Hemophagocytic Lymphohistiocytosis Patients Research Articles

Beta 2-microglobulin is an independent risk marker of acute kidney injury in adult patients with hemophagocytic lymphohistiocytosis.

The role of beta2-microglobulin (β2-MG) in predicting acute kidney injury (AKI) in hemophagocytic lymphohistiocytosis patients has been poorly studied. This study aimed to analyze the clinical characteristics of hemophagocytic lymphohistiocytosis patients and identify risk factors that predict AKI development. This retrospective observational cohort study conducted ata single-centerinvolved 938 patients diagnosedwith hemophagocytic lymphohistiocytosis, who were divided into AKI groupand non-AKI group. Patient data were collected and analyzed usingunivariate and multivariate binary logistic regression to identify potiential risk factors associated with AKI occurrence. RESULTS: Among the enrolled patients, 486 were male (51.9%), the median age was 37years (interquartile range, 28.0, 52.0), 58.4%experienced AKI. Mechanical ventilation (8.0% vs. 0.8%) and vasopressor support (21.7% vs. 4.1%) occurred at significantly higher rates in the AKI group compared to the non-AKI group, with significantly higher in-hospital mortality (5.5% vs. 1.3%) and 28-day mortality (12.8% vs. 5.4%). When β2-MG was used as a continuous variable, multifactorial analysis showed that β2-MG, transplantation, and vasopressor support were independently associated with risk for the development of AKI. The incidence ofmorbidity and mortality in patients with hemophagocytic lymphohistiocytosis complicated by AKIremains high. Monitoring levels ofβ2-MG may provide clinicians with timely indicatorsofchanges in renal function, facilitating adjustments to treatment strategies.

Inhibition of interferon gamma impairs induction of experimental epidermolysis bullosa acquisita.

Epidermolysis bullosa acquisita (EBA) is a muco-cutaneous autoimmune disease characterized and caused by autoantibodies targeting type VII collagen (COL7). The treatment of EBA is notoriously difficult, with a median time to remission of 9 months. In preclinical EBA models, we previously discovered that depletion of regulatory T cells (Treg) enhances autoantibody-induced, neutrophil-mediated inflammation and blistering. Increased EBA severity in Treg-depleted mice was accompanied by an increased cutaneous expression of interferon gamma (IFN-γ). The functional relevance of IFN-γ in EBA pathogenesis had been unknown. Given that emapalumab, an anti-IFN-γ antibody, is approved for primary hemophagocytic lymphohistiocytosis patients, we sought to assess the therapeutic potential of IFN-γ inhibition in EBA. Specifically, we evaluated if IFN-γ inhibition has modulatory effects on skin inflammation in a pre-clinical EBA model, based on the transfer of COL7 antibodies into mice. Compared to isotype control antibody, anti-IFN-γ treatment significantly reduced clinical disease manifestation in experimental EBA. Clinical improvement was associated with a reduced dermal infiltrate, especially Ly6G+ neutrophils. On the molecular level, we noted few changes. Apart from reduced CXCL1 serum concentrations, which has been demonstrated to promote skin inflammation in EBA, the expression of cytokines was unaltered in the serum and skin following IFN-γ blockade. This validates IFN-γ as a potential therapeutic target in EBA, and possibly other diseases with a similar pathogenesis, such as bullous pemphigoid and mucous membrane pemphigoid.

Somatic mutations in FAS pathway increase hemophagocytic lymphohistiocytosis risk in patients with T- and/or NK-cell lymphoma

AbstractAlthough significant progress has been made in understanding the genetic basis of primary hemophagocytic lymphohistiocytosis (HLH), the pathogenesis of secondary HLH, the more prevalent form, remains unclear. Among the various conditions giving rise to secondary HLH, HLH in patients with lymphoma (HLH-L) accounts for a substantial proportion. In this study, we investigated the role of somatic mutations in the pathogenesis of HLH-L in a cohort of patients with T- and/or natural killer–cell lymphoma. We identified a 3-time higher frequency of mutations in FAS pathway in patients with HLH-L. Patients harboring these mutations had a 5-time increased HLH-L risk. These mutations were independently associated with inferior outcome. Hence, our study demonstrates the association between somatic mutations in FAS pathway and HLH-L. Further studies are warranted on the mechanistic role of these mutations in HLH-L.

A Retrospective Review of Secondary Hemophagocytic Lymphohistiocytosis (HLH) and Dengue-associated HLH from a Teaching Hospital in Singapore.

