An Update on the Clinical Management of Cutaneous ...

An Update on the Clinical Management of Cutaneous Molluscum Contagiosum Harrison P. Nguyen, BA1,2 and Stephen K. Tyring, MD, PhD, MBA2,3 Baylor College of Medicine, Houston, TX, USA Department of Dermatology, University of Texas Health Science Center at Houston, Houston, TX, USA 3 Center for Clinical Studies, Houston, TX, USA 1

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ABSTRACT

Molluscum contagiosum is a poxvirus infection of the skin that is commonly observed in children. The molluscum contagiosum virus (MCV) expresses several gene-products that are involved in its pathogenesis and evasion of the host immune system. MCV can be transmitted both to other sites of the body and to other individuals through direct physical contact as well as fomites. While diagnosis is generally straightforward clinically, management of molluscum contagiosum is controversial. Several treatment options are available for the destruction of individual lesions, but there is insufficient evidence for therapeutic intervention being any more effective than natural, spontaneous resolution. Complex cases, such as infection occurring in immunocompromised patients and in mucocutaneous sites, require an alternative approach to management. Molluscum contagiosum continues to represent a burden on children and parents worldwide. Key words: molluscum contagiosum, viral infection, pediatric skin disease

Background Molluscum contagiosum is a cutaneous viral infection that is commonly observed in both healthy and immunocompromised children. The infection is caused by a member of the Poxviridae family, the molluscum contagiosum virus (MCV). Molluscum contagiosum presents as single or multiple small white or flesh-colored papules that typically have a central umbilication. The central umbilication may be difficult to observe in young children and, instead, may bear an appearance similar to an acneiform eruption. The lesions vary in size (from 1 mm to 1 cm in diameter) and are painless, although a subset of patients report pruritus in the area of infection.1 On average, 11-20 papules appear on the body during the course of infection and generally remains a self-limiting disease. However, in immunosuppressed patients, molluscum contagiosum can be a severe infection with hundreds of lesions developing on the body. Extensive eruption is indicative of an advanced immunodeficiency state. Eruption of molluscum contagiosum usually begins in a localized area of the skin, though the infection can be transmitted to other regions of the body – such as genital, perineal, pubic, and surrounding skin – through autoinoculation. Since MCV can be sexually transmitted, child abuse should be considered when the genital or perineal areas are infected, but autoinoculation is usually the most common source of genital infection.2 Most cases of sexually transmitted molluscum manifest as papules localized exclusively to the genital area. A 2010 Spanish study reported that sexually transmitted molluscum contagiosum had increased three-fold in its regional hospital from 1987 to 2007.3 Rarely, molluscum contagiosum can also spread to the oral region – potentially from the genitalia during oral sex – as well as to the conjunctiva and cornea.4,5 The latter scenario may result in chronic conjunctivitis or superficial punctate keratitis,

which complicates the treatment of lesions in the orbital region. In atopic patients, eczema can develop around the papules approximately a month after onset. The eczema, which has also been observed in non-atopic children, occurs in upwards of 30% of patients and, importantly, increases the risk of autoinoculation since patients are more likely to scratch the eczematous region, spreading the viral particles to other areas of the body.6 The chronic conjunctivitis and eczema associated with molluscum contagiosum subside spontaneously when the lesions are eradicated. Pre-existing eczema may also predispose children to the infection; 62% of children with molluscum contagiosum in Australia reported a history of eczema.7 MCV is transmitted through close physical contact with an infected individual or with a fomite.8 There were an estimated 280,000 patient visits per year for molluscum contagiosum in the United States alone during the 1990s.9 While the data is limited, several studies have estimated the worldwide prevalence to be between 5% and 7.5% of children, but the number increases to 5%-18% within the human immunodeficiency virus (HIV) positive population and even reaches 30% among acquired immunodeficiency syndrome (AIDS) patients with a CD4+ count under 100/mL.10-12 The infection is also observed at a higher frequency in certain geographic areas with tropical climates– such as Congo, Fiji, and Papua New Guinea – where the incidence can approach 20% in all children.13 It is not known whether this increased prevalence is due to a founder effect-associated genetic susceptibility of these populations to MCV infection or whether MCV becomes more virulent in tropical conditions. Infection in immunocompetent patients is generally self-limiting and resolves on its own within 6 to 9 months. One study reported spontaneous resolution in 94.5% of patients within 6.5 months after initial infection; moreover, the same study reported that 23%

