Splenectomy Does Not Improve Survival in Chronic Active Epstein-Barr Virus Disease Patients

Splenectomy Does Not Improve Survival in Chronic Active Epstein-Barr Virus Disease Patients | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Splenectomy Does Not Improve Survival in Chronic Active Epstein-Barr Virus Disease Patients Junzhe Wang, Xiaodan He, Deli Song, Zhengyang Song, Lin Shi, Dongfei Yin, and 2 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7233329/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 11 Nov, 2025 Read the published version in Annals of Hematology → Version 1 posted 7 You are reading this latest preprint version Abstract Purpose We aimed to evaluate the clinical value of splenectomy as a treatment for Chronic active Epstein-Barr virus disease (CAEBVD). Methods We retrospectively reviewed the clinical data from clinical records of patients received splenectomy in our institution from October 1, 2014, to October 1, 2024. The splenectomy cohort (n = 16) was matched to non-splenectomy controls (n = 32) at a 1:2 ratio using propensity scores derived from gender, age, baseline EBV-DNA copies, whether with HLH, and whether received Allo-HSCT. A total of 48 CAEBVD patients were enrolled in this study. Results Splenectomy cannot minimize the EBV-DNA copies in peripheral blood. The median OS of patients who received splenectomy was 86 (95CI%: 0-183.402) months, while that of patients without splenectomy was 23 (95CI%: 0-99.468) months. There was no statistically significant difference between the two groups (P = 0.189). In the CAEBVD with HLH subgroup, there was no significant difference in survival times between patients with and without splenectomy (P = 0.423). A total of 18 patients received Allo-HSCT. The time to WBC and PLT engraftment between the non-splenectomy group and splenectomy group showed no significant difference (P = 0.788, P = 0.407). Conclusion Splenectomy demonstrated no significant benefit in reducing EBV copies and symptom relief, and suggests splenectomy fails to prolong patient survival supporting its limited role in CAEBVD management. Chronic active Epstein-Barr virus infection Splenectomy Outcome Figures Figure 1 Figure 2 Figure 3 Introduction Epstein-Barr virus (EBV), a member of the gamma-herpesvirus family, is a ubiquitous virus that infects over 90% of adults exhibiting latent infection 1 . EBV infection is linked to malignant tumors and lymphoproliferative diseases, such as B-lineage lymphoproliferative diseases or lymphomas. EBV initiates infection by engaging CD21 (CR2) and CD35 (CR1) complement receptors on B-cell membranes 2 , 3 . It is frequently asymptomatic, a self-limiting disease, or presents as infectious mononucleosis (IM)-like symptoms, including fever, swollen lymph nodes, and hepatosplenomegaly 4 . Chronic active Epstein-Barr virus disease (CAEBVD) is an EBV-associated lymphoproliferative disease (LPDs), in which EBV infects T and/or natural killer (NK) cells. Persistent or recurrent IM-like symptoms, high-level EBV-DNA copies in peripheral blood, and multi-organ involvement characterize it. However, the mechanism of EBV infection of T cells is still elusive. The recent study showed that CAEBVD originates from the infected HSCs, eventually involving multiple cell lineages 5 . CAEBVD is heterogeneous, some clinical courses may progress to hemophagocytic lymphohistiocytosis (HLH), leukaemia/lymphoma, or multiple organ failure. There are no standard regimens for CAEBVD; allogeneic hematopoietic stem cell transplantation (Allo-HSCT) is the only curative therapy 6 , 7 . Splenectomy is a useful diagnostic and therapeutic tool for haematological benign and malignant diseases. A diagnostic splenectomy may be required when there is a high suspicion of malignancy or when staging the disease 8 , 9 . As a major peripheral immune organ, the spleen plays an important role in the modulation of the immune system and the maintenance 10 . The role of the splenectomy in relapsed and refractory HLH of unknown etiology has been illustrated. However, it remains unclear whether splenectomy can reduce the risks of infection and bleeding by modulating immune function to improve blood parameters. Meanwhile, allo-HSCT remains the only potentially curative treatment for CAEBVD. The impact of massive splenomegaly on post-transplant survival and engraftment time also warrants attention. This paper aims to systematically evaluate the role of splenectomy in the treatment of CAEBVD, focusing on its potential benefits, limitations, and mechanisms of action. Presently, there are limited studies that specifically analyze the effects of splenectomy on the survival of CAEBVD patients. Therefore, in this retrospective study, we aimed to evaluate the impact of splenectomy on the diagnosis and therapeutic of CAEBVD patients. Methods Patients CAEBVD patients who had been treated with splenectomy in the Beijing Friendship Hospital department from October 1, 2014, to October 1, 2024, were enrolled in the study. Each patient who underwent splenectomy was individually matched with two control patients without splenectomy. The splenectomy cohort (n = 16) was matched to non-splenectomy controls (n = 32) at a 1:2 ratio derived from gender, age, baseline EBV-DNA load, whether with HLH, and to receive Allo-HSCT. There was no significant difference in baseline characteristics between the two groups (Table A1). A total of 48 patients with CAEBVD were included in the study. Among them, 16 patients underwent splenectomy, while 32 did not. Patients who had a splenectomy due to traumatic splenic rupture were excluded from this study. The study was conducted according to the guidelines of the Declaration of Helsinki and was approved by the Ethics Committee of the Beijing Friendship Hospital. Our Ethics Committee supported the informed consent exemption for this retrospective study. Diagnostic criteria CAEBVD was defined as: (1) Sustained or recurrent IM-like symptoms persist for more than 3 months; (2) Elevated EBV genome load in the peripheral blood (PB) or the tissue lesion; (3) EBV infection of T or NK cells in the affected tissues or the PB; (4) Exclusion of other possible diagnoses: primary infection of EBV (infectious mononucleosis), autoimmune diseases, congenital immunodeficiencies, HIV, and other immunodeficiencies requiring immunosuppressive therapies or underlying diseases with potential immunosuppression. Patients who fulfilled criteria (1–4) were diagnosed with CAEBVD. Statistical analysis The Mann-Whitney U test or independent sample T-test was used to compare continuous variables. χ 2 or the Fisher exact test was employed to compare categorical variables. Survival was estimated by the Kaplan-Meier method. The log-rank test was used to compare survival times. Values of p < 0.05 were statistically significant. Propensity score matching Propensity score matching was used to ensure a comparable sample between patients who received splenectomy and those who did not. The propensity score of each included patient was calculated. Covariates were selected based on prognostic indicators of OS and baseline differences between the 2 groups. We matched 2 non-splenectomy patients to 1 patient who received splenectomy using the nearest neighbor method with a caliper width of 0.02. Comparability of the groups after matching was assessed by inspection of the balance of baseline variables. After being matched, 16 patients in the splenectomy group and 32 patients in the non-splenectomy group were selected. Result Clinical features 16 CAEBVD patients who underwent splenectomy were enrolled in this study, consisting of 7 males and 9 females. The median age at disease onset was 22.5 (range 13–60) years. All patients were found to have enlarged spleens after abdominal ultrasound. The baseline data of the patients were summarized in Table 1 . Of the 11 patients who underwent PET-CT scans, 10 patients were found increased radioactivity distribution, and 1 patient had no detectable abnormality in radioactivity distribution. On the reasons for splenectomy in 16 patients, 3 patients had splenectomy as a complication of treatment for splenectomy, 8 patients received diagnostic splenectomy for cytopenia of unknown cause, and 5 for HLH of unknown cause. All 16 patients’ histopathologic results in the spleens, 10 of whom were diagnosed with EBV-TPLD, 5 cases were diagnosed as EBV-T/NKPLD, and the remaining 1 was diagnosed as EBV infection with spleen congestion. 15 patients EBER (+), 1 patient EBER (-). 