Lymphohistiocytosis In Adults 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.

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 >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.

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.

Secondary Hemophagocytic Lymphohistiocytosis in Adults: Experience from a Safety Net Hospital Serving an Underserved Population

Introduction: Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening condition, driven by an overactivation of the immune system, which causes inflammatory tissue damage potentially leading to organ failure and death. Secondary HLH in adults is a rare clinical entity and diagnosis often is delayed due to low index of clinical suspicion or limited availability of sophisticated testing. Therefore, evidence related to overall outcomes in underserved populations remains scarce. Methods: After institutional review board approval, we retrospectively reviewed charts of patients 18 years or above, with a diagnosis of hemophagocytic lymphohistiocytosis at our institution between 2015-2021. Data on baseline characteristics, cause of HLH and overall outcomes were collected and analyzed. SAS v9.4 was used for statistical analysis. Results: A total of 17 patients were included for the analysis. Majority patients were males (10/17, 58.8%) and mean age was 41.1 ± 17.1 years. Most patients lacked insurance coverage (12/17, 70.6%); in patients with insurance coverage, Medicaid was the most common primary payer (5/6, 83.3%). 8/17 (47.1%) patients were African Americans, similarly Caucasians (8/17, 47.1%), followed by Hispanics (1/17, 5.9%). Fever was noted to be the most common presentation (12/17, 70.6%), followed by abdominal pain, vomiting and cough which were present only in 3/17 (17.6%) patients. Splenomegaly/ hepatosplenomegaly was the most common finding on imaging (7/17, 41.2%). Laboratory investigations were consistent with with cytopenias (16/17, 94.1%) and transaminitis (13/17, 76.5%) in majority of the patients. Bone marrow biopsy was performed to aid in diagnosis in 8/17 (47.1%) patients, out of which, hemophagocytosis was noted only on 4/17 (23.5%). NK- cell activity was tested in 8/17 (47.1%) patients and was noted to be low. Soluble interleukin-2 receptor-alpha/CD25 was tested in 7/17 (41.2%) patients and ranged from 345-6,029 units/ml and was helpful in diagnosis (>2400 units/ml) only in 3/7 (42.9%) patients. Underlying infection was the most common cause of HLH (8/17, 47.1%), out of which, majority had HIV (5/8, 62.5%). 4 out of 5 patients with HIV had disseminated histoplasmosis (80%). 4/17 (23.5%) patients were noted to have underlying rheumatologic disease; the cause of HLH was deemed to unknown in 4 patients (4/17, 23.5%)). One patient was diagnosed with an underlying malignancy, i.e., acute myeloid leukemia (1/17, 5.9%). Majority patients were managed in intensive care unit setting (10/17, 58.8%). Patients managed in ICU setting had a lower median platelet count nadir than those managed on the floor (40,000 cells/cu. mm vs 52,000 cells/ cu. mm, p=0.04). However, no significant difference in the median platelet count, white blood cell count or median hemoglobin levels on presentation was noted between the two groups (p>0.05). Majority patients were managed with steroids alone (9/17, 52.9%), followed by steroids+steroid-sparing agents (4/17,23.5%), anti-fungal agents alone (2/17, 11.8%) and steroids+intravenous anti-globulin and anti-fungal agent (1/17, 5.9%). One patient (1/17, 5.9%) was only conservatively managed. Complete recovery was noted in majority of the patients (13/17, 76.5%), while 4/17 (23.5%) patients died during their hospital stay. 2 out of the 4 patients (50%) who died had underlying rheumatological disease, while the remaining two patients had acute myeloid leukemia and cellulitis respectively. Conclusion: Majority of the cases of secondary HLH in our cohort of underserved adults were noted to be related to infectious causes. Contrary to existing literature, HIV was noted to be the predominant cause in these patients (as opposed to Epstein-Barr virus). HLH in patients with HIV should prompt investigation for underlying histoplasmosis. Patients with a lower platelet nadir appear to be at greater risk of escalation of level of care. HLH related to infections is associated with a relatively favorable outcome, which may explain the relatively lower overall mortality in our study population. Clinical presentation was widely non-specific, warranting a high index of suspicion for secondary HLH, to allow prompt diagnosis in these patients. Investigations such as bone marrow biopsy and interleukin-2 receptor-alpha/CD25 may not aid in diagnosis in many patients and may not be included in initial evaluation for HLH in resource-limited settings.