Real-world data on the outcome of Asian patients with secondary hemophagocytic lymphohistiocytosis (HLH), especially on dengue-associated HLH, are limited to small case series. This is a retrospective records review of adult patients with secondary HLH between 2015 and 2020. Thirty-two adult patients were followed up for a median of 6.6 months (range 0.1 - 75 months). 15 had underlying lymphomas, and 12 had viral infections. Hemophagocytosis was seen in 28 of 29 patients with a bone marrow biopsy. 100% and 76.5% of patients with and without an underlying malignancy required HLH-directed therapy and blood product transfusion. 12 of 15 patients with lymphomas were treated with additional chemotherapy. Patients with malignancy-associated HLH had poorer survival than non-malignancy-associated HLH (median overall survival (OS) 1.5 months versus not reached, p-value 0.003). The 1-year survival rates of patients with malignancy-associated HLH, HLH with unknown etiologies, and infection-associated HLH were 0.133 (95% CI: 0.036 - 0.484), 0.400 (95% CI: 0.137 - 1.000) and 0.833 (95% CI: 0.647 - 1.000), respectively. Malignancy significantly increased the risk of death compared to infection-associated HLH (HR 9.37, p-value 0.003). Eight patients were diagnosed with dengue-associated HLH with a median HSCORE of 240 (98-99% probability of HLH). Their mean ferritin was 34,740 ng/mL. Three patients required blood product transfusion, 5 required corticosteroids and/or etoposide, with a median duration of treatment of 31 days. Their overall survival rate was 87.5%. Our study highlights the stark contrast in the survival of secondary HLH patients with and without an underlying malignancy. We also present one of the world's most extensive case series of dengue-associated HLH.

HLH as an additional warning sign of inborn errors of immunity beyond familial-HLH in children: a systematic review.

Hemophagocytic Lymphohistiocytosis (HLH) is a rare and life-threatening condition characterized by a severe impairment of the immune homeostasis. While Familial-HLH (FHL) is a known cause, the involvement of other Inborn Errors of Immunity (IEI) in pediatric-HLH remains understudied. This systematic review aimed to assess the clinical features, triggers, laboratory data, treatment, and outcomes of pediatric HLH patients with IEI other than FHL (IEInotFHL), emphasizing the importance of accurate identification and management. A systematic search for studies meeting inclusion criteria was conducted in PubMed, EMBASE, MEDLINE, and Cochrane Central. Quality assessment was performed through JBI criteria. A comprehensive search yielded 108 records meeting inclusion criteria, involving 178 patients. We identified 46 different IEI according to IUIS 2022 Classification. Combined immunodeficiencies, immune dysregulation disorders, and phagocyte defects were the IEI most frequently associated with HLH. In 75% of cases, HLH preceded the IEI diagnosis, often with an unrecognized history of severe infections. Triggers reflected the specific infection susceptibilities within IEI groups. Liver and central nervous system involvement were less common than in FHL cases. Treatment approaches and outcomes varied, with limited long-term follow-up data, limiting the assessment of therapeutic efficacy across IEI groups. A comprehensive evaluation encompassing immunological, infectious, and genetic aspects is essential in pediatric-HLH. Relying solely on FHL or EBV susceptibility disorders tests is insufficient, as diverse other IEI can contribute to HLH. Early recognition of HLH as a potential warning sign can guide timely diagnostic investigations and facilitate tailored therapeutic interventions for improved outcomes. https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=371425, PROSPERO, CRD42022371425.

Comparison of different treatment regimens and analysis of prognostic factors in secondary hemophagocytic lymphohistiocytosis in adults: A single-center retrospective study.

Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening disease caused by immune hyperactivation. The overall survival (OS) of adults with secondary HLH remains suboptimal and new treatment strategies are needed. This study aimed to compare the efficacy of different regimens in the treatment of secondary HLH in adults and analyze the prognostic factors affecting patient survival. The clinical data of 245 adults with secondary HLH admitted to our hospital from January 2016 to October 2021 were analyzed retrospectively. The patients were divided into 3 groups according to different treatment regimens: corticosteroids therapy + chemotherapy + supportive treatment group (JHZ group), chemotherapy + supportive treatment group (HZ group) and corticosteroids therapy + supportive treatment group (JZ group). The clinical efficacy was compared among the 3 groups after treatment, and progression-free survival (PFS) and overall survival (OS) were calculated. Additionally, risk factors associated with prognosis were also analyzed with Cox regression analysis. The objective response rate (ORR) in the JHZ group was higher than that in the HZ group and JZ group, but there was no significant difference between the 3 groups. Also, the patients in the JHZ group had the longest OS and median PFS. Further Cox regression analysis suggested that hyperbilirubinemia was an independent risk factor for OS in secondary HLH patients. A combination of corticosteroids therapy, chemotherapy and supportive therapy is superior to the other 2 regimens in the clinical benefit in the treatment of secondary HLH in adults, and thus may be a preferred and feasible treatment regimen. Moreover, hyperbilirubinemia was a risk factor for prognosis that has crucial guiding significance for clinical treatment of patients with secondary HLH.

