Adult Secondary Hemophagocytic Lymphohistiocytosis Research Articles

Effect of Plasma Epstein-Barr Virus Nucleic Acid Loads on the Clinical Features and Prognosis in Adult Secondary Hemophagocytic Lymphohistiocytosis

To investigate the effect of pre-treatment plasma Epstein-Barr virus (EBV) DNA copy number on the clinical features and prognosis of patients with adult secondary hemophagocytic lymphohistiocytosis(sHLH). The clinical characteristics, survival rate, and prognostic factors of 171 patients with adult sHLH treated at Jiangsu Province Hospital from June 2017 to January 2022 were retrospectively analyzed in this study. Patients were divided into three groups, including the EBV DNA-negative group(<5.0×102 copies/ml), lower EBV-DNA loads group(5.0×102-8.51×104 copies/ml), and higher EBV-DNA loads group(＞8.51×104 copies/ml), according to pre-treatment plasma EBV-DNA copy number. Cox regression model was established for screening prognostic factors. Adult sHLH survival prediction model was constructed and realized through the nomogram based on EBV-DNA load after adjusted the factors affecting survival of etiology and treatment strategy.Concordance index (C-index) and calibration curves were calculated to verify model predictive and discriminatory capacity. Among 171 adult sHLH patients, 84 patients were not infected with EBV (EBV DNA-negative group), and 87 with EBV (EBV DNA-positive group, 48 lower EBV-DNA loads group and 39 higher EBV-DNA loads group). Consistent elevations in the levels of liver enzymes (ALT and AST), LDH, TG, β 2-microglobulin and ferritin across the increasing of EBV-DNA load (all P <0.05), while the levels of fibrinogen decrease (P <0.001). The median follow-up time was 52 days (range 20-230 days), and 123 patients died. The overall survival (OS) rate of patients in EBV DNA-positive group was lower than that in EBV DNA-negative group (median OS: 40 days vs 118 days, P <0.001). Higher EBV-DNA loads had worse OS (median OS: 24 days vs 45 days vs 118 days, P <0.0001 for trend) compared to lower EBV-DNA loads and EBV DNA-negative group. Multivariate Cox analysis revealed that higher EBV-DNA loads (P =0.005), fibrinogen≤1.5 g/L (P ＝0.012), ferritin (P ＝0.041), associated lymphoma (P ＝0.002), and anti-tumor based strategy (P ＝0.001) were independent prognostic factors for OS. The C-indexes of 30 day, 90 days, 365 days survival rate were all greater than 0.8 of the nomogram model and calibration curves provided credibility to their predictive capability. Subgroup analysis showed that patients with higher EBV-DNA loads had a significantly worse prognosis in adult sHLH who were women, ferritin＞5 000 μg/L, β2-microglobulin＞7.4 mmol/L and regardless of age, etiologies, HScore points. The EBV-DNA load is a strong and independent predictor for survival in patients with sHLH. The prognostic nomogram based on EBV-DNA loads was dependable and provides a visual tool for evaluating the survival of adult sHLH.

Association of a decreased platelet count with poor survival in patients with adult secondary hemophagocytic lymphohistiocytosis.

We aimed to examine the association between baseline platelet count (PLT) and the prognosis of adult secondary hemophagocytic lymphohistiocytosis (sHLH). Data from 292 patients with pretreatment platelet counts were retrospectively analysed from January 2016 to December 2020. We categorized platelet count into quartiles. Multivariable Cox proportional hazards models and restricted cubic splines (RCS) were used to evaluate the relationship between platelet count and mortality. During a median follow-up of 53 (interquartile ranges, 17-223) days, a total of 208 deaths occurred. After adjusting for multiple variables, a non-linear and inverse relationship was observed between platelet count and mortality in sHLH patient (P for nonlinearity=0.002). For non- lymphoma-associated haemophagocytic lymphohistiocytosis (non-LHLH), a similar curve was also observed (P for nonlinearity =0.028). Decreased PLT (PLT Q4) was associated with an increased risk of mortality (adjusted hazard ratio: 1.97; 95% confidence interval: 1.28-3.04; Ptrend =0.005). Similar results were observed in the LHLH subgroup (adjusted hazard ratio: 1.84; 95% confidence interval: 1.05-3.24; Ptrend =0.024) but not in the non-LHLH subgroup (Ptrend =0.266). Baseline platelet count demonstrated a nonlinear and inverse association with an increased risk of mortality among adult sHLH patients. This method is used to identify sHLH patients with inferior overall survival due to its low cost and universal availability.