13 patients with other tissue involvement, bone marrow involvement was present in 7 patients, lymph node in 6 patients, skin in 1 patient, and liver in 6 patients. Table 1 Baseline Clinical Characteristics of CAEBVD Patients Undergoing Splenectomy patients Gender Age F18-FDG PET/CT scan of spleen(SUV) Histopathology of spleen Spleen infiltration (EBER+) Other tissues 1 Female 21 2.7 EBV-TPLD + Lymphatic node 2 Female 32 - EBV-T/NKPLD + Lymphatic node; Liver 3 Female 22 - EBV infection, spleen congestion + BM; Skin; Liver 4 Female 33 8.1 EBV-TPLD with hemophagocytosis + No 5 Female 16 5.8 EBV-TPLD + Liver 6 Female 13 4.3 EBV-TPLD + Liver 7 Male 22 4.1 EBV-TPLD - BM; Lymphatic node 8 Male 28 - EBV-T/NKPLD with hemophagocytosis + Lymphatic node; Liver 9 Female 34 - EBV-T/NKPLD + BM 10 Female 23 2.5 EBV-TPLD + BM 11 Male 19 4.71 EBV-TPLD with hemophagocytosis + No 12 Female 17 4.5 EBV-TPLD + BM; Lymphatic node 13 Male 29 2.8 EBV-T/NKPLD + BM 14 Male 15 no detectable abnormality in radioactivity distribution EBV-TPLD with hemophagocytosis + Lymphatic node 15 Male 60 nonuniformly increased radioactivity distribution EBV-TPLD + No 16 Male 55 - EBV-T/NKPLD + BM; Liver BM: Bone marrow Table 2 Changes in Clinical Symptoms and Laboratory Parameters Before and After Splenectomy Patients Initial symptoms Symptoms after splenectomy Diagnosed with HLH Laboratory parameters before splenectomy Laboratory parameters after splenectomy 1 Fever Fever No Cytopenia Liver dysfunction 2 skin rash Skin rash；Fever No Cytopenia，Liver dysfunction，Increased serum LDH Anemia，Liver function abnormalities，Increased serum LDH 3 Subcutaneous sarcoidosis Subcutaneous sarcoidosis No Cytopenia，Liver dysfunction Liver dysfunction 4 Fever Fever No Cytopenia Elevated platelets 5 Asymptomatic Fever No Cytopenia，Coagulopathy Coagulopathy 6 Fever Fever Yes Cytopenia，hypofibrinogenemia，hyperferritinaemia，high concentrations of sCD25 Elevated platelets，hypofibrinogenemia 7 Fever Fever Yes Cytopenia，Liver dysfunction，Hyperferritinaemia；Hemophagocytosis in the BM，hyperferritinaemia Liver dysfunction，hyperferritinaemia，Hyperferritinaemia；Hemophagocytosis in the BM 8 Fever Fever Yes Cytopenia，Liver dysfunction Unknown 9 Fever Asymptomatic Yes Cytopenia，hyperferritinaemia，hypertriglyceridemia，Liver dysfunction，hyperferritinaemia Elevated platelets 10 Fever Asymptomatic No Cytopenia Elevated platelets 11 Fever Asymptomatic Yes Cytopenia，Liver dysfunction，hypofibrinogenemia，hyperferritinaemia，hypertriglyceridemia hypofibrinogenemia，hypertriglyceridemia 12 Fever Fever No Cytopenia Unknown 13 Fever Fever Yes Cytopenia，Liver dysfunction，hyperferritinaemia Unknown 14 Fever Skin rash；Fever Yes Cytopenia，Liver dysfunction，hyperferritinaemia，high concentrations of sCD25 Liver dysfunction 15 Fever Fever Yes Cytopenia no 16 Fever Fever Yes Cytopenia，hyperferritinaemia，hyperferritinaemia，high concentrations of sCD25，low NK cell activity Unknown Symptoms and Laboratory parameters post-splenectomy As shown in Table 2 , of the 9 patients with HLH, 5 patients were newly diagnosed with HLH, and 4 patients developed HLH after a clinical course of CAEBVD. Most patients (13/16) had fever initially, and 3 patients were in short-term remission after splenectomy. Furthermore, WBC (P = 0.005, Z= -2.803), PLT (P = 0.018, Z= -2.366) significantly increased after splenectomy. There were no statistically significant differences in terms of HB (P = 0.236, Z= -1.185), ALT (P = 0.180, Z= -1.342), and AST (P = 0.465, Z= -0.73). As demonstrated in Fig. 1, splenectomy cannot minimize the EBV-DNA copies in peripheral blood. In addition, 6 patients who received Allo-HSCT, 5 patients showed a downward trend in EBV-DNA copies and long-term conversion after transplantation, and 1 patient relapsed. (Fig. 2) Clinical Outcomes in CAEBVD Patients Following Splenectomy The median follow-up time lasted 21 months (1- 131 months). During the follow-up period, 25 patients (52.1%) died. Most patients died of disease exacerbation (11/48), 7 patients died of infection, 2 patients died of multiple organ failure, and 5 patients died of acute graft versus host disease (GVHD). The median OS of patients who received splenectomy was 86 (95CI%: 0-183.402) months, while that of patients without splenectomy was 23 (95CI%: 0-99.468) months. There was no statistically significant difference observed between the two groups (P = 0.189, Fig. 3 ). Furthermore, we analyzed the 27 CAEBVD patients with HLH. Of them, 9 cases had splenectomy. There was no significant difference in survival times between patients with and without splenectomy (P = 0.423). In the group of patients without HLH, there was no significant difference in survival times between patients with and without splenectomy (P = 0.284). Discussion CAEBVD is an EBV-associated T or NK cell lymphoproliferative disease. The clonal expansion of EBV-infected T or NK cells is thought to play a central role in the pathogenesis of CAEBVD 11 , 12 . Currently, there is no standard treatment for CAEBVD. Allo-HSCT is still the effective treatment for CAEBVD 6 , 7 . Antiviral therapy, immunomodulatory agents, and conventional chemotherapy struggle to maintain long-term efficacy 13 , 14 . Chemotherapy can reduce CAEBVD activity to some extent, but its effect is usually transient and the rate of CR is insufficient 11 , 13 . Several studies have reported the positive clinical benefits of programmed cell death receptor 1 (PD-1) inhibitors, JAK inhibitors in CAEBVD patients 15 – 17 . PD-1 inhibitors can restore the function of cytotoxic T cells by blocking the binding of PD-1 and its ligand PD-L1, thereby reviving the immune response against EBV and cancer cells 16 , 18 , 19 . Ruxolitinib is an effective and safe option in controlling the excessive inflammation of active CAEBVD, has a significant effect on controlling the body temperature of patients and also achieves stable remission and provides an opportunity for allo-HSCT 20 , 21 . In the present study, our results showed that splenectomy cannot decrease EBV-DNA copies. EBV infection stimulates immune cells to produce several cytokines 1 , a reasonable assumption is that splenectomy reduces inflammatory cytokine production to some extent, but does not eliminate EBV and EBV-infected cells. The etiology of CAEBVD is still elusive. In the previous study, CAEBVD preferentially originates from infected HSCs. It is further stated that transplantation is the curative therapy for CAEBVD 5 . WBC and PLT can transiently increase post-splenectomy. As CAEBVD actively progresses to HLH, patients will experience recurrent cytopenia. The spleen plays important hematological functions as a storage organ, collecting platelets from the circulation that can subsequently be stored or destroyed by lymphocytes 2 , 10 . Several studies reported that splenectomy may be an effective means of diagnosing and treating HLH of unknown cause 22 – 24 . However, the outcome of splenectomy is still unknown in the CAEBVD group. As demonstrated by Ma J et al. 23 , splenectomy had significantly improved OS and PFS in HLH patients of unknown origin. It indicated that splenectomy did not prolong the survival of HLH patients with a definite diagnosis. In our study, in the subgroup of CAEBVD patients with HLH, there was no significant difference in survival times between patients with and without splenectomy. However, this result is inconclusive, possibly due to the small number of patients enrolled in this study. In addition, in this cohort, all patients received splenectomy outside our hospital, and the safety could not be ensured. We found that the engraftment time of WBC (P = 0.788) and PLT (P = 0.407) showed no statistical differences between the splenectomy group and the non-splenectomy group. In the subgroup of CAEBVD that received Allo-HSCT, 4 patients experienced graft failure, three died of infection, and one died of GVHD. Primary diagnosis, HLA disparity between recipient and donor, low stem cell dose infusion, stem cell source, major ABO blood group incompatibility, DSA levels were reported the risk factors of graft failure 25 . Additionally, the spleen serves as a valid niche for human HSCs contributing to HSC homing and hematopoiesis following HSC transplantation 26 . Our study showed that splenectomy did not affect engraftment time, but we cannot confirm the relationship between splenectomy and graft failure. The spleen is the largest lymphoid organ in the human body, playing a crucial role in modulating the immune system 10 . Splenectomy can reduce the number of inflammatory cells and the production of inflammatory