Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis： a retrospective study of 78 pediatric cases in mainland of China

Background The clinical characteristics of Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis （EBV-HLH） are largely unreported in the pediatric patients in mainland of China. The main aim of this study was to recognize the clinical features of EBV-HLH in children and to explore its prognosis and risk factors. Methods A retrospective study was performed on 78 pediatric patients with EBV-HLH who were admitted to Beijing Children＇s Hospital between 2003 and 2008. All patients＇ medical records were reviewed and analyzed. For each patient, demographic, clinical, laboratory and outcome information was collected. Statistical analysis was conducted via multivariate and univariate analysis. Results The age of onset peaked between 1-2 years and boys were more likely developed EBV-HLH. EBV-HLH occurred mainly in the serological pattern with EBV nuclear antigen （EBNA） positive （70.5%）. The overall fatality of the disease was 56.7%. Twelve of the 39 fatalities （30.8%） died rapidly within 2 months after diagnosis. Multivariate analysis revealed that not receiving chemotherapy （P=0.002）, 〉4 weeks of illness prior to diagnosis （P=0.004）, and albumin levels 〈20 g/L （P=-0.045） significantly predicted an increased fatality risk. Conclusions EBV-HLH is a severe disease with a high fatality rate that occurs mainly in the serological pattern with EBNA positive. Early initiation of chemotherapy and timely diagnosis significantly improves survival rate. Practical strategies should focus on reducing the likelihood of early death.

Hemophagocytic lymphohistiocytosis caused by primary Epstein-Barr virus in patient with Crohn's disease

We present a case of a 19-year-old man with a 6-year history of Crohn's disease(CD), previously treated with 6-mercaptopurine, who was admitted to our department for Epstein-Barr virus(EBV) infection and subsequently developed a hemophagocytic lymphohistiocytosis(HLH). HLH is a rare disease which causes phagocytosis of all bone marrow derived cells. It can be a primary form as a autosomic recessive disease, or a secondary form associated with a variety of infections; EBV is the most common, the one with poorer prognosis. The incidence of lymphoproliferative disorders was increased in patients with inflammatory bowel disease(IBD) treated with thiopurines. Specific EBV-related clinical and virological management should be considered when treating a patient with IBD with immunosuppressive therapy. Moreover EBV infection in immunosuppressed patient can occur with more aggressive forms such as encephalitis and diffuse large B cell lymphoma. Our case confirms what is described in the literature; patients with IBD, particularly patients with CD receiving thiopurine therapy, who present 5 d of fever and cervical lymphadenopathy or previous evidence of lymphopenia should be screened for HLH.

Epstein-Barr virus-induced infection-associated hemophagocytic lymphohistiocytosis with acute liver injury:A case report

BACKGROUND Hemophagocytic lymphohistiocytosis(HLH)is a severe hyperinflammatory reaction,which is rare and life-threatening.According to the pathogen,HLH is divided into genetic and acquired.The most common form of acquired HLH is infection-associated HLH,of which Herpes viruses,particularly Epstein-Barr virus(EBV),are the leading infectious triggers.However,it is difficult to distinguish between simple infection with EBV and EBV-induced infectionassociated HLH since both can destroy the whole-body system,particularly the liver,thereby increasing the difficulty of diagnosis and treatment.CASE SUMMARY This paper elaborates a case about EBV-induced infection-associated HLH and acute liver injury,aiming to propose clinical guides for the early detection and treatment of patients with EBV-induced infection-associated HLH.The patient was categorized as acquired hemophagocytic syndrome in adults.After the ganciclovir antiviral treatment combined with meropenem antibacterial therapy and methylprednisolone inhibition to inflammatory response,gamma globulin enhanced immunotherapy,the patient recovered.CONCLUSION From the diagnosis and treatment of this patient,attention should be paid to routine EBV detection and a further comprehensive understanding of the disease as well as early recognition and early initiation are keys to patients’survival.

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.

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).

Drug associated vanishing bile duct syndrome combined with hemophagocytic lymphohistiocytosis

A 28-year-old woman with untreated autoimmune disorder, demonstrated skin rash and fever after taking Amoxicillin-clavulanate and developed progressive jaundice. A bone marrow aspiration indicated an increased number of macrophages with hemophagocytosis and liver biopsy showed pure centrilobular cholestasis with necrosis and some absence of portal bile ducts. Furthermore, a serological test for Epstein-Barr virus was positive. Under treatment by liver dialysis and administration of steroids led to rapidly defervescence and clinical improvement. However, liver enzymes were still markedly elevated with persistent anemia, even after immunosuppressive treatment. The patient is currently waiting for liver transplantation. This is the ?rst description of vanishing bile duct syndrome combined with hemophagocytic lymphohistiocytosis, with underlying causes including infection, drug-induced factors and untreated autoimmune disorder.

Epstein-Barr virus associated secondary hemophagocytic lymphohistiocytosis with an unusual presentation of abdominal compartment syndrome

Hemophagocytic lymphohistiocytosis(HLH)is a cytokine storm syndrome caused by an overactive but ineffective immune reaction.Without prompt diagnosis and treatment,HLH is life-threatening.However,presenting symptoms are often nonspecific,with fatigue and fever being the most common.A high index of suspicion is therefore critical for early diagnosis and timely management.A previously healthy,65-year-old female who initially presented with fever and abdominal pain developed abdominal compartment syndrome(ACS)requiring decompressive laparotomy on hospital day 6.Intraoperative frozen sections of biopsied liver showed intense portal lymphohistiocytic infiltrates.Epstein-Barr virus DNA copy numbers escalated from 600 copies/mL after admission to 134,000 copies/mL before death.The diagnostic criteria of HLH-2004 were met.Patient expired on hospital day 12.It is important to raise awareness of ACS being an unusual presentation of HLH.Recent changes in diagnostic criteria tailored to adult HLH cases are reviewed.