Lymphoma & related disorders
Mature T/NK cell disorders
Pediatric NK/T cell disorders
Severe mosquito bite allergy
Editorial Board Member: Julie Feldstein, M.D.
Last staff update: 5 December 2024 (update in progress)
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PubMed Search: Severe mosquito bite allergy
Table of Contents
Definition / general | Essential features | Terminology | ICD coding | Epidemiology | Sites | Pathophysiology | Etiology | Clinical features | Diagnosis | Laboratory | Prognostic factors | Case reports | Treatment | Clinical images | Microscopic (histologic) description | Microscopic (histologic) images | Peripheral smear description | Positive stains | Negative stains | Sample pathology report | Differential diagnosis | Additional references | Board review style question #1 | Board review style answer #1 | Board review style question #2 | Board review style answer #2Cite this page: Barrionuevo-Cornejo C, Murga-Zamalloa CA. Severe mosquito bite allergy. PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/lymphomamosquito.html. Accessed December 17th, 2024.
Definition / general
- Severe mosquito bite allergy (SMBA) constitutes a severe skin reaction following mosquito bites associated with the neoplastic proliferation of Epstein-Barr virus (EBV) positive NK cells
Essential features
- Constitutes both skin and systemic response to mosquito bites characterized by skin necrosis, fever and malaise
- There is an absolute increase in NK cells in the peripheral blood
- Atypical EBV positive NK cells are present at the mosquito bite site
- Reported cases are predominantly in Asia, with few reports in South America
- Symptoms subside in half of patients; however, the remaining patients are at increased risk of developing more severe systemic EBV positive T / NK cell lymphoproliferative neoplasms, including T / NK systemic chronic active Epstein-Barr virus disease (sCAEBV)
Terminology
- Hypersensitivity to mosquito bites
ICD coding
Epidemiology
- Typically occurs in children; the mean age at diagnosis is 7 years old
- 10 year survival rate is ~50%
- Reference: J Am Acad Dermatol 2001;45:569
Sites
- Skin is always involved
- Peripheral blood shows an absolute increase in NK cells
Pathophysiology
- Initial mosquito bite generates a local proliferation of CD4+ T lymphocytes that mediate localized destruction
- Subsequently, CD4+ T primed lymphocytes induce the expression of the EBV related oncoprotein LMP1 in NK cells with latent EBV infection
- These ultimately lead to the oncogenic proliferation of NK cells
- Reference: J Invest Dermatol 2005;125:956
Etiology
- Mosquito bite is the initial trigger for the disease
- Most common mosquito species are Aedes albopictus, Culex pipiens and Culex tritaeniorhynchus
- Reference: Allergol Int 2021;70:430
Clinical features
- Cutaneous signs are erythema, bullae, ulcers, necrosis and scarring at the mosquito bite site
- Following the cutaneous signs, fever, general malaise and increased circulating NK cells are observed
- Initial symptoms usually resolve within 2 - 3 weeks in ~50% of patients; however, patients are at increased risk for developing other EBV positive T / NK lymphoproliferative disorders or hemophagocytic lymphohistiocytosis (HLH)
- Persistent elevated EBV counts and symptoms or progression to multiorgan failure are most consistent with the development of CAEBV or other EBV positive T / NK lymphoproliferative disorders
- References: Allergol Int 2021;70:430, J Am Acad Dermatol 2001;45:569
Diagnosis
- Physical examination and relevant clinical history of recent mosquito bites at the site of cutaneous manifestations
- Laboratory serology testing is done to detect EBV titers and molecular testing in peripheral blood is done to quantify EBV viral DNA load
- Imaging studies to assess for hepatosplenomegaly and lymphadenopathy
