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Objective: To determine the expression and diagnostic value of peripheral blood lymphocytes and functional activation status in non-Hodgkin lymphoma with hemophagocytic lymphohistiocytosis (NHL-HLH) . Methods: We retrospectively analyzed clinical data from 30 newly diagnosed NHL-HLH patients admitted to Jiangsu Province Hospital from September 2022 to September 2023. We assessed peripheral blood lymphocytes and activation status by flow cytometry. Forty newly diagnosed patients with NHL who received treatment at our hospital during the same period and had lymphocyte and functional activation indexes were selected as the control group. The differences in relative and absolute lymphocyte counts and functional activation indexes between the two groups were compared. The optimal cutoff values for continuous variables were calculated from the receiver operating characteristic curve and logistic regression analysis was used to evaluate the risk factors in NHL patients with HLH. Results: A total of 30 NHL-HLH patients were evaluated, including 12 T-cell lymphoma and 18 B-cell lymphoma patients. Forty individuals were in the control group, which included 19 T-cell lymphoma and 21 B-cell lymphoma patients. The absolute counts of CD3(+) T, CD4(+) T, CD8(+) T, and NK cells, along with the relative count of NK cells, were significantly lower in the HLH group compared with that in the control group (all P values<0.01) . The expression of CD38 and HLA-DR on CD8(+) T-cell activated subgroups was significantly higher in the NHL-HLH group compared with that in the control group (CD8(+)CD38(+)/CD8(+) T expression median: 57.4% vs 21.5%, P <0.001; CD8(+)CD38(+)/CD8(+) T expression median: 49.7% vs 33.5%, P =0.028, respectively) . In addition, CD28 expression on CD4(+) and CD8(+) T cells was significantly higher in NHL-HLH patients ( P <0.01) . ROC curve and multivariate logistic regression analyses revealed that absolute NK cell count ≤72.0 cells/μl, CD4(+)CD28(+)/CD4(+) T >94.2%, and CD8(+)CD28(+)/CD8(+) T >38.4% were risk factors for predicting the occurrence of NHL-HLH patients. The sensitivity and specificity of the regression model were 86.7% and 86.1%, respectively, with an area under the curve of 0.94 ( P <0.001) . Conclusions: In NHL patients with HLH, there was a significant reduction in the absolute number of peripheral blood lymphocyte subpopulations, whereas T-cell function was notably activated. Specifically, absolute counts of NK cells ≤72.0 cells/μl, CD4(+)CD28(+)/CD4(+) T >94.2%, and CD8(+)CD28(+)/CD8(+) T >38.4% were identified as risk factors for predicting the development of NHL-HLH patients. This will assist in early clinical diagnosis and treatment.

Objective: 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)., Methods: 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(<5.0×10 2 copies/ml), lower EBV-DNA loads group(5.0×10 2 -8.51×10 4 copies/ml), and higher EBV-DNA loads group(＞8.51×10 4 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., Results: 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, β 2 -microglobulin＞7.4 mmol/L and regardless of age, etiologies, HScore points., Conclusion: 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.

