Severe Mosquito Bite Allergy Complicated by Bacterial Infection in a 7-Year-Old Child: A Case Report and Brief Review of the Literature

T- or NK-cell type CAEBV is a systemic EBV-positive LPD that is characterized by fever, lymph node enlargement, eyelid edema, hepatosplenomegaly, and other symptoms that can persist or recur, leading to multiorgan damage and life-threatening complications such as hemophagocytic syndrome and malignant lymphoma.¹ It primarily affects adolescents and children,² with a higher incidence in East Asia and Latin America, showing marked geographic characteristics.³ Diagnostic criteria include IM-like symptoms lasting for more than 3 months, increased EBV DNA levels (>10^2.5 copies/mg), and histopathological evidence such as lymphocytes of affected organs positive for ISH for EBER, and exclusion of known immune defects, malignant tumors, or autoimmune diseases.⁴ CAEBV is stratified into systemic and cutaneous types, and the 2017 World Health Organization classification specifies that hydroa vacciniforme-like LPD and SMBA are cutaneous types.¹ 

This case report discusses CAEBV infection in a pediatric patient who presented with multiple rare and severe skin ulcers and a systemic inflammatory reaction, and who was ultimately diagnosed with SMBA.

In October 2020, a 7-year-old female was admitted to the hospital owing to multiple skin ulcerations on the bilateral lower limbs. The parents reported that 1 month prior, after being bitten by mosquitoes, the child developed a scattered rash on both lower limbs accompanied by itching and discomfort. While some of the rashes healed, others gradually expanded and developed into ulcers with redness, swelling, and suppuration (Figure 1A). The patient also experienced intermittent fever, with a maximum temperature of 40°C, accompanied by sneezing and catarrh symptoms that did not respond to antibacterial therapy. She had no history of hepatitis, tuberculosis, malaria, surgery, trauma, blood transfusion, or food or drug allergy. Four years prior, the patient experienced facial edema, conjunctival congestion, and various skin allergies that resolved following symptomatic treatment.

Physical examination on admission revealed facial swelling, especially in the periorbital region, conjunctival congestion, and edema. Multiple ulcerations and necrotic lesions were observed on both lower extremities. The largest and most severe lesion was approximately 6.0 cm in diameter, located in the posteromedial right calf. The lesion exhibited skin ulceration, subcutaneous tissue necrosis, myolemma exposure, pus accumulation with odor, and redness and swelling of the peripheral skin (Figure 1B). Additional smaller furuncles were identified in the medial left thigh and the toenail groove, with mild swelling. A new skin ulcer measuring 2.0 cm in diameter was observed on the patient’s left ankle; this ulcer increased in size during hospitalization, resulting in soft tissue loss and exposure of the aponeurosis, with the skin on the instep turning dark purple (Figure 1D, E).

Laboratory testing revealed a neutrophil count of 6950/µL (83.4%), a slightly decreased hemoglobin level, and slightly elevated aspartate aminotransferase (41 U/L), alkaline phosphatase (132 U/L), and lactate dehydrogenase (291 U/L) levels. Ultrasonography indicated splenomegaly with slightly enlarged cervical lymph nodes. 

Because of the severe wound infection and necrosis of skin and subcutaneous tissue, during the patient’s hospitalization double lower limb wound expansion surgery was performed, in addition to wound exploration and NPWT. The patient experienced another episode of high fever and swelling of the left foot following debridement. Anti-infective treatment with vancomycin was initiated, which was subsequently adjusted to linezolid in combination with meropenem following the detection of methicillin-resistant Staphylococcus aureus in pus culture. The patient was diagnosed with CAEBV after numerous EBER-positive lymphocytes were observed in residual skin dermis and subcutaneous tissues around the necrotic lesion on electron microscopy. Additionally, testing for serum EBV-viral capsid antigen immunoglobulin A antibody was positive, and the EBV DNA quantitative value was 3.55 × 10³ (copies/mg). The patient’s symptoms significantly improved following treatment with ganciclovir.

Following debridement, pathological examination of the excised tissue revealed a large amount of coagulative necrotic tissue involving the dermal, subcutaneous fascia, and muscle layers. Additionally, thickened walls with occluded lumens were present in some residual vessels, with some exhibiting fibrous necrosis. Squamous epithelial hyperplasia was evident in a few residual skin tissues, with lymphocyte infiltration in the superficial dermal layer (Figure 2A). The neoplastic cells observed were generally small to medium-sized, with mild atypia (Figure 2B). Immunohistochemistry analysis revealed high expression of CD3, CD4, and CD5, and partial expression of CD8, T-cell-restricted intracellular antigen, granzyme B, and Ki-67 (Figure 2C). Neoplastic cells were negative for CD20, CD21, CD56, and CD30. Importantly, ISH showed EBER positivity in the neoplastic cells (Figure 2D), indicating the presence of EBV in the tissue. Immunohistochemistry analysis and gene rearrangement testing both showed these tumor cells classifying as T-cell type rather than NK-cell type.

Evaluation of the disease course, laboratory findings, histological examination, immunohistochemistry, and ISH results in combination with the history of mosquito bites and skin presentation resulted in a diagnosis of SMBA. It is important to note that the proliferative lymphocytes present as the T-cell immunophenotype.

Based on the lack of evidence of multiorgan damage, hemophagocytic syndrome, or lymphoma, a treatment regimen comprising anti-inflammatory, antiviral, and symptomatic management was initiated. In addition, the patient was treated using traditional Chinese herbal medicine. After more than 2 years of follow-up, a skin scar had formed at the site of both wounds (Figure 1C, F). Notably, there were no recurrences of similar skin lesions, malignant hematologic conditions, or any other SMBA-related disorders. 

