reduces the severity of mucocutaneous
Significant developments have occurred in the availability of HSV infections. Acyclovir 400mg five times daily for 10 days is
antiviral agents over the past two decades (table I). Many of these recommended for initial genital HSV infections in transplant
recipients.[8] The same dose is used in recurrent genital infections
but the duration can be shortened to 5 days. Chronic suppression of
frequent, symptomatic genital herpes can be achieved with doses
of 400mg twice daily.[17] In immunocompetent patients, the natu-
ral history of recurrent HSV infections is for the recurrence rate to
progressively decline. In organ transplant recipients, attempts at
weaning off chronic suppressive therapy may be tried when the
degree of immunosuppression can be reduced.
Acyclovir 400mg five times daily for 5 days is recommended
for herpes labialis.[8] Topical 5% acyclovir applied five times daily
for 5 days has also been shown to accelerate lesion healing in
herpes labialis[17] and may be used in milder cases.
In severe HSV infections, intravenous acyclovir can be admin-
istered at a dosage of 5–10 mg/kg every 8 hours.[17] Close attention
to maintenance of adequate hydration is necessary when adminis-
tering intravenous acyclovir because the drug can precipitate in the
renal tubules, resulting in an obstructive nephropathy.[18]
2.3.2 Valaciclovir
Valaciclovir is the L-valine ester (prodrug) of acyclovir and
Fig. 2. Disseminated herpes simplex infection (courtesy of National Skin exhibits no activity until hydrolyzed in the intestinal wall or liver
Centre, Singapore). to acyclovir and its active metabolite.[19] Valaciclovir is rapidly
Table I. Summary of selected treatment options for viral skin infections in transplant patients
Viral infection Management Comments