Prognostic Factors of Adult Hemophagocytic Lymphohistiocytosis and Clinical Utility of HLH-2004 Diagnostic Criteria and HScore: A Real-World Multicenter Study from Thailand

Introduction: Adult hemophagocytic lymphohistiocytosis (HLH) is a rare disease with a dismal prognosis. Early diagnosis and prompt management are necessary for improved outcomes. Methods: This multicenter retrospective study investigated the etiologies, survival, and prognostic factors of HLH, including the utility of HLH-2004 criteria and HScore in real-life clinical practice. Results: A total of 147 HLH patients were identified by using a combination of hemophagocytosis identification in bone marrow and the HLH-related international classification disease-10. A total of 116 (78.9%) patients fulfilled the HLH diagnosis by HScore, while 91 (61.9%) patients fulfilled 5 of 8 HLH-2004 criteria. In Thailand, the clinical application of HLH-2004 criteria needed to be reduced from 8 to 6 due to a lack of sCD25 and natural killer cell activity tests. Using the adapted HLH-2004 with a cutoff value of 4 resulted in 132 (89.9%) cases meeting the diagnostic criteria. Among these 132 confirmed HLH patients by using adapted HLH-2004, HLH was triggered by infection (29.5%), autoimmune disease (12.9%), malignancy (40.9%), and unknown cause (16.7%). Median overall survival of HLH patients was extremely short (67 days). Ferritin >6,000 μg/L, HLH from infection, malignancy, and unknown etiology were demonstrated as independent prognostic factors for inferior survival (hazard ratio [HR] 2.47; 95% confidence interval [CI] 1.39–4.37, HR 4.69; 95% CI 1.38–15.92, HR 6.09; 95% CI 1.84–20.14, and HR 6.02; 95% CI 1.64–22.05, respectively). Conclusion: Ferritin is a helpful biomarker for HLH diagnosis and prognostic prediction. Autoimmune disease-triggered HLH has favorable outcomes. Future prospective study is required to verify the use of the adapted HLH-2004 criteria.

Clinical Features of Hepatic Manifestations among Adult Patients with Hemophagocytic Lymphohistiocytosis: A Retrospective Study

Introduction: Liver dysfunction is common in patients with hemophagocytic lymphohistiocytosis (HLH). However, whether the severity of liver injury is associated with the prognosis of patients with HLH remains to be determined. This study aims to assess the association of the severity of liver involvement with short-term prognosis among adult patients with HLH. Methods: A retrospective study was performed from January 2012 to December 2020, including 150 patients with newly diagnosed HLH and liver injury. Results: The majority of our cohort suffered from mild to moderate hepatic damage, presenting with Child-Turcotte-Pugh (CTP) class A (55, 36.7%) or B (74, 49.3%). The prevalence of acute liver failure (ALF) was 9.3% in our cohort. The overall 30-day mortality rate was 49.3% among the study population. HLH patients with ALF showed an extremely adverse prognosis, with a mortality rate as high as 92.9%. In a multivariate analysis, age ≥60 years (p = 0.016), blood urea nitrogen (BUN) ≥7 μmol/L (p p p p p Conclusion: Patients with old age, elevated BUN, and malignancy had inferior survival. CLIF-SOFA and SOFA enable more accurate prediction of early death in HLH patients with liver injury than other liver-specific and general prognostic models.

Single-Cell RNA Sequencing Reveals Contradictory Immune Microenvironment in Hemophagocytic Syndrome

