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 Table of Contents  
Year : 2017  |  Volume : 14  |  Issue : 4  |  Page : 162-166

Management challenges of epidermodysplasia verruciformis in a resource-limited setting: A retrospective review

1 Department of Medicine, Dermatology Unit, Lagos University Teaching Hospital, Lagos, Nigeria
2 Department of Medicine, College of Medicine, University of Lagos, Lagos, Nigeria

Date of Web Publication8-Nov-2017

Correspondence Address:
Erere Otrofanowei
Department of Medicine, Dermatology Unit, Lagos University Teaching Hospital, Lagos
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/jcls.jcls_94_16

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Background: Epidermodysplasia verruciformis (EV) is a rare genodermatosis with autosomal recessive inheritance linked to human papilloma virus 5 and 8. It presents with flesh-colored or hypopigmented macules and plaques on the face, neck, hands, and body. They are asymptomatic but cause great cosmetic concern to affected individuals. An immune deficient state renders patients more susceptible to it; although some have no demonstrable ill health. Diagnosis is mostly clinical; nevertheless, skin biopsy for histopathology may be performed in doubtful cases. Treatment is aimed at cosmetic removal with retinoids, Imiquimod, and keratolytics among others. The aim of this report is to document the clinical profile of patients with EV, and highlight the challenges faced in managing patients. Materials and Methods: The clinical records from January 2006 to December 2013 were reviewed. Demographic data, HIV status, and biopsy results were extracted and entered onto Microsoft Excel spreadsheet. The results were analyzed with SPSS version 18. Results: A total of 33, 326 patients were seen during the review period; 96 (0.3%) had a clinical diagnosis of EV with 45 (46.9%) males and 51 (53.1%) females. The mean age was 20.8 ± 13.4, with a range of 2–52 years. A quarter of the patients were tested for HIV and 12 (13%) were positive. Conclusions: This study documents the frequency of EV in our environment and provides a baseline for more studies. The results concur with its rare occurrence worldwide and fail to show the exact relationship between HIV infection and EV. The challenges to managing these patients are mostly due to financial constraints; hence, basic investigations and optimal treatment could not be done in many of the patients.

Keywords: Epidermodysplasia verruciformis, genodermatoses, human papiloma virus, resource limited

How to cite this article:
Otrofanowei E, Akinkugbe A, Ayanlowo O. Management challenges of epidermodysplasia verruciformis in a resource-limited setting: A retrospective review. J Clin Sci 2017;14:162-6

How to cite this URL:
Otrofanowei E, Akinkugbe A, Ayanlowo O. Management challenges of epidermodysplasia verruciformis in a resource-limited setting: A retrospective review. J Clin Sci [serial online] 2017 [cited 2020 Mar 29];14:162-6. Available from: http://www.jcsjournal.org/text.asp?2017/14/4/162/217822

  Introduction Top

Epidermodysplasia verruciformis (EV) is an uncommon genodermatosis, wherein susceptible individuals develop cutaneous diseases associated with the β-human papilloma viruses (HPVs), particularly types 5 and 8. First described by Lutz and Lewandowski in 1922, it is classically reported as being inherited in an autosomal recessive pattern.[1] An X-linked recessive inheritance has however been described, and a tenth of patients with EV are products of consanguineous marriages.[2],[3],[4] New evidence suggests a genetic heterogeneity [5] with loss of function mutation in the EVER 1 and EVER 2 genes. These genes are transmembrane channel-like (TMC) genes which have a role in T-cell mediated immune deficiency resulting in inhibition of natural apoptosis of EV HPV-infected keratinocytes, thus leading to the development of the skin lesions.[6] Apart from HPV 5 and 8, there are 17 other papilloma viruses associated with EV, designated EV-HPVs and they are HPV 9, 12, 14, 15, 17, 19–25, and 36–38. Acquired EV which is clinically similar to congenital EV is seen in the setting of immunosuppression such as in HIV/AIDS, transplant patients and lymphomas, to mention a few. The lesions are however more widespread, not limited to sun-exposed areas only but may also be seen on the trunk and back. Acquired EV is thought to be due to impaired cellular immunity resulting from the immune deficient state, rather than a genetic mutation.[5],[6],[7] There is no race or sex predilection but it is reported as rare in Africa, and there are only about 200 cases described in literature.

