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Characteristic findings on physical examination
The diagnosis of hydroa vacciniforme (HV) is based on close clinicohistopathologic correlation. HV usually starts during the first decade of life, but cases of adult onset are known. Sunlight exposure usually induces skin lesions. The name of HV reflects the clinical apearance. The primary lesion appears to contain water (hydroa) and the indented vesicles resemble smallpox (vacciniforme).
Twelve to 24 hours after sun exposure tender papules, hemorrhagic vesicles and umbilicated blisters arise on a background of edematous erythema. The lesions then enter a dry crusting phase followed by pitted vacciniform disfiguring scars, which are permanent. In some cases malaise, fever or headaches accompany the acute phase. Lesions appear typically on the face and dorsal aspects of the hands.
Mucosal involvement in HV is rare. It affects lips and tip of the tongue, both of which can be photoexposed. Most often the lower lip is affected, swollen and covered with crusted ulcers. Eye involvement is also rare, but photophobia, conjunctivitis, corneal infiltration with vascularization and anterior uveitis have been described. In patients with severe and repeated skin lesions, deformities of the external ear and nose may develop as well as contractures of the fingers (Figure 1, Figure 2).
Expected results of diagnostic studies
The histopathology of acute lesions is characterized by reticulate degeneration of keratinocytes leading to epidermal necrosis. It results in formation of multilocular intraepidermal vesicles overlying a cellular infiltrate in the dermis consisting predominantly of lymphocytes and neutrophils (Figure 3). Immunohistochemistry shows predominance of cells with a T-cell phenotype (CD4+ and CD8+), CD20+ cells are demonstrated rarely.
There are no laboratory abnormalities.
The differential diagnosis of HV includes the following entities.
Erythropoetic protoporphyria: In this condition, vesicles occur only occasionally while edema, erythema and petechiae prevail; leathery thickened skin develops on exposed areas; there is deficiency of ferrochelatase (gene is located on chromosome 18q21.3); photosensitizing protoporphyrin accumulates in red blood cells, plasma, skin and liver; histopathology of the skin lesions differs, demonstrating intense, mainly neutrophilic infiltrate in the dermis in acute lesions and varying amounts of an amorphous PAS positive, diastase resistant, hyaline-like material deposited around walls of the capillaries and throughout upper dermis.
Protoporphyrin is hepatotoxic, and hepatic failure may develop. Erythropoietic protoporphyria is transmitted mainly in autosomal dominant, sometimes in autosomal recessive pattern.
Polymorphic light eruption (PLE) occurs mainly in women. It can start at any age, occurs often in pigmented individuals. The skin lesions are typically monomorphic in a given patient (morbiliform, papular, eczematous or vesicular); they do not eventuate in vacciniform scars. Histopathology of PLE is as diverse as the clinical picture. The unifying feature is the presence of intense perivascular lymphocytic infltrate.
Juvenile spring eruption is most likely a form of PLE erupting usually in spring or summer in the first decade of life, more often in boys (longer girls’ hair seems to protect); grouped pruritic papules and vesicles appear on ears. Histology resembles erythema multiforme: mononuclear inflammatory cell infiltrate with edema evolving into subepidermal blisters.
Actinic prurigo: A prurigo type of PLE with onset early in life, more commonly in girls, erythematous, excoriated, persistent patches on light-exposed areas, particlarly on the cheeks and nose. The histopathology is not characteristic. Actinic prurigo is particularly common in Mexicans of Indian ancestry. Association with HLA DR4 (particularly DRB 407) has been described. The frequency in Mexicans may reflect the genetic background, but the effect of low socioeconomic state and protein deficiency has also been suggested to contribute.
Light provoked herpes simplex: A Tzanck smear and biopsy demonstrate multinucleated giant cells. Viral culture.
Hartnup’s disease: A rare autosomal recessive disorder with skin lesions that resemble pellagra rather than HV. There is intermittent cerebellar ataxia, psychiatric disturbances and a typical aminoaciduria. The mutation is in the SCL6A19 gene.
Bullous lupus erythematosus: Serology and histopathology permit differentiation.
Who is at Risk for Developing this Disease?
HV is very rare, apparently the rarest of photodermatoses. None of the reported series of patients with HV had more than 20 patients. The only report on the prevalence, in Scotland, estimated it at 0.34 cases per 100,000. HV is sporadic. HV appears with a predilection in lightly pigmented individuals, and reported patients were mostly of European and Oriental (Far East) descent. The black South African boy whose photograph is shown demonstrates that HV can occur in heavily pigmented individuals living in sunny parts of the world. HV affects both sexes, boys slightly more often than girls.
What is the Cause of the Disease?