Clinical Characteristics of Hemophagocytic Lymphohistiocytosis in Adults with Central Nervous System Involvement

Purpose: Central nervous system (CNS) involvement in hemophagocytic lymphohistiocytosis (HLH) is characterized by neurological symptoms/signs, CNS imaging changes, and cerebrospinal fluid abnormalities. However, most reports of CNS-HLH focused on pediatric patients, and there were few clinical studies in adult patients. Therefore, we carried out this study to investigate clinical characteristics and prognosis of adult patients with CNS-HLH. Methods: A retrospective analysis of adult patients with HLH from January 2010 to December 2021 was conducted. Clinical characteristics, assistant examination, treatment, and prognosis were analyzed. Results: Among 166 HLH patients in our center, 16 patients (9.6%) had neurological symptoms and/or assistant examinations of CNS involvement. 1 was primary HLH; 11 were secondary to malignant tumor; 3 were secondary to infection; 1 was secondary to autoimmune disease. 13 patients (81.3%) showed CNS symptoms, and the most common symptom was dizziness/headache (43.8%). 12 patients underwent cranial CT or MRI, and 9 (75%) showed changes. 7 patients underwent cerebrospinal fluid examination, and 5 (71.4%) showed abnormal results. 5 patients underwent PET-CT, and all were normal. 7 patients underwent HLH genetic testing, 1 showed homozygous mutation of UNC13D C.2588G&GT; 5 showed unknown significance heterozygous mutations of HLH related genes. For patients who received anti-HLH and/or anti-lymphoma chemotherapy, who achieved CR/PR had significantly better OS than those with NR (Not reached V.S. 8 days, P<0.001). However, Patients who received CNS-HLH therapy had no statistically significant long-term survival compared with patients who received general HLH therapy (P=0.290). As for the analyses of effective factors on survival time, rash was the only independent risk factor. Conclusions: CNS involvement in adult patients with HLH is not rare and the prognosis is poor. The clinical manifestations and etiology of these patients are heterogeneous. Early diagnosis through CNS examinations and treatment in time are essential to improve the prognosis of patients with CNS-HLH. This work was supported by 1.3.5 Project for Disciplines of Excellence, West China Hospital, Sichuan University (No. ZYJC21007). Key words: Hemophagocytic Lymphohistiocytosis; Adults; Central Nervous System; Prognosis; Retrospective Study

Hemophagocytic Lymphohistiocytosis in Adults: A Retrospective Study in a Belgian Teaching Hospital.

Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening disease, which can be primary (due to genetic mutation) or secondary to malignancy, infection and rheumatologic diseases. Data concerning Belgian patients with adult HLH are lacking. This retrospective study was performed in a teaching hospital in Belgium. All cases of adult HLH, from December 2010 to April 2022, were reviewed. Patients with more than five HLH-2004 criteria and/or HScore >80% were included in the study. The objective of our study was to describe clinical and biological characteristics of patients with HLH and attempt to look for variables associated with mortality. Fifty-two patients were included in the final analysis. Mean age (SD) of patients was 48 (18) years old, and 29 patients were of male gender (56%). The underlying diseases associated with HLH were malignancy (M-HLH) in 22 patients, infection related HLH in 20 patients, rheumatologic disease related HLH in 7 patients, idiopathic in 2 patients and secondary to pregnancy in 1 patient. Overall mortality, mortality at 30 days and 90 days were 24/52 (46%), 13/52 (25%) and 4/52 (10%), respectively. In univariate analysis, malignancy, male sex, age and disseminated intravascular coagulation (DIC) were associated with mortality (p < 0.05). In multivariate analysis, only age was significantly associated with mortality (odds ratio, 1.053; 95% confidence interval, 1.016-1.092; p 0.005). In our study, the most frequent triggers were malignancy and infectious agent followed by rheumatologic disease. Risk factors for mortality were age, male sex, malignancy and DIC, but only age remained significant in multivariate analysis. Treatment guidelines are mainly based on pediatric patients, and it is important for physician to describe adult patients' outcome to better understand this disease and adapt treatment.