• Editor: Dr. Stuart Maddin • Volume 19, Number 2 • March-April 2014

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of study participants were cured within one month after the first consultation with a dermatologist.14 It must be emphasized that spontaneous resolution primarily occurs in immunocompetent patients. In contrast, individuals with suppressed immune systems often suffer an increasing degree of recalcitrant molluscum contagiosum that is directly correlated with the level of immunodeficiency. Biology and Pathogenesis of MCV MCV is one of the largest human viruses. It is a member of the genus Molluscipoxvirus and contains a non-segmented single molecule of linear, double-stranded DNA 200-300 nm in length. The genome is covalently linked at both ends and encodes redundant, repeating sequences at both ends.15 Restriction endonuclease digestion is used to differentiate among the four subypes of molluscum contagiosum – MCV-1, MCV-1a, MCV-2, and MCV-3 – which all appear to cause very similar disease presentations.16 The genome of MCV-1 has been completely sequenced and several novel gene products involved in its pathogenesis and evasion of the immune system have been identified: MC54L, MC148, MC013L, MC159, and glutathione peroxidase.17-19 The protein MC54L prevents inflammation by binding the pro-inflammatory cytokine human interleukin-18.20 MC148 promotes viral replication by preventing infected keratinocytes from differentiating.21 MC159 interacts with Fas (CD95; a member of the tumor necrosis factor receptor family), tumor necrosis factor (TNF), and TNF-related apoptosisinducing ligand (TRAIL) to inhibit apoptosis.22 MC80R, a major histocompatibility complex (MHC) class I homolog, interferes with the host presentation of peptides specific to MCV and inhibits cell-mediated cytotoxicity of infected cells.23 Finally, infected cells express glutathione peroxidase to prevent leukocyte-mediated oxidative damage.17 Together, these viral gene products are able to maintain active infection until the host immune system gradually prevails. MCV likely enters the skin through small abrasions; this explains why eczema-prone and atopic individuals, who typically scratch inflamed areas on their skin, are more susceptible. Once MCV has penetrated the lower layers of the epidermis it begins to replicate, extending upwards, in the lower layers of the epidermis.24 The estimated incubation period varies from 14 days to 6 months. When active infection commences, the epidermis hypertrophies, extending into the underlying dermis, and characteristic molluscum bodies (also known as Henderson-Paterson bodies) form inside cells of the stratum spinosum. As infection progresses, the molluscum bodies enlarge, causing the spinosa cells to migrate upwards while hyperplasia of the basal cell layer simultaneously replaces the migrating spinosa cells. Viral structures are rarely observed in the stratum basale, and the structure of the basal lamina remains intact. The hypertrophied epidermal cells project above the skin, which forms the characteristic tumor observed in molluscum contagiosum.25 Interestingly, an inflammatory infiltrate is not observed until shortly before natural resolution of the lesion.26 Diagnosis The morphological appearance of molluscum contagiosum in most cases is sufficiently distinct to make a clinical diagnosis. 6