Hemophagocytic lymphohistiocytosis (HLH), a formidable and rare clinical syndrome impacting multiple organs, manifests as a perilous condition. However, the intricate pathophysiological mechanisms underlying HLH remain yet to be fully elucidated. In this study, we obtained peripheral blood samples from 9 HLH patients spanning the years 2018 to 2022. Employing single-cell RNA sequencing (scRNA-seq), we conducted a comprehensive analysis of the alterations in the immune microenvironment, delving into the role of EBV infection in HLH and its influence on pathogenesis. By comparing with health donor peripheral blood , we identified a total of 11 significant immune cell populations among 72,779 single-cell transcriptomes, comprising 20,337 cells from healthy controls and 52,442 cells from HLH patients. Notably, we found that the proportion of T cells increased significantly, and other immune cells decreased in HLH patients. In terms of function, we found that the overall T cell killing ability was weakened, and the factor secretion ability was enhanced. Concerning myeloid cells, the impact of CD16+ monocytes on T cells exhibited a pronounced increase, along with an enhanced ability to secrete IL-18 factors, potentially serving as the main source of cells promoting T cell function. Different subpopulations of T cells have significant changes in the pathogenesis of HLH. Remarkably, both CD4+ T cells and CD8+ T cells exhibited HLA-DR+GZMK+ cell subgroups with upregulated IFN-γ production and response, suggesting their association with the hyperinflammatory state in HLH. A correlation analysis between the proportion of HLA-DRA+ GZMK+ T cells and the severity score revealed a significant correlation (p<0.05), with the ROC curve further affirming their predictability in assessing high inflammatory activity. Among CD4+ T cells, the proportion of Treg cells and the secretion of inhibitory factors such as TGFb1 decreased. Additionally, we noted the presence of a functionally impaired subset of CBLB+CD8+ T cells, indicating the considerable variability in T cell subset functionality in HLH. Next, a comprehensive analysis of the alterations in myeloid cells, B cells, and NK cells in HLH patients was conducted. We observed a substantial reduction in the number of DC cells and immune-related functions within various myeloid cell subsets. Regarding B cells, an increase in anergy B cells was observed, whereas the population of plasma cells, an effective B cell type, exhibited a decrease. In the context of NK cells, there was a significant increase in the proportion of NK cell subsets associated with IFN-γ secretion. Moreover, EBV-infected T cells in EBV-associated HLH were identified as the principal source of IFN-γ. Through single-cell EBV-CALL analysis, we found that IFN-γ secretion was primarily attributed to EBV-infected T cells, subsequently influencing CD16+ monocytes. Additionally, IL-16 production was predominantly observed in EBV-infected CD16+ monocytes, thereby impacting lymphocytes. Moreover, Monocytes were stimulated by EBV-infected CD4+ T cells and Atypical T cells, leading to the secretion of a pro-inflammatory factors such as MIF. Furthermore, our investigation unveiled that EBNA2 could promote MYC into the nucleus and enhance the proliferation and IFN-γ secretion of T cells. In conclusion, our comprehensive analysis of the immune microenvironment changes following the onset of HLH has yielded valuable insights and novel perspectives for understanding the underlying mechanisms and potential clinical treatments of this condition.

The Identification and Characterization of Retrospective Cohorts of Secondary Hemophagocytic Lymphohistiocytosis (sHLH) Patients in the United States

Background:Hemophagocytic lymphohistiocytosis (HLH) is a rare and life-threatening hyperinflammatory syndrome induced by aberrantly activated myeloid and T cells. Primary or familial HLH (pHLH) is a genetic disorder that typically presents in young children. Secondary HLH (sHLH), which can occur at any age but is most common in adults, is triggered by infection, autoimmune disease, malignancy, or other conditions. Without treatment, HLH is universally fatal; even with existing etoposide-based regimens, survival remains low, particularly for malignancy-associated sHLH. There are no approved therapies specifically for sHLH, and most of our understanding of HLH diagnosis comes from studies of pHLH. The aim of this study is to assemble historical cohorts of sHLH patients from two, large US medical systems to better understand and refine the sHLH clinical definition, characterize demographic, clinical, and treatment characteristics, and compare survival and healthcare resource utilization (HRU) of the cohorts to matched comparison groups. Preliminary findings on the identification of sHLH patients at one US site were previously described [Broome et al., Blood (2022) 140 (Supplement 1): 5490-5491]. Data on sHLH patient identification at both sites are presented here. Methods: Two Electronic Medical Record (EMR) systems were queried to identify potential patients (site 1: 2009-May 2022 with no age restrictions and site 2: 2006-2022 patients >18 years of age). Three methods were developed for patient identification. Method 1 identified patients with any mention of an HLH-related ICD code (ICD-9 288.4; ICD-10 D76.1, D76.2, D76.3). Method 2 identified patients with combinations of an elevated ferritin value (1,000-10,000 ng/mL or >10,000 ng/mL) or a sCD25 test (predictive markers of malignancy-associated sHLH from the Optimized HLH Inflammatory [OHI] index). Method 3 identified patients with etoposide and dexamethasone treatment, removing patients receiving this treatment as part of a chemotherapy regimen. Full chart review of some cohorts was not logistically feasible because of their size (no ferritin >1,000 AND any sCD25 test, ferritin >10,000 AND no sCD25 test, and etoposide and dexamethasone treatment); in these instances, patient records were screened for a mention of HLH or MAS. At each site, one clinician reviewed all charts, and a second clinician reviewed a random sample. HLH diagnosis was assigned based on expert judgement, and all diagnostic conflicts were resolved between the two clinicians. Clinical and diagnostic data on sHLH patients were pulled from the EMR by the reviewing clinician. Results: 528 patients were identified at site 1 via the three methods and their charts were reviewed confirming 65 patients with sHLH. Likewise, among 714 charts reviewed at site 2, 188 patients were confirmed with sHLH. Among all patients with an ICD code (Method 1), 17% (56/327) were determined to have sHLH at site 1 and 33% (162/488) at site 2. Among patients reviewed with ferritin/sCD25 features (Method 2), 4% (9/200) were determined to have sHLH at site 1 and 11% (25/212) at site 2. Among patients reviewed with Method 3, 0% (0/1) were determined to have sHLH at site 1, and site 2 data were not available. (See Table 1) Additional analyses on clinical and treatment characteristics of the sHLH cohorts and survival/HRU comparisons will be presented. Conclusions: Since HLH is a rare, heterogeneous, and complex disease to diagnose and treat, HLH-related ICD codes may not accurately and sufficiently capture the spectrum of HLH patients in EMRs.Clinical indicators of disease were essential for identifying additional patients with this rare disorder. The general consistency of the findings between the two study sites supports the application of this patient identification algorithm across diverse medical centers.