The pathogenesis of HV is not fully understood. Sunlight is required to provoke eruption, and in the temperate climate the onset is usually in spring or summer. Photoprovocation not always induces the lesions and ultraviolet A seems to be more important than UVB in the induction of the lesions. Some patients do have symptoms throughout the year.
Latent EBV infection and cytotoxic T-cells that react with virus-infected cells are thought to play a significant role in the pathogenesis of HV lesions. It is suggested that HV vesicle formation is initiated by the release of infectious EBV, non- infectious EBV particles and/or EBV DNA from latently infected T-cells that underwent apoptosis in skin exposed to UVA.
In a recently published paper the lesional skin of a patient with HV predominantly contained CD68 + CD123+ plasmocytoid monocytes. Plasmocytoid monocytes are believed to mediate an antiviral response to EBV infection and to be responsible for the formation of necrotic vesicles in HV rather than CD8+ cells.
No precise genetic predisposition has been determined for HV. Rare reports of familial occurrence raise the possibility of genetic determinance.
Systemic Implications and Complications
Previously, using the term HV, two different diseases have been reported. The description above refers to a classic form, first described by Bazin in 1862. This form does not affect the general health and spontaneously resolves in adolescence or young adulthood.
The other form resembles HV only at the initial phase. Even at this stage, however, facial edema is more marked, vesiculation more extensive, ulcers larger and deeper and the lesions appear also on nonexposed areas. Patients with this severe form often have hypersensitivity to insect bites, fever, wasting and hepatosplenomegaly. The condition does not remit with age but becomes more severe.
Several of these patients died of systemic complications or malignant lymphoma. Five of 11 children with severe HV in a Japanese series progressed to overt Epstein-Barr virus ( EBV)-associated lymphoma with an NK/T-cell phenotype. Four of them had fatal hemophagocytic syndrome characterized by thrombocytopenia, leukopenia and liver damage and they died within 2 to 14 years after the onset of the disease. This severe form was named edematous scarring vasculitic panniculitis in Mexico and hydroa vacciniforme-like lymphoma in Japan, and it reflects, at least in Asia, the high endemic distibution of EBV.
A close link has been demonstrated between EBV infection and HV, EBV-encoded small nuclear RNA (EBER)-positive cells are frequently observed in the cutaneous infiltrates in both classic and severe HV, the latter having a high risk of progressing to EBV-associated malignant complications.
As the initial lesions in classic and severe forms of HV are similar and the biopsy specimens of both forms show essentially the same histopathologic features, the following laboratory tests are considered useful for differentiation: hematologic and liver function tests, the percentage of natural killer (NK) subset cells (NK-cell lymphocytosis was found in patients with severe HV), anti-EBV antibody titers and EBV DNA load in the peripheral blood.
|General measures||Medical treatment||Physical modalities|
|Sun protectionTopical sunscreensProtective clothing||Antimalarial drugs||Phototherapy narrow band UVB|
|Sun avoidance||Antiviral: acyclovir and similar agents|
|Thalidomide Cyclosporin A|
|Beta carotene, dietary fish oil|
Optimal Therapeutic Approach for this Disease
HV is almost always resilient to medical treatment and prevention appears the most important management. Several systemic agents have been proposed but their multiplicity reflects inconsistency in efficacy. Anecdotically, and in small series of patients, the following agents have been reported to be effective: antimalarials, thalidomide, cyclosporine A, beta carotene, dietary fish oil.
Chloroquine was reported to be effective when used in children in a dose of 250mg two times daily (reports in 1960s). This dose appears much too high and as management of HV usually requires at least several weeks of administration during the seasonal aggravation, the dose should not exceed 4mg/kg/day. Hydroxychloroquine also has some ocular toxicity albeit less than chloroquine, and its daily dose may be higher.
Thalidomide has been largely unsuccessful. Sedation, dizziness, peripheral neuropathy in all age groups and teratogenicity in women of child-bearing age argues against its use.
Cyclosporin A in a dose of 2 to 3mg/kg/day was effective in a patient with adult onset of HV.
As the majority of patients with HV are young, it is better to avoid systemic therapy with above-listed drugs and their possible side effects.
The role of EBV in inducing lesions of HV may offer a new approach—systemic antivirals. Four patients with EBV-associated HV (three of the four had documented elevated levels of EBV DNA copies in peripheral blood and a considerable number of infiltrating cells with EBER in the cutaneous lesions) have been recently treated with acyclovir/valaciclovir. All were reported to have fewer lesions, less scarring and increased ability to be outdoors without provoking new eruptions.
The daily dose differed: 14 to 28, 27, 64 to 72 mg/kg/day between the three patients, respectively. The dose of valaciclovir in the fourth patient was 60 mg/kg/day. The length of treatment in these patients was several weeks. The effective dose has to be defined.