Clinical features and prognostic factors of acute kidney injury caused by adult secondary hemophagocytic lymphohistiocytosis

Hemophagocytic lymphohistiocytosis is a clinical syndrome caused by a cytokine storm and phagocytosis of blood cells. Acute kidney injury is typically associated with a poor prognosis in hemophagocytic lymphohistiocytosis. In the present study, a retrospective analysis of patient data was performed to identify risk factors associated with acute kidney injury in hemophagocytic lymphohistiocytosis. All patients included in the studywere diagnosed with hemophagocytic lymphohistiocytosis between January 2009 and July 2019. Acute kidney injury was diagnosed according to the Kidney Disease Improving Global Outcomes guidelines, according to the2012update. We collected the general information of the patients, clinical manifestations, treatments, as well as laboratory data from the electronic medical records. We analyzed 600 patients with hemophagocytic lymphohistiocytosis. Serum phosphorus, need forvasopressors, heart failure, gastrointestinal symptoms, disseminated intravascular coagulation, high heart rateat admission, total bilirubin and albumin levelswere independently associated with an increased risk of developing acute kidney injury. Independent risk factors for in-hospital mortality were administration of vasopressors, acute kidney injury stage III, baseline Cystatin-C, total bilirubin, number of days of glucocorticoid therapy, fibrinogen leveland presence ofmulti-organ failure. Patients with hemophagocytic lymphohistiocytosis usually exhibit high hospital mortality, particularly in the presence ofacute kidney injury. The risk factors for the occurrence of acute kidney injury and increased mortality identified in the study may assist clinicians in the prevention of acute kidney injury, and in its timelytreatment in patients affected byhemophagocytic lymphohistiocytosis, toultimately improve prognosis.

Clinical Features and Prognostic Factors of Acute Kidney Injury Caused by Adult Secondary Hemophagocytic Lymphohistiocytosis

Background and Aims: Hemophagocytic lymphohistiocytosis (HLH ) is a clinical syndrome caused by a cytokine storm and phagocytosis of blood cells. Acute kidney injury (AKI) is typically associated with a poor prognosis in HLH. In the present study, a retrospective analysis of patient data was performed to identify risk factors associated with HLH-induced AKI. Method: All patients were diagnosed with HLH between January 2009 and July 2019. HLH was diagnosed according to the HLH-2004 criteria and AKI was diagnosed according to the Kidney Disease Improving Global Outcomes guidelines, which were last updated in 2012. We collected the general information of the patients, clinical manifestations, treatments, as well as laboratory data from the electronic medical records. Results: We analyzed 600 patients with HLH in the present study. Serum phosphorus levels, administration of vasopressor, heart failure, gastrointestinal symptoms, disseminated intravascular coagulation, high admission heart rate, total bilirubin levels and albumin levels were independently associated with an increased risk of developing AKI. Independent risk factors for in-hospital mortality in patients were administration of vasopressor, AKI stage III, baseline Cystatin-C levels, total bilirubin levels, number of days of glucocorticoid therapy, fibrinogen and multi-organ failure. Interpretation: Patients with HLH usually exhibit a high rate of hospital mortality, particularly when combined with AKI. The risk factors for the occurrence of AKI and increased mortality identified in the present study may assist clinicians in the early prevention of the disease, and in the treatment of HLH-induced AKI, to improve the prognosis of patients. Funding: This work is financially supported by grants from Sichuan Provincial Science and Technology Key R & D Projects [No. 2017SZ0113, No. 2017SZ0144 and No. 2019YFS0282], 1·3·5 project for disciplines of Excellence-Clinical Research Incubation Project, West China Hospital, Sichuan University [NO.2020HXFH049]. Declaration of Interest: None to declare. Ethical Approval: Ethical approval for the present study was obtained from The Ethical Committee of West China Hospital, Sichuan University. As we collected clinical data for retrospective analysis, the Ethics Committee waived the need for informed consent.