However, some cases can be more challenging. Using a magnifying lens or a dermatoscope to visualize the characteristic central umbilication often aids in diagnosis. If the magnifying lens does not yield a conclusive diagnosis, the clinician can biopsy the lesion and conduct either histopathological studies or polymerase chain reaction (PCR) methods. Histopathology typically demonstrates epidermal hyperplasia producing a crater filled with molluscum bodies. Molluscum bodies, which are huge (up to 35 microns) discrete ovoid intracytoplasmic inclusion bodies, appear as large acidophilic granular masses, pushing the nucleus and numerous keratohyaline granules aside. Although identification of molluscum bodies is conclusive for diagnosis of molluscum contagiosum, molluscum bodies can be sparse and difficult to visualize in some densely inflamed lesions. Intact lesions display little inflammation while ruptured lesions show a mixed inflammatory response characterized by mononuclear cells, neutrophils, and multinucleated giant cells. Brick-shaped virions can usually be seen through negative-stain transmission electron microscopy.15 Molluscum contagiosum can bear similar clinical presentation to other disorders. Rarely, they may be confused with warts and, if located on the genitalia, may be mistaken for condyloma of a human papillomavirus infection.27 Giant molluscum nodules can resemble basal cell epithelioma, keratoacanthoma, verruca vulgaris, condyloma acuminatum, or a warty dyskeratoma.28 Clinical Management In nearly all immunocompetent individuals, molluscum contagiosum is a self-limiting disease that will spontaneously resolve, usually without scarring. Allowing this natural resolution of infection without therapeutic intervention is an important and effective treatment strategy that also minimizes healthcare costs. Regardless of whether treatment is sought, it is imperative that the clinician advises the patient to avoid swimming pools, bathing with others, sharing of towels, and activities requiring physical contact with others. Current therapeutic intervention in the treatment of molluscum contagiosum is intended merely to accelerate the eradication process. A systematic review in 2009 studied the efficacy of current therapeutic options for nongenital molluscum contagiosum and concluded that there was insufficient evidence to support the use of any treatment as being definitively effective.8 Nevertheless, for the rapid resolution of individual lesions, clinical experience advocates the use of curettage, cryotherapy, and some topical agents. Therefore, the patient may wish to seek treatment for a variety of reasons, including: alleviating pruritus; minimizing autoinoculation as well as transmission to others; addressing cosmetic concerns; and preventing scarring, secondary infection, or bleeding of the lesions.8 Patients with sexually transmitted molluscum contagiosum should receive early treatment to prevent the spread of infection to future sexual partners. Early treatment is also indicated for immunosuppressed patients whose infections can become severe. Prior to beginning treatment, the clinician should conduct a full-body skin examination to identify all lesions; failure to treat all lesions may lead to continued infection and autoinoculation. Curettage, cryotherapy, and cantharidin are considered to be firstline treatment strategies due to their popularity and established


efficacy for resolution of individual lesions. Curettage involves the physical removal of lesions with the use of a curette and is the preferred choice of treatment in the Netherlands.8 Risk factors for treatment failure include a high number of lesions and concomitant atopic dermatitis. Topical anesthetics can be used to reduce the pain and discomfort associated with curettage, which can be disturbing for some children. The development of small, depressed scars following curettage is possible and should be discussed with the parents or guardians prior to treatment. Cryotherapy entails the use of a cotton-tipped swab dipped in liquid nitrogen that is applied to individual lesions for 6 to 10 seconds each. A 2010 randomized trial comparing the efficacy of cryotherapy with the immunomodulator imiquimod found cryotherapy to be effective in completely curing all patients and yielding more rapid resolution than imiquimod.29 However, cryotherapy also had an increased occurrence of adverse effects, such as pain, bullae, dyspigmentation, and mild scarring. Cantharidin – the most popular method of treatment among American dermatologists – is a topical blistering agent that is applied directly to the lesions, usually with the blunt end of a cotton swab.8 To prevent further autoinoculation or transmission, the site of treatment should then be covered with a bandage and washed with soap and water 2 to 6 hours after application. Treatments can be repeated every 2 to 4 weeks and are contraindicated for lesions located on the face, genitalia, or perianal regions. A retrospective study found 90% of children treated with cantharidin for molluscum experienced lesion clearance; the average number of patient visits to achieve complete resolution was 2.1.6 About 95% of parents of children participating in the study stated that they were satisfied with the treatment and would be willing to have their child treated again with cantharidin. Common side effects that were observed include transient burning, erythema, pain, and pruritus. Several second-line therapies have been described, which include (but are not limited to): imiquimod, sinecatechins ointment, podophyllin, potassium hydroxide, salicyclic acid, topical retinoids, oral cimetidine, pulsed dye lasers, and silver nitrate. However, the efficacy of these treatment strategies in healthy patients is controversial. A 2009 review by van der Wouden et al and a 2006 review by Brown et al analyze comparative studies involving the aforementioned second-line treatments.8 Immunocompromised patients can develop severe, persistent infection by not only MCV but also opportunistic pathogens. Treatments that lead to wound formation, such as curettage, should be avoided since wounds elevate the risk of additional infection. Instead, imiquimod applied 3 nights per week is recommended. 30 In our investigational center, the authors have achieved successful reduction of genital lesions with the use of 0.05% ingenol mebutate gel as spot treatment in a renal transplant patient. In HIV positive patients, recalcitrant lesions are sometimes resolved only after initiation of highly active antiretroviral therapy (HAART).31 Clearance of recalcitrant, refractory lesions in HIV positive patients has been achieved through the use of intravenous cidofovir, a nucleotide analog of deoxycytidine monophosphate.32 However, systemic cidofovir can be toxic on the kidneys, so topical cidofovir is currently being explored as a potential therapeutic agent. The authors achieved complete resolution of a severe case of molluscum contagiosum

