The effectiveness of the doxorubicin-etoposide-methylprednisolone regimen for adult HLH secondary to rheumatic disease.

To investigate the efficacy of the doxorubicin-etoposide-methylprednisolone, DEP) regimen as an effective treatment for adult Hemophagocytic Lymphohistiocytosis secondary to rheumatic disease and analyze prognosis in these patients. Fifty-eight adult patients diagnosed with Hemophagocytic Lymphohistiocytosis secondary to rheumatic disease admitted to Beijing Friendship Hospital from 1st Jan. 2018 to 31st Dec. 2022 were retrospectively included in this study. Patients were grouped according to previous treatment. Clinical data and laboratory characteristics of patients were retrospectively analyzed. The efficacy was evaluated every 2 weeks after initiating the first course of the DEP regimen and until the last inpatient or 31st Dec. 2023. 26 patients were included in Group A and 32 patients were included in Group B due to the previous treatment. After the first course of the DEP regimen, the overall response rate of all patients was 82.8%, with 13.8% in complete response and 69% in partial response. There was no significant statistical objective response rate between the two groups after the DEP regimen, except at 2-week. Serum ferritin, sCD25, ALT, AST, and DBIL concentrations were significantly lower at 2, 4 and 6-week than pre-treatment (P < 0.05). The overall mortality rate is 20.7% (12/58). Importantly, advanced age, initial level of HB and PLT, and central nervous system (CNS) involvement were independent poor risk factors affecting OS in bivariate analysis. The DEP regimen is effective for adult HLH secondary rheumatic disease with a high overall rate and accepted side effects.

Haemophagocytic lymphohistiocytosis caused by GATA2 deficiency: a report on three patients.

BACKGROUND: Haemophagocytic lymphohistiocytosis (HLH) is a syndrome that occurs in patients with severe systemic hyperinflammation. GATA binding protein 2 (GATA2) is a transcription factor and key component in haematopoiesis and stem cell biology. CASE PRESENTATION: Three patients with HLH, one with Mycobacterium avium infection, one with Epstein-Barr virus (EBV) infection, and one with Mycobacterium kansasii infection, were all subsequently found to have a defect in the GATA2 gene through genetic testing. CONCLUSIONS: GATA2 deficiency syndrome should be considered in patients with myelodysplastic syndrome, nontuberculous mycobacterium infection and HLH. In addition, the GATA2 gene variant may be a genetic defect that could be the cause of the primary HLH. However, further studies are needed to confirm the role of GATA2 pathogenic variants in the pathogenesis of HLH.

PD-1 Blockade-Induced Hemophagocytic Lymphohistiocytosis, a Dilemma Therapeutic Outcome in 2 Patients with CAEBV: A Case Series.

Hemophagocytic lymphohistiocytosis (HLH), whether primary or secondary, is a rare and fatal clinical syndrome of uncontrolled immune activation and inflammatory cascade. Immune checkpoint inhibitors (ICIs) induced HLH has no standard diagnostic and treatment guidelines. Early diagnosis and appropriate treatment according to different disease backgrounds are crucial. Herein, we first report 2 cases of patients with chronic active Epstein-Barr virus infection (CAEBV) who developed HLH after the use of sintilimab, a monoclonal antibody against programmed cell death protein 1 (PD-1), and the DEP (liposomal doxorubicin, etoposide, methylprednisolone) chemotherapy regimen in combination with ruxolitinib were used to successfully control the disease.

Chronic active Epstein-Barr virus disease originates from infected hematopoietic stem cells.