The Efficacy of Etoposide-Based Therapy in Adult Secondary Hemophagocytic Lymphohistiocytosis

Data supporting the use of etoposide-based therapy in hemophagocytic lymphohistiocytosis (HLH) arise largely from pediatric studies. There is a lack of comparable data among adult patients with secondary HLH. We conducted a retrospective study to assess the impact of etoposide-based therapy on outcomes in adult secondary HLH. The primary outcome was overall survival. The log-rank test was used to compare Kaplan-Meier distributions of time-to-event outcomes. Multivariable Cox proportional hazards modeling was used to estimate adjusted hazard ratios (HRs) with 95% confidence intervals (CIs). Ninety adults with secondary HLH seen between January 1, 2009, and January 6, 2020, were included. Forty-two patients (47%) received etoposide-based therapy, while 48 (53%) received treatment only for their inciting proinflammatory condition. Thirty-three patients in the etoposide group (72%) and 32 in the no-etoposide group (67%) died during follow-up. Median survival in the etoposide and no-etoposide groups was 1.04 and 1.39 months, respectively. There was no significant difference in survival between the etoposide and no-etoposide groups (log-rank p = 0.4146). On multivariable analysis, there was no association between treatment with etoposide and survival (HR for death with etoposide = 1.067, 95% CI: 0.633–1.799, p = 0.8084). Use of etoposide-based therapy was not associated with improvement in outcomes in this large cohort of adult secondary HLH patients.

The Prognosis Role of AST/ALT (De Ritis) Ratio in Patients with Adult Secondary Hemophagocytic Lymphohistiocytosis.

Purpose Secondary hemophagocytic lymphohistiocytosis (sHLH) accompanied by liver involvement, characterized by hepatomegaly and increased liver enzymes, is usually associated with elevated mortality. However, the magnitude of these associations remains unknown. Our objective was to assess the associations of the aspartate transaminase/alanine transaminase (AST/ALT, De Ritis) ratio with overall survival among adult patients with sHLH. Methods A retrospective analysis was performed on 289 patients aged 18–86 years with complete serum transaminase data at diagnosis of sHLH. Multivariate Cox regression analyses and restricted cubic splines were conducted to address the association between the De Ritis ratio and the risk of mortality. Results The median De Ritis ratio for the entire study population was 1.34 (IQR: 0.84-2.29). After a median follow-up time of 60 (range 17-227.5) days, 205 deaths occurred. After fully adjusting for hepatomegaly, albumin, fibrinogen, EBV, ferritin, etiologies, and treatment strategies, the adjusted hazard ratios (HRs) with corresponding confidence intervals (CIs) of mortality for the 2 st tertile and 3 st tertile were 1.2 (0.8-1.7) and 1.6 (1.1-2.2), respectively (P < 0.01 for trends). Restricted cubic spline confirmed a linear association between the log2-transformed De Ritis ratio and the risk of mortality. Moreover, this trend persisted in subgroups with MHLH, hyperferrinaemia, sCD25 ≤ 20,000 ng/L, patients without EBV infection, and those received treatment. Conclusions The De Ritis ratio is a strong and independent predictor for overall survival in patients with sHLH. As a readily available biomarker in routine clinical practice, it is used to identify patients with sHLH with inferior overall survival.

The prognostic role of plasma fibrinogen in adult secondary hemophagocytic lymphohistiocytosis

BackgroundIn adult patients with secondary hemophagocytic lymphohistiocytosis (sHLH), no valid immune biomarker has been available for predicting the prognosis of untreated sHLH patients.MethodsCirculating plasma levels of fibrinogen (FIB) were measured at diagnosis in 293 cases of adult sHLH. We categorized FIB levels into tertiles. Multivariable Cox proportional hazards models were used to evaluate the relationship between FIB and survival. Restricted cubic spline models and two-piecewise Cox proportional hazards models were used to address the nonlinear association between FIB and mortality.ResultsDuring a median follow-up of 52 (interquartile ranges, 18–221) days, 208 deaths occurred, with 137 deaths in malignancy-associated hemophagocytic lymphohistiocytosis (MHLH) and 71 deaths in non-malignancy-associated hemophagocytic lymphohistiocytosis (non-MHLH). After multivariable adjustment, compared with the highest tertile of FIB, the hazard ratios (HRs) with 95% confidence intervals (CIs) of survival for tertile 2 and tertile 1 were 1.06 (0.90–1.24) and 0.84 (0.71–0.98), respectively. The restricted cubic spline curve displayed a nonlinear and inverse relationship between FIB and mortality. Furthermore, the threshold effect analysis demonstrated that the inflection point for the curve was at an FIB level of 1.76 g/L. The HRs (95% CIs) for survival were 0.68 (0.55–0.83) and 1.08 (0.96–1.21) on the left and right side of the inflection point, respectively.ConclusionsThese results suggest that plasma fibrinogen is nonlinearly and inversely associated with the risk of mortality in adult secondary hemophagocytic lymphohistiocytosis.

