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Chronic active Epstein-Barr virus infection (CAEBV) is a prototype of EBV-associated T- and/or NK-cell (EBV+ T/NK-cell) lymphoproliferative disorders. Most subtypes of these are lethal. We established a unified treatment strategy composed of step 1 (immunochemotherapy: steroids, cyclosporine A, and etoposide), step 2 (multi-drug block chemotherapy)...
Context in source publication
Context 1
... current classification of EBV-associated T-and/or NK- cell (EBV + T/NK-cell) lymphoproliferative disorders (5, 6) and their requirement for HSCT are listed in Table 1. The treatment is the same between CAEBV and its related diseases, i.e., hypersensitivity to mosquito bites (HMB) and severe-type hydroa vacciniforme (sHV). ...
Citations
... Based on a composite reference standard that relies on the type of LPDs, its stage and clinical presentation, and patients' characteristics (especially age and comorbidities), these diseases are managed by taking advantage of several treatment options, including chemotherapy, immunotherapy, bone marrow transplant, and external beam radiation therapy as single agents or combined [6][7][8][9]. Since the stage at diagnosis is one of the main prognostic factors in most LPDs, precocious diagnosis has a significant impact on treatment and recovery procedures. ...
Background/Objectives: We conducted a comprehensive investigation to explore the pathological expression of the CXCR4 receptor in lymphoproliferative disorders (LPDs) using [⁶⁸Ga]Ga-Pentixafor PET/CT or PET/MRI technology. The PICO question was as follows: What is the diagnostic role (outcome) of [⁶⁸Ga]Ga-Pentixafor PET (intervention) in patients with LPDs (problem/population)? Methods: The study was written based on the reporting items for systematic reviews and meta-analyses (PRISMA) 2020 guidelines, and it was registered on the prospective register of systematic reviews (PROSPERO) website (CRD42024506866). A comprehensive computer literature search of Scopus, MEDLINE, Scholar, and Embase databases was conducted, including articles indexed up to February 2024. To the methodological evaluation of the studies used the quality assessment of diagnosis accuracy studies-2 (QUADAS-2) tool. Results: Of the 8380 records discovered, 23 were suitable for systematic review. Fifteen studies (on 571 LPD patients) focused on diagnosis and staging, and eight trials (194 LPD patients) assessed treatment response. Conclusions: The main conclusions that can be inferred from the published studies are as follows: (a) [⁶⁸Ga]Ga-Pentixafor PET may have excellent diagnostic performance in the study of several LPDs; (b) [⁶⁸Ga]Ga-Pentixafor PET may be superior to [¹⁸F]FDG or complementary in some LPDs variants and settings; (c) multiple myeloma seems to have a high uptake of [⁶⁸Ga]Ga-Pentixafor. Overall, this technique is probably suitable for imaging, staging, and follow-up on patients with LPD. Due to limited data, further studies are warranted to confirm the promising role of [⁶⁸Ga]Ga-Pantixafor in this context.
... Within this context, there are two subsets of lymphocytes: T cell and B cell disorders. Various genetic mutations have been identified as potential contributors to LPD, which can either be iatrogenic (resulting from medical intervention) or acquired (7)(8)(9). ...
Introduction: Lymphocytosis is characterized by an elevation in the absolute lymphocyte count (ALC) to over 4000 lymphocytes per microliter among adults. In lymphocytosis, the important matter is whether lymphocytosis is a benign reactive condition or a neoplastic lymphoproliferative disorder (LPD), which can be determined by immunophenotyping methods by flow cytometry. Objectives: Due to the need to use flow cytometry to confirm the diagnosis of patients with lymphocytosis, the purpose of this study was to compare the frequency of benign reactive lymphocytosis and LPDs in patients with persistent lymphocytosis using flow cytometry in the peripheral blood and report the results based on the patient’s demographic characteristics. Materials and Methods: This study was a cross-sectional study and the study population was all peripheral blood samples referred to Seyed Al-Shohada hospital in Isfahan to study the cause of absolute and persistent lymphocytosis by immunophenotyping analysis through flow cytometry between 2015 and 2020. Inclusion criteria were patients over 18 years of age with absolute lymphocytosis in complete blood count (CBC) or peripheral blood smear (PBS) who were examined by flow cytometry. Results: This study involved 222 samples, 139 (62.6%) of the cases were male. The mean age was 60.41 (15.91) years. All samples had absolute lymphocytosis and were divided into two groups: benign, with 62 (27.9%), and malignant, with 160 (72.1%). Conclusion: The relationship between gender and malignancy showed that the male gender was associated with an increased risk of malignancy. The mean age between the two groups of malignant and benign was determined by independent t test, and it was shown that the mean (±standard deviation) age of malignant cases is higher than the mean age of benign cases. It is recommended that cases of suspected lymphoproliferative cases and cases with cell counts below the lymphocytosis threshold be investigated in separate studies.