DELAYED HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS (HLH) DIAGNOSIS IN A PATIENT WITH PULMONARY SARCOIDOSIS AND NEWLY DIAGNOSED T-CELL LYMPHOMA: A CASE REPORT

DELAYED HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS (HLH) DIAGNOSIS IN A PATIENT WITH PULMONARY SARCOIDOSIS AND NEWLY DIAGNOSED T-CELL LYMPHOMA: A CASE REPORT

Practice patterns and outcomes of hemophagocytic lymphohistiocytosis in adults: a 2-decade provincial retrospective review.

Hemophagocytic lymphohistiocytosis (HLH) is a heterogeneous, life-threatening clinical syndrome. There are scarce data on the quality of care in HLH or data comparing treatment patterns and outcomes between different triggers. We aimed to examine quality-of-care indicators and outcomes in adults with various HLH triggers. In this multi-centre retrospective cohort study of adult HLH in the province of Alberta, Canada (1999-2019), we examined quality indicators including diagnostic testing, time to diagnosis and treatment and trigger identification. We also compared treatment regimens and outcomes across HLH triggers. Logistic regression was used to identify predictors of etoposide use. Overall survival (OS) was estimated using the Kaplan-Meier method. We identified 97 patients; 66 (68%) were male. Triggers included malignancy (36%), infection (35%), autoimmune disease (21%) and idiopathic/others (8%). Specialized tests such as sCD25 (53%) and natural killer degranulation assay (19%) were under-performed, as were testing for infectious triggers. Etoposide was administered in only 33 (34%). Neutropenia, hyperbilirubinemia and hyperferritinemia, but not age, sex and comorbidities, were significant predictors of etoposide use. At median follow-up of 32months, median OS was 18.8months. Worse OS was seen in malignancy-associated and idiopathic HLH (log-rank P < 0.001). Our study showed low rates of specialized testing such as sCD25 and a low rate of etoposide use. Development of a standardized provincial protocol has the potential to improve quality of care in adult HLH.

Spectrum and trigger identification of hemophagocytic lymphohistiocytosis in adults: A single-center analysis of 555 cases.

Limited data are available about the underlying causes of hemophagocytic lymphohistiocytosis (HLH) in adults. We collected and analyzed the data of 555 cases of adult HLH. HLH in 242 patients were malignancies-related and lymphoid malignancies (42.0%, 233/555) were the most common causes. Aggressive natural killer-cell leukemia, diffuse large B-cell lymphoma, and extranodal natural killer/T-cell lymphoma, nasal type were the most common specified pathological subtypes. Epstein-Barr virus (EBV) (69.0%, 100/145) was the most common pathogen among the cases of infections-related HLH (26.1%, 145/555). Malignancies-related HLH showed male preponderance, more common splenomegaly, more severe anemia and thrombocytopenia, and significantly elevated soluble CD25. In patients with abnormal lymphoid cells in the bone marrow (BM) and increased EBV DNA copy number, 48.9% (45/92) of them were aggressive natural killer-cell leukemia. In patients with abnormal lymphoid cells in the BM and normal EBV DNA copy number, 66.2% (47/71) of them were B-cell non-Hodgkin lymphoma. In patients with elevated EBV DNA copy number but no abnormal lymphoid cells in the BM, 71.0% (98/138) of these cases were EBV infection. In conclusion, lymphoid malignancy is the most common underlying cause of adult HLH, followed by EBV infection. Based on the BM morphology and EBV load, we developed a diagnostic flow for rapid determination of the triggers for HLH.

Outcomes of allogeneic hematopoietic stem cell transplantation for primary hemophagocytic lymphohistiocytosis in adults.

Allogeneic hematopoietic stem cell transplantation (HSCT) is the only curative approach for primary hemophagocytic lymphohistiocytosis (pHLH), but data on adult patients are scarce. Here we present an 8-year experience on HSCT for adult pHLH to reveal the benefits and risks in this population. A total of 29 adult pHLH patients entered this study, at a median follow-up of 29months (3-112months), the 5-year probability of survival was 60%. Six patients rejected HSCT, of whom 1 alive in complete response (CR). In 23 patients who underwent HSCT, 5-year survival post-HSCT overall was 73%, and in haploidentical HSCT (haplo-HSCT) cases, 71%. Patients who achieved CR at HSCT had a better outcome than those of partial response (92% vs. 47%, p=0.013). Neither the use of HLA mismatched donor (75% vs. 72%, p=0.996) nor the use of donor with monoallelic mutation (74% vs. 71%, p=0.901) affected the prognosis. Hemophagocytic lymphohistiocytosis status of CR at HSCT was a positive prognostic factor. We concluded that HSCT is a promising method to cure adult-onset pHLH. Achieving CR before HSCT contributes to better outcome. Haplo-HSCT is safe and effective for adult pHLH patients, donors with monoallelic mutations in pHLH related genes but normal cytotoxic functions are reliable.