Objective: To investigate the expression and clinical significance of soluble Fas (sFas) and sFasL in patients with secondary hemophagocytic lymphohistiocytosis (sHLH)., Methods: From September 2015 to December 2020, 86 sHLH patients who met the HLH2004 diagnostic criteria were collected. They were divided into 55 cases in the MAHLH group and 31 cases in the NonMAHLH group according to the etiology. Thirty healthy persons were chosen as the normal control group, and 20 patients with systemic lupus erythematosus (SLE) were chosen as the disease control group. The expression levels of sFas and sFasL in the serum of patients with each group were detected by ELISA, and the clinical data were collected for statistical analysis. The significance of sFas and sFasL in sHLH was analyzed by ROC curve., Results: Serum levels of sFas and sFasL in patients with newly diagnosed sHLH were significantly higher than those in disease control group and normal control group ( P <0.01). The levels of sFas and sFasL in MAHLH group were significantly higher than those in nonMAHLH (infection related HLH and autoimmune disease related HLH) group ( P <0.01). The serum levels of sFas and sFasL in 17 newly treated patients with sHLH (17/86) after treatment were significantly lower than those before treatment ( P <0.01). The serum sFas level in newly diagnosed sHLH patients was positively correlated with SF( r =0.35), sCD25( r =0.79) and sFasL( r =0.73). The serum sFasL level was positively correlated with SF( r =0.39), sCD25( r =0.64) and sFas( r =0.73). Compared with the NonMAHLH group, the area under the ROC curve was 0.707 (95% CI : 0.593-0.821) (P=0.0015). The optimal critical value for diagnosing MAHLH by sFas level was 12 743 pg/ml, and the sensitivity and specificity were 70.9% and 71% respectively. Compared with the NonMAHLH group, the area under the ROC curve was 0.765(95% CI : 0.659-0.87)( P <0.01). The median OS time of sFas high expression group (≥16798.5 pg/ml) and sFasL high expression group (≥4 785 pg/ml) was significantly shorter than that of the low expression group ( P <0.001)., Conclusion: Serum levels of sFas and sFasL can be used for the early diagnosis and differential diagnosis of sHLH disease, and are the factor related to the poor prognosis of sHLH.

This study aimed to examine the association between low T3 syndrome and overall survival (OS) in patients with secondary hemophagocytic lymphohistiocytosis (sHLH). The study consisted of 111 consecutive patients hospitalized due to newly diagnosed sHLH with detailed thyroid hormone profiles on admission. Low T3 syndrome was found in 75.7% of the studied sHLH population. After a median follow-up of 83 (interquartile range 25-365) days, there were 60 (71.4%) cumulative deaths in the low T3 syndrome group and 13 (48.1%) in the euthyroid group. Survival analysis showed a lower survival probability for patients with low FT3 than for those with normal FT3 (median OS, 60 vs. 365 days, p  = .011). In the multivariate analysis, low T3 syndrome was an independent prognostic factor for OS (HR = 2.474; 95% CI 1.351-4.532, p  = .003). Low T3 syndrome is frequently found and associated with worse outcomes in patients with sHLH.

Objective: To investigate the significance of plasma pentraxin 3 (PTX3) in patients with secondary hemophagocytic lymphohistiocytosis (sHLH). Methods: Plasma PTX3 levels were tested by ELISA in 48 newly diagnosed sHLH patients, 18 healthy volunteers and 9 lymphoma controls in the First Affiliated Hospital of Nanjing Medical University from January 2017 to July 2019. Clinical parameters were collected, and the correlations with PTX3 levels were analyzed. Results: PTX3 level in newly diagnosed group was significantly higher than that of healthy control group [16.29(1.17-66.00) vs. 0.76(0.01-7.86) μg/L, P< 0.01]. Patients with lymphoma-associated HLH(LHLH) had higher plasma level of PTX3 than Fhose with infection-associated HLH (IHLH) [24.29(3.36-66.00) vs. 9.56(1.17-36.50)μg/L, P< 0.05]. Plasma PTX3 levels in 48 sHLH patients were positively correlated with serum ferritin ( P< 0.05). Receiver operating characteristic (ROC) curve for plasma PTX3 levels of sHLH and healthy controls produced a cutoff value at 3.9 μg/L, with its 86.7% sensitivity and 94.4% specificity. And ROC analysis showed that PTX3 17.5 μg/L was the critical value for diagnosis of LHLH from non-LHLH group, that the sensitivity and specificity were 63.0% and 76.2% respectively. The 1-year overall survival (OS) rate in patients with PTX3≥17.5 μg/L was significantly lower in those with PTX3<17.5 μg/L (18.5% vs. 75.8%, P< 0.01). Conclusion: These results indicate the potential of PTX3 as a biomarker for diagnosis and prognosis in patients with sHLH.