Adverse Prognostic Factors in Adult Secondary Hemophagocytic Lymphohistiocytosis: Results from Two Tertiary Academic Centers

Adverse Prognostic Factors in Adult Secondary Hemophagocytic Lymphohistiocytosis: Results from Two Tertiary Academic Centers

Soluble interleukin-2 receptor (sIL-2r) level is a limited test for the diagnosis of adult secondary hemophagocytic lymphohistiocytosis.

Soluble interleukin-2 receptor (sIL-2r) level is used as a diagnostic tool in hemophagocytic lymphohistiocytosis (HLH). However, evidence supporting its use among adults is inadequate. We conducted a retrospective study to assess the performance characteristics of sIL-2r for the diagnosis of adult HLH. One hundred thirty-two adults with sIL-2r levels sent for evaluation of HLH over a ten-year period were included. Sixty-five (49%) met criteria for HLH. Mean sIL-2r was significantly higher among patients with HLH relative to all patients without HLH (12942U/ml vs. 6308U/mL, P=.00311). However, when comparing mean sIL-2r in the HLH group to those in the non-HLH group with primary diagnoses of hematologic malignancy (8911U/mL), sepsis (7127U/mL), and rheumatologic disease (4624U/mL), no significant differences were found (P=.241, P=.178, and P=.0607, respectively). There was only weak correlation between sIL-2r and diagnosis of HLH (r=.253). The standard cutoff sIL-2r>2400 U/ml yielded a sensitivity of 89.2% and specificity of 38.8%. The area under the curve for the corresponding receiver-operator curve was 0.691, consistent with a poor discriminating ability for the diagnosis of HLH. sIL-2r is a limited test for the diagnosis of adult secondary HLH, and its role in this setting should be reevaluated.

Reevaluating the role of ferritin in the diagnosis of adult secondary hemophagocytic lymphohistiocytosis.

The standard diagnostic criteria for hemophagocytic lymphohistiocytosis (HLH) include hyperferritinemia to >500ng/mL. This ferritin threshold is based on pediatric data, and evidence for its application among adults with secondary HLH is lacking. We conducted a retrospective study assessing the relationship between extreme hyperferritinemia and adult secondary HLH at our institution. All adult inpatients seen over a 10-year period, with serum ferritin >5000ng/mL, were included. Among 1055 patients with serum ferritin >5000ng/mL, there were 69 cases of HLH (HLH prevalence of 6.5%). Mean ferritin among HLH patients was 70398ng/mL (SD 122908), median 40019ng/mL (IQR 16051-68326). The prevalence of HLH only reached 50% as serum ferritin approached 90000ng/mL. A variety of conditions were contributory to hyperferritinemia, most commonly bacterial sepsis (33%), hematologic malignancy (29%), renal failure (24%), and liver injury (18%). The optimal cutoff ferritin for diagnosis of HLH was 16000ng/mL (sensitivity 79.4%, specificity 79.2%, PPV 20.9%, and NPV 98.2%). The threshold ferritin levels used in diagnostic criteria for adult secondary HLH are too low to be clinically relevant, and efforts should be undertaken to revise them upward. Similar reappraisals should be taken of the other criteria used to diagnose adult HLH.

Risk factors of early death in adult patients with secondary hemophagocytic lymphohistiocytosis: a single-institution study of 171 Chinese patients