ABSTRACT: Chronic active Epstein-Barr virus (EBV) disease (CAEBV) is a lethal syndrome because of persistent EBV infection. When diagnosed as CAEBV, EBV infection was observed in multiple hematopoietic lineages, but the etiology of CAEBV is still elusive. Bone marrow and peripheral cells derived from 5 patients with CAEBV, 1 patient with EBV-associated hemophagocytic lymphohistiocytosis, and 2 healthy controls were analyzed. Multiple assays were applied to identify and characterize EBV-infected cells, including quantitative polymerase chain reaction, PrimeFlow, and single-cell RNA-sequencing (scRNA-seq). Based on scRNA-seq data, alterations in gene expression of particular cell types were analyzed between patients with CAEBV and controls, and between infected and uninfected cells. One patient with CAEBV was treated with allogeneic hematopoietic stem cell transplantation (HSCT), and the samples derived from this patient were analyzed again 6 months after HSCT. EBV infected the full spectrum of the hematopoietic system including both lymphoid and myeloid lineages, as well as the hematopoietic stem cells (HSCs) of the patients with CAEBV. EBV-infected HSCs exhibited a higher differentiation rate toward downstream lineages, and the EBV infection had an impact on both the innate and adaptive immunity, resulting in inflammatory symptoms. EBV-infected cells were thoroughly removed from the hematopoietic system after HSCT. Taken together, multiple lines of evidence presented in this study suggest that CAEBV disease originates from the infected HSCs, which might potentially lead to innovative therapy strategies for CAEBV.

Prognostic scoring system for pediatric Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis based on baseline characteristics: A multicenter retrospective study.

BACKGROUND: The prognosis of pediatric Epstein-Barr virus (EBV)-associated hemophagocytic lymphohistiocytosis (EBV-HLH) varies. This study aimed to identify high-risk children early. PROCEDURE: Data from 264 children (0-14 years of age), diagnosed with EBV-HLH at six centers in China between January 2016 and December 2021, were analyzed. Patients were randomly divided into derivation (n = 185) and verification (n = 79) cohorts. A Cox regression model was used to explore risk predictors and establish a prognostic scoring system for death events that occurred during the follow-up period. RESULTS: Chronic active EBV infection (CAEBV) history (hazard ratio [HR] 1.82 [95% confidence interval, CI: 1.02-3.26]; p = .0441), plasma EBV-DNA more than 104  copies/mL (HR 2.89 [95% CI: 1.62-5.16]; p = .0003), pulmonary infection (HR 2.24 [95% CI: 1.06-4.75]; p = .0353), digestive tract hemorrhage (HR 2.55 [95% CI: 1.35-4.82]; p = .0041), and hypoxemia (HR 3.95 [95% CI: 2.15-7.26]; p < .0001) were independent risk factors. Accordingly, the CAEBV history, plasma EBV-DNA copy number, pulmonary infection hemorrhage of digestive tract, hypoxemia prognostic scoring system (CEPHO-PSS) were developed, which separated patients into low- (0-1 points), middle- (2-3 points), and high- (4-8 points) risk groups. Survival curves for the three groups exhibited statistically significant differences (p < .0001). Internal and external verification of CEPHO-PSS was performed using receiver operating characteristic (ROC) and calibration curves in the derivation and verification cohorts, respectively, confirming good accuracy and applicability. CONCLUSIONS: The CEPHO-PSS identified three risk groups with statistically significant differences in survival curves. It was based on the baseline characteristics, and can give clinicians a convenient check for risk prediction.

Case Report: HAVCR2 mutation-associated Hemophagocytic lymphohistiocytosis.

Germline HAVCR2 mutation has been reported to be associated with subcutaneous panniculitis-like T-cell lymphoma (SPTCL) leading to Hemophagocytic lymphohistiocytosis (HLH). Several studies have indicated that HAVCR2 mutation can cause HLH even in the absence of lymphoma, though the exact mechanism remains unclear. In this article, we reported five cases of HAVCR2 mutation-associated HLH. Our analysis revealed an elevated level of IL-1RA in the serum of these patients. Furthermore, we investigated the potential mechanisms underlying HLH associated with HAVCR2 mutation based on changes in cytokine levels. Our findings suggest that HAVCR2 mutation may represent a distinct genetic defect underlying HLH, differing from traditional primary HLH.

PDIA4 Is a Host Factor Important for Lymphocytic Choriomeningitis Virus Infection.

