Adult Hemophagocytic Lymphohistiocytosis Research Articles

Secondary hemophagocytic lymphohistiocytosis in adults

Secondary hemophagocytic lymphohistiocytosis in adults

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.

Histiocytic necrotizing lymphadenitis with hemophagocytic lymphohistiocytosis in adults: A single-center analysis of 5 cases.

Histiocytic necrotizing lymphadenitis (HNL) is a self-limited inflammatory disease of unknown pathogenesis. A very small fraction of patients with HNL could develop hemophagocytic lymphohistiocytosis (HLH), a hyperinflammatory disorder. These patients are diagnosed as HNL with HLH (HNL-HLH). HNL-HLH in the pediatric population has been systemically studied, however, the clinical, laboratory, and radiological features and outcomes of adult patients with HNL-HLH remain to be explored. We aimed to explore the clinical, laboratory, and radiological features and outcomes of adult patients with HNL-HLH. We collected the clinical data of patients with HNL-HLH admitted to the First Affiliated Hospital of Nanjing Medical University from October 2010 to June 2015. All the patients underwent lymph node biopsy and have a pathological diagnosis of HNL. The age, gender, clinical presentation, lymph node signs, laboratory findings and imaging data, and pathological findings of the patients were collected. In this study, we reported five adult patients with HNL-HLH. All five patients showed enlarged lymph nodes and prolonged fever. Laboratory findings were consistent with the diagnosis of HLH. 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) showed enlarged lymph nodes with increased FDG uptake and splenic hypermetabolism could be present. All the patients responded well to corticosteroids and had a good prognosis. Two of the five patients were diagnosed with systemic lupus erythematosus during the follow-up. Our study demonstrated that adult patients with HNL-HLH showed distinct clinical, laboratory, and radiological features. And the prognosis is good and patients could be managed with steroids and supportive care.

Prognostic factors of adult hemophagocytic lymphohistiocytosis and clinical utility of HLH-2004 diagnostic criteria and HScore: A real-world multicenter study from Thailand.

Adult hemophagocytic lymphohistiocytosis (HLH) is a rare disease with a dismal prognosis. Early diagnosis and prompt management are necessary for improved outcomes. 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. 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%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). 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 use of the adapted HLH-2004 criteria.

Tuberculosis-Associated Hemophagocytic Lymphohistiocytosis: Diagnostic Challenges and Determinants of Outcome.

Tuberculosis (TB) can induce secondary hemophagocytic lymphohistiocytosis (HLH), a severe inflammatory syndrome with high mortality. We integrated all published reports of adult HIV-negative TB-associated HLH (TB-HLH) to define clinical characteristics, diagnostic strategies, and therapeutic approaches associated with improved survival. PubMed, Embase, and Global Index Medicus were searched for eligible records. TB-HLH cases were categorized into (1) patients with a confirmed TB diagnosis receiving antituberculosis treatment while developing HLH and (2) patients presenting with HLH of unknown cause later diagnosed with TB. We used a logistic regression model to define clinical and diagnostic parameters associated with survival. We identified 115 individual cases, 45 (39.1%) from countries with low TB incidence (<10/100 000 per year). When compared with patients with HLH and known TB (n = 21), patients with HLH of unknown cause (n = 94) more often had extrapulmonary TB (66.7% vs 88.3%), while the opposite was true for pulmonary disease (91.5% vs 59.6%). Overall, Mycobacterium tuberculosis was identified in the bone marrow in 78.4% of patients for whom examination was reported (n = 74). Only 10.5% (4/38) of patients tested had a positive result upon a tuberculin skin test or interferon-γ release assay. In-hospital mortality was 28.1% (27/96) in those treated for TB and 100% (18/18) in those who did not receive antituberculosis treatment (P < .001). Tuberculosis should be considered a cause of unexplained HLH. TB-HLH is likely underreported, and the diagnostic workup of patients with HLH should include bone marrow investigations for evidence of Mycobacerium tuberculosis. Prompt initiation of antituberculosis treatment likely improves survival in TB-HLH.