Clinically, EV is characterized by the early onset (mostly in childhood) of multiple hypopigmented or flesh-colored flat warts, pityriasis, versicolor-like lesions which follow the isomorphic phenomenon.[8] These are typically seen on sun-exposed areas of the body such as the face, neck, upper arms, and shoulders though generalized presentations are seen, especially in immune deficient states. They are otherwise asymptomatic but cause significant morbidity because of the cosmetic disfigurement and may be fatal with the development of nonmelanoma skin cancers (NMSCs) as the EV HPVs have great oncogenic potential.[9],[10] Patients with EV may be either immune competent or deficient, and HPV is considered a normal commensal by some authors due to its high prevalence in immune-competent persons.[10]

A clinical diagnosis is easily made, but a skin biopsy and HPV DNA typing will confirm a working diagnosis of EV. Common histological features seen in EV skin biopsies are similar to those of seborrheic keratosis and verrucae plana; with hyperkeratosis, hypergranulosis, and acanthosis.[8],[11] Some authors, however, describe large, clear, oval, or rounded cells in the granular layer as EV-specific cells on histology, whereas others describe dysplasia in histology samples from patients with acquired EV. Larger studies are needed to confirm these findings.[12],[13]

A long-term sequel of EV is the tendency to NMSCs, especially squamous cell carcinomas. This may be seen in the third to fifth decades of life in congenital EV patients, or much earlier in immune-compromised persons. Studies are still ongoing to determine the exact relationship between duration of ultraviolet radiation (UVR) exposure, skin phototype, EV HPVs, and NMSCs.[7],[10],[14] Literature reports no racial predilection, but with the prolonged exposure to the UV radiation of Africans in the tropics, there is a need for more studies on this virus and skin cancers as it relates to in the dark skin Africans.

We report the clinical and epidemiological findings of clinically diagnosed EV patients presenting in a dermatology clinic in Lagos, Nigeria over an 8-year period.

  Materials and Methods Top

This was a retrospective analysis, whereby clinical records of patients seen at the Dermatovenereology clinic of the Lagos University Teaching Hospital (LUTH) in the years 2006 through 2013 were reviewed. LUTH is a federal government-run tertiary health-care provider with about 800 inpatient beds. It is situated in Surulere, a busy urban metropolis of Lagos state, which is the commercial capital of Nigeria. Lagos state has a population of about 17 million as officially recorded by the state. The dermatovenereology outpatient clinic is situated at an annexed site in Yaba; about 4 km from the main hospital. It is easily accessed by commuters and pedestrians.

A total of 33,326 patients were seen during the period being reviewed. Case notes of patients clinically diagnosed to have EV (96 of them) were retrieved and information on demographic data, retroviral status, biopsy findings, and treatment administered were extracted. These data were entered onto Microsoft Excel spreadsheet and analyzed with SPSS version 18.0 edition (PASW Statistics for Windows, Version 18.0. Chicago: SPSS Inc.).

