Hydroa Vacciniforme

Hydroa vacciniforme (HV) is a rare, chronic photodermatosis of unknown origin occurring in childhood that exists within the spectrum of Epstein-Barr virus–related lymphoproliferative disorders. These range from classic HV to fatal lymphoma.[1]

Recurrent vesicles on sun-exposed skin that heal with vacciniform or varioliform scarring characterize HV. The histopathologic features are distinctive and demonstrate intraepidermal reticular degeneration and cellular necrosis.[2] Most cases remit spontaneously by late adolescence.[3] See the image below.

Characteristic vesicular lesions occur on sun-exposed skin and heal with varioliform scarring.

The etiology of hydroa vacciniforme (HV) is uncertain. HV may be a distinct entity distinguished by scarring or may occur within the spectrum of polymorphous light eruption. Skin lesions occur on sun-exposed skin, such as the face, ears, and hands. There is an association between HV occurrence and latent Epstein-Barr virus (EBV) infection, particularly if necrotic lesions are present.[4] T cells positive for EBV-encoded small nuclear RNA (EBER) have been detected in the cutaneous infiltrates of some patients with HV. Ultraviolet-induced cutaneous lesions with histopathology consistent with HV have also been shown to contain EBER-positive cells.[5] In general, the EBV DNA blood load is higher in patients with HV than in patients with other photosensitivity disorders.[6]

The development of hydroa vacciniforme (HV) lesions and their distribution suggest a causal relationship between HV and ultraviolet (UV) exposure, although the pathogenetic mechanism remains unknown.[7] Ultraviolet A (UV-A) radiation is most often implicated, although some older studies suggest ultraviolet B (UV-B) as the causal agent.[8] Two reports of HV in siblings have been documented, suggesting a genetic component to HV.[9] Some cases have occurred in the setting of hematopoietic malignancy. Moreover, HV can be caused by a recent or latent EBV infection.[5]

Frequency

The frequency of HV varies according to country but is estimated to be around 0.34 cases per 100,000 people.

Sex

Males have a higher incidence of HV than females. Males who are affected may also have a longer course of disease than females.[10]

Age

HV predominately affects children aged 3-16 years.[2] In many cases, there is a bimodal age distribution of early childhood (age 1-7 y) and around puberty (age 12-16 y).[8] The mean duration from onset of symptoms to resolution is 9 years. Resolution of symptoms typically occurs in adolescence or young adulthood, although symptoms persist throughout life in some patients.[10] Cases of HV in infants and elderly persons have also been described.[11]

Ethnicity

Asians and Latin Americans are more likely to develop severe HV, which includes facial edema, multiple vesicles, and extensive scarring in both sun-exposed and sun-protected skin.[1]

The prognosis is uncertain; classic hydroa vacciniforme (HV) typically remits by adolescence. No mortality is associated with classic HV, but those with lymphoid atypia, rimming of lipocytes, and Amerindian heritage are at significant risk of progression and death. Classic chemotherapy is associated with adverse outcomes.[12]

Patients are advised regarding strict sun avoidance, frequent application of high SPF sunscreens with UV-A blocking agents, and protective clothing.

Commonly, mild burning, itching, or stinging in exposed sites begins a few hours or days after sun exposure. Vesicles heal with varioliform scarring.[4] The initial onset of lesions occurs in spring, with recurrences in summer months.

Constitutional symptoms can occur but are uncommon. Oral and ocular symptoms can occur but are extremely rare.

Skin and mucous membranes[13] are the primary sites affected by hydroa vacciniforme (HV). Ocular involvement is uncommon and usually occurs along with an HV outbreak of the face.[14]

Skin findings are as follows:

• Tense, edematous papules progress to clear, then, cloudy discrete vesicles.

• Lesions become umbilicated, necrotic papules on an erythematous base.

• Papules heal with hypopigmented depressed scars.

Eye findings are as follows[14, 4] :

• Mild keratoconjunctivitis

• Corneal clouding and stellate keratotic precipitates in the cornea, indicating an inflammatory keratitis (one report[15] )

• Conjunctivitis and vesicular eruptions of the conjunctiva

• Corneal infiltration with vascularization

• Keratouveitis

Other symptoms are as follows:

• Photo-onycholysis

• Limited partial absorption of bone and cartilage in severe HV

• Earlobe mutilation and flexion contracture of a digit (reported in 1 patient)[16]

Severe HV may present with the following[17] :

• High-grade fever

• Liver damage

• Ulcerative indurated lesions

• Edematous swelling of the cheeks, ears, lips, and eyelids

Complications are rare in hydroa vacciniforme (HV). The most common severe sequela is the varioliform scarring.

Consider the following laboratory studies:

• Complete blood cell count to investigate constitutional symptoms
• Measurement of EBV DNA; best detected with whole blood rather than serum or plasma: EBV DNA in peripheral blood mononuclear cells (PBMCs) provides a diagnostic indicator of hydroa vacciniform (HV) ^[29]
• Cell free EBV DNA in plasma, as it may be related to serious complications like hemophagocytic lymphohistiocytosis ^[29]
• Viral culture of blister fluid to rule out herpes virus infection
• Erythrocyte sedimentation rate and antinuclear antibody, anti-Ro, and anti-La antibody tests to rule out bullous lupus erythematosus
• Plasma or serum porphyrin assay to exclude cutaneous porphyrias
• DNA repair studies to rule out xeroderma pigmentosum

Imaging studies are not routinely obtained as part of the workup of hydroa vacciniforme (HV).