Caebv Disease Originates from Infected Hematopoietic Stem Cells

Background Chronic active Epstein-Barr Virus (EBV) disease (CAEBV) is lethal syndrome due to persistent EBV infection. When diagnosed as CAEBV, EBV infection was observed in multiple hematopoietic lineages, but the etiology of CAEBV is still elusive. Methods Bone marrow and peripheral cells derived from five CAEBV patients, one EBV-associated hemophagocytic lymphohistiocytosis (EBV-HLH) patient, and two healthy controls were analyzed. Multiple assays were applied to identify and characterize EBV-infected cells, including quantitative PCR (qPCR), PrimeFlow and single-cell RNA-sequencing (scRNA-seq). Based on scRNA-seq data, alterations in gene expression of particular cell types were analyzed between CAEBV patients and controls, and between infected and uninfected cells. One CAEBV patient was treated with allogeneic hematopoietic stem cell transplantation (HSCT), and the samples derived from this patient were analyzed again six month after HSCT. Results EBV infected the full spectrum of the hematopoietic system including both lymphoid and myeloid lineages, so as hematopoietic stem cells (HSCs) in the CAEBV patients. EBV-infected HSCs exhibited a higher differentiation rate towards 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. Conclusions Token together,multiple lines of evidence presented in this study suggest that CAEBV disease originates from the infected hematopoietic stem cells. Figure 1. EBV-infected HSCs were detected in CAEBV patients with multiple assays.

The Lymphocyte Subsets Activation Profiles in Peripheral Blood May Contribute to the Diagnosis of Natural Killer/T-Cell Lymphoma-Associated Hemophagocytic Lymphohistiocytosis

The lymphocyte subsets activation profiles in peripheral blood may contribute to the diagnosis of natural killer/T-cell lymphoma-associated hemophagocytic lymphohistiocytosis Background: Hemophagocytic lymphohistiocytosis (HLH) is a rampant and potentially fatal systemic hyperinflammation characterized by dysfunction of macrophages and cytotoxic T cells. Natural killer/T-cell lymphoma (NKTCL) has been reported to be one of the most common etiologies of HLH among hematologic neoplasms. Although, the diagnosis of natural killer/T-cell lymphoma-associated hemophagocytic lymphohistiocytosis (NK/T-LAHS) refers to the HLH-2004 diagnostic guidelines for primary HLH, most of them are based on non-specific clinical features. Identification of the immunophenotype characteristics is important for the diagnosis of NK/T-LAHS. In this study, we investigated the lymphocyte subsets activation profiles of peripheral blood mononuclear cells (PBMC) from NKTCL patients, and preliminarily screened molecular marker with potential diagnostic value for NK/T-LAHS. Methods: This study retrospectively collected peripheral blood samples from 58 patients diagnosed with NKTCL in Sun Yat-sen University Cancer Center from September 2020 to December 2022. Among them, 29 patients had HLH at the time of enrollment, and peripheral blood samples from 10 healthy people were collected as the control group. NKTCL was diagnosed according to the 2016 WHO classification of malignant lymphoma. All HLH patients met HLH-2004 diagnostic criteria and primary HLH was excluded. Flow cytometric staining of PBMC was performed on BD Fortessa according to the manufacturer's instructions. All samples were analyzed by Flowjo（V10）software. The ROC curve was drawn according to the percentage of lymphocyte subsets to determine the optimal cutoff threshold. RStudio 4.2.1 was used to calculate the sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) and likelihood ratio (LR) of the related indicators. Graphpad prism 8.0.1 and SPSS 26.0 (IBM) was used for drawing and statistical analysis. All statistical tests were two-sided, and p＜0.05 were considered statistically significant. Results:The median age of 58 patients was 41 (range, 18-83) years old, and 10 patients (17.2%) had poor performance status (ECOG PS≥2). Forty-two patients (72.4%) were stage III-IV, and 26 patients (44.8%) had PINK-E score≥3. Firstly, we compared the immune cell activation profiles between healthy donors, NKTCL patients with or without HLH. We observed that the proportion of functionally activated T cells, NK cells, NKT cells that expressed CD86, CD69, or HLADR was significantly higher than healthy donors ( p＜0.05), except for CD86+NK cell levels was no significance between the three groups (Figure1). In addition, the percentage of CD86+NK/T cells, CD69+NK cells, HLADR+NK cells and HLADR+NKT cells were significantly higher than NKTCL patients without HLH and healthy controls( p＜0.05), and no significant difference of these immune cells subsets between those non-HLH patients and healthy controls was observed (Figure1). Based on the significance of these lymphocyte subsets in NKTCL patients with and without HLH, we evaluated the diagnostic value of CD86+NKT cells, CD69+NK cells, HLADR+NK cells, and HLADR+NKT cells in NK/T-LAHS patients by ROC analysis to determine the optimal diagnostic threshold. We observed that HLADR+NK > 15.9% could better distinguish NK/T-LAHS from non-HLH patients, with a sensitivity of 0.759 (95%CI: 0.603-0.914) and specificity of 0.828(95%CI:0.690-0.965), and the AUC was 0.775 (95%CI:0.647-0.904) (Table 1). HLADR+NK cells may have potential application value for the diagnosis of NK/T-LAHS. Conclusions: These activated T cells, NK cells, and NKT cells that express functional activation markers was increased in NK/T-LAHS patients. Among them, HLADR+NK > 15.9% could better distinguish NK/T-LAHS from NKTCL patients without HLH and healthy donors, which may be a potential biomarker for the diagnosis of NK/T-LAHS patients and contribute to better management.