- Reference: J Dermatol 2023;50:e198
Laboratory
- Elevation of EBV DNA load (> 1,000/ug DNA)
- Elevation of EBV VCA IgG titers
- Absolute lymphocytosis, with an increase in circulating NK cells
- Elevation of IgE levels
- Ferritin may be elevated
- Reference: Allergol Int 2021;70:430
Prognostic factors
- Mild / better prognosis: resolution of symptoms and no extracutaneous organ involvement after 1 year of initial diagnosis
- Moderate prognosis: recurrent disease with transient systemic symptoms (liver damage, lymphadenopathy, not including multiorgan damage)
- Severe prognosis
- Overlap with hydroa vacciniforme lymphoproliferative disorder
- Fulfilled criteria for systemic CAEBV
- Association with HLH or progression to EBV+ T / NK lymphomas
- Reference: J Dermatol 2023;50:e198
Case reports
- 2 year old girl with hemorrhagic and necrotic skin lesions following a mosquito bite (index case) (Arch Dermatol 1990;126:362)
- 14 year old patient with onset of skin lesions in the left leg following a mosquito bite (Blood 2019;133:999)
- 14 year old boy with hemorrhagic bullae in bilateral lower extremities following mosquito bites (Pediatr Dermatol 2022;39:443)
- 17 year old boy experienced waxing and waning edematous skin lesions whenever bitten by mosquitoes (Ann Lab Med 2020;40:80)
Treatment
- Only in cases with severe complications (e.g., CAEBV), a combination of cytotoxic chemotherapy is necessary and includes CHOP (cyclophosphamide, adriamycin, vincristine, prednisolone) and high dose cytosine arabinoside (Int J Hematol 2005;82:437)
Clinical images
Contributed by Eberth Quijano, M.D. and Natalia Soto, M.D.
Skin at the mosquito bite site
Ulcer at mosquito bite site
Microscopic (histologic) description
- Skin biopsy findings include intraepidermal bullae and epidermal necrosis
- Dense perivascular infiltrates of lymphocytes that extend to the subcutaneous adipose tissue
- Angiovascular destruction is present
- Subset of the lymphocytic infiltrates includes EBV positive NK cells with variable morphology, including large and atypical forms
- Neoplastic elements are less frequently constituted by EBV positive T cells with atypical features
- Background small T and B cell lymphocytes and macrophages are present
- Reference: Blood 2012;119:673
Microscopic (histologic) images
Contributed by Carlos Barrionuevo-Cornejo, M.D., Ph.D.
Perivascular dermal infiltrates
Ulceration of skin
Subcutaneous adipose lymphocytic infiltrates
Perivascular and angiocentric infiltrates
Vascular necrosis
Small to medium atypical lymphocytes
CD3 positive atypical cells
CD56 positive atypical cells
Granzyme B positivity
EBER in situ hybridization
Peripheral smear description
- Peripheral smear is remarkable for absolute lymphocytosis, predominantly composed of large granular lymphocytes characterized by a moderate cytoplasm with granulations
- Lymphocytes show no definitive atypical features, defined as irregular nuclear contours, high N:C ratios or prominent nucleoli
Positive stains
- Neoplastic cells show an NK cell immunophenotype and are positive for CD56, TIA1, granzyme B, cytoplasmic CD3 and EBV (EBER ISH or LMP1 IHC) (Blood 2019;133:999, Ann Lab Med 2020;40:80, Arch Dermatol 1990;126:362)
- CD30 can be positive in a subset of the atypical elements (Pediatr Dermatol 2022;39:443)
- Rarely do the neoplastic elements show a T cell phenotype and are positive for CD3, CD5, CD7 and EBV (EBER ISH or LMP1 IHC) (Semin Diagn Pathol 2020;37:32)
Sample pathology report
- Skin, punch biopsy:
- Intraepidermal necrosis with atypical lymphocytic infiltrates with EBV positive NK cells (see comment)
- Comment: Per clinical history, the biopsy site corresponds to a mosquito bite with severe epidermal necrosis and bullae and may be consistent with severe mosquito bite allergy. Correlation with peripheral blood NK cell counts and EBV titers are required for confirmation.