cytokines 27 , 28 . In CAEBVD patients, EBV infection leads to a relatively higher level of inflammation, and a significantly higher level of IFN-γ production was found in the infected cells 5 . JS Wang et al 27 . reported that the negative correlation between IFN-γ and disease condition in HLH patients, however there was no change in peripheral blood IFN-γ levels after splenectomy. The spleen is a lymphoid organ that is related to hemopoietic and immunity 29 . An enlarged spleen may act as a reservoir for malignant cells in some malignant hematologic tumors, potentially accelerating disease progression. Splenectomy serves not only in the diagnosis but also in reducing the tumor burden 30 . Several studies reported that splenectomy creates more chances for patients with an unknown origin of HLH 23 , 24 . However, the diagnostic and therapeutic role of splenectomy in patients with CAEBVD is unclear. In this cohort, 13 patients were EBV-DNA positive at initial diagnosis, and 13 patients were subsequently found to have other tissue and organ involvement. Most patients who underwent splenectomy in the presence of EBV-DNA positive peripheral blood. In total, 21 patients were diagnosed with splenic enlargement, and 11 of their spleens were smaller than before or even returned to standard size, and there were no positive effects of splenectomy on the clinical outcomes of CAEBVD patients. Our study concluded that this is unnecessary. CAEBVD should be suspected if the patient has recurrent IM-like symptoms such as fever, abnormal liver function, skin rash, enlarged liver, spleen, and lymph nodes, etc., accompanied by peripheral blood or tissue EBV copies positivity. It is necessary to consider the possibility of CAEBVD, and to improve the relevant examination 11 . Conclusion Splenectomy did not significantly reduce peripheral blood EBV-DNA load or relieve clinical symptoms. These findings suggest limited efficacy of splenectomy for both diagnostic and therapeutic purposes in CAEBVD patients. Declarations Supplementary Materials: Table S1: Baseline characteristics after propensity score matching; After PSM matching, there were no significant differences in gender, age, EBV-DNA load, whether with HLH, and whether received Allo-HSCT between the two groups. Author Contributions：ZW, JSW conceptualized the study, Junzhe Wang conducted the analyses and draft the manuscript; All authors contributed to interpreting the results and subsequent edits of the manuscript and had final responsibility for the decision to submit for publication. Funding Source：This study was supported by the National Natural Science Foundation of China (No. 82370185). Institutional Review Board Statement: The study was conducted according to the guidelines of the Declaration of Helsinki and was approved by the Ethics Committee of the Beijing Friendship Hospital. Our Ethics Committee supported the informed consent exemption for this retrospective study. Informed Consent Statement: Informed consent was obtained from all the subjects involved in the study. Data Availability Statement: The datasets generated and analyzed for this study are not publicly available as they contain information that could compromise participant privacy and consent but are available from the corresponding author on reasonable request to the extent allowed by data protection legislation. Conflicts of Interest: The authors declare no conflicts of interest. References Yao Y, Kong W, Yang L, Ding Y, Cui H. Immunity and Immune Evasion Mechanisms of Epstein–Barr Virus. Viral Immunol. 2023;36(5):303–317. Damania B, Kenney SC, Raab-Traub N. 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Masui H, Shindo M, Inoue Y, et al. Successful treatment of severe splenic lymphoma‑associated hemophagocytic syndrome by splenectomy and subsequent chemotherapy: A case report. Oncol. Lett. 2024;27(5):222. Additional Declarations No competing interests reported. Supplementary Files TableS1Baselinecharacteristicsafterpropensityscorematching.docx Supplementary Materials: Table S1: Baseline characteristics after propensity score matching; After PSM matching, there were no significant differences in gender, age, EBV-DNA load, whether with HLH, and whether received Allo-HSCT between the two groups. Cite Share Download PDF Status: Published Journal Publication published 11 Nov, 2025 Read the published version in Annals of Hematology → Version 1 posted Editorial decision: Revision requested 15 Sep, 2025 Reviews received at journal 08 Sep, 2025 Reviewers agreed at journal 19 Aug, 2025 Reviewers invited by journal 17 Aug, 2025 Editor assigned by journal 30 Jul, 2025 Submission checks completed at journal 30 Jul, 2025 First submitted to journal 28 Jul, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-7233329","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":502631261,"identity":"2b574c72-6b9c-48a7-9524-3c70fe24c6ea","order_by":0,"name":"Junzhe Wang","email":"","orcid":"","institution":"Beijing Friendship Hospital","correspondingAuthor":false,"prefix":"","firstName":"Junzhe","middleName":"","lastName":"Wang","suffix":""},{"id":502631262,"identity":"a5548f8a-dfe0-4691-9a3e-72c244398225","order_by":1,"name":"Xiaodan He","email":"","orcid":"","institution":"Beijing Friendship 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Wang","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA1klEQVRIiWNgGAWjYLACxgYGBn4kNpFaJBtI1mJwgFgtBsfPHn75c4ednPHxw0838zDYyG44wPzsAV4tZ/LSLCTPJBubnUkzu83DkGa84QCbuQE+LWYHcswMDNuYE7fd4GEDajmcuOEAD5sEXi3n35gZJLbVJ26eAdbynwgtN3KMHxxsAxouAdZygLAW+xtvzBgb244bSwD9cnOOQbLxzMNsZni1SPbnGH/82VYtx99++NmNNxV2sn3Hm5/h1QIEyM4ABRUzAfUgJR8IqxkFo2AUjIIRDQALfUtrJKA2mAAAAABJRU5ErkJggg==","orcid":"","institution":"Beijing Friendship Hospital","correspondingAuthor":true,"prefix":"","firstName":"Zhao","middleName":"","lastName":"Wang","suffix":""}],"badges":[],"createdAt":"2025-07-28 11:23:28","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-7233329/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-7233329/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1007/s00277-025-06725-z","type":"published","date":"2025-11-11T15:58:01+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":89981093,"identity":"c11980b6-7034-4557-94d4-d4e0538c36dd","added_by":"auto","created_at":"2025-08-27 06:24:13","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":125753,"visible":true,"origin":"","legend":"\u003cp\u003eEBV-DNA load before and after splenectomy\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-7233329/v1/de8d6a9f339885ff173c218b.png"},{"id":89981122,"identity":"409a9bfd-409d-4d88-8573-efc83ec2882f","added_by":"auto","created_at":"2025-08-27 06:24:16","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":349077,"visible":true,"origin":"","legend":"\u003cp\u003eEBV-DNA load trends relative to splenectomy and Allo-Hsct\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-7233329/v1/38d33a80f4764e3534d2b22f.png"},{"id":89981129,"identity":"9052da81-9afc-4879-97ca-3f204627dfab","added_by":"auto","created_at":"2025-08-27 06:24:17","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":42229,"visible":true,"origin":"","legend":"\u003cp\u003eSurvival times between patients with and without splenectomy\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-7233329/v1/f0c7024d83e7fbbac3ec9fab.png"},{"id":96105080,"identity":"d009830a-9ce7-4707-8bd6-b353e390b90c","added_by":"auto","created_at":"2025-11-17 16:08:20","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1106564,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7233329/v1/be9cdb8c-11f2-4d75-bc6d-9242076758fa.pdf"},{"id":89981110,"identity":"b4efa522-9e22-4cb3-b653-f936127c303d","added_by":"auto","created_at":"2025-08-27 06:24:16","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":16919,"visible":true,"origin":"","legend":"\u003cp\u003eSupplementary Materials: Table S1: Baseline characteristics after propensity score matching; After PSM matching, there were no significant differences in gender, age, EBV-DNA load, whether with HLH, and whether received Allo-HSCT between the two groups.\u003c/p\u003e","description":"","filename":"TableS1Baselinecharacteristicsafterpropensityscorematching.docx","url":"https://assets-eu.researchsquare.com/files/rs-7233329/v1/a2adc58a33cc02031a16559d.