HSV Genital herpes: In severe cases, IV acyclovir 5–10 mg/kg every 8 hours
acyclovir 400mg 5×/day for 10 days Ganciclovir and valganciclovir known to be effective
valaciclovir 1000mg tid for 10 days against HSV
famciclovir 500mg bid for 7 days Other alternatives for acyclovir-resistant HSV:
Chronic suppression: foscarnet
acyclovir 400mg bid cidofovir
valaciclovir 500mg bid trifluridine
famciclovir 250mg bid
Herpes labialis:
acyclovir 400mg 5×/day for 5 days
topical 5% acyclovir 5×/day for 5 days
topical 1% penciclovir every 2 hours for 4 days
VZV Chickenpox: VZV vaccination prior to renal transplantation shown to be
IV acyclovir 10 mg/kg every 8 hours for 7 days of benefit for some children at risk of primary VZV
Herpes zoster: infection
acyclovir 800mg 5×/day for 7–10 days Following exposure to VZV infection, high-risk transplant
valaciclovir 1000mg tid for 7 days patients may require passive immunization with VZV
famciclovir 500mg tid for 7 days hyperimmune globulin within 72 hours of exposure
brivudine 125mg daily for 7 days recently found to
be useful
ganciclovir and valganciclovir also known to be
effective
CMV Acute CMV infection: Foscarnet and cidofovir are alternatives that can be
IV ganciclovir 5 mg/kg bid for 14 days followed by considered in ganciclovir-resistant cases
oral ganciclovir 1000mg tid for total of 6 weeks
valganciclovir 900mg daily shown to be useful in
prevention of CMV disease
EBV Treatment largely supportive Reduction of immunosuppressive therapy may be needed
PTLD has been treated with IV immunoglobulin, in cases of PTLD
acyclovir, and ganciclovir
HHV-6, HHV-7 Treatment largely supportive
Few reports on specific antiviral drugs
HHV-8 Localized cases: Higher tumor burden may require use of interferons,
excision paclitaxel, vincristine, bleomycin, and adriamycin, among
radiation others
cryotherapy
topical alitretinoin
HPV Multiple treatment options including cryotherapy, laser Transplant recipients are unlikely to ever be totally clear
surgery, electrocautery, salicylic acid, cantharidin, of HPV infection
trichloroacetic acid, intralesional bleomycin Oral retinoids should be considered in transplant
Podophyllum (podophyllin), podofilox (podophyllotoxin), recipients with multiple warts and history of squamous
imiquimod can be considered for genital warts cell carcinomas
Retinoids: topical, oral Regular surveillance and sun protection should be
emphasized
Molluscum contagiosum Cryotherapy, electrocautery, trichloroacetic acid,
cantharidin, other physical methods (e.g. extraction of
core using needle, repeated tape stripping)
bid = twice daily; CMV = cytomegalovirus; EBV = Epstein-Barr virus; HHV = human herpesvirus; HPV = human papillomavirus; HSV = herpes simplex
virus; IV = intravenous; PTLD = post-transplant lymphoproliferative disorder; tid = three times daily; VZV = varicella-zoster virus.
18 Tan & Goh
and almost completely converted to acyclovir by hepatic enzymes, lates have been from AIDS patients undergoing multiple courses
and an oral dose of valaciclovir 1000mg results in blood concen- of acyclovir for established infection,[24] the risk factors for devel-
trations of drug similar (area under the curve) to those of intrave- opment of resistance have not been well defined. In the organ
nous acyclovir.[19] transplant recipient, acyclovir resistance may be suspected if there
For initial episodes of herpes genitalis in transplant patients, a are very frequent breakthrough recurrences or persistent
dose of 1000mg three times daily for 10 days is recommended, and mucocutaneous HSV infection. Aciclovir-resistant HSV infec-
for recurrent genital infection a dose of 1000mg twice daily for 5 tions will require therapy with alternative agents. Use of
days is sufficient.[8] For continuous suppressive therapy of genital ganciclovir and valganciclovir is discussed in sections 4.3.1 and
herpes, valaciclovir 500mg twice daily is recommended. 4.3.2.
Valaciclovir was recently approved by the US FDA for 1-day oral
2.4.1 Foscarnet
treatment of patients aged ≥12 years with orolabial HSV infec-
Foscarnet is a non-nucleoside pyrophosphate analog that is
tions.[20] The recommended regimen is a 1-day course of
active against herpesviruses. It acts by inhibition of virus-specific
valaciclovir 2g taken twice daily (12 hours apart). However, there
DNA polymerases and reverse transcriptases.[25] It can be effec-
are no specific recommendations for the use of valaciclovir for
tively administered topically[26] or intravenously but needs to be
herpes labialis in transplant recipients. Very high doses of
administered in large volumes because of its nephrotoxicity.[27]
valaciclovir taken for prolonged periods of time are contraindi-
Adverse effects include renal insufficiency and metabolic distur-
cated for immunocompromised patients; a syndrome of thrombot-
