Treatment of human papillomavirus in childhood with Tratamento do papiloma vírus humano na infância com creme de Abstract: In children, lesions caused by the human papillomavirus (HPV) constitute a significant epidemi-
ological issue and a therapeutic dilemma, particularly in the case of anogenital warts. The treatment of
anogenital warts in children is a challenge, since standard treatments are generally painful and require the
patient to be anesthetized. Imiquimod, a topical immune response modifier, constitutes an alternative ther-
apeutic agent for the treatment of HPV. The present report describes four cases in which treatment with
topically applied imiquimod 5% cream was implemented with successful results.
Keywords: Aminoquinolines; Human papillomavirus 6; Human papillomavirus 11; Interferon inducers;
Papillomavirus infections
Resumo: Lesões decorrentes da infecção pelo papilomavírus humano na infância, em especial as verrugas
anogenitais, são um importante problema epidemiológico e terapêutico. O tratamento das verrugas
anogenitais na infância é um desafio terapêutico. Os tratamentos convencionais geralmente são dolorosos
e necessitam de anestesia geral. O imiquimode, um imunomodulador tópico, constitui uma alternativa te-
rapêutica. Serão descritos quatro casos tratados com sucesso utilizando creme de imiquimode a 5% aplica-
do topicamente.
Palavras-chave: Aminoquinolinas; Indutores de interferon; Infecções por papillomavirus; Papillomavirus 6
humano; Papillomavirus 11 humano
Received on 02.07.2009.
Approved by the Advisory Board and accepted for publication on 31.07.2009. * Study conducted at the Outpatient Clinic of Sexually Transmitted Diseases, Department of Clinical Dermatology, Teaching Hospital, FAMUSP, São Paulo, SP, Brazil.
Conflict of interest: None / Conflito de interesse: Nenhum Financial funding: None / Suporte financeiro: Nenhum Preceptor, Dermatology Department of the Teaching Hospital, School of Medicine, University of São Paulo (FMUSP), São Paulo, SP, Brazil.
Currently participating in a doctoral program at the Department of Dermatology, School of Medicine, University of São Paulo (FMUSP). Collaborating physician at the Department of Dermatology, School of Medicine, University of São Paulo (FMUSP), São Paulo, SP, Brazil.
Masters degree in Dermatology from the Department of Dermatology, School of Medicine, University of São Paulo (FMUSP). Physician, Department of Dermatology of the Teaching Hospital, School of Medicine, University of São Paulo (FMUSP), São Paulo, SP, Brazil.
Doctorate degree in Medicine from the Department of Dermatology, School of Medicine, University of São Paulo (FMUSP). Assistant physician, Department of Clinical Dermatology and investigator at the Medical Research Laboratory, LIM 53, of the Teaching Hospital, School of Medicine, University of São Paulo (FMUSP), São Paulo, SP, Brazil.
Doctorate degree in Medicine from the Department of Dermatology, School of Medicine, University of São Paulo (FMUSP). Faculty, Dermatology Department, University of Campinas (UNICAMP). Head of the Division of Sexually Transmitted Diseases/AIDS of the Brazilian Society of Dermatology. Professor of the Department of Dermatology, School of Medicine, University of São Paulo (FMUSP), São Paulo, SP, Brazil.
2010 by Anais Brasileiros de Dermatologia An Bras Dermatol. 2009;84(5):549-53. Brandt HRC, Fernandes JD, Patriota RCR, Criado PR, Belda W Jr INTRODUCTION
Case 2
Lesions resulting from the human papillo- A one-year old male patient. His mother report- mavirus infection, particularly genital warts, in child- ed multiple perianal lesions of six months’ duration.
hood constitute a significant epidemiological issue and Skin-colored papules were found in the perianal a therapeutic dilemma. 1 The principal sites affected by region (Figure 2). Previous treatment with 25% the human papillomavirus (HPV) in children are the podophyllin was unsuccessful. The child was born at extremities and the face, anogenital warts being less term following an uncomplicated vaginal delivery. His common in childhood. 2 The mode of HPV transmis- parents had no HPV-associated lesions.
sion remains controversial, but includes perinataltransmission, auto- and hetero-inoculation, sexual Case 3
abuse and possibly indirect transmission via fomites. 3 A two-year old girl. Her mother reported geni- Anogenital lesions detected during a child’s first year tal lesions of four months’ duration. Multiple skin- of life are generally acquired perinatally. Nevertheless, colored papules were found in the vulvar and perianal doubts persist with respect to the origin of new lesions region. The child was born at term following an that appear between the first and third years of life. 4 uncomplicated vaginal delivery. Gynecological exami- Treatment of extensive condylomatous lesions nation revealed signs of a ruptured hymen and other in childhood represents a therapeutic problem.