A Case of Orbital Infarction Syndrome in a Patient with Hemophagocytic Lymphohistiocytosis

Purpose: To report a case of orbital infarction syndrome in a patient with hemophagocytic lymphohistiocytosis (HLH).Case summary: A 70-year-old woman with diabetes mellitus and hypertension was referred to the Department of Ophthalmology for sudden-onset left upper eyelid ptosis after being diagnosed with HLH. After 3 days, the best corrected visual acuity in the right eye was 0.8, while there was no light perception in the left eye. In the left eye, the ocular motility examination showed limitations in all fields of gaze. On fundus examination, optic disc pallor, retinal hemorrhage, and narrowed retinal arteries were observed in the left eye. Fluorescein angiography showed no blood flow in the retinal arteries and veins in the left eye. On neck computed tomography angiography, the left distal internal carotid artery was narrowed. Orbit computed tomography showed exophthalmos and extraocular muscle hypertrophy in the left eye. Orbit magnetic resonance imaging confirmed optic nerve edema, enhancement of the optic nerve sheath, and high signal intensity of the intraocular fat in the left eye. Slit-lamp examination revealed ischemia of the anterior segment and ischemic necrosis of the eyelid in the left eye. The patient was diagnosed with orbital infarction syndrome.Conclusions: Several factors may lead to ischemia of the orbital tissues in patients with HLH, including coagulopathy, an increased incidence of blood clots, and inflammation in the orbit. It is necessary to consider the possibility of orbital infarction syndrome when HLH patients present with visual loss, ocular movement limitations, and anterior segment ischemia.

Predictive model for early death risk in pediatric hemophagocytic lymphohistiocytosis patients based on machine learning

BackgroundHemophagocytic Lymphohistiocytosis (HLH) is a rare and life-threatening disease in children, with a high early mortality rate. This study aimed to construct machine learning model to predict the risk of early death using clinical indicators at the time of HLH diagnosis. MethodsThis observational cohort study was conducted at the National Clinical Research Center for Child Health and Disease. Data was collected from pediatric HLH patients diagnosed by the HLH-2004 protocol between January 2006 and December 2022. Six machine learning models were constructed using the Least Absolute Shrinkage and Selection Operator (LASSO) to select key clinical indicators for model construction. ResultsThe study included 587 pediatric HLH patients, and the early mortality rate was 28.45 %. The logistic and XGBoost model with the best performance after feature screening were selected to predict early death of HLH patients. The logistic model had an AUC of 0.915 and an accuracy of 0.863, while the XGBoost model had an AUC of 0.889 and an accuracy of 0.829. The risk factors most associated with early death were the absence of immunochemotherapy, decreased TC levels, increased BUN and total bilirubin, and prolonged TT. We developed an online calculator tool for predicting the probability of early death in children with HLH. ConclusionsWe developed the first web-based early mortality prediction tool for pediatric HLH to assist clinicians in risk stratification at diagnosis and in developing personalized treatment protocols. This study is registered on the China Clinical Trials Registry platform (ChiCTR2200061315).

Genetic and clinical characteristics of primary hemophagocytic lymphohistiocytosis in children.