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Splenectomy Does Not Improve Survival in Chronic Active Epstein-Barr Virus Disease Patients","fulltext":[{"header":"Introduction","content":"\u003cp\u003eEpstein-Barr virus (EBV), a member of the gamma-herpesvirus family, is a ubiquitous virus that infects over 90% of adults exhibiting latent infection\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e. EBV infection is linked to malignant tumors and lymphoproliferative diseases, such as B-lineage lymphoproliferative diseases or lymphomas. EBV initiates infection by engaging CD21 (CR2) and CD35 (CR1) complement receptors on B-cell membranes\u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e,\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u003c/sup\u003e. It is frequently asymptomatic, a self-limiting disease, or presents as infectious mononucleosis (IM)-like symptoms, including fever, swollen lymph nodes, and hepatosplenomegaly\u003csup\u003e\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u003c/sup\u003e. Chronic active Epstein-Barr virus disease (CAEBVD) is an EBV-associated lymphoproliferative disease (LPDs), in which EBV infects T and/or natural killer (NK) cells. Persistent or recurrent IM-like symptoms, high-level EBV-DNA copies in peripheral blood, and multi-organ involvement characterize it. However, the mechanism of EBV infection of T cells is still elusive. The recent study showed that CAEBVD originates from the infected HSCs, eventually involving multiple cell lineages\u003csup\u003e\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u003c/sup\u003e. CAEBVD is heterogeneous, some clinical courses may progress to hemophagocytic lymphohistiocytosis (HLH), leukaemia/lymphoma, or multiple organ failure. There are no standard regimens for CAEBVD; allogeneic hematopoietic stem cell transplantation (Allo-HSCT) is the only curative therapy\u003csup\u003e\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e,\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e\u003cp\u003eSplenectomy is a useful diagnostic and therapeutic tool for haematological benign and malignant diseases. A diagnostic splenectomy may be required when there is a high suspicion of malignancy or when staging the disease\u003csup\u003e\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e,\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u003c/sup\u003e. As a major peripheral immune organ, the spleen plays an important role in the modulation of the immune system and the maintenance\u003csup\u003e\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u003c/sup\u003e. The role of the splenectomy in relapsed and refractory HLH of unknown etiology has been illustrated. However, it remains unclear whether splenectomy can reduce the risks of infection and bleeding by modulating immune function to improve blood parameters. Meanwhile, allo-HSCT remains the only potentially curative treatment for CAEBVD. The impact of massive splenomegaly on post-transplant survival and engraftment time also warrants attention. This paper aims to systematically evaluate the role of splenectomy in the treatment of CAEBVD, focusing on its potential benefits, limitations, and mechanisms of action. Presently, there are limited studies that specifically analyze the effects of splenectomy on the survival of CAEBVD patients. Therefore, in this retrospective study, we aimed to evaluate the impact of splenectomy on the diagnosis and therapeutic of CAEBVD patients.\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003ePatients\u003c/p\u003e\u003cp\u003eCAEBVD patients who had been treated with splenectomy in the Beijing Friendship Hospital department from October 1, 2014, to October 1, 2024, were enrolled in the study. Each patient who underwent splenectomy was individually matched with two control patients without splenectomy. The splenectomy cohort (n = 16) was matched to non-splenectomy controls (n = 32) at a 1:2 ratio derived from gender, age, baseline EBV-DNA load, whether with HLH, and to receive Allo-HSCT. There was no significant difference in baseline characteristics between the two groups (Table A1). A total of 48 patients with CAEBVD were included in the study. Among them, 16 patients underwent splenectomy, while 32 did not. Patients who had a splenectomy due to traumatic splenic rupture were excluded from this study. The study was conducted according to the guidelines of the Declaration of Helsinki and was approved by the Ethics Committee of the Beijing Friendship Hospital. Our Ethics Committee supported the informed consent exemption for this retrospective study.\u003c/p\u003e\u003cp\u003eDiagnostic criteria\u003c/p\u003e\u003cp\u003eCAEBVD was defined as: (1) Sustained or recurrent IM-like symptoms persist for more than 3 months; (2) Elevated EBV genome load in the peripheral blood (PB) or the tissue lesion; (3) EBV infection of T or NK cells in the affected tissues or the PB; (4) Exclusion of other possible diagnoses: primary infection of EBV (infectious mononucleosis), autoimmune diseases, congenital immunodeficiencies, HIV, and other immunodeficiencies requiring immunosuppressive therapies or underlying diseases with potential immunosuppression. Patients who fulfilled criteria (1–4) were diagnosed with CAEBVD.\u003c/p\u003e\u003ch2\u003eStatistical analysis\u003c/h2\u003e\u003cp\u003eThe Mann-Whitney U test or independent sample T-test was used to compare continuous variables. χ\u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u003c/sup\u003e or the Fisher exact test was employed to compare categorical variables. Survival was estimated by the Kaplan-Meier method. The log-rank test was used to compare survival times. Values of p \u0026lt; 0.05 were statistically significant.\u003c/p\u003e\u003cp\u003ePropensity score matching\u003c/p\u003e\u003cp\u003ePropensity score matching was used to ensure a comparable sample between patients who received splenectomy and those who did not. The propensity score of each included patient was calculated. Covariates were selected based on prognostic indicators of OS and baseline differences between the 2 groups. We matched 2 non-splenectomy patients to 1 patient who received splenectomy using the nearest neighbor method with a caliper width of 0.02. Comparability of the groups after matching was assessed by inspection of the balance of baseline variables. After being matched, 16 patients in the splenectomy group and 32 patients in the non-splenectomy group were selected.\u003c/p\u003e"},{"header":"Result","content":"\u003cp\u003eClinical features\u003c/p\u003e\n\u003cp\u003e16 CAEBVD patients who underwent splenectomy were enrolled in this study, consisting of 7 males and 9 females. The median age at disease onset was 22.5 (range 13\u0026ndash;60) years. All patients were found to have enlarged spleens after abdominal ultrasound. The baseline data of the patients were summarized in Table \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e. Of the 11 patients who underwent PET-CT scans, 10 patients were found increased radioactivity distribution, and 1 patient had no detectable abnormality in radioactivity distribution. On the reasons for splenectomy in 16 patients, 3 patients had splenectomy as a complication of treatment for splenectomy, 8 patients received diagnostic splenectomy for cytopenia of unknown cause, and 5 for HLH of unknown cause. All 16 patients\u0026rsquo; histopathologic results in the spleens, 10 of whom were diagnosed with EBV-TPLD, 5 cases were diagnosed as EBV-T/NKPLD, and the remaining 1 was diagnosed as EBV infection with spleen congestion. 15 patients EBER (+), 1 patient EBER (-). 13 patients with other tissue involvement, bone marrow involvement was present in 7 patients, lymph node in 6 patients, skin in 1 patient, and liver in 6 patients.