bances. Foscarnet is used mainly for the treatment of cytome-
ic microangiopathy has been described in about 3% of patients
galovirus (CMV) retinitis in AIDS patients but can be used when
with HIV infection as well as in bone marrow and renal transplant
absolutely indicated for the treatment of aciclovir-resistant HSV
recipients who were receiving high doses of the drug.[21] These
infections.
patients received valaciclovir 8 g/day for a median of 53 days
(range 8–100 days). 2.4.2 Cidofovir
Cidofovir is another nucleotide analog with good activity
2.3.3 Famciclovir
against HSV. Cidofovir is active against HSV strains with a
Famciclovir is a synthetic acyclic purine analog derived from
deficient or altered TK because, unlike acyclovir, it is phosphoryl-
guanine. It is a prodrug of penciclovir, a nucleoside analog that
ated only by cellular enzymes and not by HSV-specified en-
effectively inhibits replication of HSV-1 and HSV-2.[22]
zymes.[28] Both topical and intravenous forms of cidofovir are
Penciclovir has a mechanism of action similar to that of acyclovir.
available, but intravenous administration has the potential for
Compared with acyclovir, famciclovir achieves intracellular renal toxicity.[29]
concentrations of the active drug penciclovir that are 100 times
those achieved with acyclovir. The half-life of famciclovir is 11 2.4.3 Trifluridine
hours, which means that three-times-daily administration is possi- Trifluridine is a potent antiviral agent but is too toxic to be
ble for primary HSV infection and twice-daily administration is administered systemically. It can be used to treat ophthalmic HSV
possible for recurrent infections.[22] Aciclovir-resistant HSV infections and has been used in a series of 26 patients with AIDS
strains are also resistant to famciclovir. As with acyclovir, dosage and mucocutaneous herpes unresponsive to acyclovir.[30]
adjustments need to be made in patients with renal impairment.
3. Varicella-Zoster Virus
Famciclovir 500mg twice daily for 7 days can be used for initial
episodes of genital herpes and 250–500mg twice daily can be
administered for chronic suppression. 1% Penciclovir applied 3.1 Epidemiology
topically every 2 hours for 4 days can be used for herpes labialis.[8]
Varicella-zoster virus (VZV) [HHV-3] infection manifests as
2.4 Treatment of Aciclovir-Resistant HSV
chickenpox, while herpes zoster results from reactivation of VZV
located in nerve roots. More than 90% of adults have had VZV by
In vitro resistance to acyclovir can result from TK-deficient, the time they are in their 20s and thus harbor latent infection in
TK-altered, or DNA polymerase-resistant strains of HSV. TK their dorsal root ganglia.[3] Young pediatric transplant recipients
deficiency is the most common mechanism of resistance of HSV without pre-existing immunity to VZV are at risk of developing
to acyclovir.[23] Although the majority of aciclovir-resistant iso- primary VZV infections after exposure to chickenpox.[31] Before
acyclovir became available, VZV was responsible for considera- crusted erosions and scabs. In the normal individual, the crusts
ble morbidity and mortality in these patients.[31] A primary VZV may persist for 2–3 weeks. However, herpes zoster in the organ
infection in the transplant patient can be devastating, with up to transplant recipient may be prolonged for several months, and the
33% of untreated cases disseminating and causing hemorrhagic disease has been found to clear after immunosuppressants are
pneumonia and skin lesions, encephalitis, hepatitis, and dissemi- reduced. Disseminated zoster can also occur with involvement of
nated intravascular coagulation.[8] Herpes zoster is common in three or more dermatomes or a generalized rash that is mistaken
transplant recipients and occurs in up to 13% of renal transplant for chickenpox. In immunocompromised patients, recurrent
patients.[32] The incidence of herpes zoster in immunosuppressed herpes zoster can occur.[34]
patients is increased 20- to 100-fold, and the severity of the disease The diagnosis of VZV is made clinically, and routine laborato-
is also increased.[33] In a recent review from a center in Canada, the ry tests are not useful. A Tzanck smear may be performed.
overall incidence of herpes zoster following solid-organ transplan- Definitive diagnosis of VZV infection can be achieved through
tation was 8.6% with a median time to onset of 9 months; herpes viral cultures. Immunofluorescent staining with monoclonal an-
zoster in these patients was also associated with high rates of tibodies can also be used to confirm VZV infection or reactiva-
cutaneous scarring (18.7%) and post-herpetic neuralgia tion.[3] Serologic tests can provide a retrospective diagnosis of
(42.7%).[34] VZV infection.
3.2 Cutaneous Manifestations 3.3 Treatment
VZV infections are often diagnosed on the basis of their clinical