To analyze the genetic variation and prognosis of primary hemophagocytic lymphohistiocytosis (pHLH) in children and the clinical features of isolated central nervous system HLH (CNS-HLH). We retrospectively analyzed the clinical and genetic data of 480 HLH children admitted to our hospital from September 2017 to September 2022. There were 66 patients (13.75%) with pHLH, and the median age was 3.21years (0.17-12.92years). Variants in UNC13D (22/66, 33.33%), PRF1 (20/66, 30.30%) and XIAP (11/66, 16.67%) were the most common. More CNS involvement was observed in pHLH patients than in secondary hemophagocytic lymphohistiocytosis (sHLH) patients (50% vs. 25.3%, P = 0.001). Eight pHLH patients had isolated CNS-HLH at onset, which progressed to systemic HLH within 10-30days to several years. Among them, five patients who underwent hematopoietic stem cell transplantation (HSCT) survived without CNS sequelae, and the three patients who did not undergo HSCT died of disease progression or recurrence. Determination of natural killer (NK) cell cytotoxicity and CD107a levels had low sensitivity and specificity in the diagnosis of pHLH, especially in patients with PRF1 and XIAP mutations. The 3-year overall survival (OS) was significantly lower in pHLH patients than in sHLH patients (74.5% ± 14.7% vs. 89.2% ± 3.53%, P = 0.021) and in patients with CNS involvement than in those without (53.8% ± 26.07% vs. 94.4% ± 10.58%, P = 0.012). There was a significant difference in OS among pHLH patients with different gene variants (P = 0.032); patients with PRF1 variants had poor 3-year OS, and patients with XIAP variants had good 3-year OS (50% ± 28.22% and 100%, respectively). pHLH patients with distinct variants have different prognoses. Isolated CNS-HLH patients are easily misdiagnosed, and HSCT may be beneficial for these patients. Determination of NK cell cytotoxicity and CD107a levels cannot precisely distinguish pHLH from sHLH.

Hemophagocyte morphology and hypertriglyceridemia correlate with diagnosis of hemophagocytic lymphohistiocytosis in patients with bone marrow hemophagocytes.

To investigate laboratory and bone marrow findings that can help predict a diagnosis of hemophagocytic lymphohistiocytosis (HLH) for patients who have demonstrated hemophagocytes (HPCs) in the bone marrow. A total of 57 cases from 48 patients with HPCs present on bone marrow examination were included. The numbers and morphologic characteristics of HPCs with ingested nucleated cells (nHPC) were counted. Pertinent medical history, relevant laboratory values, and flow cytometry data at the time of bone marrow biopsy were collected. A total of 24 patients fulfilled diagnostic criteria for HLH, and the remaining 24 patients did not. By using HLH-2004 cutoffs, only hypertriglyceridemia (≥265 mg/dL) was significantly associated with HLH diagnosis. The HLH cases more frequently had nHPC-ingesting granulocytic cells (gHPC) (75.9% vs 24.1%, P = .009). The percentage of gHPC to all nHPC was also significantly higher in HLH cases (median, 15.4% vs 0%; P = .0002). Both triglyceride level (area under the curve [AUC] = 0.88, P < .0001) and gHPC percentage (AUC = 0.81, P = .0005) were significant in predicting HLH diagnosis. Finally, no overt immunophenotypic abnormality was noted for 19 HLH cases with available flow cytometry data. The presence of hypertriglyceridemia and more frequent gHPC has predictive value for HLH diagnosis in patients with bone marrow HPC.

The Dosage Recommendation of Cyclosporin in Children with Hemophagocytic Lymphohistiocytosis based on Population Pharmacokinetic Model.

Cyclosporin is one of the therapeutic regimens for hemophagocytic lymphohistiocytosis (HLH); however, the optimal dosage of cyclosporine in children with HLH is unknown. It has been found that piperacillin-tazobactam affects the cyclosporine pharmacokinetic process in pediatric HLH patients. Thus, the purpose of the present study was to recommend cyclosporin dosage for pediatric HLH with and without piperacillin- tazobactam. A previously established cyclosporine population pharmacokinetic model for pediatric HLH patients has been used in this study to recommend optimal dosage based on Monte Carlo simulation. The pediatric HLH patients have been included in eight weight groups (5, 10, 20, 30, 40, 50, 60, 70 kg) for sixteen dosages (1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16 mg/kg), split into one dose or two doses. The optimal cyclosporin dosages for children having HLH without piperacillin-tazobactam have been found to be 15, 13, 12, 11, 10, and 9 mg/kg, split into two doses for weights of 5-7, 7-10, 10-20, 20-28, 28-45, and 45-70 kg, respectively. For children with HLH, optimal cyclosporin dosages with piperacillin-tazobactam have been found to be 8 and 7 mg/kg, split into two doses for weights of 5-20 and 20-70 kg, respectively. It is the first time that the cyclosporin dosage regimens for HLH in children have been developed based on Monte Carlo simulation, and the initial dosage optimizations of cyclosporine in pediatric HLH patients have been recommended.