ABSTRACTBackground: Adult secondary hemophagocytic lymphohistiocytosis (HLH) is a potentially life-threatening syndrome characterized by excessive activation of mononuclear-phagocytic system resulting in hyperinflammatory response. To date, the factors influencing early death of HLH are still not fully elucidated.Patients and Methods: We did a retrospective study of 171 adult patients with newly diagnosed HLH at our institution from January 2012 to April 2018. All patients’ clinical features, laboratory findings, treatments and prognosis were reviewed.Results: The median age was 49 years (range, 18–88 years), and 110 (64.3%) were male. The major underlying trigger of HLH was malignancy (88/171, 51.5%), especially non-Hodgkin lymphoma. In a multivariate analysis, age ≥54 years (P = 0.002), platelet ≤39.5 × 109/L (P = 0.028), activated partial thromboplastin time (APTT) ≥54 sec (P = 0.048), triglyceride ≥3.23 mmol/L (P < 0.001), lactate dehydrogenase (LDH) ≥1300 U/L (P = 0.012) and malignancy (P = 0.001) were significantly associated with early death in HLH. Then, patients were classified into four groups according to the number of risk factors at the time of diagnosis: low risk (zero, one or two risk factors), low intermediate risk (three risk factors), high intermediate risk (four risk factors) and high risk (at least five risk factors), with the 30-day overall survival (OS) of 92.4%, 58.8%, 30.0% and 4.8%, respectively (P < 0.001).Conclusions: Patients with old age, thrombocytopenia, prolonged APTT, hypertriglyceridemia, elevated LDH and malignancy had inferior survival. It is important to identify those patients at risk of early death, which may guide treatment and reduce mortality.

High concentration of miR-133 is a useful marker for the diagnosis of lymphoma- associated hemophagocytic syndrome.

Lymphoma associated hemophagocytic syndrome (LAHS) is one of the major adult secondary hemophagocytic lymphohistiocytosis (HLH). Early diagnosis and treatment contribute to improved outcome. No enlarge lymph nodes can often delay the diagnosis of underlying lymphoma. To find out criteria distinguishing LAHS from HLH induced by benign diseases. clinical characteristic and laboratory feature of 31patients with HLH (10 benign disease-associated HLH and 21 LAHS) were analyzed retrospectively. No significantly differences were observed in the levels of LDH, IL-6, IL-10, TNF-α; however, the level of CRP (C reactive protein) and the mean level of sIL-R (soluble interleukin-2 receptor) were higher in patients with LAHS than those with benign disease associated disease associated HLH while ferritin levels were higher in benign disease associated HLH than in LAHS. Consequently, the serum sIL-2R/ferritin ratio of patients with LAHS was markedly higher than that of patients with benign disease associated HLH (0.33 ± 0.23 vs 5.82 ± 3.26, P= 0.0001). In addition, we found out that the mean level of miR-133 (microRNA-133) was significant higher in LAHS than in benign disease associated HLH (18.83 ± 10.44 vs 5.82 ± 3.26, P⩽ 0.0001). Serum miR-133 is a new very useful marker for diagnosing of LAHS, but it need further confirmation by further clinical studies.

A Case Series of Adult Secondary Hemophagocytic Lymphohistiocytosis Treated at Weill Cornell Medical College