Usefulness of Interleukin-18 as a Diagnostic Biomarker to Differentiate Adult-Onset Still's Disease With/Without Macrophage Activation Syndrome From Other Secondary Hemophagocytic Lymphohistiocytosis in Adults.

BackgroundInterleukin (IL)-18 is markedly elevated in systemic inflammatory diseases that cause the ‘cytokine storm’ such as adult-onset Still’s disease (AOSD) and hemophagocytic lymphohistiocytosis (HLH). The differences in IL-18 between AOSD and HLH, especially in adults, is uncertain. Macrophage activation syndrome (MAS), a form of secondary HLH, is often difficult to differentiate cases of AOSD that include MAS from other secondary HLH. In this case-control study, we investigated whether serum IL-18 levels could be a useful biomarker for the differential diagnosis of AOSD with or without MAS (AOSD group) and other secondary HLH in adults (adult HLH group).Patients and MethodsWe enrolled 46 patients diagnosed with AOSD including 9 patients with MAS and 31 patients in the adult HLH group, which excluded AOSD-associated MAS. The clinical features and laboratory data were compared between the AOSD and adult HLH groups. In addition, we subdivided the AOSD group (with or without MAS) and the adult HLH group (whether lymphoma-associated or not) and compared the four groups. A logistic regression analysis was used to identify factors with high efficacy in differentiating the two groups, followed by a receiver operating characteristic (ROC) curve analysis to evaluate the differential diagnostic ability of IL-18. We analyzed the correlation between IL-18 and various laboratory parameters in the AOSD group.ResultsSerum IL-18 levels of patients in the AOSD groups were significantly higher than those of the adult HLH groups, and were closely correlated with ferritin, soluble interleukin-2 receptor (sIL-2R), and other laboratory data. Univariate and multivariate logistic regression analyses revealed that IL-18, sIL-2R, and ‘arthralgia or arthritis’ are independent factors useful in the differential diagnosis of AOSD from adult HLH. In the differential diagnosis of both groups, the area under the curve obtained from the ROC curve of IL-18 with a cutoff value of 18,550 pg/mL was 0.91 (95% confidence interval 0.83–1.00; sensitivity 90.3%, specificity 93.5%), and the differential diagnosis ability of IL-18 was superior to that of other laboratory data.ConclusionsIL-18 could be a useful biomarker for the differential diagnosis of AOSD and adult HLH.

