Abstract
Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening, virus-triggered immune disease. Hypersensitivity to mosquito bite (HMB), a presentation of Chronic Active Epstein-Barr Virus infection (CAEBV), may progress to HLH. This study aimed to investigate the immunologic difference between the HMB episodes and the HLH episodes associated with EBV infection. Immunologic changes of immunoglobulins, lymphocyte subsets, cytotoxicity, intracellular perforin and granzyme expressions, EBV virus load and known candidate genes for hereditary HLH were evaluated and compared. In 12 HLH episodes (12 patients) and 14 HMB episodes (4 patients), there were both decreased percentages of CD4+ and CD8+ and increased memory CD4+ and activated (CD2+HLADR+) lymphocytes. In contrast to HMB episodes that had higher IgE levels and EBV virus load predominantly in NK cells, those HLH episodes with virus load predominantly in CD3+ lymphocyte had decreased perforin expression and cytotoxicity that were recovered in the convalescence period. However, there was neither significant difference of total virus load in these episodes nor candidate genetic mutations responsible for hereditary HLH. In conclusion, decreased perforin expression in the HLH episodes with predominant-CD3+ EBV virus load is distinct from those HMB episodes with predominant-NK EBV virus load. Whether the presence of non-elevated memory CD4+ cells or activated lymphocytes (CD2+HLADR+) increases the mortality rate in the HLH episodes remains to be further warranted through larger-scale studies.
Highlights
The Epstein-Barr virus (EBV) infects B cells through surface CD21 in healthy individuals who are often asymptomatic or may present as infectious mononucleosis (IM) [1]
Known candidate mutations of SH2D1A/SAP, PRF1, UNC13D, STX11, STXBP2, XIAP, and ITK can inhibit the exocytotic process of polarization, docking, priming, and fusion in cytotoxic T/natural killer (NK) cells, subsequently lead to defective cytotoxicity and overwhelming hemophagocytic lymphohistiocytosis (HLH) in some rare hereditary and sporadic cases [16,17,18,19,20]
To understand the possible mechanisms of Hypersensitivity to mosquito bite (HMB) transformation into fulminant HLH, we evaluated and compared immunologic
Summary
The Epstein-Barr virus (EBV) infects B cells through surface CD21 in healthy individuals who are often asymptomatic or may present as infectious mononucleosis (IM) [1]. Patients with chronic active EBV (CAEBV) infection may have IM-like chronic symptoms such as fever and lymphadenopathy, and serologic evidence of persistent EBV infection [4,5,6,7,8,9]. CAEBV can be exacerbated into fulminant (catastrophic) hemophagocytic lymphohistiocytosis (HLH) [10,11,12,13,14] and present with cytopenia, coagulopathy, central nervous system symptoms, and lipid changes, aside from IM-like features [15]. Hypersensitivity to mosquito bite (HMB) is a unique feature characterized by bulla formation with intense erythema on mosquito-bitten sites, escar healing and systemic manifestations like fever, lymphadenopathy, and splenomegaly [21,22]. Around 70% of CAEBV patients present as the HMB episode (HMBCAEBV) and have the potential of developing fulminant HLH [23]
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