... 14 The only curative treatment for severe HV-LPD and the broader category of disease, CAEBV, has been HSCT. 18,19 Unfortunately, death as a result of relapse or sequela of CAEBV may occur post-HSCT. 10 Therapies that have demonstrated some benefit or temporary remission include multiagent chemotherapy, radiotherapy, immunomodulators, anti-inflammatory agents including corticosteroids, antiviral agents, and allogeneic EBV-specific cytotoxic T-lymphocytes. ...
Key Clinical Message
Hydroa vacciniforme‐like lymphoproliferative disorder (HV‐LPD) is a rare cutaneous form of chronic active Epstein–Barr virus (CAEBV) that presents with vesicular lesions induced by sun‐exposure. Arterial aneurysm is a rare but potentially fatal complication of CAEBV and HV‐LPD.
... Thus, we believe that surgery appears to be an important part of the treatment algorithm for severe GI CAEBV. Based on the three-step (cooling, cytoreduction, and reconstruction) treatment strategy for CAEBV proposed by Swada et al. [25], surgery could be integrated into the "cooling" after the patient's condition was improved by HLH-2004 like chemotherapy. Nevertheless, the timing of surgical intervention and the necessity of preventative resection of large intestinal tumor masses or intestinal segments with large ulcers before chemotherapy have yet to be elucidated. ...
Chronic active EBV infection (CAEBV) is a lymphoproliferative disorder of T- or NK-cell type in Asian countries. CAEBV involving the gastrointestinal tract (GI CAEBV) is a rare condition with poor prognosis that may rapidly progress with hemophagocytic lymphohistiocytosis (HLH) and life-threatening complications such as GI bleeding and/or perforation. The approach to CAEBV with GI tract involvement (GI CAEBV) is still an unmet clinical need. In this case series study, we summarized the clinical features, treatment, and prognosis of seven cases of GI CAEBV with HLH, particularly focusing on its prognosis and the possible salvage therapy combining surgery, novel therapeutic agents, and/or autologous(auto-) hematopoietic stem cell transplantation (HSCT) based on successful cases from our center. GI CAEBV is often misdiagnosed as inflammatory bowel diseases and certain infections. The key to its early recognition is the integrative consideration of its systemic manifestation, serum virology, endoscopic, and imaging findings along with pathology. Surgical intervention should not be hesitated when life-threatening GI complications occur. Resection of the involved bowel segment is an effective way of controlling bleeding and reducing tumor burden. In addition to upfront allogeneic HSCT, new therapeutic modalities including PD-1 antibody and auto-HSCT may be effective in certain patients.
... The clinical manifestations are mainly persistent IM-like symptoms, including fever, interstitial pneumonia, persistent lymphadenopathy, splenomegaly and impaired liver function [3]. In the absence of treatment, this progressive disease develops with severe complications, such as opportunistic infections, multi-organ failure, hemophagocytic lymphohistiocytosis (HLH) and lymphoma [4,5] and has a high mortality rate. Kimura et al. reported that 35 (42.7%) out of 82 CAEBV patients died within 5 months to 12 years after onset of CAEBV [6]. ...
Background
Chronic active Epstein-Barr virus infection (CAEBV) is a rare but life-threatening progressive disease. Human leukocyte antigen (HLA)-haploidentical hematopoietic stem cell transplantation (haplo-HSCT) is the best choice as sometimes HLA-matched donor is not accessible. However, graft-versus-host-disease (GVHD) following transplantation remains a major cause of treatment failure and elevated mortality. Post-transplant cyclophosphamide (PTCy) has recently emerged for effective GVHD prophylaxis in a haploidentical setting in many hematologic malignancies. Here, we report the performance of PTCy for GVHD prophylaxis in a series of CEABV patients treated with haplo-HSCT.
Methods
Consecutive pediatric CAEBV patients who were treated with haplo-HSCT and give PTCy for GVHD prophylaxis were analyzed. 1-year GVHD and relapse-free survival (GRFS), overall survival (OS) and cumulative incidence of moderate-to-severe chronic GVHD (cGVHD) were estimated.