  Results Top

A total of 96 (0.3%) patients were clinically diagnosed with EV. There were 51 males and 45 females, with a male: female ratio of 1.13:1. The mean age of the study population was 20.8 years ± 3.43 with a range of 2–52 years. Patients who were <10 years of age made up the most frequent group [Table 1]. All the patients (100%) had lesions predominantly on the face. Skin biopsies were carried out in only 2 patients with histology (hematoxylin and eosin stain) suggestive of seborrheic keratosis with the presence of hyperkeratosis, papillomatosis, and acanthosis. Retroviral screening was carried out in 23 patients, half of whom were positive. Management consisted of application of 5% topical Imiquimod cream or combination of varying strengths (5%–15%) of salicylic acid and Tretinoin creams to affected areas thrice weekly. Antiretroviral therapy was also administered as required, and the anti-helminthic levamisole was given to all patients for its immunomodulatory property. The patients were also counseled on the long-term sequelae of skin cancers, sun protection measures, their proper use, and the need for compliance. It was noted that the lesions only minimally improved after at least 6–8 weeks of use and most of the patients discontinued therapy on account of cost implications and poor response to treatment [Figure 1], [Figure 2], [Figure 3], [Figure 4]. No patient had any skin cancers at the time of writing this report though some of the patients had been lost to follow-up within this 8-year review.
Figure 1: Multiple flesh-colored flat-topped plaques on the forehead

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Figure 2: Same patient in Figure 1 6 months after therapy with Tretinoin and sulfur salicylic acid minimal improvement of the plaques

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Figure 3: Eight-year-old retroviral disease patient with widespread epidermodysplasia verruciformis

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Figure 4: Same patient in Figure 3 with no significant change 6 weeks later

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Table 1: Baseline demographic data

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  Discussion Top

EV is a rare disease worldwide, and this is confirmed in this review, where it was seen in 0.3% of cases in a specialist center over an 8-year period.

It was first described in 1979 in Northern Nigeria by Jacyk and Subbuswamy who also confirmed its rarity.[15] It is, however, possible that many cases are not referred to the dermatology clinic and go undiagnosed or are left alone and managed with home remedies.

The slight male preponderance was statistically significant, and this may be due to the fact that males have more sun exposure (through work and play) than the opposite sex. This finding is at variance with the common view that females seek medical care more than males for cosmetic reasons, as the overt lesions are more worrying to the patients with EV than the long-term sequelae of skin cancers which are indolent and covert. The predominantly young age group noted in this review is in concordance with the few reported cases worldwide, and this may be related to the developing immune status of that age group. The predominant facial affectation is in keeping with the sun-exposed areas which are the common sites of involvement.[8] Nigeria is a tropical country, north of the equator with high temperatures most of the year. It is therefore not surprising that cases are detected here where there is prolonged exposure to UV rays when outdoors or even indoors at daytime as windows are rarely fitted with UV protection.

A positive retroviral status may render one more susceptible or result in more severe and bizarre clinical presentations extending beyond the sun-exposed areas. Studies from Zimbabwe suggested a rare coinfection of EV with HIV,[14],[16] but our series revealed a 50% EV-HIV coinfection though only one-third of the patients carried out the HIV test. Retroviral screening is not a routine test carried out in our center, and patients' consent must be sought before screening. Further comment on EV-HIV coinfection can therefore not be made in this study. It is not known if the HIV virus activates the EVER genes in susceptible individuals, especially as HPV is quite prevalent as a skin commensal, or if the presence of HIV in the system makes an individual more prone to the EV-HPV in an immune reconstitution inflammatory syndrome manner.[17] Further studies are needed to clarify this, but the rarity of the disease hinders such studies.

Management of EV consists of counseling, medical, and surgical therapies as necessary after the diagnosis is made. In our series, the challenge to management starts with inability to perform a biopsy in all patients with a clinical diagnosis of EV. While the disease is mostly clinical, a pathological diagnosis as well as genetic testing is desired. Biopsies were carried out in only 0.02% of the study population for reasons of financial constraints in this resource-poor setting.