Treatments and Outcomes of Lymphoma-Associated Hyperinflammation- a Report from the HLH in Adults Working Group for the Histiocyte Society

Purpose: Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening inflammatory syndrome. Lymphoma is the most common cause of HLH in adults. Previous studies have indicated poor patient outcomes in lymphoma-associated HLH. The recently introduced optimized HLH inflammatory (OHI) index has improved prognostication and identification of the hyper-inflammatory phenotype of lymphoma; however, more comprehensive information on treatments and outcomes in a large cohort in the contemporary era is necessary. Our study aimed to investigate the clinical features, treatments, and outcomes of lymphoma-associated HLH through a multi-national effort by the HLH in Adults Working Group of the Histiocyte Society (NCT05898477). Methods: We conducted a multicenter, retrospective study evaluating patients diagnosed with lymphoma and hyperinflammation, defined by fulfilling 5/8 HLH diagnostic criteria or the OHI index from 2003-2022. Clinical characteristics were summarized using median and interquartile ranges (IQR). Survival analysis employed Kaplan-Meier curves and the log-rank test, considering HLH diagnosis as the zero time-point. Results: The analysis encompassed 181 patients with lymphoma: 55% had B-cell non-Hodgkin lymphoma (NHL), 35% had natural killer (NK) cell or T-cell lymphoma, and 10% had classical Hodgkin lymphoma. 35% of patients were from China, 21% from the USA, 17% from Israel, 16% from Europe, and 11% from Japan. Of the entire cohort, 157 (87%) patients met the HLH-2004 criteria, and 153 (83%) met the OHI index; The median age at HLH diagnosis was 60 years (IQR, 45-68), and 59% were males. 50% of patients presented with HLH before/at the time of lymphoma diagnosis (median time to lymphoma diagnosis 9 days), while 50% developed HLH after the initial lymphoma diagnosis (median time to HLH diagnosis 181 days). The median values of hemoglobin, absolute neutrophil count (ANC), and platelet count at HLH diagnosis were 8.6 g/dL, 2.1 K/microL, and 54.7 K/microL, respectively. The median values of triglycerides and fibrinogen were 241 mg/dL and 250 mg/dL, respectively. Interestingly, the median values for ANC, triglycerides, and fibrinogen fell outside the HLH-2004 diagnostic threshold. The median and interquartile ranges for ferritin and sCD25 (sIL-2r) were 3017 ng/mL (1337-8958) and 14098 U/mL (7894-39916), respectively. 48% of physicians altered their initial treatment approach due to the HLH diagnosis. Of these instances, 48% were treated with dexamethasone and etoposide outside of a formal treatment protocol, 11% with the HLH-94/2004 protocol, 24% with DEP regimen (liposomal doxorubicin, etoposide, and methylprednisolone), and 4% with DEP and ruxolitinib. Dexamethasone alone was used in 15% of the patients, while another 4% were treated with anakinra +/- steroids. After a median follow-up duration of 2.1y (range, 0.005-6.1), the median overall survival was 0.58 years. 46% of the patients died from multi-organ dysfunction/HLH, 17% from single-organ dysfunction, 16% from infection or septic shock, and 8% from bleeding. The risk of mortality among T-cell or NK cell lymphoma was higher than B-cell lymphoma (HR 1.7, 95% CI 1.16-2.61, Figure 1A). Finally, patients positive for the OHI index alone at diagnosis had a higher mortality risk (Figure 1B) compared to those positive for both the OHI index and HLH-2004 (HR 2.5; CI 1.26 - 4.8) or those positive for HLH-2004 alone (HR 3.72; CI- 1.62-8.58). Conclusions: Preliminary findings from this large multi-institutional study show that the overall survival for patients with lymphoma and HLH remains poor despite the institution of HLH-specific therapies. In nearly half of the cases, the physicians altered lymphoma treatment to control HLH, primarily through dexamethasone and etoposide-based or DEP regimens. Although B-cell lymphoma was our cohort's most common cause of HLH, overall survival was worse among those with T-cell or NK cell lymphoma, suggesting that the underlying lymphoma type might drive the prognosis even in cases with hyperinflammation. The most common causes of death included multi-organ dysfunction and infection. The OHI index-positive patients experienced higher mortality risk than those meeting the HLH-2004 criteria. The study is ongoing, and we plan to present data on the differential effects of treatment regimens at the meeting.

