Hemophagocytic lymphohistiocytosis: Recent progress in the pathogenesis, diagnosis and treatment

Hemophagocytic lymphohistiocytosis(HLH) is a hyperinflammatory syndrome that develops as a primary(familial/hereditary) or secondary(non-familial/hereditary) disease characterized in the majority of the cases by hereditary or acquired impaired cytotoxic T-cell(CTL) and natural killer responses. The molecular mechanisms underlying impaired immune homeostasis have been clarified, particularly for primary diseases. Familial HLH(familial hemophagocytic lymphohistiocytosis type 2-5, Chediak-Higashi syndrome, Griscelli syndrome type 2, Hermansky-Pudlak syndrome type 2) develops due to a defect in lytic granule exocytosis, impairment of(signaling lymphocytic activation molecule)-associated protein, which plays a key role in CTL activity [e.g., X-linked lymphoproliferative syndrome(XLP) 1], or impairment of X-linked inhibitor of apoptosis, a potent regulator of lymphocyte homeostasis(e.g., XLP2). The development of primary HLH is often triggered by infections, but not in all. Secondary HLH develops in association with infection, autoimmune diseases/rheumatological conditions and malignancy. The molecular mechanisms involved in secondary HLH cases remain unknown and the pathophysiology is not the same as primary HLH. For either primary or secondary HLH cases, immunosuppressive therapy should be given to control the hypercytokinemia with steroids, cyclosporine A, or intravenous immune globulin, and if primary HLH is diagnosed, immunochemotherapy with a regimen containing etoposide or anti-thymocyte globulin should be started. Thereafter, allogeneic hematopoietic stem-cell transplantation is recommended for primary HLH or secondary refractory disease(especially EBVHLH).

Treatment of Epstein-Barr virus-related hemophagocytic lymphohistiocytosis:Study protocol of a prospective pilot study

In this manuscript, a number of debatable issues related to the diagnosis and treatment of Epstein-Barr virus-related hemophagocytic lymphohistiocytosis(EBVHLH) will be addressed. Considering the heterogeneous nature of EBV-HLH, diagnostic efforts are required toclarify the precise nature of the disease at diagnosis, the number of EBV genome copies in peripheral blood, and localization of the EBV genome in lymphoid cells(B, T, or natural killer cells). Although the majority of cases of EBV-HLH develop without evidence of immunodeficiency, some cases have been found to be associated with chronic active EBV infection, genetic diseases such as X-linked lymphoproliferative disease(XLP, type 1, or type 2), or familial HLH(FHL, types 2-5). Due to such background heterogeneity, the therapeutic results of EBV-HLH have also been found to vary. Patients have been found to respond to corticosteroids alone or an etoposide-containing regimen, whereas other patients require hematopoietic stem cell transplantation. Thus, decision-making for optimal treatment of EBVHLH and its eventual outcome requires evaluation in consideration of the precise nature of the disease. A protocol for a pilot study on the treatment of patients with EBV-HLH is presented here.

Management of adult Langerhans cell histiocytosis based on the characteristic clinical features

To find out the most appropriate management,clinical features of 18 cases of adult multisystem langerhans cell histiocytosis(LCH) have been analyzed. The patients comprising of 9 males and 9 females were median age of 36 years,ranging from 18-53 years at diagnosis. Regarding the initial symptoms,7 patients(2 males and 5 females) showed central diabetes insipidus(CDI) and other endocrine symptoms with thickened pituitary stalk or a mass at the hypothalamic region. Additional 2 patients initiated the disease with CDI with no immediate diagnosis. In the remaining patients,the diseasebegun with single(n = 3) or multiple(n = 1) spinal bone lesion(s) in 4 patients(all males),with multiple bone lesions in 3 patients(1 male and 2 females),with single skull lesion in one female patient and with ambiguous symptoms including hypothyroidism in the remaining one male patient. We also recognized the correlation between pregnancy/childbirth and LCH in 4 patients. In terms of treatment,9 patients received systemic immuno-chemotherapy alone,of which the majority received vinblastine-based chemotherapy while 4 received 2-chlorodeoxyadenosine. Five had a combination of immuno-chemotherapy with surgical resection or radiotherapy,2 had immunotherapy alone,2 had surgical resection followed by observation alone to date. Three patients received hematopoietic stem cell transplantation after extensive chemotherapy. In terms of outcome,15 patients are alive(9 with active disease,6 without active disease),with a median of 66 mo(range 17-166 mo),two died of disease while the remaining 1 lost to follow-up. Based on these results,we think that early diagnosis and rapid introduction of appropriate treatment are essential,in order to overcome the problems relevant to adult LCH.