Severe mosquito bite hypersensitivity, EBV induced D82.-

Severe mosquito bite allergy (SMBA) is an iatrogenically induced, chronically active EBV infection with local and systemic symptoms (CAEBV) that predominantly affects adolescents and children from East Asian countries. It is virtually unknown in European and (non-indigenous) American populations. SMBA is characterized by insect bite-provoked skin lesions with local swelling, erythema, blisters and torpid ulcers that heal with scarring over time. The cutaneous symptoms are often accompanied by systemic inflammatory reactions (fever, aching limbs, lymphadenopathy), symptoms that indicate the systemic nature of the disease.

Note: In cell cultures, ^CD4+ T cells, but not ^CD8+ T cells or NK cells, can react to the salivary gland extracts of mosquitoes. Cocultivation of NK cells and ^CD4+ T cells activated by mosquito extracts leads to the expression of EBV lytic cycle proteins in the NK cells as well as the viral oncogene "Latent Membrane Protein 1(LMP1) (Asada H et al. 2003; Asada H et al. 2005). LMP1 expression could be one of the causes of the "pseudolymphoma-like" proliferation after mosquito bites.

Hydroa vacciniforme-like lymphoproliferative disease, EBV-induced (HV-LPD) and severe mosquito bite allergy (SMBA) are both cutaneous forms of Epstein-Barr virus (EBV)-associated T/natural killer (NK) cell lymphoproliferative disease and are closely related to chronic active EBV disease (CAEBV) and EBV-associated hemophagocytic lymphohistiocytosis (EBV-HLH). The vast majority of patients with SMBA have an increased number of EBV-infected NK cells in their blood. The clinical symptoms of HV-LPD and SMBA often overlap in the same patient and can lead to more severe disease states corresponding to "chronic active EBV disease = CAEBV).

In rare cases, "hemophagocytic lymphohistiocytosis" can occur as a late complication of EBV-NK-LPD (Dupuy E et al. 2022).

At the beginning of the disease, the symptoms and signs may subside spontaneously without local treatment. Antiviral therapy is recommended after diagnosis.

In uncomplicated cases, insect bite-induced ulcers heal without new disease-related symptoms and EBV DNA levels remain normal. However, recurrences after new mosquito bites are possible. Long-term follow-up is recommended.

There is an increased risk of systemic lymphoproliferative diseases in children with "Severe mosquito bite allergy (SMBA)". Poor outcomes are usually associated with the development of systemic Epstein-Barr virus (EBV)-associated T/natural killer (NK)-LPD (EBV-NK-LPD) disease.

Epstein and Barr discovered EBV in 1964 when they were investigating Burkitt's lymphoma in African children. EBV(HHV-4) is a double-stranded DNA virus that belongs to the gamma subtype of the herpesvirus family and has a worldwide infection rate of over 90 % in adults. However, if the immunological balance is disturbed, clonal proliferation of EBV-infected cells can occur, leading to EBV-related lymphoproliferative diseases. These B-, T- and/or NK-cell-derived diseases are characterized by a broad clinical-pathological spectrum ranging from indolent, self-limiting and localized diseases to systemic highly aggressive lymphomas.

In addition, individuals with some primary immunodeficiency syndromes or acquired immunosuppressive diseases may also have severe lymphoproliferative EBV infections. It has been reported that most patients with SMBA have high serum IgE level, high EBV load and NK cell lymphocytosis in biopsy.

Asada et al. suggested that the pathogenesis of SMBA may be EBV reactivation in EBV-infected NK cells induced by CD4+ T cells stimulated by mosquito salivary gland extract and triggering a strong allergic skin reaction.

Wang Y et al. (2023):A 7-year-old Japanese female patient was hospitalized due to recurrent fever, skin allergies and multifocal severe ulcerative necrotic skin lesions on both lower limbs. The patient had a history of facial angioedema 4 years previously. Various "skin allergies" were known. The parents reported that one month earlier, after being bitten by mosquitoes, the child had developed erythema of both lower limbs, accompanied by itching and discomfort. While some patches healed, others gradually spread, developing into plaques with a tendency to ulcerate and periulcerous swelling and suppuration. The patient suffered from intermittent fever with a maximum temperature of 40 °C, accompanied by sneezing and catarrh symptoms that did not respond to antibacterial therapy.

Findings: A facial swelling with eyelid edema and conjunctivitis was conspicuous. Several ulcers were found on both lower extremities. The largest and most severe lesion with purulent debritus had a diameter of about 6.0 cm. Additional smaller furunculoid infiltrates were noted on the medial left thigh. A fresh ulcer with a diameter of 2.0 cm was detectable on the patient's left ankle. This ulcer enlarged torpidly within a few days, resulting in soft tissue loss and exposure of the aponeurosis.

Laboratory: Neutrophilic leukocytes: 6,950/µl (83.4 %), HB slightly decreased, alkaline phosphatase (132 U/l), lactate dehydrogenase (291 U/l). Ultrasound examination showed splenomegaly and a slightly enlarged cervical lymph node.

Histology: Marked diffuse lymphocytic infiltration of the entire dermis and subcutaneous adipose tissue. Lymphoid cells were small to medium in size and showed slight atypia.

Immunohistology: This revealed high expression of CD3, CD4 and CD5 and partial expression of CD8, granzyme B and Ki-67. The cells were negative for CD20, CD21, CD56 and CD30. The lymphocytic cells showed EBER positivity, indicating the presence of EBV in the tissue. Both the immunohistochemical analysis and the gene rearrangement test showed that these tumor cells were of the T-cell type rather than the NK-cell type.

Diagnosis: Detection of numerous EBER-positive lymphocytes in the biopsy. Positive serum test for EBV virus capsid antigen immunoglobulin A antibodies; the quantitative EBV DNA value was 3.55 × 103 (copies/mg).

As there was no evidence of multi-organ involvement, hemophagocytic syndrome or EBV-induced lymphoma, a treatment regimen of anti-inflammatory, antiviral antibiotic and symptomatic measures was initiated. After a follow-up period of more than two years, all ulcers had healed without scarring.

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