Differences in Diagnostic Characteristics and Outcomes in Adults with Malignancy-Associated and Non-Malignancy-Associated Hemophagocytic Lymphohistiocytosis (HLH)

Introduction: Hemophagocytic lymphohistiocytosis (HLH) is a rare syndrome characterized by life-threatening inflammation. In adults, roughly 50% of HLH manifests in association with an underlying malignancy (most commonly lymphoma), and the remaining cases are due to infection, autoimmune disease, late presentations of genetically-driven HLH, and sometimes multifactorial or idiopathic causes. Although the majority of prospective data for HLH are derived from children, survival outcomes for non-malignant causes of adult HLH (nmHLH) are thought to rival pediatric HLH; however, outcomes for malignancy-associated HLH (mHLH) appear to be substantially worse (~10-30% 5-year overall survival) in the literature. As diagnostic and prognostic models for HLH outcomes have primarily been constructed using pediatric data, attempts have been made to develop diagnostic indices applicable to adult HLH (particularly mHLH). Here, we summarize the clinical and laboratory characteristics of mHLH and nmHLH in a retrospective observational study, and evaluate the role for common diagnostic tools for adult HLH. Methods: Patients &amp;gt;18 years old, fulfilling at least five of the HLH-2004 diagnostic criteria with at least 3 months of follow-up (among survivors) were enrolled. All included patients received definitive HLH therapy, including cancer-directed therapy when appropriate, but those receiving only systemic steroids were excluded. Treatment-related HLH, such as HLH occurring with immune effector cell therapy or hematopoietic cell transplantation, was excluded. Clinical and laboratory parameters reflect the most recent values on or prior to diagnosis and treatment initiation. Differences between mHLH and nmHLH were assessed with two-tailed t-test or Wilcoxon test. Survival outcomes are estimated by Kaplan-Meier. Multivariate analysis was performed using Cox proportional hazards and compared using logrank test. Results: 42 adults were diagnosed with HLH requiring HLH-specific therapy (23 mHLH, 19 nmHLH) between 3/2016 and 3/2023 with a median age of 50 (range 21-75). Of the mHLH cases, 44% were due to T/NK cell lymphomas; 52% were B cell lymphomas including 26% Hodgkin. Of the nmHLH cases, most were due to infection (47%); while others were deemed to be idiopathic (26%) or genetic (16%). All patients with mHLH had fever (v 84% in nmHLH); 91% met cytopenia criteria (v 68%), and absolute neutrophil count (ANC), hemoglobin (Hgb), and platelet count (plt) were all statistically lower than in nmHLH (mean ANC 3.2 v 11.3; Hgb 7.8 v 8.5; plt 43 v 88; p&amp;lt;0.05). Mean soluble interleukin-2 (sIL2) level was significantly higher in mHLH (39,579 pg/mL v 18,484) after adjusting for a single outlier. All other HLH-2004 diagnostic parameters were not statistically different between mHLH and nmHLH, including ferritin and sIL2/ferritin index. All mHLH patients had an underlying lymphoma and met the optimized HLH inflammatory (OHI) index except a single patient with leukemia; 4 patients with nmHLH did not meet the OHI index. In 79% of patients, the HLH94 regimen was incorporated in the induction regimen; the remaining utilized chemotherapy or antibiotics, with and without adjunctive steroids. 4 cases proceeded to allogeneic transplantation. Relapse rates were high, with median relapse-free survival (RFS) being 37 days (23 v 47 days for mHLH and nmHLH, respectively); median overall survival (OS) was 96 days (86 v 149 days). RFS/OS was not statistically different between mHLH and nmHLH. Age was a significant predictor of OS but not RFS; no other diagnostic parameter was predictive, including degree of ferritin or sIL2 elevation. 13 patients were alive at the time of last follow-up (6 mHLH, 7 nmHLH). Conclusions: In this single center retrospective study, both mHLH and nmHLH requiring HLH-directed therapy demonstrated poor survival outcomes in adults. The degree of cytopenias and sIL2 elevation were more significant in mHLH in comparison with nmHLH. The OHI index identified all cases of lymphoma-associated HLH but neither ferritin nor sIL2 levels were predictive of survival. These data emphasize the need for therapeutic advances for management of adults with mHLH and nmHLH and continued optimization of diagnostic criteria for adult HLH.

