Central Nervous System Involvement in Hemophagocytic Lymphohistiocytosis in Adults: A Retrospective Analysis of 96 Patients in a Single Center.

BACKGROUND: Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening clinical syndrome. Central nervous system (CNS) involvement is a severe complication, which can lead to rapid disease development and higher morality. However, this has not been given enough attention in adult HLH. Therefore, we carried out this study to analyze the clinical features, laboratory findings, treatment outcomes, and other characteristics of adult HLH with CNS involvement. METHODS: A retrospective analysis of 96 adult patients with HLH combined with CNS involvement between June 2003 and December 2016 was conducted. Clinical features, cerebrospinal fluid (CSF) features, image changes, and therapeutic outcomes were analyzed. RESULTS: Among the 96 patients, 86 had various CNS symptoms and 33 (38.4%) had already presented symptoms before the HLH diagnosis was confirmed. A total of 59 patients received CSF examinations and showed abnormalities in 23 patients (39.0%). Seventy patients received imaging examinations and the results showed fifty patients with imaging changes (71.4%). Fifty-seven patients received multiple rounds of repeated intrathecal injection therapy and 35 patients improved (61.4%). As for the multiple analyses of effective factors on survival time, the results showed that the effects of combined Epstein-Barr virus (EBV) infection (P = 0.026, Exp(B) = 2.309, 95% confidence interval [CI] [1.108, 4.823) and intrathecal injection therapy (P = 0.013, Exp(B) = 0.422, 95% CI [0.214, 0.831]) on the survival time of the CNS-HLH patients were significant. CONCLUSIONS: Complication with EBV infection is a risk factor, and intrathecal injection is a protective factor. CNS involvement in HLH is not rare, which can result in a poor prognosis. Multiple rounds of repeated intrathecal injection therapy can improve the prognosis of CNS-HLH patients.

Multivariate analysis of prognosis for patients with natural killer/T cell lymphoma-associated hemophagocytic lymphohistiocytosis.

OBJECTIVE: A major cause of hemophagocytic lymphohistiocytosis (HLH) is malignant neoplasms of the blood system, among which NK/T cell lymphoma is one of the most common risk factors. Patients with NK/T cell lymphoma hemophagocytic lymphohistiocytosis (NK/T-LAHS) have a worse prognosis and higher mortality. We aimed to explore the factors that affect the prognosis of NK/T-LAHS. METHODS: Clinical data of 42 patients with NK/T-LAHS diagnosed by Beijing Friendship Hospital from June 2008 to June 2016 were analyzed retrospectively. The survival time was counted until 1 August 2016. RESULTS: For the 42 NK/T-LAHS patients, 1-month survival rate was 48.9%, 2-month survival rate was 36.7%, 3-month survival rate was 28.8%, 6-month survival rate was 23.0%, and 12-month survival rate was 15.4%. NK/T-LAHS patients who underwent allogeneic hematopoietic stem cell transplantation (Allo-HSCT) (p = 0.000), exhibited peripheral blood Epstein-Barr virus (EBV)-positivity (p = 0.004), and achieved overall response (OR) remission after initial induction therapy (p = 0.007) had statistical significance. CONCLUSION: NK/T-LAHS is a disease of poor prognosis and high mortality. NK/T-LAHS patients who achieved OR remission after the initial induction therapy had a better prognosis than non-remission patients and Allo-HSCT was an effective way to prolong the survival of NK/T-LAHS patients. However, EBV positivity in peripheral blood was a poor prognostic factor in NK/T-LAHS patients.

Application of an improved flow cytometry-based NK cell activity assay in adult hemophagocytic lymphohistiocytosis.

Low or absent natural killer (NK) cell activity is included as one of the HLH-2004 diagnostic criteria. To improve the diagnosis of HLH, we aimed to establish a rapid and reliable NK cell activity assay that avoids the use of radioactivity. The K562 cell line, as standard NK target cells, was engineered to stably express enhanced green fluorescent protein (EGFP), which can be quantified by flow cytometry. The EGFP-flow cytometry method for measuring NK cell activity was improved by double staining of early and late apoptotic target cells. Whole-blood samples from healthy volunteers were assessed with this method, which demonstrated that optimal conditions were effector-target ratio of 10:1 and incubation time of 4 h. This method was further evaluated for samples from 113 HLH patients and 64 healthy volunteers. Mean NK cell activity in either primary or secondary HLH patients was significantly lower (P < 0.001) than in healthy individuals (20.23 ± 4.12%). Furthermore, primary HLH patients (10.76 ± 2.54%) exhibited even lower (P < 0.001) NK cell activity compared with secondary HLH patients (15.01 ± 3.62%). We have optimized and implemented this method in clinically relevant samples.

[Treatment outcomes and prognostic analysis of 61 Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis].

OBJECTIVE: To investigate the outcomes, survival status, and the prognostic factors of Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis (EBV-HLH) patients. METHODS: A retrospective study was carried out to analyze the clinical data of 61 EBV-HLH cases, from January 2008 to July 2014. Prognostic factors were analyzed through COX model (single factor and multiple factors). RESULTS: A total of 246 patients with HLH were diagnosed, among which 102 cases were with EBV infection (including 61 EBV-HLH, 36 lymphoma associated HLH, 5 primary HLH. Among the 61 cases, 40 were male and 21 were female, with a ration of 1.9:1. The median age was 28 years (range, 12-78). 1, 3, 6 and 12-month overall survival rates of 61 EBV-HLH were 65.6%, 47.5%, 32.4%, and 25.0%, respectively. The median follow-up time was 3 (0.5-28) months. 12 patients didn't use etoposide within 4 weeks after diagnosis, while HLH-94 protocol was used in 33 patients and HLH-2004 protocol was used in 16 patients. Response rates of theses three groups were 33.3%, 51.5%, and 43.8%, respectively (P=0.401). There was statistically difference between the group without etoposide and the HLH-94/ HLH-2004 group in the overall survival rate (P=0.033). Serum albumin level (P=0.033) and whether EBV could became negative (P=0.010) were independent predictors for EBV-HLH. CONCLUSION: EBV-HLH patients have severe clinical feature and poor prognosis. Early application of immune chemotherapy based on etoposide can improve survival. Serum albumin level and whether EBV can become negative are independent prognostic factors for survival.