on the face of an HIV patient in 2 months following treatment with topical cidofovir compounded into a 2% ointment. Atopic dermatitis patients are at greater risk for scar formation with increasing number of lesions, so curettage is not advisable. Prior to treatment of the molluscum lesions, the physician should address the atopic dermatitis with corticosteroids and antihistamines. Other immunomodulatory agents may be useful in long-term therapy of atopic dermatitis, but these drugs may facilitate MCV infection.26 Javed and Tyring, in a published case report, achieved complete remission of molluscum contagiosum in an atopic pediatric patient using ingenol mebutate 0.015% gel.33 Not only was there complete clearance of lesions in the treated area, but untreated lesions located in distant regions also resolved. Ingenol mebutate has been approved by the US FDA for the treatment of actinic keratosis. The proposed mechanism involves lesion necrosis and neutrophil-mediated, antibodydependent cellular cytotoxicity.34 Periocular lesions should be referred to an ophthalmologist for further treatment. Conclusion Currently, there is no FDA approved therapy for molluscum contagiosum and there is no widely accepted standard of care. Many pediatricians favor spontaneous resolution over aggressive therapy. However, research should continue to be conducted in hope of finding an answer to this common, pediatric infectious disease. In addition, sexually transmitted molluscum should be treated not only for the benefit of the patient, but also to prevent spread to sexual partners. Most importantly, standardized therapy should be developed for immunocompromised patients, who may suffer both physically and psychologically from widespread molluscum, especially on the face and genitalia. Future studies should investigate outcome measures such as recurrence and transmission rates, disease-related quality of life, and scarring. A standardized outcome measure for each treatment would facilitate comparative assessment. References 1. Rogers M, Barnetson RSC. Diseases of the skin. In: McIntosh N, Helms P, Smyth R, et al. editors. Forfar and Arneil’s textboook of pediatrics. 5th ed. New York: Churchill Livingstone, (2008). 2. Bargman H. Is genital molluscum contagiosum a cutaneous manifestation of sexual abuse in children? J Am Acad Dermatol. 1986 May;14(5 Pt 1):847-9. 3. Villa L, Varela JA, Otero L, et al. Molluscum contagiosum: A 20-year study in a sexually transmitted infections unit. Sex Transm Dis. 2010 Jul;37(7):423-4. 4. Whitaker SB, Wiegand SE, Budnick SD. Intraoral molluscum contagiosum. Oral Surg Oral Med Oral Pathol. 1991 Sep;72(3):334-6. 5. Rao VA, Baskaran RK, Krishnan MM. Unusual cases of molluscum contagiosum of eye. Indian J Ophthalmol. 1985 Jul-Aug;33(4):263-5. 6. Silverberg NB, Sidbury R, Mancini AJ. Childhood molluscum contagiosum: experience with cantharidin therapy in 300 patients. J Am Acad Dermatol. 2000 Sep;43(3):503-7. 7. Braue A, Ross G, Varigos G, et al. Epidemiology and impact of childhood molluscum contagiosum: a case series and critical review of the literature. Pediatr Dermatol. 2005 Jul-Aug;22(4):287-94. 8. van der Wouden JC, van der Sande R, van Suijlekom-Smit LW, et al. Interventions for cutaneous molluscum contagiosum. Cochrane Database Syst Rev. 2009(4):CD004767. 9. Molino AC, Fleischer AB, Jr., Feldman SR. Patient demographics and utilization of health care services for molluscum contagiosum. Pediatr Dermatol. 2004 Nov-Dec;21(6):628-32.