Secondary Hemophagocytic Lymphohistiocytosis in Adults: A Single Institution Case Series

Introduction: Hemophagocytic lymphohistiocytosis (HLH) is a severe hyperinflammatory syndrome caused by the abnormal activation of macrophages and T cells. The primary form, resulting from lymphocyte-related mutations, is more common in children, while the secondary (acquired) form known as sHLH prevails in adults. sHLH is often triggered by infections or malignancies (Mal-HLH) but can also be induced by autoinflammatory disorders called macrophage activation syndrome (MAS; or MAS-HLH). We present a retrospective case series of adults treated for sHLH at a single institution from 2012 to 2023. Methods: Retrospective data was collected using the EDW database, and 36 patients were identified using ICD 9/10 codes 288.4 and D76.1 for HLH. Subsequently, a manual review of electronic medical records was conducted; criteria for inclusion were age &amp;gt;18 years at the time of diagnosis and meeting HLH-2004 criteria ( Panel-1). Results: Out of the 36 patients reviewed, 11 met the criteria and were included in the analysis. These cases occurred between 2015 and 2023. The median age at diagnosis was 52 (range 18 to 81). The female-to-male ratio in our study was 4:7. Most patients (73%) were white. Additionally, 45% of the patients were immunocompromised. 91% of the patients presented with fever, while only 45% had splenomegaly. Trilineage cytopenias were observed in all patients. In our study, 5/11 had hypofibrinogenemia, and 6/11 had hypertriglyceridemia. Hemophagocytosis was evident in 91% of the patients. Natural Killer (NK) cell activity was measured in 4 patients, and all exhibited low or no NK cell activity. In 10 out of 10 patients, soluble IL-2 receptors were elevated. None of the patients in the study had hepatomegaly, but all had transaminitis and hyperbilirubinemia, and 82% had elevated alkaline phosphatase levels. Elevated lactate levels were observed in 78% of patients, and 27% had a rash. Neurological features were observed in 6 out of 10 patients. Lactate dehydrogenase was elevated in all patients with a median value of 1551 U/L (range 354 - 3689) Presumed etiologies for sHLH included malignancy (4), infection (3), autoimmune disease (3), and unknown cause (1). Treatment was highly individualized based on the underlying trigger and was guided by the HLH-94 protocol ( Panel-2). All patients received high-dose steroids, 6/11 received etoposide, and 2 received intrathecal therapy for neurological involvement. Conclusion: At a median follow-up period of 16 days, five patients had died. The survival rates at 30 days and 1 year were 45% and 27%, respectively. The overall mortality rate was 55%. While mortality rates were 75% in the Mal-HLH arm and 67% in the infectious arm, all patients with MAS-HLH survived while performing the study indicating a better prognosis for patients with this type of HLH.

Severe adult hemophagocytic lymphohistiocytosis (HLHa) correlates with HLH-related gene variants

The contribution of genetic factors to the severity of adult hemophagocytic lymphohistiocytosis (HLHa) remains unclear. We sought to assess a potential link between HLHa outcomes and HLH-related gene variants. Clinical characteristics of 130 HLHa patients (age≥ 18 years and HScore≥ 169) and genotype of 8 HLH-related genes (LYST, PRF1, UNC13-D, STX11, STXBP2, RAB27A, XIAP, and SAP) were collected. Atotal of 34 variants found in only 6 genes were selected on the basis of their frequency and criteria predicted to impair protein function. Severity was defined by refractory disease to HLH treatment, death, or transfer to an intensive care unit. HLHa-associated diseases (ADs) were neoplasia (n= 49 [37.7%]), autoimmune/inflammatory disease (n= 33 [25.4%]), or idiopathic when no AD was identified (n= 48 [36.9%]). Infectious events occurred in 76 (58.5%) patients and were equally distributed in all ADs. Severe and refractory HLHa were observed in 80 (61.5%) and 64 (49.2%) patients, respectively. HScore, age, sex ratio, AD, and infectious events showed no significant association with HLHa severity. Variants were identified in 71 alleles and were present in 56 (43.1%) patients. They were distributed as follows: 44 (34.4%), 9 (6.9%), and 3 (2.3%) patients carrying 1, 2, and 3 variant alleles, respectively. In a logistic regression model, only the number of variants was significantly associated with HLHa severity (1 vs 0: 3.86 [1.73-9.14], P= .0008; 2-3 vs 0: 29.4 [3.62-3810], P= .0002) and refractoriness (1 vs 0: 2.47 [1.17-5.34], P= .018; 2-3 vs 0: 13.2 [2.91-126.8], P= .0003). HLH-related gene variants may be key components to the severity and refractoriness of HLHa.