3.3.1 General Measures
presentation. The chickenpox rash begins on the face and scalp
and spreads rapidly to the trunk, with relative sparing of extremi- General measures for the treatment of VZV infection or reacti-
ties. New lesions appear in successive crops, but their distribution vation include the use of saline compresses, histamine H1 receptor
remains central. Vesicles often appear earlier and in larger num- antagonists for pruritus associated with chickenpox, and
bers in areas of inflammation such as diaper rash, sunburn, or analgesics for pain relief in herpes zoster. Post-herpetic neuralgia
eczema.[33] Vesicles also develop in the mucous membranes of the can be a difficult problem. Pain clinics or units can be very helpful
mouth, most commonly over the palate, but may also appear on in the long-term management of these patients. While the manage-
other mucosal surfaces including the urinary tract, vagina, and ment of post-herpetic neuralgia will not be discussed further in this
conjunctivae. A distinctive feature of varicella is the simultaneous article, therapeutic modalities include the use of capsaicin cream,
presence of lesions at all stages of development – erythematous tricyclic antidepressants such as amitriptyline, and antiepileptic
papules, vesicles, erosions, and crusts. drugs such as carbamazepine.[35] Gabapentin was approved as a
Herpes zoster is well recognized by its most distinctive feature treatment for this condition by the FDA in May 2002 and is a
– the localization of the rash. The painful vesicular eruption is promising drug for the relief of pain in post-herpetic neuralgia.[36]
almost always unilateral, does not cross the midline, and is gener- 3.3.2 Specific Therapy
ally limited to the area of skin innervated by a single sensory Chickenpox in the organ transplant recipient should be treated
ganglion (figure 3). Early lesions consist of erythematous papules with intravenous acyclovir 10 mg/kg every 8 hours for 7 days.[37]
and vesicles, which are followed by larger hemorrhagic bullae and For uncomplicated herpes zoster, high-dose oral acyclovir and
other nucleoside analogs such as valaciclovir and famciclovir can
be used. The recommended doses are acyclovir 800mg five times
daily for 7–10 days, valaciclovir 1000mg 8-hourly for 7 days, and
famciclovir 500mg 8-hourly for 7 days.
3.3.3 Brivudine
Brivudine, an analog of thymidine, has been shown to have
stronger antiviral effects against VZV than acyclovir, and the
efficacy of brivudine has been documented in a number of clinical
Fig. 3. Herpes zoster affecting thoracic dermatome (courtesy of National trials in patients with herpesvirus-related infections, particularly in
Skin Centre, Singapore). patients with herpes zoster.[38] A double-blind study of 608 immu-
20 Tan & Goh
nocompetent herpes zoster patients showed that oral brivudine macular rash.[44] The presentation can resemble a mononucleosis-
125mg once daily significantly reduced the incidence of post- type syndrome. Cutaneous involvement is present in 10–20% of
herpetic neuralgia compared with acyclovir.[39] patients with systemic CMV infection and is a sign of a poor
prognosis. Cutaneous lesions may also include ulcers, morbilli-
3.3.4 Preventive Measures
form rashes, petechiae, purpuric eruptions, necrotic papules, and
Young pediatric transplant recipients without pre-existing im-
vesiculobullous eruptions.[45] Chronic CMV infections are associ-
munity to VZV are at risk of developing primary VZV infections
ated with risk of organ rejection and atherosclerosis, and also
after exposure to chickenpox.[3] Vaccination with the VZV vaccine
predispose the transplant recipient to higher risk of bacterial and
is one approach to the prevention of primary and reactivated VZV
fungal infections.[44]
infections in transplant recipients. However, it is important to note
Histologic diagnosis of CMV infection is suggested by the
that the current VZV vaccine is a live, attenuated vaccine, and its
presence of large intranuclear inclusions with a surrounding halo
administration is appropriate only prior to transplantation since
in endothelial cells. Confirmation of the diagnosis requires dem-
these vaccines are contraindicated in organ transplant recipients.
onstration of the virus from skin, urine, throat washings, and buffy
VZV vaccination prior to renal transplantation has been shown to
coat. Serology can also be used. Analysis of serum for CMV
be of benefit to children at risk of primary VZV infection,[40] but
antibodies is useful for determining prior CMV infection, but the
the vaccine had little effect on the incidence or severity of varicella
transplant recipient’s ability to mount an increasing antibody
infection after liver transplantation.[41] Following exposure to vari-
response may be blunted. Active CMV infection can also be
cella infection, high-risk transplant recipients may also be given
determined by detecting CMV DNA in peripheral blood samples
passive immunization with VZV hyperimmune globulin within 72
through PCR techniques.[46]
hours of exposure.[3]
4. Cytomegalovirus 4.3 Treatment
4.3.1 Ganciclovir
4.1 Epidemiology
Ganciclovir is a nucleoside analog that differs from acyclovir
Human CMV (HHV-5) infects 40–60% of the population in by a single carboxyl side chain. This structural change increases
developed countries, with the infection rate increasing with age.[42] the activity of the drug against CMV approximately 50-fold com-
CMV is found in oropharyngeal secretions, blood, semen, urine, pared with acyclovir.[47] Ganciclovir can be administered both
vaginal secretions, and breast milk. CMV is transmitted in utero intravenously and orally. Since the drug undergoes renal excre-
during the first 6 months of life by exposure to the mother’s genital tion, the dose must be reduced in patients with impaired renal
secretions and breast milk, and by oral and respiratory secretions function. Ganciclovir is indicated for the treatment of acute CMV
in the preschool age group. Sources of CMV infection in organ infection, but other herpesviruses such as HSV-1, HSV-2, and
transplant recipients include reactivation of latent virus or donor- VZV are also susceptible to the drug. For acute CMV infections,
transmitted virus. CMV is a labile virus and is readily inactivated intravenous ganciclovir 5 mg/kg twice daily is administered for 14
by lipid solvents, pH <5, heat, and UV light for 5 minutes.[43] days followed by oral ganciclovir 1g three times daily for up to a
total of 6 weeks.[8]
4.2 Cutaneous Manifestations
4.3.2 Valganciclovir
Symptomatic CMV infection occurs in 20–60% of all trans- Valganciclovir is a new antiviral agent that can be administered
plant recipients and is a significant cause of mortality and morbidi- orally and has greater bioavailability than ganciclovir.[3] A recent
ty in these patients.[43] The patient at highest risk of symptomatic study has demonstrated that oral valganciclovir 900mg once daily
disease is a CMV-seronegative recipient matched with a CMV- was as clinically effective and well tolerated as oral ganciclovir 1g
seropositive donor (D+/R–). These patients develop a primary three times daily for CMV prevention in high-risk solid-organ
infection after transplantation. CMV is the most common and transplant recipients.[48] Valganciclovir is rapidly converted to
single most important viral infection in organ transplant recipients. ganciclovir, and systemic exposure to the parent drug is low and
However, the cutaneous manifestations are nonspecific. Acute short in duration; the bioavailability of ganciclovir from val-
CMV infection is associated with fever, malaise, leukopenia, and a ganciclovir is ten times that of the original ganciclovir formula-
tion.[49] The usual regimen of valganciclovir is 900mg twice daily is a potent inhibitor of EBV DNA polymerase and can therefore
for 3 weeks with dose adjustments for renal insufficiency.[49] inhibit EBV replication. PTLD has been treated with intravenous
immunoglobulin,[59] acyclovir,[60] and ganciclovir.[61] Reduction of
4.3.3 Other Drugs
immunosuppressive therapy may be crucial.
Foscarnet and cidofovir are alternative drugs that can be used in
cases of ganciclovir-resistant CMV infections.
6. Human Herpesvirus (HHV) Types 6 and 7
5. Epstein-Barr Virus
HHV-6 and HHV-7 are members of the β-herpesvirus sub-
Epstein-Barr virus (EBV) [HHV-4] causes infectious
group. HHV-6 was discovered and first isolated in 1986 from
mononucleosis, Burkitt lymphoma, nasopharyngeal carcinoma,
circulating lymphocytes of patients with lymphoproliferative dis-
and post-transplant lymphoproliferative disorder (PTLD). EBV is
orders.[62] HHV-7 was discovered in 1990 from CD4+ T cells of a
excreted in saliva and spread by close contact, often infecting
healthy individual.[63]
hosts at a young age.
5.1 Epidemiology 6.1 Epidemiology
EBV is a ubiquitous herpesvirus. Antibodies to EBV can be