[A multicenter retrospective etiological analysis of 601 patients with hemophagocytic lymphohistiocytosis in China].

OBJECTIVE: To investigate the prevalence and etiology of hemophagocytic lymphohistiocytosis (HLH) in different age groups. METHODS: Clinical data of patients with HLH were retrospectively collected from June 2005 to March 2014 in 49 hospitals in China. These patients were divided into child, youth, middle-aged and elderly groups according to the age of onset; meanwhile divided into primary HLH group, infection-associated HLH group, tumor-associated HLH group, rheumatic disease-associated HLH group according to the etiology. Prevalence rates, gender and underlying diseases of each group were retrospectively analyzed. RESULTS: A total of 601 patients were included in the study, age ranging from 1 month to 82 years. The median age of onset was 27 years and 26 years respectively in males(316 cases) and females (285 cases) without statistical significance (P=0.622). There were 171 in child group (28.5%); 262 in youth group(43.6%); 104 in middle-aged group(17.3%); 64 in elderly group(10.6%). The most common causes were infections in child group, malignancies and infections in youth group, malignancies in middle-aged group as well as elderly group. There were 48 patients in primary HLH group(8.0%), 197 in infection-associated HLH group(32.78%), 208 in tumor-associated HLH group(34.61%), 56 in rheumatic disease-associated HLH group(9.32%). Patients with primary HLH were significantly younger than those with secondary HLH (P<0.001), however the tumor-associated HLH group was the eldest. Primary HLH, infection-associated HLH and tumor-associated HLH had more male patients but without statistical significance (P=0.196), while rheumatic disease-associated HLH was mostly female patients (P<0.001). CONCLUSIONS: HLH is not a disease peculiar to children, instead, it may occur in all ages. There are a variety of etiology in different age groups, and a possible link between sex and HLH development. In clinical practice, due attention should be paid to the patients with suspected HLH. Positive relevant inspections may aid in the final diagnosis.

[Clinical analyses of 80 hemophagocytic lymphohistiocytosis patients with Epstein-Barr viremia].

OBJECTIVE: To analyze the clinical characteristics, treatment and prognosis of hemophagocytic lymphohistiocytosis (HLH) patients with Epstein-Barr viremia (EBV). METHODS: A retrospective study was conducted to analyze the clinical data of 80 HLH patients aged ≥ 14 years with EBV-DNA >1 000 copies/ml in peripheral blood from 2008 to 2013. RESULTS: There were EBV-HLH (n = 46), HLH-associated lymphoma (n = 30) and primary HLH (n = 4). Among the relevant laboratory parameters, inter-group statistical differences existed only in alanine transaminase (ALT) and aspartate aminotransferase (AST) (P = 0.021, 0.035). The median follow-up period was 2.0 (0.5-20.0) months. And the 1-month, 3-month, 6-month and 12-month overall survival rates were 58.8%, 37.5%, 29.7% and 19.6% respectively. CONCLUSIONS: HLH patients with EBV have a pernicious clinical course with a poor prognosis. And it makes little sense for distinguishing HLH-associated lymphoma from EBV-HLH through routine laboratory tests.

[Clinical characteristics of 192 adult hemophagocytic lymphohistiocytosis].

OBJECTIVE: To analyze the clinical manifestations, laboratory data, therapy, and prognosis in patients with hemophagocytic lymphohistiocytosis (HLH). METHODS: A retrospective study was carried out in 192 adult patients with HLH between 2003 and 2013. RESULTS: Of the 192 cases, 70 cases were secondary to cancer and 64 cases secondary to infection. According to HLH-2004 criteria, the coincidence rate of indices were: fever (98.96%), high level of serum ferritin (94.27%), increased level of soluble interleukin- 2 receptor(sCD25) (94.79%), decreased or absent activity of NK cells (94.27%), cytopenias (80.73%), splenomegaly (80.21%), emophagocytosis in bone marrow, spleen or lymph nodes (74.48%), hypofibrinogenemia (50.52%), hypertriglyceridemia (37.50%). In addition, 94.27% of patients were presented with liver dysfunction, 96.35% with infections, and 75.52% with coagulopathy. Incidences of central nervous system symptoms and rash were 19.27% and 20.31%, respectively. Among cancer, infection and rheumatic group, there were statistically differences on white blood cells (WBC), platelet (PLT), sCD25, alanine aminotransferase, aspartate aminotransferase, total bilirubin and globulin(GLO) (P<0.05). The differences of WBC, PLT, albumin (ALB), GLO, brain natriuretic peptide, creatinine, urea nitrogen between survival group and death group had statistical significance. CONCLUSION: The secondary HLH occurs from various underlined diseases. Cancer, especially T- cell lymphoma, is the main cause, Secondly, it is EB virus infection. The diagnostic sensitive indicators are Persistent fever, higher level of serum ferritin, low or absent NK-cell activity, and increased sCD25 were the most valuable parameters for diagnosis. Cytopenias were not common in early phase of HLH secondary to rheumatic diseases. WBC, PLT, ALB, GLO could be used as the preliminary parameters for diagnosis. Cardiac insufficiency, renal insufficiency and coagulation dysfunction play important roles in prognosis.