Epidemiology, characteristics, and outcomes of adult haemophagocytic lymphohistiocytosis in the USA, 2006–19: a national, retrospective cohort study

Haemophagocytic lymphohistiocytosis (HLH) is a rare and life-threatening syndrome characterized by an excessive inflammatory response. Limited data exist on adult HLH. In this national, retrospective cohort study, we analysed data from the US National Inpatient Sample database collected between October 1, 2006 and December 31, 2019. Using the International Classification of Diseases (ICD) codes, we identified all adult patients who were admitted non-electively with the diagnosis of HLH. We described demographic characteristics, triggers, and associated conditions. Trends of diagnosis, treatment, and in-hospital mortality were analysed using joinpoint models. In-hospital mortality rates were compared using multivariable logistic regression models that adjusted for demographic characteristics and associated conditions. Finally, we described resource utilization outcomes including cost of hospitalization and length of stay. We identified 16,136 non-elective adult HLH admissions. The population pyramid showed a bimodal distribution, with peaks in young adults (16-30 years) and older adults (56-70 years). Joinpoint regression analysis revealed a significant increase in HLH incidence per 100,000 admissions over the study period (Average Annual Percent Change [APC]=25.3%, p<0.0001), and no significant change in rates of in-hospital mortality (slope=-0.01; p=0.95) or administration of in-hospital HLH treatment (slope=0.46, p=0.20). The most common associated conditions were malignancy (4953 admissions [30.7%]), infections (3913 admissions [24.3%]), autoimmune conditions (3362 admissions [20.8%]), organ transplant status (639 admissions [4%]), and congenital immunodeficiency syndromes (399 admissions [2.5%]). In-hospital mortality was higher in older adults and males. Furthermore, Congenital immunodeficiency syndromes had the worst in-hospital mortality rate (mortality rate 31.1%, adjusted OR 2.36 [1.56-3.59]), followed by malignancies (mortality rate 28.4%, adjusted OR 1.80 [1.46-2.22]), infections (mortality rate 21.4%, adjusted OR 1.33 [1.10-1.62]), other/no trigger (mortality rate 13.6%, adjusted OR 0.73 [0.58-0.92]), autoimmune (mortality rate 13%, adjusted OR 0.72 [0.57-0.92]), and post-organ transplant status (mortality rate 14.1%, adjusted OR 0.64 [0.43-0.97]). The overall mean length of stay was 14.3±13.9 days, and the mean cost of hospitalization was $54,900±59,800. We provide insight into the burden of adult HLH in the USA. The incidence has been increasing and the outcomes remain dismal. This signifies the growing need for the development of updated diagnosis and treatment protocols that are specific to adult HLH. None.

Successful management of adult hemophagocytic lymphohistiocytosis with an etoposide-containing regimen: Case report and literature review

Objective: Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening disorder characterized by a hyperimmune response. Although HLH is well described in the pediatric population, less is known about the appropriate management in adults. Despite the inclusion of etoposide in HLH society protocols, some clinicians refrain from using it due to its cytotoxicity and potential adverse effects. Case: We report here the case of a 43-year-old male presenting with fever and pancytopenia, who was diagnosed with HLH following further evaluation. The patient immediately started the HLH-2004 initial protocol, which consisted of dexamethasone, etoposide, cyclosporine, and IVIG. Symptoms improved after 2 weeks of treatment. Subsequent bone marrow biopsy showed normal results, and the patient achieved complete remission, leading to the termination of treatment in the 12th week of the protocol. At 8 months post-treatment, the patient remained recurrence-free with normal hematological and biochemical test results. Conclusion: This case underscores the importance of considering etoposide-containing regimens, particularly for medically fit patients.

Good prognosis of adult hemophagocytic lymphohistiocytosis associated with the germline HAVCR2 mutation

Hemophagocytic lymphohistiocytosis (HLH) in adults may be idiopathic or secondary to various conditions. Recent studies identified germline hepatitis A virus-cellular receptor 2 (HAVCR2) mutations in subcutaneous panniculitis-like T-cell lymphoma (SPTCL) with HLH. The roles of this mutation in HLH, especially in idiopathic group, have never been explored. Of the 65 HLH cases, we detected germline HAVCR2Y82C mutations in nine (13.8%) cases (five SPTCL and four idiopathic HLH). Other causes of HLH were hematologic malignancies excluding SPTCL (32.3%), idiopathic HLH without HAVCR2 mutation (29.2%), infections (15.3%), and autoimmune diseases (9.2%). Germline HAVCR2 mutation was significantly associated with less anemia and better survival. This defines a distinct subgroup of HLH.

