Epstein-Barr Virus and Hemophagocytic Lymphohistiocytosis.
ABSTRACT: Epstein-Barr virus (EBV) is a ubiquitous virus that infects nearly all people worldwide without serious sequela. However, for patients who have genetic diseases which predispose them to the development of hemophagocytic lymphohistiocytosis (HLH), EBV infection is a life-threatening problem. As a part of a themed collection of articles on EBV infection and human primary immune deficiencies, we will review key concepts related to the understanding and treatment of HLH.
Project description:Hemophagocytic lymphohistiocytosis (HLH) is rare and life threatening syndrome. There are only a few reported cases of HLH with GI symptoms. We describe the case of an 18 months old boy who presented with a history of fever for 40 days, abdominal distention and hepatosplenomegaly. Abdominal x-ray showed a pneumoperitoneum. Urgent laparotomy was done which revealed an isolated cecal perforation. The histopathological findings in the subsequent resected bowel was HLH with evidence of positive EBV Barr infection.
Project description:Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis (EBV-HLH) is the most frequent subtype of secondary HLH triggered by infections. Previous studies have shown that ~30 % or more of patients with EBV-HLH do not respond to standard therapy. This study investigated the efficacy and safety profile of a modified DEP regimen in combination with PEG-aspargase (L-DEP) as a salvage therapy for refractory EBV-HLH.In this study from October 2014 to October 2015, 28 patients with refractory EBV-HLH received a L-DEP regimen at the Beijing Friendship Hospital, Capital Medical University. Treatment efficacy and adverse events were evaluated at 2 and 4 weeks after L-DEP treatment.Median EBV-DNA concentrations before and 2 weeks after receiving the L-DEP regimen were 9.6?×?10(5) (1.5?×?10(4)?-?1?×?10(9)) copies/mL and 2.2?×?10(5) (3.8?×?10(2)?-?1.2?×?10(7)) copies/mL, respectively; the post-treatment values were significantly lower than that of the pretreatment (P?=?0.048). Nine of the 28 study patients achieved complete response (CR) and 15 partial response (PR), resulting in an overall response rate of 85.7 % (CR+PR). Four patients who did not achieve response died within 4 weeks of receiving L-DEP. Thirteen of the 24 patients who achieved partial or complete response received subsequent allogenic hematopoietic stem cell transplantation (allo-HSCT). Ten of these 13 patients survived until 1 March 2016. The major adverse effects of the L-DEP regimen were high serum amylase concentrations, abnormal liver function, and coagulation disorders.This study suggests that L-DEP is a safe and effective salvage therapy prior to allo-HSCT for refractory EBV-HLH and increases the possibility of such patients receiving allo-HSCT. A prospective multicenter large-scale clinical trial that aims to validate the L-DEP regimen for refractory EBV-HLH is currently underway (ClinicalTrails.gov Identifier: NCT02631109).
Project description:A 61-year-old male presented with worsening dyspnoea and constitutional symptoms for few weeks followed by bloody diarrhoea and loss and fever. Physical exam revealed tachycardia, respiratory distress, and splenomegaly without lymphadenopathy. Work up showed pancytopenia, hypofibrinogenemia, acute kidney injury requiring haemodialysis, high ferritin level, positive IgG and IgM for EBV and positive soluble CD25. Chest CT scan showed bilateral pulmonary nodules. Lung biopsy showed intravascular pulmonary histiocytosis while bone marrow biopsy was negative for hemophagocytes. A diagnosis of hemophagocytic lymphohistiocytosis (HLH) was made based on fulfilling the diagnostic criteria and systemic steroids were initiated, which improved the patient's condition gradually with resolution of dyspnoea, AKI and pancytopenia. Repeat chest CT scan showed resolution of bilateral pulmonary nodules. The patient was transferred to a tertiary centre to receive HLH-specific therapy. We present a rare presentation of HLH with steroid-responsive bilateral pulmonary nodules and a rare histopathologic finding of pulmonary intravascular histiocytosis, which has never been described in HLH or the lung tree.
Project description:Liver failure with hemophagocytic lymphohistiocytosis (HLH) is a life-threatening syndrome with high mortality. The aim of this study was to decipher clinical and laboratory characteristics of hemophagocytic lymphohistiocytosis after definite diagnosis of liver failure and to provide clues for early diagnosis and treatment of HLH in patients with liver failure. Eleven patients diagnosed with liver failure and HLH were retrospectively investigated in this study. All patients presented with jaundice, persistent high-grade fever, pancytopenia, splenomegaly, evidence of hemophagocytes in the bone marrow and laboratory abnormalities indicating HLH. The average interval from the earliest diagnosis of liver failure to a definitive diagnosis of HLH was 17.27 days. Six (54.55%) patients died during follow-up. For patients with liver failure after admission and subsequently definitively diagnosed with HLH, bilirubin and INR were significantly decreased. HLH is definitely diagnosed at an intermediate or late stage when patients have already suffered from liver failure. The initial dose of glucocorticoid (methylprednisolone) was decreased to 1-1.5?mg/kg/d and gradually reduced thereafter. In conclusion, for patients with liver failure, HLH should be screened as early as possible upon persistent fever, splenomegaly and unexplained pancytopenia. For patients with liver failure and HLH, the dosage of glucocorticoid should be reduced to avoid serious side effects.