CARDIAC TAMPONADE AS A PRESENTING FEATURE OF METASTATIC GI CARCINOMA

TOPIC: Critical Care TYPE: Fellow Case Reports INTRODUCTION: Hemophagocytic lymphohistiocytosis (HLH) is a rare but life-threatening disease. It is characterized by abnormalities in immunoregulation due to a non-malignant proliferation of lymphocytes and secretion of inflammatory cytokines. HLH is typically associated with acquired immunodeficiencies such as in hematopoietic stem cell transplantation. We present a case of a young woman who was treated in our ICU for confirmed HLH which was attributed to an Epstein-Barr virus (EBV) infection that reactivated during her post-transplant immunosuppression. CASE PRESENTATION: A 46-year-old female presented to her primary care physician with gradual dyspnea, spontaneous gum bleeding and lower extremity bruising. She was diagnosed with anemia during her pregnancy. Eventually developed leukopenia and pancytopenia. She was later diagnosed with aplastic anemia and underwent a conditioning regimen prior to peripheral blood stem cell transplantation (PBSCT) with cyclophosphamide, fludarabine, total body irradiation, and rabbit anti-thymocyte globulin (ATG). She had an allogeneic PBSCT from a 10/10 HLA-matched unrelated donor (MUD). Her pre-transplant workup was positive EBV IgG. Donor pre-transplant workup was negative for EBV. Post-transplant immunosuppression consisted of rituximab and tacrolimus. Two months post-transplant, she was admitted for non-neutropenic fevers and diagnosed with Clostridium difficile colitis, acute kidney injury, EBV viremia (>800000 IU/ml), and widespread lymphadenopathy concerning for EBV-associated biopsy proven monomorphic PTLD. She was treated with two doses of Rituximab. Due to worsening encephalopathy, liver function tests and metabolic acidosis, ICU transfer initiated for continuous renal replacement therapy (CRRT). She developed acute respiratory failure and septic shock; was intubated, requiring vasopressors. During her ICU stay, HLH was considered. Bone marrow aspiration and biopsy performed confirmed HLH. High dose dexamethasone therapy was initiated. She also received two doses of Etoposide and a dose of tocilizumab in ICU. She was successfully extubated to high flow nasal cannula. Next Day, given her worsening mental status; Emapalumab (GAMIFANT, Novimmune SA), a fully human anti–IFN-gamma monoclonal antibody for HLH, was administered. Her cognitive function further declined, and she progressed to multiorgan failure and death. DISCUSSION: Aplastic anemia is a hematologic disorder characterized by pancytopenia and bone marrow aplasia. Bone marrow transplantation and immunosuppressive therapy are the modalities currently used, with success rates ranging 60% to 80%. Most treatment options for EBV-HLH have unclear effectiveness in adults. CONCLUSIONS: Despite trying rituximab, dexamethasone, etoposide, tocilizumab and Emapalumab, our transplant patient exhibits a unique and ambiguous intersection of EBV-associated refractory HLH, unresponsive to treatments. REFERENCE #1: Imashuku S, Kuriyama K, Sakai R, Nakao Y, Masuda S, Yasuda N, et al. Treatment of Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis (EBV-HLH) in young adults: a report from the HLH study center. Med Pediatr Oncol. 2003;41(2):103-9. REFERENCE #2: Fox CP, Shannon-Lowe C, Gothard P, Kishore B, Neilson J, O'Connor N, et al. Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis in adults characterized by high viral genome load within circulating natural killer cells. Clin Infect Dis. 2010;51(1):66-9. REFERENCE #3: Locatelli F, Jordan MB, Allen C, Cesaro S, Rizzari C, Rao A, et al. Emapalumab in Children with Primary Hemophagocytic Lymphohistiocytosis. N Engl J Med. 2020;382(19):1811-22. DISCLOSURES: No relevant relationships by Padmastuti Akella, source=Web Response No relevant relationships by Saira Imran, source=Web Response No relevant relationships by Aizaaz Khan, source=Web Response No relevant relationships by Kevin Lazo, source=Web Response

Hemophagocytic lymphohistiocytosis in adults: A key issue in the COVID-19 era.

Hemophagocytic lymphohistiocytosis (HLH) is a syndrome characterized by persistent activation of the mononuclear phagocytic system, systemic inflammation, and hypercytokinaemia, which can lead to liver failure, “sepsis-like syndrome” and ultimately, to multiple organ failure and death. These disorders can be divided into primary and secondary (or reactive), the first, also known as familial HLH, is a genetic condition of childhood, which affects the function of TCD8 and NK cells, and usually presents in the first year of life. The secondary HLH affects mainly adults and adolescents and, it's more related to dysregulation of the immune system. In face of the COVID-19 pandemic and several reports of HLH by SARS-CoV-2, it is necessary to discuss the pathophysiology of HLH in adults more clearly. Thus, we present, for the first time, a didactic approach using illustrations and tables, compiling the most recent and relevant information to better understand this entity.

Clinical Characteristics and Outcomes of Hemophagocytic Lymphohistiocytosis-Associated Lymphoma: A Case-Control Study