\u003c/p\u003e\n\u003ctable id=\"Tab1\" border=\"1\" class=\"fr-table-selection-hover\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003eBaseline Clinical Characteristics of CAEBVD Patients Undergoing Splenectomy\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003epatients\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eGender\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eAge\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003eF18-FDG PET/CT scan of \u0026nbsp;spleen(SUV)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eHistopathology\u0026nbsp;of\u0026nbsp;spleen\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eSpleen\u0026nbsp;infiltration\u0026nbsp;(EBER+)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eOther tissues\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eFemale\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e21\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2.7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003eEBV-TPLD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e+\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eLymphatic\u0026nbsp;node\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eFemale\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e32\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003eEBV-T/NKPLD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e+\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eLymphatic\u0026nbsp;node; Liver\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eFemale\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e22\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003eEBV infection, spleen congestion\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e+\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eBM; Skin; Liver\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eFemale\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e33\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e8.1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003eEBV-TPLD\u0026nbsp;with\u0026nbsp;hemophagocytosis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e+\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eFemale\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e16\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e5.8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003eEBV-TPLD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e+\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eLiver\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eFemale\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e13\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e4.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003eEBV-TPLD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e+\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eLiver\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMale\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e22\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e4.1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003eEBV-TPLD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eBM; Lymphatic\u0026nbsp;node\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMale\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e28\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003eEBV-T/NKPLD\u0026nbsp;with\u0026nbsp;hemophagocytosis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e+\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eLymphatic\u0026nbsp;node; Liver\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eFemale\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e34\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003eEBV-T/NKPLD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e+\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eBM\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eFemale\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e23\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003eEBV-TPLD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e+\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eBM\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e11\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMale\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e19\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e4.71\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003eEBV-TPLD\u0026nbsp;with\u0026nbsp;hemophagocytosis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e+\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e12\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eFemale\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e17\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e4.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003eEBV-TPLD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e+\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eBM; Lymphatic\u0026nbsp;node\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e13\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMale\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e29\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2.8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003eEBV-T/NKPLD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e+\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eBM\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e14\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMale\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e15\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eno detectable abnormality in radioactivity \u0026nbsp;distribution\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003eEBV-TPLD\u0026nbsp;with\u0026nbsp;hemophagocytosis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e+\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eLymphatic\u0026nbsp;node\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e15\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMale\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e60\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003enonuniformly increased \u0026nbsp;radioactivity distribution\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003eEBV-TPLD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e+\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e16\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMale\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e55\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003eEBV-T/NKPLD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e+\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eBM; Liver\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colspan=\"8\"\u003e\n \u003cp\u003eBM: Bone marrow\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\n\n\u003cbr\u003e\n\n\n\n\n\n\n\n\n\n\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"661\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"6\" style=\"width: 100%;\"\u003e\n \u003cp\u003eTable 2 Changes in Clinical Symptoms and Laboratory Parameters Before and After Splenectomy\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 6.5053%;\"\u003e\n \u003cp\u003ePatients\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 12.8593%;\"\u003e\n \u003cp\u003eInitial symptoms\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14.3722%;\"\u003e\n \u003cp\u003eSymptoms\u0026nbsp;after\u0026nbsp;splenectomy\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9.98487%;\"\u003e\n \u003cp\u003eDiagnosed\u0026nbsp;with\u0026nbsp;HLH\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 31.4675%;\"\u003e\n \u003cp\u003eLaboratory parameters before \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;splenectomy\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 24.8109%;\"\u003e\n \u003cp\u003eLaboratory parameters after \u0026nbsp; splenectomy\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 6.5053%;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 12.8593%;\"\u003e\n \u003cp\u003eFever\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14.3722%;\"\u003e\n \u003cp\u003eFever\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9.98487%;\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 31.4675%;\"\u003e\n \u003cp\u003eCytopenia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 24.8109%;\"\u003e\n \u003cp\u003eLiver\u0026nbsp;dysfunction\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 6.5053%;\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 12.8593%;\"\u003e\n \u003cp\u003eskin\u0026nbsp;rash\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14.3722%;\"\u003e\n \u003cp\u003eSkin\u0026nbsp;rash；Fever\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9.98487%;\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 31.4675%;\"\u003e\n \u003cp\u003eCytopenia，Liver\u0026nbsp;dysfunction，Increased\u0026nbsp;serum\u0026nbsp;LDH\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 24.8109%;\"\u003e\n \u003cp\u003eAnemia，Liver\u0026nbsp;function\u0026nbsp;abnormalities，Increased\u0026nbsp;serum\u0026nbsp;LDH\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 6.5053%;\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 12.8593%;\"\u003e\n \u003cp\u003eSubcutaneous\u0026nbsp;sarcoidosis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14.3722%;\"\u003e\n \u003cp\u003eSubcutaneous sarcoidosis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9.98487%;\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 31.4675%;\"\u003e\n \u003cp\u003eCytopenia，Liver\u0026nbsp;dysfunction\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 