Use of beta carotene has been claimed to have some success in HV, although more often it has proved to be disappointing.
Systemic photoprotection with fish oil dietary supplements—MAxEPA capsules containing 30% omega-3 polyunsaturated fatty acids, 5 capsules daily for 3 months. In two of the three children treated a reduced sensitivity to UV-induced erythema was observed as well as some clinical improvement. Fish oil is at least a non-toxic alternative. It is, however, rather unpalatable and produces fetid breath.
Narrow band UVB was tried in two studies comprising, however, small number of patients, five and four, respectively. Six patients of nine found it beneficial.
The efficacy of the above listed medications has been claimed in single cases or small series of patients. Other reports did not confirm their value in the treatment of HV. In light of the above and as the majority of patients with HIV are children, it is better to avoid systemic therapy and the possible side effects associated with their administration.
Prevention of the deleterious effects of ultraviolet is most important—clothing, broad-spectrum sunscreens. The condition in its classic form remits usually during adolescence.
Systemic antivirals may be tried in patients with serologic and histopathologic evidence of EBV infection. The daily dosage and duration of treatment is, however, not defined.
Testing for porphyrins, particularly protoporphyrins, is recommended when the patient is initially seen. When the test is negative and there is no family history of erythropoietic protoporphyria (usually autosomal dominant), repeated testing is not needed. ANA should also be assessed.
Identification of the wavelength responsible for the provocation of skin lesions may help to choose the most appropriate sunscreen. Thus, sun protection remains the key factor in management. Patients or parents of children affected should be informed on the role of sun exposure and the value of sun protection.
When, rarely, the systemic medications are used, their risk/benefit ratio has to be explained.
Unusual Clinical Scenarios to Consider in Patient Management
Severe form of HV resembles the classic HV only initially. But even at this stage, facial swelling is usually very severe, numerous vesicles and deep nodules and ulcers develop.
The lesions are located also in the sun-covered areas. Finding of such very severe skin involvement should alert a clinician to the possibility of the severe form. The course of the disease will help to make the correct diagnosis. Persistent fever, wasting, spleen and liver enlargement usually develop and skin lesions continue to appear irrespective of sun exposure.
As EBV is considered to play a crucial role in the pathogenesis of severe HV, anti-EBV antibody titers and EBV DNA load in peripheral blood should be assessed. The extracutaneous involvement of severe HV is also confirmed by hematologic and liver function tests.
Association of severe HV with various lymphoproliferative diseases has been described. HV-like lymphomas are mainly of a T-cell lineage: CD8+, NK or T/NK cells. A condition similar to CD30+ lymphomatoid papulosis, cases with predominant CD4+ cells and progressing to large granular lymphocytic leukemia have also been reported.
It usually takes years for the process to progress to overt hematologic neoplasm. The atypical lymphoid infiltrates in the dermis and subcutaneous tissue, often with angiocentric and angiodestructive features, were found in skin lesions of very variable morphology: swellings, vesicles with indurated base, necrotic areas.
Detection of HV-like lymphoma may require several biopsies. The histopatholgic diagnosis is not easy as the smoldering stage is difficult to assess.
Virtually all patients with HV-like lymphoma are from Asia or Latin America, whereas HV has a worldwide distribution. Genetic background, EBV subtypes or other unknown environmental factors may be a sign.
What is the Evidence?
Sonnex, TS, Hawk, JL. “Hydroa vacciniforme: a review of ten cases”. Br J Dermatol. vol. 118. 1988. pp. 101-108. (Ten patients were investigated and followed up. Only broad spectrum sunscreens provided UV protection. Chloroquine was helpful in two patients. Mepacrine, hydroxychloroquine, beta carotene were all ineffective.)
Gupta, G, Man, I, Kemmet, D. “Hydroa vacciniforme: a clinical and follow-up study of 17 cases”. J Am Acad Dermatol. vol. 42. 2000. pp. 208-213. (A review of 17 patients with HV. Spontaneous clearing had occurred in nine of them with mean duration of disease being 9 years. Eight patients were sensitive to UVA on monochromator phototesting. All patients were treated with broad-spectrum sunscreens. Of the five patients treated with narrow band UVB, three improved with increased tolerance to sunlight and reduction in disease severity. No systemic medications were used.)
Ruiz-Maldonado, R, Parilla, FM, Orozco-Covarubias, M, Ridaura, C, Tamayo-Sanchez, L, Duran McKister, C. “Edematous, scarring vasculitic panniculitis: A new multisystemic disease with malignant potential”. J Am Acad Dermatol. vol. 32. 1995. pp. 37-44. (A retrospective clinicopathologic study of 14 Mexican children with HV designated as severe led to description of edematous scarring vasculitic panniculitis—a novel multisystemic disease with malignant potential, EBV studies were not performed. It appears to be the first report on severe hydroa vacciniforme associated with lymphoproliferative lesions.)