Introduction :Hemophagocytic lymphohistiocytosis (HLH) is frequently associated with malignancies, specifically with lymphoma. It is an heterogeneous and life-threatening disease. HLH is associated with aggressive lymphomas and a worse outcome (1). There is no consensus about the optimal treatment in this group of patients (2). This study compares the characteristics and outcomes of patients with HLH-associated lymphoma to non-HLH-associated lymphoma; and assess the impact of HLH on the survival of patients with lymphoma.Patients and methods :We included 33 adults (age ≥18 years) from 1998 to 2016, with HLH-associated lymphoma. HLH was diagnosed with 5/8 HLH-04 diagnostic criteria and for lymphomas we used the WHO 2008 classification. to determine if there were differences between lymphoma with or without HLH, a control group of patients diagnosed in the same time period with non-HLH-associated lymphoma (n = 66) was randomly selected. To assess the impact of HLH on overall survival (OS), another matched control group was selected by clinical stage, type of lymphoma and the same chemotherapy regimen (n = 33).Results:The patients with HLH-associated lymphoma were younger (37 vs 54 years, p=0.006). Among the clinical characteristics and laboratory abnormalities, patients with HLH-associated lymphoma presented more frequently with higher fever (100 vs 39.39% p <0.001), hepatomegaly (81.82 vs 30.30%, p <0.001), splenomegaly (81.82 vs 27.27% p <0.001), advanced clinical stages III / IV (90.91 vs 59.09%, p <0.001), B symptoms (96.97 vs 77.77%, p=0.004), cutaneous involvement (33.33 vs 7.58%, p = 0.003), liver disease (51.52 vs. 13.6%, p <0.001), higher ferritin levels (4547 vs 274 ug / L, p <0.001) and more lymphopenia (0.43 vs 1.12x109 / L, p=0.001) (table 1). Patients with HLH-associated lymphoma had a worse 2 year-OS (41 vs. 87.4%, p<0.001). The most common type of HLH-associated lymphoma was T-cell non-Hodgkin's lymphoma (NHL) (54.55%) followed by B-cell NHL (27.27%) and Hodgkin's lymphoma (HL) (18.18%). When comparing patients with non-HLH-associated lymphoma matched by clinical stage, lymphoma type, and treatment with patients with HLH-associated lymphoma, the OS at 2-year was lower in the latter group (41 vs 65%, p = 0.038) figure 1. We analyze by lymphoma subtype, and the presence of HLH had only a significant impact in the T cell NHL survival (2 year-OS of 28.8 vs 55.9%, p = 0.011).Conclusion :HLH is associated with advanced lymphomas in young patients. Our results showed that HLH impacts on the OS in patients with T-cell NHL, but we found no significant different outcomes in patients with B-cell NHL and HL with the presence of HLH. Prospective studies are needed to confirm this results.Bibliography:1.-Parikh SA, Kapoor P. Prognostic factors and outcomes of adults with hemophagocytic lymphohistiocytosis. Mayo Clin Proc. 2014;89(4): 484-492.2.-Daver N, McClain K. A consensus review on malignancy-associated hemophagocytic lymphohistiocytosis in adults. Cancer. 2017;00(0):1-12. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Current status of the diagnosis and treatment of hemophagocytic lymphohistiocytosis in adults.

Hemophagocytic lymphohistiocytosis (HLH) is a syndrome of defective apoptosis, a disruption of the regulatory pathway that terminates immune and inflammatory responses. Fever, cytopenia, splenomegaly, and/or hemophagocytosis are typical findings of this syndrome. HLH can be induced by genetic disorders (familial) or secondary causes. Familial HLH is rare, while secondary causes in adults include infection, autoimmunity, and malignancy. HLH in adults tends to be confused with or misdiagnosed as sepsis, mainly due to similar clinical manifestations and laboratory findings, which make it difficult to diagnose HLH rapidly and adopt immunosuppressive agents and/or chemotherapy adequately. Treatment of pediatric HLH using HLH-2004 or multi-agent chemotherapy can be applied in adult patients, although the dose and type of drug need to be adjusted. It is highly recommended that allogenic hematopoietic stem cell transplantation should be used in patients who become reactivated or are refractory to the initial treatment as soon as possible to improve survival. Future clinical trials are warranted to determine more suitable treatments for adult patients with HLH.

Characteristics and predictors of post-transplant-associated hemophagocytic lymphohistiocytosis in adults.

Hemophagocytic lymphohistiocytosis (HLH) is an uncontrolled hyperinflammatory disorder driven by an overactive immune system that results in high mortality. Post-transplant-associated hemophagocytic lymphohistiocytosis (PT-HLH) is a type of secondary HLH that occurs following allogeneic hematopoietic stem cell transplantation (allo-HSCT). The clinical features of PT-HLH remain unclear and diagnostic and prognostic tools have not yet been established. Here, we retrospectively evaluated the clinical manifestations and outcomes of PT-HLH in 94 patients who underwent allo-HSCT. According to our PT-HLH criteria (hyperferritinemia and increased macrophage count in bone marrow), PT-HLH occurred in 12 patients (12.8%). The PT-HLH patients showed splenomegaly (P = .001), a higher risk of engraftment failure (P = .013), and an increased percentage of macrophages and hemophagocytes in bone marrow aspirates (P = .0009 and P = .0006, respectively). Moreover, univariate and multivariate analyses revealed that the survival rate was lower in PT-HLH patients than non-PT-HLH patients (P = .0017 and P = .034, respectively). This study defines the clinical features of PT-HLH and PT-HLH criteria that could be useful tools for diagnosing PT-HLH.