Background: Hemophagocytic Lymphohistiocytosis (HLH) is an often-fatal syndrome of uncontrolled immune activation caused by dysregulation of macrophages and lymphocytes resulting in increased levels of inflammatory cytokines and significant tissue damage. Familial HLH (FHL) is characterized by germline mutations in genes affecting the cytolytic function of Natural Killer (NK) cells and cytotoxic T cells. Secondary HLH is triggered by an infectious, rheumatologic, malignant or autoimmune condition. While FHL is well characterized in the pediatric population, there are currently no available prospective data guiding the diagnosis and treatment of secondary HLH in the adult patient. Here we present 7 cases of adult secondary HLH that were identified and treated at Weill Cornell Medical College in a period of two years. We highlight the presentation and etiology of secondary HLH and the importance of prompt recognition and early treatment. We also explore the relationship of immunosuppressive and antiretroviral therapy with adult secondary HLH. Methods: Between July 2014 and July 2016, 7 adult patients &gt;18 years old were identified at Weill Cornell Medical College, NY that met criteria and were treated for adult secondary HLH. All 7 patients had 5 out of 8 of the following findings established in the HLH-2004 guidelines: fever ≥ 38.5 C°, splenomegaly, cytopenias affecting 2 of 3 lineages in the peripheral blood (hemoglobin &lt;9 g/dL, platelets &lt;100x103/mL, neutrophils &lt;1x103/mL), hypertriglyceridemia (fasting &gt;265 mg/dL) and/or hypofibrinogenemia (&lt;150 mg/dL), hemophagocytosis in the bone marrow, spleen, lymph nodes or liver, low or absent NK cell activity, ferritin &gt;500 ng/mL and elevated sIL2R. Molecular testing was sent to identify pathologic mutations associated with FHL. Patients were treated with chemotherapy and immunotherapy based on the pediatric HLH-94 protocol, as well as treatment targeted at an underlying malignancy or infection. Patient demographics and clinical characteristics, underlying etiology of secondary HLH and treatment modalities were compared. Results: All 7 patients included in this study met criteria for secondary HLH as defined above. The median age at diagnosis was 42 (range 22-68 years) with a male predominance of 6:1. The majority of patients identified as Caucasian (4/7, 57%) and the remaining 3 patients were Hispanic, African American and Haitian. Five out of 7 (71%) patients had been on immunosuppressive therapy prior to diagnosis, 3 patients had Inflammatory Bowel Disease (IBD) and 3 patients were on Emtricitabine and Tenofovir at the time of diagnosis. The median ferritin at diagnosis was 4,589 ng/mL (range 2,127-10,500 ng/mL) with a peak median ferritin of 10,500 ng/mL (range 3,093-306,320 ng/mL). The sIL2R at diagnosis ranged from 1,000-112,200 pg/mL (reference &lt;1,033 pg/mL). Patient clinical manifestations are summarized in Table 2. All patients presented with fevers, elevated ferritin, cytopenias and splenomegaly and 6/7 (86%) patients had evidence of hemophagocytosis in the bone marrow or liver. Four patients (57%) had secondary HLH due to an infection and 3 (43%) had an underlying malignancy. All patients received Etoposide and Dexamethasone and 4 patients received 2ndline treatment either for an underlying malignancy or for refractory HLH. The median time from presentation to initiation of treatment was 4 weeks (range 1-12 weeks). At the time of this report, 3 patients had died (43%) of which 2 had an underlying malignancy, 3 were alive and 1 patient was lost to follow up. Discussion: Diagnosis of adult secondary HLH remains a challenge due to overlap in symptoms and lack of specificity of laboratory findings. Treatment is often postponed due to delayed recognition of this disease. A high degree of medical suspicion in the appropriate clinical context should prompt early treatment with an Etoposide-containing regimen. Interestingly, we found 4 patients with autoimmune conditions on immunosuppressive therapy, 2 of which were also on antiretroviral treatment. Further investigation is needed to elucidate the association of these findings in adult secondary HLH. Molecular mutational testing is of interest in identifying possible underlying genetic predisposition for adult secondary HLH and further studies are warranted in this area. Disclosures Ritchie: Celgene: Consultancy, Other: Travel, Accomodations, Expenses, Speakers Bureau; Novartis: Consultancy, Other: Travel, Accommodations, Expenses, Research Funding, Speakers Bureau; Incyte: Consultancy, Speakers Bureau; Ariad: Speakers Bureau; Pfizer: Consultancy, Research Funding; Astellas Pharma: Research Funding; Bristol-Meyers Squibb: Research Funding; NS Pharma: Research Funding.

Viral etiology, clinical and laboratory features of adult hemophagocytic lymphohistiocytosis.

Secondary hemophagocytic lymphohistiocytosis (SHLH) is a potentially fatal hyperinflammatory syndrome with a heterogeneous etiology and has nonspecific clinical and laboratory findings. The diagnosis and treatment of adult SHLH is challenging because the etiology of the disease is difficult to identify, and the majority of reported cases are pediatric patients. The aim of this study was to describe the etiology, clinical characteristics, and outcomes of adult SHLH. Fifty‐four adult patients who fulfilled the criteria of SHLH were enrolled in the study. Viral etiology, blood biomarkers, and clinical manifestations of SHLH were analyzed in these patients. Twenty‐four SHLH patients had viraemia, whereas 30 SHLH patients were secondary to other diseases. Epstein‐Barr virus (EBV) was the most common virus that associated SHLH among all viruses studied. Severe SHLH patients with EBV‐viraemia presented significantly high levels of ferritin, lactate dehydrogenase, aspartate transaminase (AST), and alanine transaminase (ALT). Positively relationships existed between EBV DNA titers and levels of AST and ALT (P < 0.05). The prognosis of SHLH patients with EBV viraemia was worse than that of non‐EBV SHLH and non‐viral SHLH. Our data reveal that EBV is the major pathogen in virus‐associated SHLH, and EBV load influence disease development in SHLH patients with EBV infection that prognosis is worse than other viruses associated SHLH. J. Med. Virol. 88:541–549, 2016. © 2015 Wiley Periodicals, Inc.