Objective: To investigate the expression and clinical significance of soluble B7-H3 (sB7-H3) in patients with secondary hemophagocytic lymphohistiocytosis (sHLH)., Methods: The plasma samples of 85 newly diagnosed sHLH patients from December 2012 to April 2018 were collected. The patients were divided into lymphoma-related HLH（LHLH）group and infection-related HLH（IHLH）group. The expression of sB7-H3 in plasma was detected by ELISA, and the clinical data were collected for analysis. Fifteen healthy people were chosen as control group., Results: The expression level of sB7-H3 in lymphoma-related HLH and infection-related HLH group significant increased as compared with the control group, (P＜0.05), and the expression level of sB7-H3 in lymphoma-related HLH group was significant higher than that in infection-related HLH group [(35.75± 9.90) vs (28.70±8.95) ng/ml)] (P＜0.001). There were no significant statistical difference in the expression of some clinical factors (including age, fever, splenomegaly, ANC, Plt, FIB, calcium ion, serum albumin, LDH, serum ferritin, sCD25) in lymphoma-related HLH and infection-related HLH group (P＞0.05). The evaluation of expression and significance of sB7-H3 in sHLH by using ROC curve, showed that the area under ROC curve comparison of patients in lymphoma-related HLH group and infection-related HLH group was 0.718 (95% CI 0.610-0.810) (P=0.0002), and predicting the sensitivity and specificity of the lymphoma-related HLH patients were 77.36% and 59.38%, respectively. The best cut-off value of patients in sB7-H3 was 29.81 ng/ml, the overall survival time of sB7-H3 high-expression group (≥29.81 ng/ml) was significant shorter than that in low-expression group (＜29.81 ng/ml) (24 vs 440 d) (P＜0.001). The clinical factors affecting the survival status of sHLH patients were neutrophils, albumin, serum ferritin, serum calcium ions and sB7-H3 levels., Conclusion: sB7-H3 associates with poor prognosis of sHLH patients, and may be involved in disease progression.

Objective: To investigate the clinical characteristics of secondary hemophagocytic lymphohistiocytosis (sHLH) complicated with capillary leak syndrome (CLS) . Methods: The clinical and laboratory data of 87 sHLH patients, who were treated in our hospital between January 2015 and December 2017, were retrospectively analyzed. Depending on whether they were complicated with CLS, 21 sHLH patients were classified as the CLS-sHLH group, while 66 were classified as the non-CLS-sHLH group. The differences of clinical manifestations, laboratory tests, treatment and prognosis between the two groups were compared. Results: There was no significant difference in the etiology of sHLH between the CLS-sHLH group and the non-CLS-sHLH group ( P >0.05) . The neutrophil, fibrinogen and albumin levels in the CLS-sHLH group were lower than those in the non-CLS-sHLH group, while the triacylglycerol levels were higher than those in the non-CLS-sHLH group ( P <0.05) . Varying degrees of edema, weight gain, hypotension, hypoproteinemia, oliguria and multiple serous effusions were observed in the CLS-sHLH group. Among them, there were 15 patients that CLS get improved, and the medial time of improvement was 7 (5-14) days. The other 6 patients did not get remission, while they died within 6-30 days. The median overall survival of the CLS-sHLH group was lower than that of the non-CLS-sHLH group (75 days vs not reached, P =0.031) . Conclusions: There may be no correlation between the cause of sHLH and the occurrence of CLS. Severity of neutropenia, fibrinogen and albumin levels, and triglyceride levels may be accompanied for sHLH patients complicated with CLS. Patients with sHLH who complicated with CLS have a poor prognosis. Active treatment of HLH and its primary disease, reasonable fluid replacement and oxygen supply are crucial, which can effectively control disease progression.

