Epstein‐Barr Virus–Associated Hemophagocytic Lymphohistiocytosis in Adults Characterized by High Viral Genome Load within Circulating Natural Killer Cells

Fox, Christopher P.; Shannon-Lowe, Claire; Gothard, Philip; Kishore, Bhuvan; Neilson, Jeffrey R.; O’Connor, Nathan; Rowe, Martin

doi:10.1086/653424

Cited by 53 publications

(45 citation statements)

References 17 publications

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“…It is well established that EBV and its antigens induce massive release of cytokines, thereby activating monocytes/macrophages and causing damage in multiple organs [11]. A series of Japanese-based studies have found that T cells and NK cells are targeted by EBV infection in patients with EBV-HLH [12, 13]. Fox et al [13] reported abundant EBV genomes (12,900–1,816,550 genomes/10 6 cells) in the circulating NK cells of such patients.…”

Section: Discussionmentioning

confidence: 99%

PEG-aspargase and DEP regimen combination therapy for refractory Epstein–Barr virus-associated hemophagocytic lymphohistiocytosis

Wang

Lin

et al. 2016

J Hematol Oncol

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BackgroundEpstein–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.MethodsIn 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.ResultsMedian EBV-DNA concentrations before and 2 weeks after receiving the L-DEP regimen were 9.6 × 105 (1.5 × 104 − 1 × 109) copies/mL and 2.2 × 105 (3.8 × 102 − 1.2 × 107) 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.ConclusionsThis 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).

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Section: Discussionmentioning

confidence: 99%

PEG-aspargase and DEP regimen combination therapy for refractory Epstein–Barr virus-associated hemophagocytic lymphohistiocytosis

Wang

Lin

et al. 2016

J Hematol Oncol

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“…This disease is also frequently seen in east Asian countries, 11 and involves a clonal expansion of EBV ϩ T or NK cells, which produce inflammatory cytokines that induce the activation of macrophages and hemophagocytosis. [21][22][23] Apart from these systemic diseases, accumulating evidence indicates that 2 cutaneous diseases, hydroa vacciniforme and severe mosquito bite allergy, are closely associated with EBV ϩ T or NK cells. Hydroa vacciniforme is characterized by recurrent vesiculopapules usually occurring on sunexposed areas and seen in children and adolescents.…”

Section: Introductionmentioning

confidence: 99%

EBV-associated T/NK–cell lymphoproliferative diseases in nonimmunocompromised hosts: prospective analysis of 108 cases

Kimura¹,

Ito

Kawabe

et al. 2012

Blood

371

474

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“…In EBV-related haemophagocytic lymphohistiocytosis, EBV-infected CD8 T cells and natural killer cells are thought to trigger haemophagocytosis and the associated ‘cytokine-storm’/systemic inflammatory response syndrome (SIRS) directly 2–4…”

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confidence: 99%

Minimal T-cell requirements for triggering haemophagocytosis associated with Epstein-Barr virus-driven B-cell proliferation: a clinical case study

Daikeler

Tzankov

Höenger

et al. 2011

Annals of the Rheumatic Diseases

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The pathophysiology of Epstein-Barr virus (EBV)-associated haemophagocytosis remains poorly understood. 1 In EBVrelated haemophagocytic lymphohistiocytosis, EBV-infected CD8 T cells and natural killer cells are thought to trigger haemophagocytosis and the associated 'cytokine-storm'/systemic infl ammatory response syndrome (SIRS) directly. 2 -4 By contrast, in the context of uncontrolled proliferation of EBV-infected B cells, hyperactively responding EBV-specifi c T cells are assumed to mediate haemophagocytosis/SIRS. 5 Both the quantity and quality of such deregulated EBV-specifi c T-cell reactivity remain undefi ned. Unique insight into basic aspects of the postulated T-cell requirements necessary to trigger haemophagocytosis was provided by the case of a 37-year-old woman with mixed connective tissue disease (ribonucleoprotein-Ab positive, severe pulmonary arterial hypertension, polyarthritis, pericarditis and oesophageal sclerosis). Immunosuppression with azathioprine and ciclosporin, as well as a 3-month trial of oral cyclophosphamide due to progressing pulmonary arterial hypertension was ineffective, yet worsened pre-existing lymphopenia. Based on the severe and cyclophosphamide-resistant course of the disease the indication for haematopoietic stem cell transplantation (HSCT) was established. Before induction-therapy EBV-specifi c MHC I restricted T-cell reactivity was detectable using ELISpot technology, 6 and EBV replication (whole-blood PCR) was controlled ( fi gure 1 ). Subsequent conditioning (cyclophosphamide/ ATG) further depleted CD4 and CD8 T cells and EBV-specifi c T-cell reactivity became undetectable ( fi gure 1 ). Post-HSCT, the patient developed undulant low-grade fevers. Two months post-HSCT she was admitted with fever and coughing. Within 48 h, pulmonary infi ltrations developed, and empiric antimicrobial therapy was initiated. Intriguingly, on the day of hospitalisation, CD8 (and to a lesser extent CD4) T-cell numbers had increased, and strong MHC I and, on this occasion also, MHC II-restricted EBV-specifi c T-cell responses could be elicited ( fi gure 1 ). Indicating immunological ineffi ciency of these responses, however, at the same time increasing EBV viral loads were detected in the blood ( fi gure 1 ), and viral DNA was also found in the bronchial fl uid. Ferritin levels reached greater than 65 000 ng/ml (normal values 10-200 ng/ml). Despite anti-CD20 monoclonal antibody therapy administered on day 4 of hospitalisation multi-organ failure developed, and 1 week after admission the patient died.On pathological examination diffuse alveolar damage and EBVassociated pneumonia were found ( fi gure 2A ). Mononucleosislike EBV-associated lymphoproliferation was observed involving the spleen, lymph nodes, kidneys, liver and basal ganglia. T-cell numbers in the lymph nodes were decreased ( fi gure 2B-D ). In-situ hybridisation identifi ed B-cell blasts expressing EBV-RNA in all of the above locations ( fi gure 2A and B ). No evidence of EBV infection of T cells or natural killer cells was fou...

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Epstein‐Barr Virus–Associated Hemophagocytic Lymphohistiocytosis in Adults Characterized by High Viral Genome Load within Circulating Natural Killer Cells

Cited by 53 publications

References 17 publications

PEG-aspargase and DEP regimen combination therapy for refractory Epstein–Barr virus-associated hemophagocytic lymphohistiocytosis

PEG-aspargase and DEP regimen combination therapy for refractory Epstein–Barr virus-associated hemophagocytic lymphohistiocytosis

EBV-associated T/NK–cell lymphoproliferative diseases in nonimmunocompromised hosts: prospective analysis of 108 cases

Minimal T-cell requirements for triggering haemophagocytosis associated with Epstein-Barr virus-driven B-cell proliferation: a clinical case study

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