24.8109%;\"\u003e\n \u003cp\u003eLiver\u0026nbsp;dysfunction\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 6.5053%;\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 12.8593%;\"\u003e\n \u003cp\u003eFever\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14.3722%;\"\u003e\n \u003cp\u003eFever\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9.98487%;\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 31.4675%;\"\u003e\n \u003cp\u003eCytopenia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 24.8109%;\"\u003e\n \u003cp\u003eElevated\u0026nbsp;platelets\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 6.5053%;\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 12.8593%;\"\u003e\n \u003cp\u003eAsymptomatic\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14.3722%;\"\u003e\n \u003cp\u003eFever\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9.98487%;\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 31.4675%;\"\u003e\n \u003cp\u003eCytopenia，Coagulopathy\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 24.8109%;\"\u003e\n \u003cp\u003eCoagulopathy\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 6.5053%;\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 12.8593%;\"\u003e\n \u003cp\u003eFever\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14.3722%;\"\u003e\n \u003cp\u003eFever\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9.98487%;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 31.4675%;\"\u003e\n \u003cp\u003eCytopenia，hypofibrinogenemia，hyperferritinaemia，high\u0026nbsp;concentrations\u0026nbsp;of\u0026nbsp;sCD25\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 24.8109%;\"\u003e\n \u003cp\u003eElevated\u0026nbsp;platelets，hypofibrinogenemia\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 6.5053%;\"\u003e\n \u003cp\u003e7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 12.8593%;\"\u003e\n \u003cp\u003eFever\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14.3722%;\"\u003e\n \u003cp\u003eFever\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9.98487%;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 31.4675%;\"\u003e\n \u003cp\u003eCytopenia，Liver\u0026nbsp;dysfunction，Hyperferritinaemia；Hemophagocytosis\u0026nbsp;in\u0026nbsp;the\u0026nbsp;BM，hyperferritinaemia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 24.8109%;\"\u003e\n \u003cp\u003eLiver\u0026nbsp;dysfunction，hyperferritinaemia，Hyperferritinaemia；Hemophagocytosis\u0026nbsp;in\u0026nbsp;the\u0026nbsp;BM\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 6.5053%;\"\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 12.8593%;\"\u003e\n \u003cp\u003eFever\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14.3722%;\"\u003e\n \u003cp\u003eFever\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9.98487%;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 31.4675%;\"\u003e\n \u003cp\u003eCytopenia，Liver\u0026nbsp;dysfunction\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 24.8109%;\"\u003e\n \u003cp\u003eUnknown\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 6.5053%;\"\u003e\n \u003cp\u003e9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 12.8593%;\"\u003e\n \u003cp\u003eFever\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14.3722%;\"\u003e\n \u003cp\u003eAsymptomatic\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9.98487%;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 31.4675%;\"\u003e\n \u003cp\u003eCytopenia，hyperferritinaemia，hypertriglyceridemia，Liver\u0026nbsp;dysfunction，hyperferritinaemia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 24.8109%;\"\u003e\n \u003cp\u003eElevated\u0026nbsp;platelets\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 6.5053%;\"\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 12.8593%;\"\u003e\n \u003cp\u003eFever\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14.3722%;\"\u003e\n \u003cp\u003eAsymptomatic\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9.98487%;\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 31.4675%;\"\u003e\n \u003cp\u003eCytopenia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 24.8109%;\"\u003e\n \u003cp\u003eElevated\u0026nbsp;platelets\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 6.5053%;\"\u003e\n \u003cp\u003e11\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 12.8593%;\"\u003e\n \u003cp\u003eFever\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14.3722%;\"\u003e\n \u003cp\u003eAsymptomatic\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9.98487%;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 31.4675%;\"\u003e\n \u003cp\u003eCytopenia，Liver\u0026nbsp;dysfunction，hypofibrinogenemia，hyperferritinaemia，hypertriglyceridemia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 24.8109%;\"\u003e\n \u003cp\u003ehypofibrinogenemia，hypertriglyceridemia\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 6.5053%;\"\u003e\n \u003cp\u003e12\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 12.8593%;\"\u003e\n \u003cp\u003eFever\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14.3722%;\"\u003e\n \u003cp\u003eFever\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9.98487%;\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 31.4675%;\"\u003e\n \u003cp\u003eCytopenia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 24.8109%;\"\u003e\n \u003cp\u003eUnknown\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 6.5053%;\"\u003e\n \u003cp\u003e13\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 12.8593%;\"\u003e\n \u003cp\u003eFever\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14.3722%;\"\u003e\n \u003cp\u003eFever\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9.98487%;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 31.4675%;\"\u003e\n \u003cp\u003eCytopenia，Liver\u0026nbsp;dysfunction，hyperferritinaemia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 24.8109%;\"\u003e\n \u003cp\u003eUnknown\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 6.5053%;\"\u003e\n \u003cp\u003e14\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 12.8593%;\"\u003e\n \u003cp\u003eFever\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14.3722%;\"\u003e\n \u003cp\u003eSkin\u0026nbsp;rash；Fever\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9.98487%;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 31.4675%;\"\u003e\n \u003cp\u003eCytopenia，Liver\u0026nbsp;dysfunction，hyperferritinaemia，high\u0026nbsp;concentrations\u0026nbsp;of\u0026nbsp;sCD25\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 24.8109%;\"\u003e\n \u003cp\u003eLiver\u0026nbsp;dysfunction\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 6.5053%;\"\u003e\n \u003cp\u003e15\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 12.8593%;\"\u003e\n \u003cp\u003eFever\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14.3722%;\"\u003e\n \u003cp\u003eFever\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9.98487%;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 31.4675%;\"\u003e\n \u003cp\u003eCytopenia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 24.8109%;\"\u003e\n \u003cp\u003eno\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 6.5053%;\"\u003e\n \u003cp\u003e16\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 12.8593%;\"\u003e\n \u003cp\u003eFever\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14.3722%;\"\u003e\n \u003cp\u003eFever\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9.98487%;\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 31.4675%;\"\u003e\n \u003cp\u003eCytopenia，hyperferritinaemia，hyperferritinaemia，high\u0026nbsp;concentrations\u0026nbsp;of\u0026nbsp;sCD25，low\u0026nbsp;NK\u0026nbsp;cell\u0026nbsp;activity\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 24.8109%;\"\u003e\n \u003cp\u003eUnknown\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eSymptoms and Laboratory parameters post-splenectomy\u003c/p\u003e\n\u003cp\u003eAs shown in Table \u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e, of the 9 patients with HLH, 5 patients were newly diagnosed with HLH, and 4 patients developed HLH after a clinical course of CAEBVD. Most patients (13/16) had fever initially, and 3 patients were in short-term remission after splenectomy. Furthermore, WBC (P\u0026thinsp;=\u0026thinsp;0.005, Z= -2.803), PLT (P\u0026thinsp;=\u0026thinsp;0.018, Z= -2.366) significantly increased after splenectomy. There were no statistically significant differences in terms of HB (P\u0026thinsp;=\u0026thinsp;0.236, Z= -1.185), ALT (P\u0026thinsp;=\u0026thinsp;0.180, Z= -1.342), and AST (P\u0026thinsp;=\u0026thinsp;0.465, Z= -0.73). As demonstrated in Fig. 1, splenectomy cannot minimize the EBV-DNA copies in peripheral blood. In addition, 6 patients who received Allo-HSCT, 5 patients showed a downward trend in EBV-DNA copies and long-term conversion after transplantation, and 1 patient relapsed. (Fig. 2)\u003c/p\u003e\n\u003cp\u003eClinical Outcomes in CAEBVD Patients Following Splenectomy\u003c/p\u003e\n\u003cp\u003eThe median follow-up time lasted 21 months (1- 131 months). During the follow-up period, 25 patients (52.1%) died. Most patients died of disease exacerbation (11/48), 7 patients died of infection, 2 patients died of multiple organ failure, and 5 patients died of acute graft versus host disease (GVHD). The median OS of patients who received splenectomy was 86 (95CI%: 0-183.402) months, while that of patients without splenectomy was 23 (95CI%: 0-99.468) months. There was no statistically significant difference observed between the two groups (P\u0026thinsp;=\u0026thinsp;0.189, Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003e). Furthermore, we analyzed the 27 CAEBVD patients with HLH. Of them, 9 cases had splenectomy. There was no significant difference in survival times between patients with and without splenectomy (P\u0026thinsp;=\u0026thinsp;0.423). In the group of patients without HLH, there was no significant difference in survival times between patients with and without splenectomy (P\u0026thinsp;=\u0026thinsp;0.284).\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eCAEBVD is an EBV-associated T or NK cell lymphoproliferative disease. The clonal expansion of EBV-infected T or NK cells is thought to play a central role in the pathogenesis of CAEBVD\u003csup\u003e\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e,\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u003c/sup\u003e. Currently, there is no standard treatment for CAEBVD. Allo-HSCT is still the effective treatment for CAEBVD\u003csup\u003e\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e,\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u003c/sup\u003e. Antiviral therapy, immunomodulatory agents, and conventional chemotherapy struggle to maintain long-term efficacy\u003csup\u003e\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e,\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u003c/sup\u003e. Chemotherapy can reduce CAEBVD activity to some extent, but its effect is usually transient and the rate of CR is insufficient\u003csup\u003e\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e,\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u003c/sup\u003e. Several studies have reported the positive clinical benefits of programmed cell death receptor 1 (PD-1) inhibitors, JAK inhibitors in CAEBVD patients\u003csup\u003e\u003cspan additionalcitationids=\"CR16\" citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u003c/sup\u003e. PD-1 inhibitors can restore the function of cytotoxic T cells by blocking the binding of PD-1 and its ligand PD-L1, thereby reviving the immune response against EBV and cancer cells\u003csup\u003e\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e,\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e,\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e\u003c/sup\u003e. Ruxolitinib is an effective and safe option in controlling the excessive inflammation of active CAEBVD, has a significant effect on controlling the body temperature of patients and also achieves stable remission and provides an opportunity for allo-HSCT \u003csup\u003e\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e,\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e\u003cp\u003eIn the present study, our results showed that splenectomy cannot decrease EBV-DNA copies. EBV infection stimulates immune cells to produce several cytokines\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e, a reasonable assumption is that splenectomy reduces inflammatory cytokine production to some extent, but does not eliminate EBV and EBV-infected cells. The etiology of CAEBVD is still elusive. In the previous study, CAEBVD preferentially originates from infected HSCs. It is further stated that transplantation is the curative therapy for CAEBVD\u003csup\u003e\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u003c/sup\u003e. WBC and PLT can transiently increase post-splenectomy. As CAEBVD actively progresses to HLH, patients will experience recurrent cytopenia. The spleen plays important hematological functions as a storage organ, collecting platelets from the circulation that can subsequently be stored or destroyed by lymphocytes\u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e,\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e\u003cp\u003eSeveral studies reported that splenectomy may be an effective means of diagnosing and treating HLH of unknown cause\u003csup\u003e\u003cspan additionalcitationids=\"CR23\" citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e\u003c/sup\u003e. However, the outcome of splenectomy is still unknown in the CAEBVD group. As demonstrated by Ma J et al.\u003csup\u003e\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e\u003c/sup\u003e, splenectomy had significantly improved OS and PFS in HLH patients of unknown origin. It indicated that splenectomy did not prolong the survival of HLH patients with a definite diagnosis. In our study, in the subgroup of CAEBVD patients with HLH, there was no significant difference in survival times between patients with and without splenectomy. However, this result is inconclusive, possibly due to the small number of patients enrolled in this study. In addition, in this cohort, all patients received splenectomy outside our hospital, and the safety could not be ensured.\u003c/p\u003e\u003cp\u003eWe found that the engraftment time of WBC (P\u0026thinsp;=\u0026thinsp;0.788) and PLT (P\u0026thinsp;=\u0026thinsp;0.407) showed no statistical differences between the splenectomy group and the non-splenectomy group. In the subgroup of CAEBVD that received Allo-HSCT, 4 patients experienced graft failure, three died of infection, and one died of GVHD. Primary diagnosis, HLA disparity between recipient and donor, low stem cell dose infusion, stem cell source, major ABO blood group incompatibility, DSA levels were reported the risk factors of graft failure\u003csup\u003e\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e\u003c/sup\u003e. Additionally, the spleen serves as a valid niche for human HSCs contributing to HSC homing and hematopoiesis following HSC transplantation\u003csup\u003e\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e\u003c/sup\u003e. Our study showed that splenectomy did not affect engraftment time, but we cannot confirm the relationship between splenectomy and graft failure.\u003c/p\u003e\u003cp\u003eThe spleen is the largest lymphoid organ in the human body, playing a crucial role in modulating the immune system\u003csup\u003e\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u003c/sup\u003e. Splenectomy can reduce the number of inflammatory cells and the production of inflammatory cytokines \u003csup\u003e\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e,\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e\u003c/sup\u003e. In CAEBVD patients, EBV infection leads to a relatively higher level of inflammation, and a significantly higher level of IFN-γ production was found in the infected cells\u003csup\u003e\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u003c/sup\u003e. JS Wang et al\u003csup\u003e\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e\u003c/sup\u003e. reported that the negative correlation between IFN-γ and disease condition in HLH patients, however there was no change in peripheral blood IFN-γ levels after splenectomy.