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

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…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

View full text Add to dashboard Cite

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).

show abstract

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

View full text Add to dashboard Cite

show abstract

“…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

361

474

View full text Add to dashboard Cite

show abstract

“…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…”

mentioning

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

View full text Add to dashboard Cite

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...

show abstract

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

Contact Info

Product

Resources

About