Mammalian arenaviruses are rodent-borne zoonotic viruses, some of which can cause fatal hemorrhagic diseases in humans. The first discovered arenavirus, lymphocytic choriomeningitis virus (LCMV), has a worldwide distribution and can be fatal for transplant recipients. However, no FDA-approved drugs or vaccines are currently available. In this study, using a quantitative proteomic analysis, we identified a variety of host factors that could be needed for LCMV infection, among which we found that protein disulfide isomerase A4 (PDIA4), a downstream factor of endoplasmic reticulum stress (ERS), is important for LCMV infection. Biochemical analysis revealed that LCMV glycoprotein was the main viral component accounting for PDIA4 upregulation. The inhibition of ATF6-mediated ERS could prevent the upregulation of PDIA4 that was stimulated by LCMV infection. We further found that PDIA4 can affect the LCMV viral RNA synthesis processes and release. In summary, we conclude that PDIA4 could be a new target for antiviral drugs against LCMV.

Development and evaluation clinical-radiomics analysis based on T1-weighted imaging for diagnosing neonatal acute bilirubin encephalopathy.

Purpose: To investigate the value of clinical-radiomics analysis based on T1-weighted imaging (T1WI) for predicting acute bilirubin encephalopathy (ABE) in neonates. Methods: In this retrospective study, sixty-one neonates with clinically confirmed ABE and 50 healthy control neonates were recruited between October 2014 and March 2019. Two radiologists' visual diagnoses for all subjects were independently based on T1WI. Eleven clinical and 216 radiomics features were obtained and analyzed. Seventy percent of samples were randomly selected as the training group and were used to establish a clinical-radiomics model to predict ABE; the remaining samples were used to validate the performance of the models. The discrimination performance was assessed by receiver operating characteristic (ROC) curve analysis. Results: Seventy-eight neonates were selected for training (median age, 9 days; interquartile range, 7-20 days; 49 males) and 33 neonates for validation (median age, 10 days; interquartile range, 6-13 days; 24 males). Two clinical features and ten radiomics features were finally selected to construct the clinical-radiomics model. In the training group, the area under the ROC curve (AUC) was 0.90 (sensitivity: 0.814; specificity: 0.914); in the validation group, the AUC was 0.93 (sensitivity: 0.944; specificity: 0.800). The AUCs of two radiologists' and the radiologists' final visual diagnosis results based on T1WI were 0.57, 0.63, and 0.66, respectively. The discriminative performance of the clinical-radiomics model in the training and validation groups was increased compared to the radiologists' visual diagnosis (P < 0.001). Conclusions: A combined clinical-radiomics model based on T1WI has the potential to predict ABE. The application of the nomogram could potentially provide a visualized and precise clinical support tool.

PD-1 blockade and lenalidomide combination therapy for chronic active Epstein-Barr virus infection.

OBJECTIVES: Chronic active Epstein-Barr virus infection (CAEBV) is a prototype of EBV-associated T-or NK-cell lymphoproliferative diseases. It is a disease with poor outcome. Almost all current therapies are ineffective except of allogeneic hematopoietic stem cell transplantation. METHODS: We investigated the efficacy and safety of programmed death 1 (PD-1) blockade (Sintilimab), combined with lenalidomide, which is an immunomodulatory drug, in an open-label, single-center, prospective study involving CAEBV patients. PD1 blockade 2mg/kg was given every two weeks by intravenous infusion on day 1, and lenalidomide 5mg (age<18 years)/10mg (age ≥ 18 years) was given orally once a day on day 1-14. RESULTS: As of Nov 15, 2020, 34 patients were enrolled. As of the Feb 1, 2021 analysis cut-off date, 24 cases completed at least 3 courses and were assessed for efficacy. The overall response rate is 54.2% (13/24, 45.8% complete response; 8.3% partial response). EBV-DNA copies in PBMC decreased significantly (p = 0.002). The proportion of CD8+T cells in lymphocytes increased (p = 0.007). The comparative analysis between response group and non-response group showed the proportion of Effector Memory CD8+ T cells and cytokines of CTLs activation (IFN-γ, CD27, CD30, MIG, IP-10) increased significantly in Response-group after treatment. Whole-exome sequencing generated from peripheral blood and saliva samples reveal that Non-Response group had a higher somatic mutational load of copy number variation in background. With a median follow-up time of 17.8 months, 22 of 24 patients were alive with an estimated survival probability of 91.3% at 1 year. All 34 patients were assessed for safety evaluation. The possible drug-related adverse events were reported in 17 (50%) patients. CONCLUSIONS: PD-1 blockade combined with lenalidomide was an effective and safe therapy for CAEBV patients. The significant therapeutic effect and the different characteristics between response and non-response group, provides a possible predictive value for CAEBV treatment option.