evidence of vaginal trauma. Following meticulous Ablative procedures and laser surgery are painful and evaluation, signs of sexual abuse were detected.
usually require general anesthesia. Topicalimiquimod 5% cream has been successfully used for Case 4
the treatment of condyloma acuminata in adults; how- An 18-month old girl. Her mother reported gen- ever, its use in children has yet to be established. 5 ital lesions of six months’ duration. Multiple skin-col-ored papules were found in the perianal region. The CASE REPORTS
child was born at term following an uncomplicated Case 1
vaginal delivery. Gynecological examination showed A two-year old boy. His mother reported dis- no abnormalities. Past history of sexual abuse.
seminated perianal lesions over the previous 12 A virological study of the lesions in the first months, increasing in number and size. Multiple con- three patients using polymerase chain reaction (PCR) fluent brownish papules were observed, affecting the resulted in positivity for HPV-6 and HPV-11 in all three scrotum and perineal and inguinal regions (Figure 1).
cases. PCR was not performed in case 4. In all four Previous treatment with 70% trichloroacetic acid was cases, histopathology was compatible with condyloma.
unsuccessful. The child had been born at term follow- Other findings included papillomatosis and acantho- ing an uncomplicated vaginal delivery. His mother sis, thickening and lengthening of the skin ridges, asso- reported having had genital warts during pregnancy.
ciated with koilocytosis. Serology for syphilis, hepati- The father was evaluated and no evidence was found tis B and C and HIV was negative in all four cases.
of any genital lesions or extragenital warts.
The four cases were treated topically with FIGURE 1: Case 1. Multiple brownish, confluent papules affecting
FIGURE 2: Case 2. Multiple papules converging in skin-colored
the scrotum, perianal and inguinal regions, prior to treatment plaques in the perianal region, prior to treatment An Bras Dermatol. 2010;85(4):549-53. Treatment of human papillomavirus in childhood with imiquimod 5% cream imiquimod 5% cream applied at home three times a or trichloroacetic acid and podophyllotoxin. Methods week. Complete regression of the lesions occurred of physical destruction of lesions include cryotherapy, after three weeks of use in cases 1 (Figure 3) and 3, and laser, electrocauterization and surgical excision. 10 after four weeks in cases 2 and 4 (Figure 4). Treatment Physical methods are often painful, may result in scar- was continued for a total of six weeks in all cases. Only ring and require the use of anesthesia. Recurrence of one adverse event was recorded, consisting of moder- the lesions is common. These repeated and painful ate erythema on the perilesional skin identified in case applications on the genitalia of a child may lead to psy- 1; however, the condition improved as treatment pro- gressed. After six months of follow-up, no new clinical Treatments based on the chemical or physical lesions were found in any of the four cases.
destruction of the infected keratinocytes do notdirectly inhibit the infection or viral replication. Each DISCUSSION
therapeutic option has its own inherent advantages In adults, the transmission of genital warts and disadvantages, and there is no medication up to occurs mainly by sexual contact. Genital warts in the present time that effectively eliminates HPV. 12 childhood may be acquired through nonsexual con- The innate immune system, which defends the tact. Condyloma acuminatum has been described in host against viruses, is composed of natural killer cells 1-2% of cases of child sexual abuse, and 50-75% of the and activated macrophages. Viral infection of the lym- cases of genital warts in children are a consequence of phocytes results in the production of antiviral cytokines, the interferons, which activate various associated with child sexual abuse more frequently mechanisms that act against the virus in cells that are than subtypes 2 and 3. 7 Perinatal transmission of gen- not yet infected, rendering them resistant to infection.
ital warts from infected mothers to the external geni- Specific adaptive immune responses are then activat- talia of their infants has been well-documented. 8 ed, principally by cytotoxic T-cells, auxiliary T cells HPV transmission through close contact with their and antibodies that neutralize the virus, preventing carers has also been reported. Due to the possibility reinfection and dissemination in extracellular phases.