Epstein and Barr discovered EBV in 1964 while studying Burkitt lymphoma in African children.⁵ EBV is a double-stranded DNA virus belonging to the γ subtype of the herpesvirus family, with a global infection rate of over 90% in adults.⁶ Cell-mediated immunity plays a major role in primary EBV infection, and in most cases the virus remains latent in the memory B cells, resulting in no obvious clinical symptoms. However, when this balance is disrupted, EBV-infected cells undergo clonal proliferation, leading to EBV-related LPDs, which include B-, T-, and NK-cell-derived conditions with a broad clinicopathological spectrum ranging from indolent, self-limiting, and localized conditions to highly aggressive lymphomas.⁷ In 1988, Jones et al⁸ first reported cases of clonally proliferating EBV-infected T-cells. CAEBV is an intractable and progressive disease, and symptoms include persistent or recurrent inflammation that harbor EBV-infected clonally proliferating T or NK cells.⁹

SMBA is a rare type of CAEBV that is characterized by local skin swelling, erythema, bullae, skin ulceration, and scarring following a mosquito bite, often accompanied by IM-like systemic inflammatory reactions.¹⁰ The patient in the current case report had a history of mosquito bites that resulted in skin allergies, rash, and conjunctival congestion during the early stages. Subsequently, she developed a high fever, eyelid swelling, and multiple skin ulcerations in both lower limbs, with some ulcers exhibiting extensive necrosis. Importantly, the focal distribution of lymphocytes with positive EBER staining was identified in the residual tissues. The patient also exhibited serological evidence of EBV infection, with DNA virus copy numbers exceeding 1000 and concomitant abnormal liver function, splenomegaly, and other systemic symptoms. 

This case was noteworthy because the focal lesion was complicated by S aureus infection, resulting in a relatively wide area of necrosis and suppuration. Detection of EBV infection by histological examination enabled timely antiviral treatment to prevent disease progression. When clinicians come across these kinds of infectious lesions, it is essential to consider the possibility of concurrent EBV infection to avoid missed diagnosis. In addition, persons with some primary immunodeficiency syndromes or acquired immunosuppressive diseases can also have severe EBV infection, that is to say, attention should be paid to differentiation when the clinical manifestations are similar to CAEBV.¹¹

It has been reported that most patients of SMBA exhibit a high serum IgE level, high EBV load, and NK-cell lymphocytosis in the biopsy.⁴ Asada¹² et al surmised that the pathogenesis of SMBA might be EBV reactivation in EBV-infected NK cells, which are induced by CD4+ T-cells that are stimulated by mosquito salivary gland extract, causing a strong skin allergic response. IM-like symptoms probably develop due to immune responses against EBV lytic antigens with potent antigenicity and other viral components produced upon EBV reactivation.¹⁰ In the current case report, the cutaneous lymphocyte immunophenotypes were CD3 and CD4, with no expression of CD56, and genetic rearrangement testing indicated T-cell rather than NK-cell phenotype. EBV is monoclonal in almost all cases by EBV terminal repeat analysis.¹³ While a few reports had suggested that the affected cells in SMBA are T-cell types.^14,15 The etiology remains unknown, more case accumulation and large case studies are needed.

At the onset of this disease symptoms and signs may resolve spontaneously without local treatment. However, children with SMBA are at increased risk for systemic diseases.¹⁶ The poor outcomes are usually accompanied by the development of systemic forms of EBV-NK-LPD. Hemophagocytic lymph histiocytosis is among the most dangerous complications of end-stage EBV-NK-LPD.¹⁶ EBV DNA quantity has been suggested as a prognostic factor.¹⁷ Kimura¹⁸ et al reported a 10-year survival rate of 50% in 12 patients with NK-cell type CAEBV (including hypersensitivity to mosquito bites [ie, SMBA]). Notably, 30% to 70% of patients with systemic CAEBV exhibit SMBA symptoms, which indicates an overlap in the disease spectrum between these diseases, especially of the NK type.¹⁰ In the current case, antiviral therapy was initiated after confirmation of SMBA. This therapy was effective in treating the infection, possibly owing to the low viral load and a favorable host immune response because this was her first illness.

A conservative symptomatic approach is recommended for mild SMBA, whereas hematopoietic stem cell transplantation is recommended for advanced cases.¹⁶ In the current case, the skin ulcers healed with no new disease-related symptoms, and EBV DNA levels remained normal for over 2 years. However, it is possible that the patient could remain healthy for a time but experience a relapse after the next mosquito bite. Thus, long-term follow-up will continue.

As a single case report, it has inherent limitations. Additionally, the tumor cell phenotype of this case is rare and requires further study. In the current case, the patient may stay healthy for a while, but she could suffer a relapse and deterioration in the days ahead, and the EBV copy number could increase again for some reasons; therefore, long-term follow-up is necessary. 

SMBA is a subtype of CAEBV that is characterized by severe skin ulceration in conjunction with systemic clinical manifestations. SMBA may occur in combination with other diseases such as bacterial infections, and it is easily missed or misdiagnosed. Physicians should determine EBV DNA load in blood and conduct skin biopsies in patients—especially children—who present with skin ulcers and systemic symptoms. SMBA could expand new diagnostic and therapeutic approaches to the ulcerative skin diseases.

The current case exhibited CAEBV infection with symptoms of mosquito bite hypersensitivity as the primary manifestation. Such patients should be closely monitored for LPDs or hematological malignancy.