Results
A total of 8 patients ranging from 2 to 15 years old were included. Among them, 4 patients had early complications after haplo-HSCT. Counts of T-cell subsets increased within 6 months post transplantation, indicating an immune reconstitution. Only 1 patient developed grade II acute GVHD, and 2 patients had moderate cGVHD. One patient died from diffuse alveolar hemorrhage within the first year after transplantation. The 1-year GRFS rate, OS rate and cumulative incidence of moderate-to-severe cGVHD were 62.5%, 87.5% and 25.0%, respectively.
Conclusion
Our findings suggest that, among CAEBV patients treated with haplo-HSCT, PTCy may be an alternative choice for the prevention of GVHD.
... ± 4.9% vs. 54.5% ± 15.0%, P = 0.016), but there was no significant difference in the 3-year EFS (85.0% ± 8.0% vs. 54.5% ± 15.0%, P = 0.239); however, the median time from onset to treatment was shorter in the RIC-HSCT group (14.5 months) than the MAC-HSCT group (3 years), which may have conferred a survival advantage to the RIC-HSCT group. 25 Gotoh et al. 26 reported that the MAC-HSCT group had a higher incidence of transplant-related mortality (3/5) than the RIC-HSCT group (1/10), but the RIC-HSCT group had a higher recurrence rate than the MAC-HSCT group (30% vs. 11%). We used a modified MAC regimen. ...
Importance:
Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is considered the only effective treatment for chronic active Epstein-Barr virus infection (CAEBV). The clinical efficacy and safety of allo-HSCT with different conditioning regimens in children with CAEBV remain unclear.
Objective:
To evaluate the effectiveness and safety of allo-HSCT with the modified myeloablative conditioning (MAC) regimen for children with CAEBV and also the factors affecting the outcomes.
Methods:
We retrospectively analyzed children with CAEBV who underwent allo-HSCT with the modified MAC regimen at Beijing Children's Hospital, Capital Medical University from October 2016 to June 2021. Data related to the clinical manifestations, engraftment, and outcome were extracted from the medical records.
Results:
The cohort comprised 41 patients (24 males, 17 females) with a median transplantation age of 92.6 (60.4, 120.7) months and a median follow-up time of 28.2 (15.3, 40.2) months. Four patients (9.8%) died, among which three died from primary disease relapse, and one died from grade IV acute graft-versus-host diseases (aGVHD) after stopping treatment. The 3-year overall survival (OS) and 3-year event-free survival (EFS) rates were 88.8% ± 5.4% and 85.0% ± 5.7%, respectively. The 3-year OS and EFS did not significantly differ between the patients with hemophagocytic lymphohistiocytosis (HLH) and the patient without HLH (87.7% ± 6.8% vs. 91.7% ± 8.0%, P = 0.790; 85.0% ± 6.9% vs. 84.6% ± 10.0%, P = 0.921), or among the patients with complete remission, partial remission, and activity disease before HSCT (all P > 0.05). Multivariate analysis showed that grade III-IV aGVHD was a risk factor for mortality (Hazards ratio: 11.65, 95% confidence interval: 1.00, 136.06; P = 0.050).
Interpretation:
Allo-HSCT with the modified MAC regimen is safe and effective for pediatric CAEBV. This treatment benefits patients with HLH or active disease. Patients with Grade III-IV aGVHD may be associated with worse outcomes.
... e treatment strategy of HLH is divided into two main aspects: the shortterm strategy is mainly to control the excessive inflammatory state, and the long-term strategy is to correct the potential immune deficiency and control the primary disease, which means that the potential etiology of HLH strongly affects the prognosis of HLH, and the prognosis of tumor-related HLH is the worst [11]. e results of two famous clinical studies on HLH, HLH-94 and HLH-2004, as well as other clinical observation studies on different types of HLH, believe that allo-HSCT is the only means to overcome the impact of primary diseases on the long-term survival of HLH patients and improve the overall survival rate [12][13][14]. However, a large sample of clinical studies also found that in the group of patients who did not receive allo-HSCT, the death rate of 2/3 was mainly concentrated in the first 8 weeks of the induction treatment period after diagnosis, especially in patients who died in 6-8 weeks because of refractory disease progression and organ failure, while the peak of death of 1/3 was concentrated in those who had not received allo-HSCT 120 days after diagnosis [5]. ...
Background:
The mortality risks for secondary hemophagocytic lymphohistiocytosis in the induction stage and investigated prognostic factors need to be further discussed.