To a large extent, treatment is unsuccessful and the following have been tried with varying degrees of success: application of topical Imiquimod, retinoids, and keratolytics. Levamisole is an antihelminthic which has immune-modulatory effect when given at higher doses and has been used, either alone or in combination with Cimetidine to treat recalcitrant warts.[18],[19] Imiquimod is an immune-response modifier with antitumorigenic effects initially approved for treating anogenital warts but has since been approved for topical treatment of actinic keratosis and basal cell carcinomas among other skin tumors.[20] In our series, 5% Imiquimod was used thrice weekly in patients who could afford it, with only mild improvement noted after 2 months. This poor response was also recorded by Răducan et al.[21] It is possible that longer use of Imiquimod may result in complete or almost complete clearance of lesions in the immunocompetent patients as noted by Lowe et al.[14],[22] However, our patients mostly pay out of pocket for health care and usually default after a short while, due to financial constraints. Generic 5% topical Imiquimod cream costs an average of $130 for a 24-sachet pack which may last for 8 days as prescribed. The minimum wage of a Nigerian civil servant is about $50 per month.[23]

Most of the patients employed the more affordable combination of 0.1% Tretinoin cream applied at night with 5%–15% sulfur salicylic acid ointment applied during the day with minimal improvement. Sulfur salicylic acid is well known for its slow, but definite keratolytic effect among others and it has been used successfully for the treatment of warts when topically administered.[24],[25] The use of Acitretin as well as chemical peeling with trichloroacetic acid has been advocated, but these were not used in our patients.

None of the patients in this review consented to surgical therapeutic options after counseling. Surgical therapies such as cryotherapy, microdermabrasion, and electrocautery are suggested, but the need for caution with the use of these cannot be overemphasized as the EV lesions Koebnerize, thus may worsen, and the skin phototype of majority of our patients has a tendency to form keloids. As 100% of the study population had lesions on the face, it is not surprising that they all opted out of the surgical therapies as keloids are even more of a cosmetic problem than EV. The above reasons limit the therapeutic options in the dark skin patients, but combination therapy with 5% Imiquimod and cryotherapy may improve outcome.[22]

Literature informs of the late sequelae of tendency to NMSCs [9],[26] but none of the patients in this study had, or has a skin cancer at the time of writing this report (though a few are lost to follow-up). In a series of Nigerian patients with EV, none developed skin cancer, while in a South African series; only one of 20 patients had malignant transformation of the lesions.[15],[27] This low incidence of skin cancers in African patients may be attributable to the protective effect of melanocytes in dark skin. All patients in this study were counseled on the need for sun-protective practices including, but not limited to the use of sunscreens. Long-term follow-up of the patients is ongoing and may give more information on the sequelae of the disease.

Finally, the need for genetic analysis on patients in our climes cannot be overemphasized. This will likely reveal more clinically relevant information on this disease and explain why current therapy is not very effective. This may ultimately improve patient management.

  Conclusions Top

EV is a rare disease, but it is seen in Africans in both immune-competent and immune-incompetent individuals. The tropical climate and outdoor lifestyle of the populace may be contributory. The major limitation of this report is its retrospective review which forestalls access to some pertinent information. A community study would have allowed for better extrapolation of results. The major challenge to the management of our patients is the resource-poor setting where this study was undertaken, the fact that our patients mostly pay out-of-pocket, thus limited finances forestall adequate investigations, treatment, and follow-up. Another important challenge to managing our patients is the likelihood of keloid formation and Koebnerization of the lesions, which may occur with the destructive therapeutic techniques available. Further prospective studies to include biopsies for histopathology and HPV DNA typing will be required to improve our understanding and management of the disease.

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Conflicts of interest

There are no conflicts of interest.

  References Top

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Orth G. Genetics of epidermodysplasia verruciformis: Insights into host defense against papillomaviruses. Semin Immunol 2006;18:362-74.  Back to cited text no. 3
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Lowe SM, Katsidzira L, Meys R, Sterling JC, de Koning M, Quint W, Acquired epidermodysplasia verruciformis due to multiple and unusual HPV infection among vertically-infected, HIV-positive adolescents in Zimbabwe. Clin Infect Dis 2012;54:e119-23.  Back to cited text no. 14
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  [Figure 1], [Figure 2], [Figure 3], [Figure 4]

  [Table 1]


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