Treatment of hemophagocytic lymphohistiocytosis in patients in the intensive care unit

Hemophagocytic lymphohistiocytosis (HLH) is ahyperinflammatory syndrome characterized by hyperferritinemia. Adifferentiation is made between hereditary and acquired forms. In contrast to children, almost all cases in adult patients consist of acquired secondary HLH. Infections, malignancies and autoimmune diseases are frequent triggers of secondary HLH. More recently, cases of HLH have also been described in association with immunotherapy, e.g., when using chimeric antigen receptor (CAR) T‑cell treatment. In critically ill patients in the intensive care unit (ICU), sepsis represents the major differential diagnosis of HLH due to the frequently similar clinical presentation. Sometimes both sepsis and HLH are present at the same time. An early diagnosis and timely initiation of immunosuppressive treatment are essential for the further course and prognosis of HLH. Therefore, HLH should be considered as apossible diagnosis in critically ill patients with persistent fever and additional compatible symptoms (e.g., splenomegaly, neurological symptoms) or laboratory parameters (e.g., hyperferritinemia, cytopenia of two or three cell lines, increased transaminases). The diagnosis of HLH is made on the basis of the HLH-2004 criteria. The HScore can be used to estimate the probability of the presence of HLH. Corticosteroids given at high doses are the cornerstone of HLH treatment. Furthermore, immunoglobulins, etoposide, anakinra or ruxolitinib can complement treatment depending on the HLH trigger. The course of HLH depends on the timely initiation of treatment, the underlying trigger and the response to treatment. Despite progress in terms of diagnostics and targeted treatment, the prognosis of critically ill HLH patients is still poor.

Exploring the Clinical Spectrum and Hematological Patterns of Hemophagocytic Lymphohistiocytosis: A Comprehensive Study

Background: Hemophagocytic Lymphohistiocytosis (HLH) presents a challenging disorder characterized by complex manifestations resulting from dysregulated immune responses. This study aims to enhance our understanding of the clinical and hematological spectrum of HLH, focusing on adult patients. Methods: A retrospective-prospective observational study was conducted involving 64 adult HLH patients meeting HLH-2004 criteria. Comprehensive hematopathological assessments were performed, encompassing clinical parameters, hematological markers, and mortality rates. Data analysis utilized SPSS Version 20.0 for descriptive statistics. Results: The most frequent clinical manifestations were fever (100%), splenomegaly (87.5%), bicytopenia (73.4%), hypertriglyceridemia (60.9%), hyperferritenemia (48.4%), hypofibrinogenemia (32.8%), and pancytopenia (26.6%). We observed that leucopenia was present in majority of patients (62.5%), and leukocytosis was present in 17.2% patients. About 65.6% had mild to moderate thrombocytopenia, followed by 14.1% patients with severe thrombocytopenia, 14.1% had normal platelet count and 6.3% had thrombocytosis. Conclusion: The study revealed a diverse clinical spectrum within adult HLH patients, including universal fever, varied hematological irregularities, and mortality rates of 7.8%. These findings emphasize the complexity of HLH and the importance of early diagnosis and tailored interventions for improved outcomes. This study contributes valuable insights to the understanding of HLH's intricate clinical and hematological aspects, informing more informed diagnostic and therapeutic strategies for this complex disorder. Keywords: Hemophagocytic lymphohistiocytosis (HLH), Clinical characteristics, Laboratory tests, Prognosis

A novel prognosis-prediction model based on coagulation indicators in secondary hemophagocytic lymphohistiocytosis

Secondary hemophagocytic lymphohistiocytosis (HLH) is a life-threatening disease. In the present retrospective study, we aimed to investigate coagulation disorders and their outcome implications in patients with secondary HLH. We evaluated clinical characteristics and the relationship between coagulation indices and prognosis in HLH patients (n = 141). The information, including clinical symptoms, laboratory indicators, and coagulation indices, was evaluated. Coagulation disorders and bleeding events occurred in 95 (67.4%) and 60 (42.6%) patients, respectively. A coagulation index analysis primarily showed elevated levels of D-Dimer, the international standardized ratio (INR), prothrombin time (PT), activated partial thromboplastin time (APTT), and thrombin time (TT), while the prothrombin activity, fibrinogen levels, and platelet levels were significantly decreased. Dominant disseminated intravascular coagulation (DIC) occurred in 76 patients (53.9%). Patients with lymphoma-associated hemophagocytic syndrome (LAHS) frequently exhibited apparent coagulation disorders. Multivariate analysis revealed that age ≥ 29.5 years, bleeding events, APTT ≥ 47.3 s, fibrinogen ≤ 1.68 g/L, and absolute neutrophil counts (ANC) of ≤ 1.21 × 109/L were independent prognostic factors. We thereby devised a prognostic scoring system and stratified patients into low-risk (0–2 points), intermediate-risk (3–4 points), and high-risk (5–7 points) groups, and the 1-year overall survival rates in the above-mentioned groups were 66.40%, 40.00%, and 2.30%, respectively (P < 0.0001). In conclusion, coagulation dysfunctions and bleeding tendencies were common characteristics in HLH patients. We constructed a novel prognostic score model based on APTT, fibrinogen level, ANC, age, and bleeding events, which had superior prognostic value compared with these markers alone.