Modified DEP regimen as induction therapy for lymphoma-associated hemophagocytic lymphohistiocytosis: a prospective, multicenter study.

PURPOSE: Hemophagocytic lymphohistiocytosis (HLH), especially lymphoma-associated HLH (LA-HLH), is a refractory immune disorder with high mortality. There is still no consensus regarding the ideal treatment for LA-HLH. METHODS: We performed a prospective multicenter study (NCT04077905) to explore the efficacy of a modified DEP regimen as induction therapy for LA-HLH. Twenty-eight patients from 6 clinical centers in China were enrolled between September 2019 and July 2021. We evaluated the efficacy of the modified DEP induction therapy 4 weeks after the initiation of treatment. RESULTS: The results showed that the overall response rate was 89.3% (25/28 patients), whereby 28.6% (8/28 patients) achieved a complete response and 60.7% (17/28 patients) were in partial response. Ferritin and soluble CD25 levels were decreased significantly 4 weeks after the modified DEP induction therapy (P = 0.001 and P = 0.00016, respectively), while platelet count and total bilirubin improved significantly (P = 0.004 and P = 0.001, respectively). The 1-year overall survival rate of all patients was 34.5%, with a median survival of 6.5 months (range 0.5-19 months). Patients with LA-HLH who underwent a stem cell transplantation had a significantly better prognosis than those not achieving complete response 4 weeks after modified DEP induction therapy (P = 0.034). CONCLUSION: Our study suggests that the modified DEP regimen is a safe and effective induction therapy for LA-HLH. Timely stem cell transplantation can improve the prognosis of patients with LA-HLH. TRAIL REGISTRY NUMBER: NCT04077905. URL: https://clinicaltrials.gov/ct2/show/NCT04077905?id=NCT04077905&draw=2&rank=1 .

Misdiagnosis of adult primary hemophagocytic lymphohistiocytosis as NK/T-cell lymphoma: A case report.

We reported a case of a 19-year-old male patient with central nervous system symptoms as the main clinical manifestations, and multiple intracranial and abdominal occupying lesions visualized by imaging examinations, who was initially misdiagnosed as NK/T-cell lymphoma but poorly responsive to the treatment. Finally, he was diagnosed as familial hemophagocytic lymphohistiocytosis type-2 by genome sequencing, perforin test and pedigree study. The patient survived well after allogeneic hematopoietic stem cell transplantation. Central nervous system symptoms could be the main clinical manifestations in patients with primary hemophagocytic lymphohistiocytosis , whose early-stage manifestations of blood system were usually atypical, easily leading to misdiagnosis. In clinical practice, primary hemophagocytic lymphohistiocytosis should be considered in patients with central nervous system symptoms and unknown causes. The combination of rapid immunological function test and genome sequencing contributes to the diagnosis of primary hemophagocytic lymphohistiocytosis.

The Treatment Based on Ruxolitinib and Amphotericin B is Effective for Relapsed Leishmaniasis-Related Hemophagocytic Lymphohistiocytosis: A Case Report and Literature Review.

Background: Hemophagocytic lymphohistiocytosis (HLH) is known as a life-threatening syndrome, and Leishmania is the most common protozoan that triggers infection-related HLH. It is thus important to find the root cause and treat it effectively. Case Report: This paper reports a 44-year-old man who developed antisynthetase antibody syndrome previously. The patient progressed rapidly to the extent of meeting the HLH-2004 diagnostic criteria, despite the unknown etiology. Although the patient was promptly treated in line with the HLH-1994 protocol to achieve remission, he still relapsed after glucocorticoid reduction. Afterwards, it was found out that HLH was secondary to Leishmania infection. The symptoms of HLH were alleviated quickly by the treatment with Ruxolitinib and Amphotericin B. Conclusion: Etiological screening plays a crucial role in leishmaniasis-related HLH. An experienced pathologist and real-time PCR are essential for treating Leishmania. The treatment of Ruxolitinib and Amphotericin B proved effective in alleviating the relapse of visceral leishmaniasis-related HLH.