External Validation of the HLH-2004 Diagnostic Criteria and H-Score for Diagnosis of Hemophagocytic Lymphohistiocytosis in Adults

Introduction: Hemophagocytic lymphohistiocytosis (HLH) is a hyperinflammatory syndrome associated with multi-organ failure and death. Diagnosis in adult patients is currently based on the HLH-2004 diagnostic criteria; however, these criteria were developed for pediatric HLH and have not been formally validated in adults. An alternative diagnostic score, the H-score, was developed for adults with reactive HLH. There have been few external validation studies comparing the diagnostic accuracy between the HLH-2004 criteria and H-score, mostly in critically ill patients. In this external validation study, we aimed to compare the discriminatory power of these two diagnostic criteria in predicting HLH in a multicenter cohort of adults with suspected HLH. Methods: We identified all adult inpatients (≥18 years) with an International Classification of Diseases (ICD) code for HLH in the province of Alberta, Canada from January 1999 to December 2019. Following independent chart review by two reviewers, cases were classified as positive, negative, or indeterminate cases of HLH. The HLH-2004 diagnostic criteria and H-score were determined for each case. The following performance characteristics of the diagnostic scoring systems were calculated: sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV). C-statistic was calculated from the receiver operator curve (ROC) analysis. Results: Data on 101 patients were collected. The median age was 46 years (range 18-88), 66 (65%) were male. Active malignancy within 6 months of presentation, infections, and autoimmune diseases were present in 31%, 36%, and 18%, respectively. Of the 96 patients who underwent bone marrow aspirate and biopsy, hemophagocytosis was present in 79 (82%). Using chart review as the gold standard, 89 (88%) patients were determined to have HLH, whereas 5 (5%) and 7 (7%) were reclassified as negative and indeterminate cases, respectively. 83 (82%) patients met ≥5 of the 8 HLH-2004 diagnostic criteria; using the HLH-2004 criteria missed 8 cases of HLH. The sensitivity and specificity of HLH-2004 criteria was 91.0% and 83.3%, respectively, with a PPV of 97.6% and an NPV of 55.6%. The median overall H-score was 238 (range 129-337). An H-Score cut-off of &amp;gt;169 (established as the optimal cut-off from the original derivation and validation paper) predicted HLH with a sensitivity of 95.5%, specificity of 16.7%, PPV of 89.5%, and NPV of 33.3%. The discriminatory power improved with an H-Score cut-off &amp;gt;210, with a sensitivity of 86.5%, specificity of 66.7%, PPV of 95.1%, and NPV of 40.0%. The c-statistics for the HLH-2004 criteria and the H-Score were 0.872 and 0.737, respectively. In the malignant subgroup, all patients fulfilled the HLH-2004 criteria and all were deemed to have HLH upon chart review. All but one had an H-Score &amp;gt;169, with a median H-Score of 238 (range 168-304) in the malignant group. Conclusion: In our highly selected patient population with suspected HLH, the HLH-2004 had better discriminatory power than the H-Score, with a high sensitivity and specificity and excellent c-statistic &amp;gt;0.80. An H-Score cut-off of &amp;gt;169 was highly sensitive but non-specific in identifying adults with HLH. The validity and applicability of our study is limited by a high prevalence of chart-confirmed HLH in our sample. We are completing ongoing data collection to expand our validation study in a cohort of adults with hyperferritinemia who underwent bone marrow evaluation and/or sCD25 testing. Disclosures Sun: Sanofi: Other: Advisory board; Octapharma: Other: Advisory board; Octapharma: Research Funding; Novo Nordisk: Other: Advisory board; Pfizer: Other: Advisory board.