Objective: To investigate the clinical significance of serum calcium concentrations and albumin levels in patients with secondary hemophagocytic lymphohistiocytosis (sHLH) . Methods: The clinical and laboratory data of 68 patients with newly diagnosed sHLH from April 2013 to April 2016, and 20 healthy controls were retrospectively analyzed. The patients were classified as the clinical remission group and the progression group according to the response criteria. To explore the changes of serum calcium concentrations and albumin levels in the patients, its correlations with other laboratory indexes and the impact on survival. Results: ①The serum calcium concentrations and albumin levels in lymphoma-related HLH group and non-tumor HLH group were lower than control group ( P <0.05) ; The serum calcium concentrations and albumin levels in the clinical remission group after treatment was higher than that before treatment ( P <0.01) , while in the progression group the serum calcium concentrations after treatment decreased ( P =0.002) , the albumin levels did not changed significantly ( P =0.086) .②The serum calcium concentrations in newly diagnosed sHLH patients was positively correlated with ANC, PLT, HGB ( P <0.05) , and negatively with ferritin ( P <0.05) ; The overall survival (OS) was significantly longer in patients with serum calcium concentration≥1.92 mmol/L than that<1.92 mmol/L (266 d vs 95 d, P =0.006) . ③The serum albumin levels in newly diagnosed sHLH patients was positively correlated with ANC, HGB ( P <0.05) , and negatively with ferritin ( P <0.05) ; The overall survival was longer in patients with serum albumin level ≥ 26.7 g/L than that<26.7 g/L (263 d vs 95 d, P =0.023) . ④The serum calcium concentrations in patients before treatment was positively correlated with serum albumin levels ( P <0.001) , and no significant correlation was found in control group ( P =0.079) . Conclusion: The serum calcium concentrations and albumin levels have clinical significance for disease diagnosis, decision-making therapy and treatment outcomes in the patients with sHLH.

Objective: To investigate the expression levels and clinical significance of serum high mobility group box 1 (HMGB-1) in patients with secondary hemophagocytic lymphohistiocytosis (sHLH)., Methods: Serum HMGB-1 levels were determined by using enzyme linked immunosorbent assays (ELISA) in 51 sHLH patients and 15 healthy contrlols. Other laboratory data, including soluble interleukin-2 receptor (sCD25), white blood cells (WBC), hemoglobin (Hb), platelet (Plt), fibrinogen (FIB), lactate dehydrogenase (LDH), triglyceride (TG), alanine transaminase (ALT), aspartate aminotransferase (AST), serum ferritin (SF), C reactive protein (CRP), and blood sedimentation rate (ESR) were also collected., Results: Serum HMGB-1 levels in the newly diagnosed group were significantly higher than that in the control group (P<0.01). Serum HMGB-1 levels in the newly diagnosed lymphoma-associated HLH (LHLH) group were significantly higher than that in non-HLH group, including infection-associated HLH (IHLH) and autoimmune-associated HLH (AHLH) group (P<0.05); The serum HMGB-1 levels in the clinical remission group were significantly lower than that in the newly diagnosed group (P<0.05), however, serum HMGB-1 was not decreased significantly in the progression/relapsed group, compared with the newly diagnosed group (P>0.05). Serum HMGB-1 levels in newly diagnosed sHLH patients positively correlated with sCD25 (r=0.62, P<0.01) and ESR (r=0.55, P<0.05). The receiver operating characteristic curves (ROC) for serum HMGB-1 levels of sHLH patients and healthy controls produced a cutoff value at 15.3 µg/L, with its 90% sensitivity and 99% specificity, respectively. In addition, an optimal cutoff value for HMGB-1 was 27.4 µg/L in the patients LHLH and non-HLH (AHLH+IHLH) with 96% sensitivity and 81% specificity, separately., Conclusion: Serum HMGB-1 levels possesses an important clinically significance for disease diagnosis, differential diagnosis, evaluation of nosographic activity and treatment efficacy in the patients with sHLH.

This study was aimed to detect the peripheral blood serum neopterin (Npt) level in the patients with hemophagocytic lymphohistiocytosis (HLH) and to explore its significance in HLH. The enzyme-linked immunosorbent assay (ELISA) was applied to detect the serum Npt level and sCD25 level in 20 HLH patients before and after treatment and 15 healthy controls. The results indicated that the serum Npt and sCD25 levels in HLH patients were significantly higher than those in healthy controls (P < 0.0001). The serum Npt and sCD25 levels in the HLH group decreased significantly after treatment, respectively (P < 0.0001). The correlation analysis of Npt with sCD25 before and after treatment showed that they had significant correlation (r = 0.81, P < 0.05 before treatment; r = 0.65, P < 0.05 after treatment). Meanwhile, the level of serum Npt and ferritin had a significant correlation in newly diagnosed HLH patients (r = 0.55, P < 0.05). It is concluded that the serum Npt may play an important role in the HLH pathogenesis, the enhancement of Npt levels has an important significance for diagnosis and evaluation for HLH.