\u003c/p\u003e\u003cp\u003eThe spleen is a lymphoid organ that is related to hemopoietic and immunity\u003csup\u003e\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e\u003c/sup\u003e. An enlarged spleen may act as a reservoir for malignant cells in some malignant hematologic tumors, potentially accelerating disease progression. Splenectomy serves not only in the diagnosis but also in reducing the tumor burden\u003csup\u003e\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e\u003c/sup\u003e. Several studies reported that splenectomy creates more chances for patients with an unknown origin of HLH\u003csup\u003e\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e,\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e\u003c/sup\u003e. However, the diagnostic and therapeutic role of splenectomy in patients with CAEBVD is unclear. In this cohort, 13 patients were EBV-DNA positive at initial diagnosis, and 13 patients were subsequently found to have other tissue and organ involvement. Most patients who underwent splenectomy in the presence of EBV-DNA positive peripheral blood. In total, 21 patients were diagnosed with splenic enlargement, and 11 of their spleens were smaller than before or even returned to standard size, and there were no positive effects of splenectomy on the clinical outcomes of CAEBVD patients. Our study concluded that this is unnecessary. CAEBVD should be suspected if the patient has recurrent IM-like symptoms such as fever, abnormal liver function, skin rash, enlarged liver, spleen, and lymph nodes, etc., accompanied by peripheral blood or tissue EBV copies positivity. It is necessary to consider the possibility of CAEBVD, and to improve the relevant examination\u003csup\u003e\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eSplenectomy did not significantly reduce peripheral blood EBV-DNA load or relieve clinical symptoms. These findings suggest limited efficacy of splenectomy for both diagnostic and therapeutic purposes in CAEBVD patients.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003eSupplementary Materials: Table S1: Baseline characteristics after propensity score matching; After PSM matching, there were no significant differences in gender, age, EBV-DNA load, whether with HLH, and whether received Allo-HSCT between the two groups. \u003c/p\u003e\n\n\u003cp\u003eAuthor Contributions：ZW, JSW conceptualized the study, Junzhe Wang conducted the analyses and draft the manuscript; All authors contributed to interpreting the results and subsequent edits of the manuscript and had final responsibility for the decision to submit for publication.\u003c/p\u003e\n\n\u003cp\u003eFunding Source：This study was supported by the National Natural Science Foundation of China (No. 82370185). \u003c/p\u003e\n\n\u003cp\u003eInstitutional Review Board Statement: The study was conducted according to the guidelines of the Declaration of Helsinki and was approved by the Ethics Committee of the Beijing Friendship Hospital. Our Ethics Committee supported the informed consent exemption for this retrospective study.\u003c/p\u003e\n\n\u003cp\u003eInformed Consent Statement: Informed consent was obtained from all the subjects involved in the study. \u003c/p\u003e\n\n\u003cp\u003eData Availability Statement: The datasets generated and analyzed for this study are not publicly available as they contain information that could compromise participant privacy and consent but are available from the corresponding author on reasonable request to the extent allowed by data protection legislation.\u003c/p\u003e\n\n\u003cp\u003eConflicts of Interest: The authors declare no conflicts of interest.\u003c/p\u003e\n\n\n"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eYao Y, Kong W, Yang L, Ding Y, Cui H. 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Haematol.\u003c/em\u003e 2021;194(3):638\u0026ndash;642. \u003c/li\u003e\n\u003cli\u003eMa J, Jiang Z, Ding T, et al. Splenectomy as a diagnostic method in lymphoma-associated hemophagocytic lymphohistiocytosis of unknown origin. \u003cem\u003eBlood Cancer J.\u003c/em\u003e 2017;7(2):e534\u0026ndash;e534. \u003c/li\u003e\n\u003cli\u003eJing-Shi W, Yi-Ni W, Lin W, Zhao W. Splenectomy as a treatment for adults with relapsed hemophagocytic lymphohistiocytosis of unknown cause. \u003cem\u003eAnn. Hematol.\u003c/em\u003e 2015;94(5):753\u0026ndash;760. \u003c/li\u003e\n\u003cli\u003eOzdemir ZN, Civriz Bozdağ S. Graft failure after allogeneic hematopoietic stem cell transplantation. \u003cem\u003eTransfus. Apher. Sci.\u003c/em\u003e 2018;57(2):163\u0026ndash;167. \u003c/li\u003e\n\u003cli\u003eBedel A. Spleen route accelerates engraftment of human hematopoietic stem cells. 2021; \u003c/li\u003e\n\u003cli\u003eWang J, Han W, Gao Z, et al. 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Lett.\u003c/em\u003e 2024;27(5):222. \u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"annals-of-hematology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"aohe","sideBox":"Learn more about [Annals of Hematology](http://link.springer.com/journal/277)","snPcode":"277","submissionUrl":"https://submission.nature.com/new-submission/277/3","title":"Annals of Hematology","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"Chronic active Epstein-Barr virus infection, Splenectomy, Outcome","lastPublishedDoi":"10.21203/rs.3.rs-7233329/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7233329/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003ePurpose\u003c/h2\u003e\u003cp\u003eWe aimed to evaluate the clinical value of splenectomy as a treatment for Chronic active Epstein-Barr virus disease (CAEBVD).\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e\u003cp\u003e We retrospectively reviewed the clinical data from clinical records of patients received splenectomy in our institution from October 1, 2014, to October 1, 2024. The splenectomy cohort (n\u0026thinsp;=\u0026thinsp;16) was matched to non-splenectomy controls (n\u0026thinsp;=\u0026thinsp;32) at a 1:2 ratio using propensity scores derived from gender, age, baseline EBV-DNA copies, whether with HLH, and whether received Allo-HSCT. A total of 48 CAEBVD patients were enrolled in this study.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e\u003cp\u003eSplenectomy cannot minimize the EBV-DNA copies in peripheral blood. The median OS of patients who received splenectomy was 86 (95CI%: 0-183.402) months, while that of patients without splenectomy was 23 (95CI%: 0-99.468) months. There was no statistically significant difference between the two groups (P\u0026thinsp;=\u0026thinsp;0.189). In the CAEBVD with HLH subgroup, there was no significant difference in survival times between patients with and without splenectomy (P\u0026thinsp;=\u0026thinsp;0.423). A total of 18 patients received Allo-HSCT. The time to WBC and PLT engraftment between the non-splenectomy group and splenectomy group showed no significant difference (P\u0026thinsp;=\u0026thinsp;0.788, P\u0026thinsp;=\u0026thinsp;0.407).\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e\u003cp\u003eSplenectomy demonstrated no significant benefit in reducing EBV copies and symptom relief, and suggests splenectomy fails to prolong patient survival supporting its limited role in CAEBVD management.\u003c/p\u003e","manuscriptTitle":"Splenectomy Does Not Improve Survival in Chronic Active Epstein-Barr Virus Disease Patients","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-08-27 06:23:33","doi":"10.21203/rs.3.rs-7233329/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2025-09-15T14:27:05+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-09-08T13:53:30+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"184996729255138084944276007506800218834","date":"2025-08-19T14:29:55+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-08-17T14:00:04+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-07-30T06:58:24+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-07-30T06:57:47+00:00","index":"","fulltext":""},{"type":"submitted","content":"Annals of Hematology","date":"2025-07-28T11:17:42+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"annals-of-hematology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"aohe","sideBox":"Learn more about [Annals of Hematology](http://link.springer.com/journal/277)","snPcode":"277","submissionUrl":"https://submission.nature.com/new-submission/277/3","title":"Annals of Hematology","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"b212f839-baa3-479f-9f70-036fb10211d1","owner":[],"postedDate":"August 27th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2025-11-17T16:02:24+00:00","versionOfRecord":{"articleIdentity":"rs-7233329","link":"https://doi.org/10.1007/s00277-025-06725-z","journal":{"identity":"annals-of-hematology","isVorOnly":false,"title":"Annals of Hematology"},"publishedOn":"2025-11-11 15:58:01","publishedOnDateReadable":"November 11th, 2025"},"versionCreatedAt":"2025-08-27 06:23:33","video":"","vorDoi":"10.1007/s00277-025-06725-z","vorDoiUrl":"https://doi.org/10.1007/s00277-025-06725-z","workflowStages":[]},"version":"v1","identity":"rs-7233329","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7233329","identity":"rs-7233329","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}