Immunologic difference between hypersensitivity to mosquito bite and hemophagocytic lymphohistiocytosis associated with Epstein-Barr virus infection.

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.

Clinical aspects, immunologic assessment, and genetic analysis in Taiwanese children with hemophagocytic lymphohistiocytosis.

BACKGROUND: Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening syndrome characterized by immune disturbance associated with certain genetic defects. This study aimed to define the clinical spectrum, immunology, and candidate genes in HLH in Taiwanese patients. PATIENTS AND METHODS: The medical records of children who met the updated diagnostic criteria and had confirmed hemophagocytosis by bone marrow aspiration between 1992 and 2007 were retrospectively evaluated. The clinical course and prognosis were analyzed. Quantitative immunoglobulin, lymphocyte subsets, cytotoxicity to K562 cells, intracellular natural killer perforin expression, and candidate genes including SH2D1A, PFR1, Mun13-4, and STX11 genes were also investigated. RESULTS: Thirty-two patients (16 male) were evaluated during the 15-year period. The underlying diseases were acute lymphoblastic leukemia, systemic lupus erythematosus, natural killer malignancy, juvenile idiopathic arthritis, and Chediak-Higashi syndrome. Epstein-Barr virus (EBV)-associated HLH was present in 12 patients, 6 of whom died, while 12 of 20 non-EBV-associated patients died despite aggressive polychemotherapy. Extreme immunoglobulin values occurred in 3 fatal cases. There was decreasing percentage of CD4, CD1656, and B-memory cells and increasing CD8, activated lymphocyte, and T-memory cells among the patients. Cytotoxicity in 14 patients and intracellular perforin expression in 13 were diminished but restored to borderline normal range during the convalescent stage. None of the mutations of SH2D1A, PFR1, Mun13-4, and STX11 genes were found. CONCLUSIONS: In the treatment of Taiwanese HLH patients, aggressive chemotherapy in EBV-associated patients and stem cell transplantation in non-EBV-associated patients are recommended to improve survival. Individualized immune dysregulation instead of the well-known candidate genetic mutations can explain the genetic variation in our cohort.