Practice Patterns and Outcomes of Hemophagocytic Lymphohistiocytosis in Adults: A Two-Decade Provincial Retrospective Review

Introduction: Hemophagocytic lymphohistiocytosis (HLH) is a rare clinical syndrome characterized by uncontrolled immune activation, resulting in multi-organ dysfunction and a high risk of death. Due to scarcity of data in adults, the diagnosis remains challenging and has been historically associated with a delayed time to diagnosis and heterogeneous practice patterns. We examined the processes of care measures and outcomes in a large cohort of adults with HLH. Methods: This multicenter, retrospective cohort study examined the epidemiology, management, and outcomes of adult inpatients (≥18 years) diagnosed with HLH in the province of Alberta, Canada from January 1999 to December 2019. Patients were identified via International Classification of Diseases (ICD) codes, and those who met the HLH-2004 diagnostic criteria were included. Chart reviews were performed to collect demographics, clinical and laboratory characteristics, process of care measures, and outcomes. Overall survival (OS) was defined as the time from hospital presentation to death. Survival analysis was performed using the Kaplan-Meier method, and differences between groups were assessed using the log-rank test. Cox proportional hazards regression was used to assess the association between time to diagnosis and the hazard of death, adjusting for patient and disease characteristics. Results: 83 patients met the HLH-2004 diagnostic criteria; 1 had a clear alternative diagnosis, hence 82 were included in the final data analysis. The median age of the cohort was 47 (interquartile range, IQR 32-62) years; 57 (70%) were male. The etiologies of HLH were as follows: malignancy (38%), infection (35%), autoimmune disease (16%), and idiopathic/others (11%). The most common clinical and laboratory findings were hyperferritinemia (100%), fever (99%), cytopenias (94%), hypofibrinogenemia and/or hypertriglycermidemia (91%), and hemophagocytosis on biopsy (89%). The median H-score was 244, with no significant difference across HLH etiologies. Interim data analysis showed that sCD25, natural killer (NK) cell activity, and molecular studies were ordered in 69%, 36%, and 29% of cases. The median length of hospitalization was 33 days (IQR 16-62), with a 30-day mortality rate of 25.6%. A majority of patients (55%) required admission to the intensive care unit (ICU) (Table 1). The median OS was 8.5 months. Patients with malignancy-associated HLH had a significantly worse median OS compared with those with non-malignancy-associated HLH (2.1 vs 54.5 months, p=0.0004; Figure 1). There were no differences in the median OS between B-cell (n=11) and T/NK lymphoproliferative disorders (n=13), or between new cancer diagnosis (n=27) and active cancer receiving chemotherapy (n=4). Age (adjusted hazards ratio, aHR 1.06, 95% CI 1.01-1.10), Charlson comorbidity index (aHR 1.4, 95% CI 1.2-1.8), and ICU admission (aHR 4.1, 95% CI 1.4-12.2) were associated with increased hazards of death on multivariable Cox proportional hazards model. Malignancy was associated with increased hazard of death on univariate analysis (HR 2.8, 95% 1.5-4.9), but did not remain as an independent prognostic factor on multivariable analysis (aHR 1.0, 95% 0.4-2.6). Sex, delayed diagnosis, or peak ferritin level were not significant predictors of mortality. The median times from presentation to diagnosis and from presentation to therapy were 10 days (IQR 2-19) and 14 days (IQR 6-25), respectively. Practice patterns varied significantly between centers without differences in survival outcome (log-rank p=0.8). Most patients (83%) received corticosteroids, whereas etoposide, intravenous gammaglobulin, and cyclosporine were administered in 38%, 34%, and 18%, respectively. Twelve (15%) patients did not receive any HLH-specific treatment, mostly in infection-associated HLH (n=8). Of the 31 patients receiving steroids and etoposide, 21 (68%), 12 (39%), and 20 (65%) receivedpneumocystis jirovecii, antiviral, and antifungal prophylaxis, respectively. Conclusion: In our two-decade provincial study, we observed that delayed diagnosis and treatment heterogeneity were common. Older age, comorbidities, and ICU admission were independent predictors of poor survival, whereas delayed diagnosis and malignant HLH were not. Development of a standardized provincial diagnostic and treatment protocol has the potential to improve the quality of care in adult HLH. Disclosures Sun: Sanofi:Other: Advisory board;Octapharma:Other: Advisory board;Pfizer:Other: Advisory board;Octapharma:Research Funding;Novo Nordisk:Other: Advisory board.