Clinical features and prognostic risk prediction of adult hemophagocytic lymphohistiocytosis: a 9-year retrospective study.

Hemophagocytic lymphohistiocytosis (HLH) has a low incidence and high mortality. In order to improve our understanding of the clinical features and prognostic risk factors of adult HLH, we analyzed the clinical characteristics and prognostic risk factors of adult HLH and developed a prognostic model to predict the overall survival (OS) of adult HLH. The clinical characteristics and survival statistics of adult patients with HLH identified at The Second Affiliated Hospital of Chongqing Medical University between February 2012 and October 2020 were retrospectively analyzed to constitute the primary cohort, while patients between 25 October 2020 and 20 March 2023 were collected at the same institution as a validation cohort for the prospective study. A total of 142 patients met the inclusion criteria, with 72 and 70 in the primary cohort and validation cohort respectively. In the primary cohort, the median OS was 102 days, with 37.5%, 34.5%, and 28.7% 1-, 2-, and 3-year OS, respectively. Univariate analysis showed that age, interleukin-10 (IL-10), interleukin-2 receptor (IL-2R), prothrombin time (PT), and indirect bilirubin (IBiL) were correlated with prognosis. Multivariate analysis showed that IL-10 and PT were independent factors affecting OS in adult patients with HLH. A prognostic model consisting of IL-2R, PT, and IL-10 and a corresponding prognostic nomogram were developed adopting the principle of minimum value of Akaike information criterion(AIC). The model has a high prediction accuracy letter (C-index = 0.708). The AUC values of 1-year, 2-year, and 3-year were 0.826, 0.865, and 0.882, correspondingly. In the validation cohort, all patients were divided into high-risk and low-risk groups, and the risk of death was significantly higher in the high-risk group than in the low-risk group (p < 0.01). The calibration curve for the model shows that the Nomogram constructed in this study is very reliable to predict the OS of HLH patients. IL-10 and PT have significant prognostic value in adult HLH. The prognostic model and the nomogram built in this study can forecast the OS of adult HLH patients.

Delay in treatment of adult hemophagocytic lymphohistiocytosis is associated with worse in-hospital outcomes.

Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening condition characterized by uncontrolled activation of the immune system leading to multiorgan failure. Timely initiation of HLH-specific treatment is believed to be essential and lifesaving. Due to the rarity of the condition in adults, there is no data available in the literature to investigate the effects of treatment delay in this age group. We used data from the National Inpatient Sample (NIS) to evaluate the inpatient practices of HLH treatment initiation over 13 years (2007-2019) and their association with clinically relevant inpatient outcomes. Patients were divided into early treatment group (<6 days) and late treatment group (≥ 6 days). We compared outcomes using multivariate logistic regression models adjusting for age, sex, race, and HLH-triggering conditions. There were 1327 and 1382 hospitalizations in the early and late treatment groups, respectively. Hospitalization in the late treatment group had higher rates of in-hospital mortality (OR 2.00 [1.65-2.43]), circulatory shock (OR 1.33 [1.09-1.63]), requiring mechanical ventilation (OR 1.41 [1.18-1.69]), venous thromboembolism (OR 1.70 [1.27-2.26]), infectious complications (OR 2.24 [1.90-2.64]), acute kidney injury (OR 2.27 [1.92-2.68]), and requiring new hemodialysis (OR 1.45 [1.17-1.81]). Additionally, we observed no significant trend in the mean time to treatment over the study period. This study shows the importance of early initiation of HLH treatment and highlights the adverse outcomes of treatment delay.

Management of Complex Infections in Hemophagocytic Lymphohistiocytosis in Adults.