Visualizing lymphocytic choriomeningitis virus infection in cells and living mice.

Mammarenavirus are a large family of enveloped negative-strand RNA viruses that include several agents responsible for severe hemorrhagic fevers. Until now, no FDA-licensed drug has been admitted for treating an arenavirus infection, and only few effective anti-arenavirus drugs have been tested in vivo. In this work, we designed a recombinant reporter arenavirus lymphocytic choriomeningitis virus that stably expressed nanoluciferase (LCMV-Nluc). The LCMV-Nluc was proved to share similar biological properties with wild-type LCMV and the Nluc intensity reliably reflected viral replication both in vitro and in vivo. Replication of the Nluc-encoding virus in living mice can be visualized by real-time bioluminescent imaging, and bioluminescence can be detected in a variety of organs of infected mice. This work provides a novel approach that enables real-time study of the arenavirus infection and is a convenient and valuable tool for screening of compounds that are active against arenaviruses in vitro and in living mice.

Epstein-Barr virus central nervous system involvement in Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis.

Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis (EBV-HLH) is a common subtype of secondary HLH. EBV plays an important part in the course. EBV can cause central nervous system (CNS) infections, and there are few clinical studies on EBV-CNS infection in EBV-HLH patients. All patients who were diagnosed as EBV-HLH and underwent cerebrospinal fluid testing admitted to our center from January 2018 to December 2019 were retrospectively analyzed. Summarized the clinical data, evaluated treatment efficacy after intrathecal injection, and investigated the correlation between EBV-CNS infection with prognosis in EBV-HLH patients. Of 37 of 57 (64.9%) EBV-HLH patients has EBV-CNS infection. The survival of EBV-HLH patients without EBV-CNS infection was significantly better than that in EBV-CNS infection patients (P = 0.018). There were no statistically significant differences in sCD25, ferritin, ALT, AST, LDH, TB, WBC, Hb, and PLT counts between two groups (all P-values > 0.05). Higher EBV-DNA load in peripheral blood was correlated with EBV-CNS infection (P < 0.001). EBV-CNS infection is an independent risk factor affecting the survival of patients (P = 0.004). The CSF cell load of patients with and without EBV-CNS infection groups was significantly different (P = 0.024). Intrathecal injection with methotrexate combined with dexamethasone can effectively decrease CSF EBV-DNA load (P = 0.017) and CSF cell load (P = 0.025). EBV-CNS infection is an independent risk factor affecting prognosis in EBV-HLH patients. Therefore, EBV-CNS infection should cause concern for EBV-HLH patients. Cerebrospinal fluid testing is necessary for all patients. Methotrexate combined with dexamethasone intrathecal injection can be an effective treatment for EBV-CNS infection.

L-DEP regimen is effective as an initial therapy for adult EBV-HLH.

We performed a single-center, prospective trial to investigate the efficacy of PEG- asparaginase combined with liposomal doxorubicin, etoposide, and methylprednisolone (L-DEP) as an initial therapy for Epstein-Barr virus driven hemophagocytic lymphohistiocytosis (EBV-HLH). None of the patients received any chemotherapy after the diagnosis of EBV-HLH between September 2019 and September 2021. The efficacy was evaluated 2 weeks and 4 weeks after initiating L-DEP primary therapy. Forty-seven eligible patients with EBV-HLH were enrolled. The overall response rate (ORR) was 80.9% (38/47, 12 in clinical CR, 26 in clinical PR) at 2 weeks after the L-DEP regimen; at 4 weeks, the ORR was 75.6% (34/45, 21 in clinical CR, 13 in clinical PR). EBV-DNA loads in blood and plasma were significantly decreased 2 and 4 weeks after the L-DEP regimen (P < 0.001). Ferritin, soluble CD25 (sCD25), triglycerides (TGs), and ultrasonic spleen longitude, and thickness were all decreased significantly 2 and 4 weeks after the L-DEP regimen (P < 0.001). Thus, the L-DEP regimen is an effective initial therapy for EBV-HLH. However, the L-DEP regimen was poor in terms of long-term prognosis and that allo-HSCT should be received as soon as possible once a complete response is achieved.