Differential diagnosis
- Chronic active EBV disease of T / NK cell type, systemic form (T / NK sCAEBV) (Blood Adv 2020;4:2918, Blood 2012;119:673, Pathogens 2018;7:28, Semin Diagn Pathol 2020;37:32, Am J Clin Pathol 2024;161:586):
- Can develop following a severe mosquito bite allergy; it is proposed that if symptoms and elevated EBV counts persist or if multiorgan damage is present, a diagnosis of CAEBV must be considered
- CAEBV is characterized by persistent high EBV titers and infectious mononucleosis symptoms for over 3 months
- Positive EBV T or NK cell infection in peripheral blood or involved tissues
- Most commonly, it involves the spleen, liver and bone marrow
- EBV infected T or NK cells lack cytological atypia and do not efface the background tissue architecture
- T cell type (59% of cases) (CD4 > CD8)
- NK cell type (CD56 positive 41% of cases)
- It often shows monoclonality by TCR gene rearrangement or EBV clonality testing; fewer cases are oligoclonal or polyclonal
- Can develop following EBV HLH; it is proposed that cases of EBV+ HLH that do not respond to initial therapies with persistent high EBV counts may constitute T / NK sCAEBV
- Hydroa vacciniforme lymphoproliferative disorder (HVLPD) (Blood 2012;119:673, Blood 2013;122:3101, Arch Dermatol 2006;142:587, Am J Surg Pathol 2010;34:1773, J Am Acad Dermatol 1999;40:283, Blood 2019;133:2753):
- Predominantly diagnosed in pediatric patients
- Characterized by cutaneous vesicles that crust and scar, limited to sun exposed areas and spontaneous resolution (classic form)
- Severe forms with systemic symptoms not restricted to sun exposed areas have been described in Asia and South America (systemic form)
- Lesions are not associated with mosquito bites
- Dermal lymphoid infiltrates include EBV positive T lymphocytes
Additional references
Board review style question #1
Which of the following is correct regarding severe mosquito bite allergy?
- Cutaneous lesions resolve spontaneously in more than 80% of the patients
- Cytologic atypia is rarely present at the biopsy site
- EBV positive NK cells are commonly identified at the mosquito bite site
- It is predominantly diagnosed in immunodeficient individuals
- Rarely, patients progress to more aggressive and systemic forms of EBV positive T / NK cell lymphoproliferative neoplasms
Board review style answer #1
C. EBV positive NK cells are commonly identified at the mosquito bite site. In severe mosquito bite allergy, neoplastic NK cells with reactivation of EBV are identified at the biopsy site. Less commonly, neoplastic EBV positive T cells are identified. Answer B is incorrect because a subset of the lymphocytic infiltrates often comprises atypical cells. Answer D is incorrect because severe mosquito bite allergy is commonly diagnosed in immunocompetent pediatric patients. Answer E is incorrect because about half of the patients will progress to more severe forms of T / NK cell lymphoproliferative disorders. Answer A is incorrect because the symptoms will resolve spontaneously in about half of patients.
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Reference: Severe mosquito bite allergy
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Board review style question #2
Which of the following is correct regarding the pathological development of severe mosquito bite allergy (SMBA)?
- Amplification of the MYC oncogene occurs in transformed B cells during disease progression
- CD4 T cells triggered by mosquito salivary gland epitopes will activate EBV in NK cells with latent EBV infection
- Development of fusions in the ALK protein will occur during oncogenic transformation
- HTLV1 infection of T lymphocytes is required for oncogenic transformation
- Mutations in the Wiskott-Aldrich syndrome gene (WASp) predispose patients to developing SMBA
Board review style answer #2
B. CD4 T cells triggered by mosquito salivary gland epitopes will activate EBV in NK cells with latent EBV infection. The pathophysiology of SMBA includes a sequence of events initiated by epitopes in the mosquito salivary glands that activate CD4 T cells that will mediate localized tissue destruction. Subsequently, the activated CD4 T cells will reactivate the EBV LMP1 protein in NK cells with latent infection, leading to its neoplastic expansion. Answer A is incorrect because amplification of the MYC oncogene is often observed in B cell lymphoproliferative neoplasms and is not reported in SMBA. Answer C is incorrect because translocations of the ALK oncogene are observed in a subset of anaplastic large cell lymphoma cases and not in SMBA. Answer D is incorrect because HTLV1 infection of T lymphocytes is observed in adult T cell leukemia and not in SMBA. Answer E is incorrect because mutations in the WASp gene predispose to immunodeficiency, which is not associated with the development of SMBA.
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