that children with external genital warts may have The complement also exerts activity on viral infec- been sexually abused, communication with the rele- tions. Toll-like receptors (TLR), which are involved in vant child protection agency is indicated if there is a recognizing the viral pathogen-associated molecular strong suspicion of abuse based on the patient’s his- patterns (PAMPs) such as TLR 2-4, 7-9, are also Treatment of lesions resulting from HPV should The persistence of HPV-induced lesions is prin- be individualized. Various sessions with different ther- cipally a consequence of defective immunosurveil- apeutic modalities may be required to achieve com- lance. 1 Modulation of the immune response by sys- plete regression of the lesions. The conventional treat- temic, topical or intralesional medication represents ment consists of chemical destruction of the lesion by an alternative treatment for viral infections. The effi- topical application of podophyllin, 5-fluorouracil, bi- cacy of this modulation is based on the regression of FIGURE 3: Case 1. Total regression of the lesions after three weeks
FIGURE 4: Case 2. Total regression of the lesions after four weeks
An Bras Dermatol. 2009;84(5):549-53. Brandt HRC, Fernandes JD, Patriota RCR, Criado PR, Belda W Jr verrucous lesions resulting from the development of quantity applied. Systemic symptoms are rare; howev- er, patients may present fatigue, fever, myalgia, alter- Imiquimod is a synthetic immunomodulator for ations to the central and peripheral nervous system and topical use. It is an aminoquinoline compound and exerts an effect on the cellular innate immune system Lesions located in the mucosa are more respon- mediated by interferon alpha and tumor necrosis fac- sive to treatment, possibly due to better absorption. 13 tor-alpha. There is also an increase in innate and The efficacy of treatment may be greater if imiquimod is acquired immunity through stimulation of the toll-like used more frequently or in combination with topical sal- receptors of the antigen-presenting cells. Activation icylic acid or retinoic acid. In refractory cases, imiquimod of the immune mediators appears to be responsible may be applied under an occlusive dressing. 13 for eradicating the HPV virus. Imiquimod induces the The application of imiquimod has proven bene- production of interferon-alpha (IFN-a) by the ker- ficial for the treatment of condyloma in adults.
atinocytes, as well as other cytokines that inhibit viral Nevertheless, its use in children is yet to be estab- replication. Imiquimod also acts on cell immunity by lished. The principal advantage for children is the activating Langerhans cells, thus increasing the pres- convenience of home treatment and the absence of entation of antigens for the T-cells. 1,11,13 pain. The number of cases in which local irritation led Imiquimod treatment of lesions resulting from a to discontinuation of treatment is minimal, and care- viral infection such as condyloma acuminatum in adults ful application, avoiding contact with normal skin or and viral warts and mollusca contagiosa in children has decreasing the frequency of use, minimizes this risk.
Complete regression of condyloma was report- lesions is achieved in 72-84% of cases, local recurrence ed in children of 6 and 19 months following applica- rates ranging from 5 to 19%. The advantage of this tion of imiquimod for 3 and 8 weeks, respectively. 11,15 treatment for children is the convenience of a treat- Despite the frequent observation of perilesional ery- ment that can be applied painlessly in the home, which thema, no significant side effects were found in the is not the case with many of the ablative therapies. 11,12 cases reported or in the cases presented here.
Imiquimod 5% cream is well tolerated, the most com- The observation of these four successfully treat- mon adverse events being erythema, burning, erosion ed cases of genital warts in childhood suggests that and hypersensitivity, which are usually limited to the imiquimod 5% cream is a safe, effective alternative site of application. Systemic absorption of imiquimod therapy that should be considered as an option to is less than 1% of the total amount applied topically and aggressive painful treatments and also to surgical is more associated with the surface area than with the An Bras Dermatol. 2010;85(4):549-53. Treatment of human papillomavirus in childhood with imiquimod 5% cream REFERENCES
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papillomavirus infection. Am J Dis Child. infections: epidemiology, pathogenesis, clinic, morphology, important differential diagnostic aspects, 10. Moresi JM, Herbert CR, Cohen BA. Treatment of current diagnostic and treatment options. An Bras anogenital warts in children with topical 0. 05% podofilox gel and 5% imiquimod cream. Pediatr Grussendorf-Conen EI, Jacobs S. Efficacy of imiquimod 5% cream in the treatment of recalcitrant warts in 11. Schaen L, Mercurio MG. Treatment of human children. Pediatr Dermatol. 2002;19:263-6.
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Pakarian F, Kaye J, Cason J, Kell B, Jewers R, Derias NW, MAILING ADDRESS / ENDEREÇO PARA CORRESPONDÊNCIA: et al. Cancer associated human papilomavirus: perinatal transmission and persistence. Br J Obstet Av. Dr. Enéas Carvalho de Aguiar, 255 - 3º andar Divisão de Clínica Dermatológica - ICHC Gutman LT, St Claire K, Herman-Giddens ME, Johnston WW, Phelps WC. Evaluation of sexually abused and Tel.fax: +55 11 3069 8002; +55 11 3088 9145 nonabused young girls for intravaginal human How to cite this article/Como citar este artigo: Brandt HRC, Fernandes JD, Patriota RCR, Criado PR, BeldaW Jr. Treatment of human papillomavirus in childhood with imiquimod 5% cream. An Bras Dermatol.
An Bras Dermatol. 2010;85(4):549-53.


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