Hemophagocytic lymphohistiocytosis (HLH) is a syndrome of excessive immune system activation and inflammatory response due to a variety of primary and secondary factors that can cause a range of clinical symptoms and, in severe cases, life-threatening conditions. Patients with HLH are at increased risk of infection due to their abnormal immune function as well as chemotherapy and immunosuppressive therapy at the time of treatment. At the same time, the lack of specific clinical features makes complex infections in HLH challenging to diagnose and treat. The management of complex infections in HLH requires a multidisciplinary and integrated approach including the early identification of pathogens, the development of anti-infection protocols and regimens, and the elimination of potential infection factors. Especially in HLH patients with septic shock, empirical combination therapy against the most likely pathogens should be initiated, and appropriate anti-infective regimens should be determined based on immune status, site of infection, pathogens, and their drug resistance, with timely antibiotic adjustment by monitoring procalcitonin. In addition, anti-infection prophylaxis for HLH patients is needed to reduce the risk of infection such as prophylactic antibiotics and vaccinations. In conclusion, complex infection in HLH is a serious and challenging disease that requires vigilance, early identification, and timely anti-infective therapy.

Diagnosis and Management of Adult Malignancy-Associated Hemophagocytic Lymphohistiocytosis.

Hemophagocytic lymphohistiocytosis (HLH) is a syndrome of severe, dysregulated inflammation driven by the inability of T cells to clear an antigenic target. When associated with malignancy (mHLH), the HLH syndrome is typically associated with extremely poor survival. Here, we review the diagnosis of secondary HLH (sHLH) syndromes in adults, with emphasis on the appropriate workup and treatment of mHLH. At present, the management of HLH in adults, including most forms of mHLH, is based on the use of corticosteroids and etoposide following the HLH-94 regimen. In some cases, this therapeutic approach may be cohesively incorporated into malignancy-directed therapy, while in other cases, the decision about whether to treat HLH prior to initiating other therapies may be more complicated. Recent studies exploring the efficacy of other agents in HLH, in particular ruxolitinib, offer hope for better outcomes in the management of mHLH. Considerations for the management of lymphoma-associated mHLH, as well as other forms of mHLH and immunotherapy treatment-related HLH, are discussed.

Immune Effector Cell-Associated Hemophagocytic Lymphohistiocytosis-Like Syndrome

T cell-mediated hyperinflammatory responses, such as cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS), are now well-established toxicities of chimeric antigen receptor (CAR) T cell therapy. As the field of CAR T cells advances, however, there is increasing recognition that hemophagocytic lymphohistiocytosis (HLH)-like toxicities following CAR T cell infusion are occurring broadly across patient populations and CAR T cell constructs. Importantly, these HLH-like toxicities are often not as directly associated with CRS and/or its severity as initially described. This emergent toxicity, however ill-defined, is associated with life-threatening complications, creating an urgent need for improved identification and optimal management. With the goal of improving patient outcomes and formulating a framework to characterize and study this HLH-like syndrome, we established an American Society for Transplantation and Cellular Therapy panel composed of experts in primary and secondary HLH, pediatric and adult HLH, infectious disease, rheumatology and hematology, oncology, and cellular therapy. Through this effort, we provide an overview of the underlying biology of classical primary and secondary HLH, explore its relationship with similar manifestations following CAR T cell infusions, and propose the term "immune effector cell-associated HLH-like syndrome (IEC-HS)" to describe this emergent toxicity. We also delineate a framework for identifying IEC-HS and put forward a grading schema that can be used to assess severity and facilitate cross-trial comparisons. Additionally, given the critical need to optimize outcomes for patients experiencing IEC-HS, we provide insight into potential treatment approaches and strategies to optimize supportive care and delineate alternate etiologies that should be considered in a patient presenting with IEC-HS. By collectively defining IEC-HS as a hyperinflammatory toxicity, we can now embark on further study of the pathophysiology underlying this toxicity profile and make strides toward a more comprehensive assessment and treatment approach.

Elevated Interleukin-10 Levels Are Associated with Low Platelet Count and Poor Prognosis in 90 Adult Patients with Hemophagocytic Lymphohistiocytosis