Massive pericardial effusion due to chronic active Epstein-Barr virus infection successfully treated with PD-1 blockade: A case report.

RATIONALE: Chronic active Epstein-Barr virus (EBV) infection (CAEBV) is a rare but life-threatening EBV-positive lymphoproliferative disorder. Currently, treatment options for CAEBV are limited. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the only way to cure CAEBV. Here, we report a rare case of CAEBV manifesting as massive pericardial effusion that was successfully treated with programmed cell death protein-1 (PD-1) blockade immunotherapy. PATIENT CONCERNS: A 36-year-old woman with intermittent chest distress and dyspnea for 8 months was admitted to our center on October 25, 2021. Laboratory tests showed leukocytopenia and elevated liver enzyme levels. Initial echocardiography revealed massive pericardial effusion. DIAGNOSIS: High levels of EBV-DNA were detected in the pericardial fluid by metagenomic next-generation sequencing. The pathological diagnosis of her left inguinal lymph node and skin lesions revealed systemic CAEBV. INTERVENTIONS: The patient received sintilimab injection at a dose of 200 mg every 2 weeks in combined with lenalidomide 10 mg once daily. OUTCOMES: The patient achieved complete resolution of pericardial effusion 5 months after PD-1 blockade immunotherapy without apparent adverse effects. LESSONS: CAEBV is a rare but life-threatening EBV-positive lymphoproliferative disease. We present a rare case of massive pericardial effusion caused by systemic CAEBV, which was successfully treated with sintilimab. This case highlights the promising curative effect of PD-1 blockade immunotherapy in systemic CAEBV, especially for patients not suitable for allo-HSCT.

Clinical characteristics and treatment of NK/T-cell lymphoma-associated HLH.

Natural killer (NK)/T-cell lymphoma-associated hemophagocytic lymphohistiocytosis (NK/T-LAHLH) is a rare and life-threatening disorder. Its clinical characteristics and appropriate treatment options are unclear. This study aimed to investigate the clinical characteristics and treatment options for this disease. We retrospectively analyzed the clinical data of 84 patients with NK/T-cell lymphoma and compared the characteristics, treatment, and survival between patients with and without HLH. Patients in the NK/T-LAHLH group were more likely to be younger age and have hepatosplenomegaly, B symptoms, neutropenia, anemia, thrombocytopenia, elevated lactate dehydrogenase levels, reduced serum albumin levels, bone marrow involvement, Ann Arbor stage III/IV, and International Prognostic Index score ≥ 3. After multivariate analysis, it was found that elevated lactate dehydrogenase and Ann Arbor stage III/IV were risk factors for HLH in patients with NK/T-cell lymphoma. After 2 weeks of therapy, 78.6% (11/14) patients who received the L-DEP/DEP regimen achieved an overall response rate of HLH, which was higher than that in 42.9% (9/21) patients who received the VP-16 + dexamethasone-based regimen. NK/T-LAHLH patients had poorer survival than non-HLH-NK/TCL patients. For NK/T-LAHLH, the L-DEP/DEP regimen may have a better response rate than the VP-16 + dexamethasone-based regimens.

Successful Treatment of Relapsed Epstein-Barr Virus-Associated Hemophagocytic Lymphohistiocytosis After Allo-HSCT with PD-1 Blockade: A Case Report.

Background: Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis (EBV-HLH) is a rare and aggressive disease with high mortality and poor prognosis. To date, allogeneic hematopoietic stem cell transplantation (allo-HSCT) remains the only way to cure EBV-HLH. However, relapse of EBV-HLH after allo-HSCT is common and remains a major challenge. Case Presentation: A 22-year-old woman with persistent fever for a month presented to our center with EBV-HLH. After induction of remission using two cycles of the L-DEP (PEG-aspargase, liposomal doxorubicin, etoposide, and high-dose methylprednisolone) regimen, the patient underwent an human leukocyte antigen (HLA)-identical sibling allo-HSCT. However, she experienced disease relapse soon after the procedure, and none of the possible treatment options achieved a sustained response. Finally, she received a sintilimab injection and achieved complete resolution of EBV-HLH. Conclusion: We summarize a case of relapsed EBV-HLH after allo-HSCT that was successfully treated with a programmed cell death protein-1 (PD-1) antibody. Further studies are needed to determine whether PD-1 blockade has therapeutic potential for relapsed EBV-HLH after allo-HSCT.