There are few epidemiologic data on the prevalence and inci-
detected in 90–95% of the population by childhood.[50] Primary
dence of infections caused by HHV-6 and HHV-7. Although
exposure to EBV occurs in early childhood. Studies in the US[51]
HHV-6 causes most cases of exanthem subitum (see section
and Britain[52] show evidence of seroconversion in 50% of children
6.2),[64] there are no consistent epidemiologic studies of this condi-
<5 years old. Primary infection is usually asymptomatic but can
tion, probably because it is usually short-lived, has a mild course,
manifest as mononucleosis in teenagers and young adults.
and is often misdiagnosed. From serologic studies, we know that
both HHV-6 and HHV-7 are ubiquitous, with primary infections
occurring in early childhood, so that the majority of older children
Acute EBV infection can cause a diffuse maculopapular rash, and adults are dually seropositive.[65] HHV-7 does not seem to
which may be accompanied by fever, pharyngitis, lymphade- have a clear association with any disease although it has been
nopathy, and malaise. Morbilliform, vesicular, erythematous, pe- reported to be responsible for some cases of exanthem subitum.[66]
techial, and purpuric exanthems have also been described.[53] EBV Data on these two herpesviruses in the context of organ transplant
infection can also trigger urticaria.[54] recipients are relatively scarce because these two viruses are
Oral hairy leukoplakia is a proliferative EBV-induced relatively newly discovered. However, there is clear evidence that
mucocutaneous epithelial cell disease that is the first pathologic they reactivate in immunosuppressed individuals. HHV-6 infec-
manifestation of replicative EBV infection.[55] Although classical- tion or reactivation has been reported in 38–60% of bone marrow
ly seen in patients with AIDS, oral hairy leukoplakia has been transplant recipients and in 31–55% of solid-organ transplant
reported in other immunosuppressed patients, including transplant recipients.[67] Likewise, HHV-7 reactivation has been reported in
recipients.[56] Lesions present as poorly demarcated keratotic areas renal transplant recipients.[68]
with a corrugated or ‘hairy’ appearance on the lateral borders of
the tongue.
The greatest risk of serious EBV disease in transplant recipients
is PTLD. PTLD is a well-known complication of organ transplan-
Exanthem subitum is characterized by a prodrome of high fever
tation. Although most post-transplant lymphomas are of B-cell
persisting for 3–5 days followed by a sudden onset of rash as the
origin,[57] post-transplant primary cutaneous T-cell lymphoma has
fever falls. The eruption consists of small macules or
been described, presenting as tumors on the face and chest.[58]
maculopapules that blanch on pressure and are often surrounded
by a whitish halo. The rash, which is usually not itchy, lasts only
5.3 Treatment
1–2 days before subsiding. HHV-6 has been reported as the cause
The treatment of EBV infection is largely supportive. Although of a febrile dermatosis associated with thrombocytopenia and
acyclovir is ineffective in the treatment of latent EBV infection, it encephalopathy in a liver transplant patient.[69]
22 Tan & Goh
6.3 Treatment Early lesions may present as reddish-blue macules and may be
inconspicuous. They can occur on any part of the body. The
Treatment of HHV-6 and HHV-7 infection is largely support- lesions may also mimic purpura, hematomas, and small angioma-
ive. There are few reports on the use of specific antiviral drugs for tous lesions (figure 4).[77] Correct identification of early lesions
these infections.[3] may require a higher index of suspicion, and biopsies should be
done on any suspicious looking lesion. Some lesions may be more
7. HHV-8 florid and grow rapidly, ulcerate and be hemorrhagic, and present
as vascular tumors. Any patient who develops reddish-blue mac-
HHV-8, or Kaposi sarcoma (KS)-associated herpesvirus
ules or plaques in the skin or oropharyngeal mucosa, or who has
(KSHV), is the most recently discovered lymphotrophic HHV.[70]
apparently infected granulomas that fail to heal, should be suspect-
KSHV is the cause of KS, which is a tumor of multicentric origin,
ed of having KS.[77] Up to 45% of organ transplant recipients may
composed of endothelium-lined vascular spaces and spindle-
also have involvement of the internal viscera, which is associated
shaped cells.
with a poor prognosis.[77]
7.1 Epidemiology
7.3 Treatment
The iatrogenic form of KS is seen in solid-organ transplant
recipients, with a prevalence of between 0.5%[71] and 5%[72] de- A detailed discussion of the treatment of KS is beyond the
pending on the patient’s country of origin. A French study showed scope of this article. Readers are directed to a recent comprehen-
that the prevalence of KS was significantly higher in liver trans- sive review on the epidemiology, clinical manifestations, and
plant recipients (1.24%) than in kidney (0.45%) and heart trans- therapy of KS.[78] One management strategy in organ transplant
plant (0.41%) recipients.[71] The incidence of KS in transplant recipients is to reduce immunosuppression. It has been well docu-
recipients is 500 times that in the general population.[72] The mented that KS in kidney transplant recipients shows remission
occurrence of KS among transplant recipients is associated with when immunosuppressive treatment is reduced or withdrawn.[79]
immunosuppressive therapy (particularly calcineurin inhibitors). However, tapering of immunosuppression, while often leading to
Case-control studies have noted that the development of KS is KS remission, also results in graft loss in >50% of cases.[80]
associated with reactivation of HHV-8 in the transplant recipi-
ent.[73] A recent study has shown that HHV-8 reactivates in trans-
plant patients who were seropositive prior to transplantation, and
that a significant number of seronegative patients seroconvert to
HHV-8 following transplantation.[74] The route of transmission
among patients who seroconvert following transplantation is un-
known, but at least three separate routes (donor organ, blood
transfusions, and caregivers) have been proposed.[74] In the US, the
KS prevalence rate among solid-organ transplant recipients (0.5%)
is lower than the estimated 20% HHV-8 seroprevalence rate
reported in the same group.[74] Among healthy adults, primary
HHV-8 infection appears to be fairly mild with no obvious signs of
clinical disease.[75]
KS may present with single or multiple skin lesions as well as