Project description:The diagnosis of hemophagocytic lymphohistiocytosis (HLH) with cerebral involvement is challenging given the rarity of HLH and its resemblance to the much more common severe sepsis. Timely diagnosis and treatment may be lifesaving. We report two cases demonstrating different and rare forms of severe brain involvement in adult patients with HLH: acute necrotizing encephalopathy, and diffuse hemorrhagic disease due to disseminated intravascular coagulation. Severe HLH with brain involvement in adults is rare. HLH with cerebral involvement should be considered in patients presenting with severe systemic inflammatory response syndrome (SIRS) but negative cultures and unusual or unexpectedly severe clinical and/or radiologic signs of cerebral dysfunction. Similar brain injury may occur in patients with cytokine storm syndrome due to COVID-19. BACKGROUND: Hemophagocytic lymphohistiocytosis (HLH) presents with fevers, rash, organomegaly, cytopenia, and increased triglycerides and ferritin (Ramos-Casals et al., 2014) . Neurologic abnormalities are reported in about one-third of patients (Cai et al., 2017), including a few cases of acute necrotizing encephalopathy (ANE) (Xiujuan et al., 2015). Coagulation abnormalities are frequent in HLH patients (Valade et al., 2015). OBJECTIVE: To raise awareness about the importance of early diagnosis and treatment of HLH with neurological involvement to prevent serious complications and demise.
Project description:Hemophagocytic lymphohistiocytosis (HLH) is a syndrome of severe immune activation with macrophage and T-cell infiltration resulting in, multi organ damage. HLH may be primary or secondary in etiology. A high index of suspicion is essential for early diagnosis and treatment. Diagnostic criteria need to be refined and newer treatment options to be explored in order to improve survival especially in adult HLH and malignancy-associated HLH (M-HLH). We report a case of malignancy associated HLH (M-HLH) in adult treated on one of the only FDA-approved protocols for adult HLH to highlight the diagnostic and therapeutic challenges of this disease entity.
Project description:Epstein-Barr virus-positive T/NK-cell lymphoproliferative disorders (EBV+ T/NK LPD) encompass a heterogeneous group of disorders, including chronic active Epstein-Barr virus infection (CAEBV), Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis (EBV-HLH), systemic EBV+ T-cell lymphoma of childhood and hydroa vacciniforme-like lymphoproliferative disorder (HVLPD) and so on, predominantly affecting children and young adults with high mortality. Patients with EBV+ T/NK LPD have overlapping clinical symptoms as well as histologic and immunophenotypic features. In this review, we summarized the clinical features of EBV+ T/NK LPD in Chinese patients from the published articles.
Project description:Hemophagocytic lymphohistiocytosis (HLH) is a syndrome of pathologic immune activation, occurring as either a familial disorder or a sporadic condition, in association with a variety of triggers. This immune dysregulatory disorder is prominently associated with cytopenias and a unique combination of clinical signs and symptoms of extreme inflammation. Prompt initiation of immunochemotherapy is essential for survival, but timely diagnosis may be challenging because of the rarity of HLH, its variable presentation, and the time required to perform diagnostic testing. Therapy is complicated by dynamic clinical course, high risk of treatment-related morbidity, and disease recurrence. Here, we review the clinical manifestations and patterns of HLH and describe our approach to the diagnosis and therapy for this elusive and potentially lethal condition.
Project description:We report an unusual case of recurrent encephalopathy due to acquired hemophagocytic lymphohistiocytosis (HLH) in a patient with propionic acidemia (PA). PA is an inherited metabolic disorder in which patients often present with encephalopathy and pancytopenia during metabolic decompensation. However, these patients may rarely develop HLH with similar presentation. This case illustrates the need to distinguish HLH induced encephalopathy from the one secondary to metabolic decompensation in these patients, as early diagnosis and treatment of HLH improves prognosis. This case also highlights the importance of considering HLH in patients presenting with unexplained encephalopathy, as early diagnosis and treatment is lifesaving in this otherwise lethal condition. To our knowledge this is the first case report of acquired HLH presenting as recurrent encephalopathy followed by complete recovery, in a metabolically stable patient with PA.
Project description:Hemophagocytic lymphohistiocytosis (HLH) are basically a heterogenous group of clinical syndromes, characterised by activation and non-malignant proliferation of benign histiocytes i.e. lymphocytes and macrophages, leading to a cytokine storm that accounts for the fever, organomegaly and multi-organ dysfunction. Two types of HLH are described, either due to known genetic defect (familial HLH/FHL) or due to some acquired cause either infection or rheumatological diseases. Here we present a case of a 3 months old baby, admitted with fever, hepatosplenomegaly and cytopenia and ultimately was diagnosed to be a case of Familial HLH type 3 due to defect in UNC13D gene as a result of compound heterozygous for two nonsense mutation resulting in the Munc13-4 protein defect.