Repetitive, broad-spectrum, UV-A phototesting may be warranted. Repetitive, broad-spectrum, low-dose UV-A irradiation can elicit lesions clinically and histologically identical to those produced by natural UV exposure, although results are inconsistent. The minimal erythemal dose of UV-B and UV-A in these patients is reduced.[30]

Early lesions reveal an epidermal, multilocular vesicle with reticular degeneration and demonstrate EBV RNA (EBER positive) in lymphocytes.[31]  A dense, perivascular, lymphohistiocytic infiltrate with vessel hemorrhage may occur in the dermis. Late lesions show epidermal and dermal necrosis with a surrounding, chronic, inflammatory infiltrate. Direct immunofluorescence study results are usually normal, except for rare reports (2 patients) of C3 deposits at the dermoepidermal junction and in the small dermal vessels.

In addition to medication and certain restrictions on activity, management of hydroa vacciniforme (HV) may include a prophylactic "hardening" course of phototherapy. In a study of four patients with HV, low-dose, narrow-band UV-B (TL-01) phototherapy, either daily or 3 times a week in the spring, was shown to confer relative photoprotection.[32] Psoralen photochemotherapy (PUVA) administered prophylactically in older patients may be effective in desensitization. After intercalating with DNA and irradiation by UV-A, methoxsalen leads to formation of DNA psoralen adducts that cross-link DNA.[33]

Consult a dermatologist for evaluation and management of hydroa vacciniforme (HV). 

Generally, no diet restrictions or requirements are indicated in the management of hydroa vacciniforme (HV).

Strict sun avoidance, appropriate clothing, and frequent application of high sun protection factor (SPF) sunscreens with UV-A blocking agents are advised.

Rigid sun avoidance may be socially devastating for the pediatric patient with hydroa vacciniforme (HV). The physician should work closely with the parents and management team in supporting and educating the child regarding this disease.

Avoiding the sun, frequently applying high SPF sunscreens with UV-A blocking agents, and wearing protective clothing may prevent episodes of hydroa vacciniforme (HV).

Patients with extracutaneous findings associated with hydroa vacciniforme (HV) should be referred to the appropriate specialist.

To date, no oral therapy reliably prevents the appearance of hydroa vacciniforme (HV) lesions. Oral antimalarials[34] and beta-carotene[35, 36, 37] may be used and are occasionally reported to be useful, especially when combined with a strict sun avoidance program. Other therapies that have been used with varying success include thalidomide, azathioprine, cyclosporine,[38] and fish oil supplementation.[39, 40, 41] Given the association with EBV, there may be some benefit to the use of antivirals such as acyclovir and valacyclovir.[4]

Class Summary

These agents suppress cutaneous lesions associated with many photodermatoses.

Hydroxychloroquine (Plaquenil)

Hydroxychloroquine can be used for the suppression of lesions in sun-sensitive disorders; its mechanism of action in HV is unknown.

Chloroquine (Aralen)

Chloroquine has anti-inflammatory activity by suppressing lymphocyte transformation and may have a photoprotective effect. It can be used for the suppression of lesions; its mechanism of action in HV is unknown.

Class Summary

These agents are yellow-orange pigments that may have photoprotective properties in selected photodermatoses.

Beta-carotene (Lumitene, B-Caro-T, A-Caro-25)

Beta-carotene's mechanism of action is not completely elucidated but it may relate to the ability of carotenoids to quench photoexcited molecular species. It reduces the severity of photosensitivity reactions in some patients with photodermatoses, especially erythropoietic protoporphyria (EPP).

Class Summary

After intercalating with DNA and irradiation by UV-A, methoxsalen leads to formation of DNA psoralen adducts that cross-link DNA. This affects gene expression by inhibiting DNA replication, mitosis, and cell division. 5-Methoxypsoralen (5-MOP, Bergapten, Psoraderm 5) has also been used, although it is not currently available in the United States.

Methoxsalen (8-MOP, Oxsoralen)

Methoxsalen inhibits mitosis by binding covalently to pyrimidine bases in DNA when photoactivated by UV-A.

Class Summary

Given the association with EBV, there may be some benefit to the use of antivirals such as acyclovir and valacyclovir.

Acyclovir (Zovirax)

Acyclovir is a synthetic purine nucleoside analogue with activity against a number of herpesviruses, including herpes simplex and varicella-zoster. It is highly selective for virus-infected cells because of its high affinity for viral thymidine kinase enzyme. This effect serves to concentrate acyclovir monophosphate into virus-infected cells. The monophosphate then is metabolized into the triphosphate active form by cellular kinases.

Valacyclovir (Valtrex)

Valacyclovir is a prodrug rapidly converted to the active drug acyclovir. It is more expensive but has a more convenient dosing regimen than acyclovir.