The Outcome of Induction Therapy for EBV-Related Hemophagocytic Lymphohistiocytosis: A Model for Risk Stratification.

Background: Epstein-Barr virus (EBV)-related hemophagocytic lymphohistiocytosis (HLH) is an abnormal inflammation caused by EBV infection, which has high mortality during induction therapy. Objectives: This study is aimed to build a model to predict the risk of death during induction therapy. Methods: The patients with EBV-HLH admitted from January 2015 to December 2018 were retrospectively reviewed. The primary outcome was death during induction therapy. The interval from receiving therapy to death or the end of induction therapy was the observing time. The patients admitted from January 2015 to December 2017 were assigned to the primary group, and the patients admitted from January to December 2018 were assigned to the validation group. Results: We included 234 patients with EBV-HLH, of whom 65 (27.4%) died during induction therapy. The middle observing time was 25 days. On the basis of the primary group, the multivariate Cox analysis demonstrated age >18 years, blood urea nitrogen, procalcitonin >2 µg/L, serum CD25, and EBV-DNA in peripheral blood mononuclear cell as the risk factors of death during induction therapy. We developed a nomogram integrating the above factors with high predictive accuracy (c-statistic, 0.86) and stratified all patients into the high-risk and the low-risk groups. On the basis of the validation group, the high-risk patients had a higher risk of death (hazard ratio, 4.93; P = 0.012). In the subgroup analysis based on patients receiving etoposide-based strategy, the mortality in high-risk and low-risk patients was 43.9 and 3.1 per 100 person-weeks, respectively. Conclusion: We developed a nomogram for risk stratification of patients with EBV-HLH receiving induction therapy.

Development of a Nomogram to Predict the Risk of Chronic Active Epstein-Barr Virus Infection Progressing to Hemophagocytic Lymphohistiocytosis.

BACKGROUND: Chronic active Epstein-Barr virus infection (CAEBV) disease is sometimes associated with an aggressive clinical course, such as hemophagocytic lymphohistiocytosis (HLH). To explore the risk factors and predict the risk of CAEBV infection progressing to HLH, a retrospective research study was conducted. METHODS: We retrospectively reviewed the medical records of 187 CAEBV-infected patients who were admitted to our center between January 2015 and December 2020. The patients were followed up until May 2021. The patients were divided into a progression-to-HLH group and a no-progression-to-HLH group. Demographic, clinical and laboratory data were collected for each patient. RESULTS: Among the 121 CAEBV-infected patients who fulfilled the study's inclusion criteria, 48 (30.7%) patients did not progress to HLH, and 73 (60.3%) patients progressed to HLH. The median time from CAEBV infection to progression to HLH was 14 months, and the cumulative incidence rate of HLH increased as the duration of follow up increased (24.9, 47.3, 55.1, and 85.2% at 1, 3, 5, and 10 years, respectively). Multivariate analyses showed that the independent risk factors for CAEBV progression to HLH were plasma EBV-DNA load (OR = 3.239, 95% CI 1.219-8.603, P = 0.018), Platelet count (OR=0.991, 95%CI 0.985-0.998, P = 0.010), elevated alanine aminotransferase (OR=1.019, 95%CI 1.005-1.034, P = 0.009) and ≥2 of 3 lineages of cytopenia (OR=8.364, 95%CI 1.062-65.839, P = 0.044). The regression coefficients (ß) from the multivariate logistic model were used to construct a model for estimating the risk of CAEBV infection progressing to HLH. The discriminatory ability of the model was good, and the area under the receiver operating characteristic (ROC) curve (AUC) was 0.925. CONCLUSION: plasma EBV-DNA load, platelet count, elevated alanine aminotransferase and ≥ 2 of 3 lineages of cytopenia increase the risk of CAEBV infection progressing to HLH. A nomogram can be used to estimate the risk of CAEBV-infected patients progressing to HLH.