Objective:
The aim of this study is to establish a clinical model for predicting early death in adult patients with secondary hemophagocytic lymphohistiocytosis. Design, Participants, and Main Measures. The baseline characteristics, laboratory examination results, and 8-week survival rate of 139 adult sHLH patients diagnosed from January 2018 to December 2018 were analyzed retrospectively, and a prognostic model was constructed with low-risk (score 0-2), medium-risk (score 3), and high-risk (score ≥ 4) as parameters. Key Results. Univariate analysis confirmed that early death was not related to the type of HLH but significantly related to the patient's response to first-line treatment. The peripheral blood cell count was significantly decreased, C-reactive protein was higher, glutamyl transpeptidase and total bilirubin were higher, albumin was significantly lower, urea nitrogen was higher, hypocalcemia and hyponatremia, deep organ hemorrhage and D-dimer increased, cardiac function damage and HLH central involvement, sCD25 increased, and EB virus infection were predictive factors of early death. In the multivariate model, patients' response to first-line treatment was a good predictor of overall survival, and hypocalcemia and deep organ bleeding were associated with poor survival. The risk factors were scored and graded according to the risk ratio. The 8-week overall survival rates of the low-risk group (82 cases), medium-risk group (36 cases), and high-risk group (21 cases) were 85.4%, 52.8%, and 23.8%, respectively (P < 0.001).
Conclusions:
The early death of sHLH patients is closely related to some laboratory examination results. Attention should be paid to identify high-risk patients, choose effective first-line induction therapy, achieve deep remission as soon as possible, prevent deep organ bleeding, correct electrolyte disorders, and improve the early survival rate of sHLH patients.
... It is worth noting that unlike most patients with CAEBV infection who require HSCT for a definitive cure, a significant proportion of patients with T cell-EBV-HLH can remain in remission without proceeding to HSCT. This finding that a proportion of patients with T cell-EBV-HLH can do well without needing HSCT aligns with similar findings by Sawada and Inoue [14] in Japanese patients. The biological basis for the difference in long-term management of T cell-EBV-HLH and CAEBV infection is still poorly understood. ...
Purpose
T cell-Epstein-Barr virus–associated hemophagocytic lymphohistiocytosis (T cell-EBV-HLH) is prevalent in East Asia and has poor prognosis. Understanding of this disease is limited, and literature regarding prevalence in North America is scarce. Herein, we summarize our experience.
Methods
A retrospective analysis of T cell-EBV-HLH patients admitted to Children’s Healthcare of Atlanta (GA, USA) from 2010 to 2020 was conducted. Additional immune studies were completed in a subset of patients.
Results
We report 15 patients (10 months–19 years of age) diagnosed with T cell-EBV-HLH. Nine patients were Hispanic, and the majority did not have primary HLH (p-HLH) gene defects. Soluble interleukin-2 receptor levels in T cell-EBV-HLH were significantly higher than other forms of secondary-HLH but comparable to p-HLH, and it correlated with disease severity at presentation. Natural killer cell function was decreased in most patients despite a negative workup for p-HLH. Depending on disease severity, initial therapy included dexamethasone or dexamethasone and etoposide. Refractory patients were managed with blended regimens that included one or more of the following therapies: combination chemotherapy, alemtuzumab, emapalumab, and nivolumab. Rituximab did not appreciably decrease EBV viremia in most patients. Non-critically ill patients responded well to immunosuppressive therapy and are long-term survivors without undergoing allogeneic hematopoietic stem cell transplantation (HSCT). Alemtuzumab resulted in inflammation flare in two of the three patients. Three patients underwent allogeneic HSCT, with disease relapse noted in one. At a median follow-up of 3 years, 10 of the 15 patients are alive.
Conclusion
T cell-EBV-HLH occurs in the USA among the non-Asian populations, especially in those who are Hispanic.
... 6,42 Expert guidelines from Osaka, Japan advocate for consolidation therapy with multi-agent chemotherapy, typically with cyclophosphamide, hydroxydaunorubicin (Adriamycin), vincristine (Oncovin), prednisone (CHOP)like regimens, prior to alloHSCT. 48,49 The expressed goals of this multi-agent cytoreduction phase are to reduce risk of pretransplant disease progression, allograft rejection, and post-transplant relapse. Other expert guidelines discuss additional immunomodulatory and EBV-specific targeted therapy. ...
... Although beyond the scope of the present article, review papers discussing therapeutic strategies in alloHSCT, post-transplant complications that can mimic HLH, and diagnostic/therapeutic considerations for potential disease flares and/or EBV-reactivation have been recently published. 48,49 International multi-centre collaboration will be required to provide definitive evidence-based guidelines for this rare disease. ...