Introduction: Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening syndrome characterized by excessive inflammatory responses. This study explored the association between laboratory characteristics and outcomes in adult patients with HLH. Methods: The adult patients diagnosed with HLH at the Second Hospital of Shanxi Medical University from September 2016 to September 2021 were retrospectively analyzed in this study. Results: A total of 90 HLH patients were included. Among them, 60% were males, with a median age at diagnosis of 54 years. More than 85% of HLH patients presented with fever, splenomegaly, and cytopenias. IL-10 and IL-6 were elevated in 93.3% and 91.1% of patients, respectively. Elevated IL-10 levels were associated with lower platelet counts (r = −0.37, p < 0.001). Infections were seen in 46.7% (42/90) of cases. 29 patients with malignancy-associated HLH had T- or NK-cell (n = 16) or B-cell (n = 12) lymphoma. Autoimmune diseases accounted for 21.1% (19/90). Treatment was variable. In total, 36 patients survived (40%). The median overall survival (OS) was 1.5 months (95% confidence intervals [CI]: 0.2–2.8 months), with a 1-year OS of 40.9%. Patients with autoimmune diseases had markedly longer survival than those triggered by infection and malignancy (p < 0.001). Multivariate Cox regression analysis indicated that treatment delays (hazard ratios 0.36, 95% CI: 0.14–0.94, p = 0.036), platelet count (2.33, 1.30–4.18, p = 0.005), and IL-10 (2.07, 1.16–3.68, p = 0.014) were independent risk factors for poor outcome. Conclusion: Infection and lymphoma are the leading causes of HLH in adult patients with heterogeneous clinical manifestations. Survival of adult HLH is frustrating, especially those associated with malignancies. Besides, elevated IL-10 levels were associated with lower platelet counts, and these two markers were independent risk factors for poor prognosis. Earlier treatment led to better outcomes.

Disparity Analysis of Clinical Features and Prognostic Evaluation of Hemophagocytic Lymphohistiocytosis in Pediatric and Adult Patients: A Retrospective Multicenter Study of 525 Cases in HHLWG

Introduction: Hemophagocytic lymphohistiocytosis (HLH) is a rare immune disorder with rapid progression and high mortality. There have been few large cohort study comparisons of pediatric and adult HLH until now. This study was designed to explore the disparity of clinical presentations and evaluate the prognosis in pediatric and adult HLH patients. Methods: Totally, 525 newly diagnosed HLH patients were included and divided into 4 groups according to age: <6, 6–18, 18–60, and >60 years (geriatric patients). Mann-Whitney U test, Kruskal-Wallis test, χ² test, and Bonferroni’s adjustment were used to explore the difference between age groups. Overall survival (OS) was estimated by using Kaplan-Meier method. The Cox proportional hazard model was used to analyze the univariable and multivariable association between prognostic factors and OS. Results: Geriatric patients had the lowest levels of hemoglobin, platelet, albumin, and the highest level of creatinine, while patients <6 years of age had the lowest values of fibrinogen, IgA, IgM and highest values of triglyceride. The trigger of HLH in patients <18 years of age was mainly EBV infection. However, lymphoma and non-EBV-driven infection were the more frequent drivers in patients aged 18–60 and >60 years, respectively. Geriatric patients were associated with highest mortality (58.8%), and 5-year OS was 43%. By contrast, 5-year OS of patients <6, 6–18, and 18–60 years was 86.1%, 74%, and 58.9%, respectively. Additionally, among patients with different etiologies (EBV, non-EBV-driven infection, and uncertain causes) and treatment regimens (HLH-04, HLH-94, and glucocorticoid regimen), geriatric patients showed lowest 5-year OS. Multivariate analysis revealed that creatinine and alanine aminotransferase were independent risk factors affecting the survival of patients aged 0–6 years, while albumin and IgG were independent factors affecting survival of geriatric patients. Conclusion: Our study showed a wide heterogeneity of clinical presentations, etiology distribution, prognostic factors, and survival outcomes in pediatric and adult HLH patients.

Case Report: A unique case of secondary hemophagocytic lymphohistiocytosis from ehrlichiosis infection

Hemophagocytic lymphohistiocytosis (HLH) is a highly detrimental syndrome that can progress to multiorgan failure, necessitating the resources of an intensive care unit, with a mortality rate as high as 40%. Secondary HLH is usually triggered by infection, most often from a viral infection or malignancy. Management of HLH in adults is challenging as treatment algorithms targeting hyperinflammation are based on pediatric protocols, such as HLH-94 and HLH-2004. To our knowledge, there are only a few reported cases of HLH secondary to ehrlichiosis infection and none in elderly patients with multiple comorbidities. Here, we present a unique case of HLH secondary to ehrlichiosis infection in an 82-year-old female successfully treated with antibiotics and steroids.