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10. Schwartz JJ, Myskowski PL. Molluscum contagiosum in patients with human immunodeficiency virus infection. A review of twenty-seven patients. J Am Acad Dermatol. 1992 Oct;27(4):583-8. 11. Stefanaki C, Stratigos AJ, Stratigos JD. Skin manifestations of HIV-1 infection in children. Clin Dermatol. 2002 Jan-Feb;20(1):74-86. 12. Koopman RJ, van Merrienboer FC, Vreden SG, et al. Molluscum contagiosum; a marker for advanced HIV infection. Br J Dermatol. 1992 May;126(5):528-9. 13. Kaye JW. Problems in therapy of molluscum contagiosum. Case report. Arch Dermatol. 1966 Oct;94(4):454-5. 14. Takemura T, Ohkuma K, Nagai H, et al. The natural history of molluscum contagiosum. Examination Treatment Dermatol Dis (Japanese). 1983;5(7): 667-70. 15. Damon IK. Poxviruses. In: Knipe DM, Howley PM, editors. Fields virology. 5th ed. Philadelphia: Lipincott Williams & Wilkins, p2963-5 (2007). 16. Nakamura J, Muraki Y, Yamada M, et al. Analysis of molluscum contagiosum virus genomes isolated in Japan. J Med Virol. 1995 Aug;46(4):339-48. 17. Senkevich TG, Bugert JJ, Sisler JR, et al. Genome sequence of a human tumorigenic poxvirus: prediction of specific host response-evasion genes. Science. 1996 Aug 9;273(5276):813-6. 18. Xiang Y, Moss B. IL-18 binding and inhibition of interferon gamma induction by human poxvirus-encoded proteins. Proc Natl Acad Sci USA. 1999 Sep 28;96(20):11537-42. 19. Bertin J, Armstrong RC, Ottilie S, et al. Death effector domain-containing herpesvirus and poxvirus proteins inhibit both Fas- and TNFR1-induced apoptosis. Proc Natl Acad Sci USA. 1997 Feb 18;94(4):1172-6. 20. Agromayor M, Ortiz P, Lopez-Estebaranz JL, et al. Molecular epidemiology of molluscum contagiosum virus and analysis of the host-serum antibody response in Spanish HIV-negative patients. J Med Virol. 2002 Feb;66(2):151-8. 21. Chen N, Baudino T, MacDonald PN, et al. Selective inhibition of nuclear steroid receptor function by a protein from a human tumorigenic poxvirus. Virology. 2000 Aug 15;274(1):17-25. 22. Garvey TL, Bertin J, Siegel RM, et al. Binding of FADD and caspase-8 to molluscum contagiosum virus MC159 v-FLIP is not sufficient for its antiapoptotic function. J Virol. 2002 Jan;76(2):697-706.

23. Smith KJ, Yeager J, Skelton H. Molluscum contagiosum: its clinical, histopathologic, and immunohistochemical spectrum. Int J Dermatol. 1999 Sep;38(9):664-72. 24. Pierard-Franchimont C, Legrain A, Pierard GE. Growth and regression of molluscum contagiosum. J Am Acad Dermatol. 1983 Nov;9(5):669-72. 25. Shelley WB, Burmeister V. Demonstration of a unique viral structure: the molluscum viral colony sac. Br J Dermatol. 1986 Nov;115(5):557-62. 26. Brown ST, Nalley JF, Kraus SJ. Molluscum contagiosum. Sex Transm Dis. 1981 Jul-Sep;8(3):227-34. 27. Ha SJ, Park YM, Cho SH, et al. Solitary giant molluscum contagiosum of the sole. Pediatr Dermatol. 1998 May-Jun;15(3):222-4. 28. Brown J, Janniger CK, Schwartz RA, et al. Childhood molluscum contagiosum. Int J Dermatol. 2006 Feb;45(2):93-9. 29. Al-Mutairi N, Al-Doukhi A, Al-Farag S, et al. Comparative study on the efficacy, safety, and acceptability of imiquimod 5% cream versus cryotherapy for molluscum contagiosum in children. Pediatr Dermatol. 2010 Jul-Aug;27(4):388-94. 30. Liota E, Smith KJ, Buckley R, et al. Imiquimod therapy for molluscum contagiosum. J Cutan Med Surg. 2000 Apr;4(2):76-82. 31. Calista D, Boschini A, Landi G. Resolution of disseminated molluscum contagiosum with Highly Active Anti-Retroviral Therapy (HAART) in patients with AIDS. Eur J Dermatol. 1999 Apr-May;9(3):211-3. 32. Meadows KP, Tyring SK, Pavia AT, et al. Resolution of recalcitrant molluscum contagiosum virus lesions in human immunodeficiency virus-infected patients treated with cidofovir. Arch Dermatol. 1997 Aug;133(8):987-90. 33. Javed S, Trying SK. Ingenol mebutate for the therapy of molluscum contagiosum. J Am Acad Dermatol. In press 2014. 34. Rosen RH, Gupta AK, Tyring SK. Dual mechanism of action of ingenol mebutate gel for topical treatment of actinic keratoses: rapid lesion necrosis followed by lesion-specific immune response. J Am Acad Dermatol. 2012 Mar;66(3):486-93.

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