Iwatsuki, K, Satoh, M, Yamamoto, T, Oono, T, Morizane, S, Ohtsuka, M. “Pathogenic link between hydroa vacciniforme and Epstein-Barr virus-associated hematologic disorders”. Arch Dermatol. vol. 142. 2006. pp. 587-95. (T-cells positive for EBER were detected in cutaneous infiltrates of 29 patients with definite, probable and severe HV. Patients with severe HV had markedly increased EBV DNA in the peripheral blood mononuclear cells, natural killer-cell lymphocytosis and complications including chronic active EBV infection, hypersensitivity to mosquito bites and hemophagocytic syndrome.
In non-severe (definite and probable HV), the amount of EBV DNA was also increased in the peripheral blood mononuclear cells though there were no hematologic abnormalities. Five patients with severe HV died of EBV-associated NK/T-cell lymphomas or hemophagocytic syndrome 2 to 14 years after onset.)
Verneuil, L, Gouarin, S, Comoz, F, Agbalika, F, Reveuil, C, Varna, M. “Epstein-Barr virus involvement in the pathogenesis of hydroa vacciniforme: an assessment of seven adult patients with long-term follow-up”. Br J Dermatol. vol. 163. 2010. pp. 174-82. (Repeated tests for EBV blood load and serologic EBV tests were performed in seven adults with HV (aged 14 to 50 years). In seven, HV started before age 13 years. At the time of inclusion to the study, four had cutaneous lesions of HV and three were in remission. The EBV DNA blood load was strongly positive in seven patients with HV and negative in 34 of 35 patients with other photosensitive disorders. Authors conclude that a positive EBV DNA load might be a useful marker in HV.)
Jeng, BH, Margolis, TP, Chandra, NS, McCalmont, TH. “Ocular finding as a presenting sign of hydroa vacciniforme”. Br J Ophthalmol. vol. 88. 2004. pp. 1478-9. (Ocular manifestations in a child with HV are reported. Patient reported initially only with ocular findings—redness, pain and photophobia. Skin lesions on the ears, lips, fingers and arms appeared 6 months later. Granulomatous anterior uveitis developed subsequently. A review of the literature on ocular involvement in HV is performed.)
Nishizawa, A, Satoh, K, Takayama, K, Yokozeki, H. “Hydroa vacciniforme with mucosal involvement, recalcitrant periodontitis and multiple virus re-activators after sun exposure”. Acta Derm Venereol. vol. 90. 2010. pp. 498-501. (Rare mucosal involvement in HV is described—cheilitis, gingivitis, periodontitis. Although EBV was negative in the skin lesions, EBV DNA was detected in the gingival lesions. The oral involvement mirrored the severity of the symptoms.)
Varughese, N, Petrella, T, Singer, M, Carlson, JA. “Plasmocytoid (CD68+ CD123+) monocytes may play a crucial role in the pathogenesis of hydroa verruciforme: a case report”. Am J Dermatopathol. vol. 31. 2009. pp. 828-33. (Skin lesions of a 13-year-old girl with HV harbored a predominantly CD68+ CD123+ infiltrate of plasmocytoid monocytes. Plasmocytoid monocytes rather than cytotoxic T-cells are thought to be responsible for the formation of necrotic vesicles in HV. The following mechanism is proposed: UV light activates latent EBV infection. Apoptosis of infected T-cells releases EBV and plasmocytoid monocytes are believed to mediate antiviral response and produce necrotic vesicles. The validity of this concept must be evaluated by examining the number of plasmocytoid monocytes in future cases of HV.)
Lysell, J, Wiegleb Edstroem, D, Linde, A, Carlsson, G, Malmros-Svennilson, J, Westermark, A. “Antiviral therapy in children with hydroa vacciniforme”. Acta Derm Venereol. vol. 89. 2009. pp. 393-7. (Four patients with EBV-associated HV were treated with acyclovir/valaciclovir with a good clinical response.)
Rhodes, LE, White, Si. “Dietary fish oil as a photoprotective agent in hydroa vacciniforme”. Br J Dermatol. vol. 138. 1998. pp. 173-8. (Three children with HV were treated with dietary fish oil. Omega-3 polyunsaturated fatty acids in fish oil were thought to increase resistance to UV-induced erythema. Three months of fish oil intake led to reduced erythemal sensitivity to UV. However, the clinical response was less satisfactory as marked improvement was seen only in one child.)
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