mucosal, lymphatic, and visceral involvement. The course of the
disease may be aggressive or indolent, with slow progression of
the disease characterized by increasing numbers of cutaneous and
mucosal lesions and by darkening of pre-existing lesions.[76] Fig. 4. Kaposi sarcoma (courtesy of National Skin Centre, Singapore).
transplant recipients, in their immunocompromised state, may

never show total wart clearance. The reasons for treating the warts
should be examined and the various modalities of treatment dis-
cussed with the patient.
8.1 Epidemiology
HPV infections occur all over the world, infecting the skin and
mucous membranes and sometimes leading to benign or malignant
epithelial tumors. HPV is one of the most frequent infections in
transplant recipients.[85] The prevalence of warts increases with the
length of graft survival, and up to 50% of renal transplant recipi-
ents with graft survival >5 years have warts.[86] HPV infection in
transplant recipients is also important because of its link to the
development of certain skin cancers, in particular, squamous cell
carcinoma.[87] An extremely diverse group of HPV types, consist-
ing mainly of epidermodysplasia verruciformis-associated HPV
types, can be detected in benign, premalignant, and malignant skin
lesions of organ transplant recipients.[87]
Fig. 5. Extensive verrucous warts (courtesy of National Skin Centre, Singa-
pore).
At least 35 of the >100 different types of HPV primarily infect
genital epithelium.[88] Renal allograft recipients are also at high
The choice of treatment for KS will also depend on the extent risk of genital HPV infection. For example, Halpert et al.[89] found
and location of the lesions: solitary lesions may be excised or cytological evidence of HPV infection in 22% of female renal
subjected to ionizing radiation,[81] while superficial and flat lesions allograft recipients compared with 2.5% of hospitalized immu-
may be treated with cryotherapy. Topical alitretinoin (9-cis-retino- nocompetent controls matched for age, race, and age at first coitus.
ic acid) gel has been reported to be useful in the treatment of A study comparing HPV16 prevalence detected by PCR among
localized AIDS-related KS.[82] This medication is available as a 133 renal allograft recipients and 145 controls showed a preva-
0.1% gel that is applied generously to the lesion initially twice lence of 47% in transplant recipients compared with 12.4% in the
daily and then increased to four times daily as tolerated. Adverse control group.[90]
effects include skin irritation, redness, pain, edema, and paraesthe-
sias. Alitretinoin is now approved by the FDA for the treatment of 8.2 Cutaneous Manifestations
cutaneous KS lesions.[83]
Common warts in transplant recipients often appear as multiple
Other established therapies for KS include interferon
hyperkeratotic or verrucous papules on the hands, fingers, or feet
and chemotherapy with cytotoxic drugs including paclitaxel, vin-
(figure 5). Periungual and subungual lesions can cause nail
cristine, vinblastine, adriamycin, and bleomycin.[84] Liposomal-
changes (figure 6). Flat warts appear as tan, brown, or pink, flat-
encapsulated doxorubicin and daunorubicin are treatment strate-
gies targeted at lowering undesired adverse effects.[78] These treat-
ments are generally considered when the tumor burden is higher.
8. Human Papillomavirus
For the purpose of this article, discussion of human papil-

lomavirus (HPV) infection is confined specifically to cutaneous
and anogenital wart infections. Therapy of HPV infections, even
in immunocompetent patients, can be difficult at times. There is no Fig. 6. Viral wart extending into subungual region (courtesy of National
single treatment that stands out as being superior; therefore, organ Skin Centre, Singapore).
24 Tan & Goh
cure rates were found to be reduced.[92] Overly aggressive freezing

should be avoided as excessive blistering can occur and there is a
risk of damage to underlying structures. Special care should be
taken in areas where superficial nerves and vessels lie, notably the
periungual and genital areas.
8.3.2 Electrodesiccation
Electrodesiccation is useful for destroying small filiform and
flat warts, especially on the face, beard, and genital area.
8.3.3 Laser Surgery

The use of the CO2 laser is attractive for the treatment of
recalcitrant warts for which the depth and width of destruction
needs to be strictly controlled, such as periungual warts and
recalcitrant plantar warts. However, use of the CO2 laser should be
limited to physicians with special training. Scarring is a potential
complication.[93] There has been a recent report of hypertrophic
scar formation following CO2 laser ablation of plantar warts in
four renal transplant recipients who were all receiving long-term
Fig. 7. Condylomata acuminata (courtesy of National Skin Centre, Singa- cyclosporine (which was considered responsible by the authors of
pore). the report).[94]
topped papules. Mosaic warts, which consist of an area of multi- 8.3.4 Salicylic Acid
ple, confluent plantar warts, can occur. Condyloma on the Salicylic acid is a keratolytic that acts by slowly destroying
anogenital mucosa may be filiform or verrucous and can become wart-infected epidermis. The resulting mild irritation may stimu-
very large (figure 7).[91] late an immune response. Salicylic acid is available in a wide
variety of preparations and is established as a simple, first-line
8.3 Treatment therapy for cutaneous warts.[95]
8.3.5 Podophyllum and Podofilox