This study was aimed to investigate the significance of 18F-FDG PET/CT in secondary hemophagocytic lymphohistiocytosis (sHLH) patients. A total of 18 patients received 18F-FDG PET/CT scan at initial diagnosis. All patients (18/18) had at least 3 organs involved, with increased FDG metabolism in different degrees. Fifteen cases (15/18) had definite underlying diseases, including infections (IAHLH), rheumatosis (RAHLH), or malignancy (MAHLH). The SUVmax of patients in MAHLH group was significantly higher than patients in IAHLH group or RAHLH group (P = 0.015, P = 0.045). Furthermore, the SUVmax of patients in IAHLH group was significantly higher than patients of RAHLH group (P = 0.043). Therefore, we concluded that 18F-FDG PET/CT may especially play important role in differential diagnosis of sHLH.

This study was aimed to detect the level of soluble interleukin-2 receptor (sCD25) and cytotoxic activity of NK lymphocytes in patients with hemophagocytic lymphohistiocytosis (HLH), and to explore their clinical significance in HLH. The enzyme-linked immunosorbent assay was used to detect the sCD25 level in serum of 20 patients with HLH, 15 healthy controls, 20 cases of acute myeloid leukemia and 20 cases of systemic lupus erythematosus. The NK cell cytotoxicity in peripheral blood of patients with HLH and controls were detected by flow cytometry with CD107a antibody labeling and LDH release assay. The results indicated that the level of sCD25 in HLH patients was significantly higher than that in healthy controls and disease groups (P < 0.001). The NK cell cytotoxicity in peripheral blood detected by both methods in patients with HLH were lower than that in healthy controls (P < 0.05), and the results detected by flow cytometry correlated significantly with those by LDH release assay (r = 0.73, P < 0.05). It is concluded that detection of sCD25 levels and NK cell activity in peripheral blood in HLH is of great value. Using flow cytometry following CD107a antibody labeling to measure NK activity is a simple, stability, reproducibility method and can be used for clinical diagnosis of HLH.

Treatment regimens of secondary hemophagocytic lymphohistiocytosis (sHLH) are complicated and individualized. CHOP regimen is well known for the treatment of adult sHLH, but it was not so effective for the 56-year-old male patient in our study. Splenomegaly, one of clinical manifestations of HLH, has urged us to investigate the role of splenectomy in HLH patients. Splenectomy is not only beneficial to confirm the underlying diseases, but also beneficial for the treatment of HLH. Here, we present a case diagnosed as sHLH who has recovered from HLH following comprehensive treatment based on splenectomy. The therapeutic value of splenectomy in sHLH needs further study., (Copyright © 2011 Elsevier Masson SAS. All rights reserved.)

This study was aimed to investigate the therapeutic efficacy of HLH-2004 chemotherapy in patients with secondary hemophagocytic lymphohistiocytosis (sHLH). 10 cases of sHLH treated with HLH-2004 regimen at our department were analyzed retrospectively. The results showed that 7 patients had clinical response to HLH-2004 regimen, while other 3 patients had no clinical response. 5 cases did not complete initial therapy of 8 weeks. Out of 5 cases, 4 died in the process of chemotherapy, 1 patient abandoned for serious side effects but finally acquired remission following 4 cycles of CHOP regimen. 5 cases underwent the whole courses of initial therapy. Out of 5 cases, 3 patients acquired remission, and other 2 were not well controlled. Out of the 3 patients who had achieved remission, one died of relapse, and other 2 patients kept remission. Out of the 2 patients who were not well controlled, one patient died, but another patient acquired remission after being discharged. It is concluded that patients with infection-associated hemophagocytic syndrome (IAHS) have high rates of remission after receiving HLH-2004 regimen combining with effective antibiotics. However, patients with HLH secondary to EBV (EBV-HLH) or lymphoma (LAHS) have low rates of remission or are easy to get relapse after remission.