... However, we recognise that several international groups still utilise cyclosporine based on historic success using it for patients with EBV-HLH and/or CAEBV. 48,49 Consolidation with alloHSCT is generally pursued for patients with familial HLH and those with systemic CAEBV, and the combination of multi-agent chemotherapy followed by alloHSCT offers the only curative option for patients with EBV + T-NHL and ANKL. The nuances of therapy for patients with persistent or refractory CAEBV and/or relapsed/refractory HLH remain undefined, and this issue represents a major challenge. ...
Epstein–Barr virus (EBV) is a ubiquitous herpesvirus with rare but severe potential for lymphoproliferative complications. EBV is associated with a variety of presentations of haemophagocytic lymphohistiocytosis (HLH). HLH is a life‐threatening hyperinflammatory syndrome that can occur in patients with genetic defects associated with dysregulation of the immune response (familial HLH) or arise in patients with underlying infection or malignancy (non‐familial or secondary HLH). EBV can both serve as the incidental trigger of familial HLH or as the driving factor in patients with selective inherited vulnerability (e.g. X‐linked lymphoproliferative disease). Alternatively, acute infection can idiosyncratically cause non‐neoplastic HLH in patients without inherited predisposition (i.e. secondary HLH), while EBV‐associated T/natural killer (NK)‐cell lymphoproliferative disorders and lymphomas can cause neoplasia‐associated HLH. The present review will discern between EBV‐associated familial and non‐familial HLH and highlight diagnostic and therapeutic considerations. Non‐familial EBV‐associated HLH is a major diagnostic dilemma, as it represents a diverse spectrum of disease ranging from highly curable (non‐neoplastic EBV‐HLH) to indolent but incurable (chronic active EBV) to acutely fatal (systemic EBV‐positive T‐cell lymphoma of childhood). Increased clinical awareness and understanding of this rare and potentially devastating subset of EBV‐related complications is desperately needed to improve survival for patients with neoplasia‐associated HLH.
... This T cell-associated EBV-HLH (T cell-EBV-HLH) has predominantly been described in patients of East-Asian origin, mainly from Japan and China [8][9][10][11][12]. The clinical course in the majority of these patients is usually fulminant, warrants urgent treatment and in several cases allogeneic hematopoietic stem cell transplantation (HSCT) [13,14]. Reports of T cell-EBV-HLH phenotype among non-Asians are scarce [15]. ...
... It is worth noting that unlike most patients with CAEBV who require HSCT for a de nitive cure, a signi cant proportion of patients with T cell-EBV-HLH can remain in remission without proceeding to HSCT. The nding that a proportion of patients with T cell-EBV-HLH can do well without needing HSCT aligns with similar ndings by Sawada et al. in Japanese patients [14]. The biological basis for the difference in long-term management of T-cell EBV HLH and CAEBV is still poorly understood. ...
Purpose
T cell-Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis (T cell-EBV-HLH) is prevalent in East Asia and has poor prognosis. Understanding of this disease is limited and literature regarding prevalence in North America is scarce. Herein, we summarize our experience.
Methods
A retrospective analysis of T cell-EBV-HLH patients admitted to Children's Healthcare of Atlanta (GA, USA) from 2010-2020 was conducted. Additional immune studies were completed in a subset of patients.
Results
We report 15 patients (10 months-19 years of age) diagnosed with T cell-EBV-HLH. Nine patients were Hispanic and the majority without primary HLH (p-HLH) gene defects. Soluble interleukin-2 receptor levels in T cell-EBV-HLH were significantly higher than other forms of secondary-HLH but comparable to p-HLH, and it correlated with disease severity at presentation. Natural-Killer cell function was decreased in most patients despite a negative workup for p-HLH. Depending on disease severity, initial therapy included dexamethasone or dexamethasone and etoposide. Refractory patients were managed with blended regimens that included one or more of these therapies - combination chemotherapy, alemtuzumab, emapalumab and nivolumab. Rituximab did not appreciably decrease EBV viremia in most patients. Alemtuzumab resulted in inflammation flare in 2 of the 3 patients. Two patients underwent allogeneic hematopoietic cell transplantation, with disease relapse noted in one. At a median follow-up of 3 years, 10 of the 15 patients are alive.
Conclusion
T cell-EBV-HLH occurs in the US among the non-Asian population, especially in those who are Hispanic. The amplitude of T cell activation noted in T cell-EBV-HLH is comparable to p-HLH.