Treatment strategies for warts in the transplant recipient in-
Podophyllum is a crude plant resin extract, and podofilox is a
volve the use of physical therapies (cryotherapy, electrosurgery,
purified active ingredient of podophyllum. Both act as antimitotic
laser vaporization) and chemical therapies (including salicylic
agents and are extensively used in the treatment of anogenital
acid, podophyllum [podophyllin], podofilox [podophyllotoxin],
warts. They are not used in the treatment of cutaneous warts as
trichloroacetic acid), as well as regular surveillance, protection
they cannot effectively penetrate a thick stratum corneum.
from sun exposure, modulation of the immunosuppressive regi-
Podophyllum is used as a 20–25% solution in ethanol (alcohol)
men, and possible use of retinoids. In the organ transplant recipi-
or tincture of benzoin and must be applied under careful medical
ent, recurrence or persistence of warts after treatment is expected.
supervision and washed off after 4–6 hours.[96] The disadvantage
8.3.1 Cryotherapy of podophyllum is the potential for complications such as burning,
Liquid nitrogen causes local ablation of tissue that contains ulcerations, and swelling of application sites. When applied in
HPV. This method of treatment can be applied to cutaneous and large volumes on florid warts, severe toxicity symptoms have been
genital warts. Cryotherapy is a useful and inexpensive treatment observed.[97]
familiar to all dermatologists. It requires repeated treatment on a Podofilox is applied to genital warts twice daily for 3 consecu-
regular basis, especially if there are multiple or large warts. tive days and then stopped for 4 days; this treatment is then
Opinions vary on how long a freeze should be applied, as well as repeated again on a weekly basis.[98] The main advantages of
the treatment intervals. In immunocompetent patients, cryotherapy podofilox are that it need not be washed off, it has low potential
repeated every 3 weeks over 12 weeks resulted in cure rates toxicity, and patient-applied podofilox is becoming widely availa-
between 60% and 80%; with longer intervals between treatments, ble.
8.3.6 Cantharidin Imiquimod is approved by the FDA for the treatment of

Cantharidin is a dried extract of Spanish fly that produces anogenital warts. In the treatment of genital warts, patients self
blistering of the skin and epidermal necrosis. Thick lesions are apply imiquimod to their genital or perianal warts three times
pared before cantharidin is painted onto the wart. The blistering weekly for up to 4 months. The cream is left on for 8 hours and
that follows is entirely intraepidermal and, therefore, no scarring then washed off.[111]
occurs.[99] Imiquimod is a promising mode of therapy for viral warts in
organ transplant recipients because it is a patient-applied, non-
8.3.7 Trichloroacetic Acid
painful form of treatment.[112]
Trichloroacetic acid causes focal destruction of the epidermis
and damage to HPV DNA.[100] Application is performed in the 8.3.11 Other Medical Treatments
office and may be repeated weekly. Other medical treatments for warts are discussed only briefly
here. These treatments either are not widely available or have not
8.3.8 Bleomycin
been evaluated sufficiently in organ transplant patients.
The exact mechanism by which intralesional bleomycin exerts
Photodynamic therapy is a newer method of treating warts.
its activity against warts is unknown. This treatment has been
This treatment depends upon the uptake by abnormal cells of a
demonstrated to be safe and effective for treating warts[101] but
chemical, usually amino-levulinic acid, involved in the porphyrin
should be reserved for recalcitrant warts unresponsive to other
pathway. Photo-oxidation is then invoked by irradiating the tissue
therapies because of its cytotoxicity and possible adverse ef-
using laser or non-laser light. This approach has been shown to be
fects.[102] Bleomycin can be injected intralesionally, but care
useful for recalcitrant foot and hand warts in a randomized,
should be taken around the nail matrix when treating periungual
double-blind trial.[113] However, the treatment is not widely availa-
warts.[103] A modified method in which a drop of bleomycin is
ble.
applied directly onto the wart and the wart is then pricked repeat-
Interferons are part of the natural defense system and have been
edly with a needle has also been shown to be effective in an
used to treat recalcitrant anogenital warts, disseminated lesions
uncontrolled study of 62 patients who had the procedure per-
frequently recurring after conventional therapy, and extensive and
formed monthly.[104] Bleomycin treatment should be avoided in
tumorous lesions for which conventional therapies are not fully
patients with Raynaud disease as the treatment may aggravate this
practicable.[114] Intralesional interferon-α-2b has been shown to be
condition.[105]
safe and effective in the treatment of genital warts.[115] However,
given the cost of treatment, interferon should be reserved for
8.3.9 Retinoids
patients who are highly motivated and have failed other simpler
Retinoids disrupt epidermal growth and differentiation, thereby
and less costly modes of therapy. In organ transplant recipients, it
reducing the bulk of the wart. Topical retinoids have been shown
is likely that warts will recur once treatment is stopped.
to be useful in children with warts.[106] There have been a number
of case reports[107] and a limited number of trials[108] showing the
effect of systemic retinoids in the treatment of warts. The advan- 8.4 Strategies for Intervention and Treatment
tage of using synthetic retinoids in renal transplant recipients is
that they are also effective in reducing actinic keratoses, they A multidisciplinary approach to the care of the organ transplant
reduce the number of keratotic skin lesions, and they have a recipient, in which the transplant physician plays the central role,
preventive role against skin cancers in these patients.[87] Oral is vital. The dermatologist has an important supporting role in
retinoids should, therefore, be considered in transplant recipients patient care. Regular surveillance of patients, advice on sun pro-
with multiple warts and a history of squamous cell carcinomas. tection, and patient education are all essential aspects of post-
transplant skin care. Modification of immunosuppressive regi-
8.3.10 Imiquimod mens in the setting of very widespread or potentially dangerous
Imiquimod is a novel compound classified as an immune viral skin infections must be discussed with the patient’s primary
response modifier. It enhances the immune response, stimulating physician before any decision is taken.
natural killer cell activity and augmenting T-cell activity.[109] Organ transplant recipients with skin problems should have
Imiquimod also induces a range of cytokines including interfer- ready access to dermatologic care as – in addition to viral skin
ons, interleukins, and tumor necrosis factor.[110] infections – they have other dermatologic problems as well. Be-
26 Tan & Goh
cause of the association between HPV and skin cancer, any 9.3 Treatment
suspicious lesion should be biopsied at an early stage.
Many of the therapies discussed for the treatment of HPV
There is an established relationship between long-term sun
(section 8.3) also apply to MC and are not discussed further here.
exposure and skin cancer. In a patient who is immunosuppressed
Standard methods of treatment for MC include liquid nitrogen,
with multiple viral warts, there is an even greater need for sun
electrocautery, cantharidin, trichloroacetic acid, and topical treti-
protection because of the association between HPV and skin
noin.[118] One easy way to treat MC is by simply removing the
cancer.[116]
umbilicated core of the lesion using a curette or needle.[121] There
has also been a study of the use of a 585nm pulsed dye laser
9. Molluscum Contagiosum
showing that the procedure was well tolerated and effective.[122]
Molluscum contagiosum (MC) is caused by the Molluscum For children, some practitioners advocate the use of adhesive tape
contagiosum virus (MCV), a member of the family Poxviridae. It for MC lesions. The sticky side of the tape is repeatedly applied to
is a poxvirus that solely infects squamous epithelia.[117] and removed from the lesion for 10–20 cycles, resulting in strip-
ping of the superficial epidermis from the top of the lesion.[118]
9.1 Epidemiology Imiquimod has been used to treat MC in HIV-positive patients[123]
and is currently used off-label for MC. Topical cidofovir gel has
MCV occurs worldwide but is more prevalent in tropical ar- also been used for severe MC.[124]
eas.[118] It affects mainly children, sexually active adults, and
individuals with impaired cellular immunity. Two distinct viral 10. Conclusion
types of MCV have been identified: MCV-I and MCV-II.[119]
The dermatologist plays a key role in early diagnosis and
MCV-I is the more common viral subtype and is present in >75%
treatment of viral skin infections in organ transplant recipients.
of lesions;[117] however, the lesions induced by the two subtypes
Close cooperation and co-management with the transplant physi-
are clinically identical. The extent of MC infections in organ
cian are essential. Many of these infections may not be completely
transplant recipients is not as well documented as for the other
eradicated and are likely to recur. Patient education, regular sur-
viral infections. In a study of skin diseases in 145 children with
veillance, and cost-effective intervention should be part of long-
organ transplants, MC affected 6.9% of patients and was the fourth
term skin care for these patients.
most common skin infection detected after warts, tinea versicolor,
and herpes simplex/zoster.[120]
Acknowledgements
9.2 Cutaneous Features No sources of funding were used to assist in the preparation of this review.
The authors have no conflicts of interest that are directly relevant to the
MC typically appears as small, firm, umbilicated papules (fig- content of this review.
ure 8). The places that are usually affected are the face, trunk,
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Am J Clin Dermatol 2006; 7 (1): 13-29

THERAPY IN PRACTICE 1175-0561/06/0001-0013/$39.95/0

© 2006 Adis Data Information BV. All rights reserved.

Viral Infections Affecting the Skin in

Hiok-Hee Tan and Chee-Leok Goh

The development of type-specific serologic assays has allowed

Viral infection Management Comments

3.2 Cutaneous Manifestations 3.3 Treatment

VZV infections are often diagnosed on the basis of their clinical

4. Cytomegalovirus 4.3 Treatment

5.1 Epidemiology 6.1 Epidemiology

EBV is a ubiquitous herpesvirus. Antibodies to EBV can be

7.2 Cutaneous Manifestations

KS may present with single or multiple skin lesions as well as

transplant recipients, in their immunocompromised state, may

For the purpose of this article, discussion of human papil-

cure rates were found to be reduced.[92] Overly aggressive freezing

8.3.3 Laser Surgery

8.3.5 Podophyllum and Podofilox

8.3.6 Cantharidin Imiquimod is approved by the FDA for the treatment of

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