Diagnosis Of Hemophagocytic Lymphohistiocytosis Research Articles

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.

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.

Implementing a Disease-specific Multidisciplinary Team and Order Set for Hemophagocytic Lymphohistiocytosis in a Pediatric Hospital.

To improve outcomes of hemophagocytic lymphohistiocytosis (HLH), prompt recognition and treatment are necessary. A HLH multidisciplinary team was implemented at our institution, and we established an electronic order set to foster uniformity in the diagnostic approach. The goal of this study is to capture the impact of this diagnostic tool. This is a retrospective study analyzing the utilization of a HLH-specific order set since time of implementation in June 2019 through December 2022. The trends in the utilization of the order set by providers were analyzed to evaluate the awareness and effectiveness of this tool. The order set was utilized 50 times, most commonly by hematology/oncology (50%) and infectious disease (26%). Utilization by providers on newly presenting patients included 4 times in the year 2019, 12 times in 2020, 16 times in 2021, and 18 times in 2022. Utilization was associated with the diagnosis of HLH in 9 patients (18%). Implementation of an HLH-specific order set facilitated a systematic method to approach patients with suspected HLH. The utilization of the order set displayed an upward trend over time, indicating support of this tool among these providers. This tool can increase awareness and early identification of HLH.

Imaging Spectrum of Neurological Manifestations of Hemophagocytic Lymphohistiocytosis in Pediatrics: A Case Series.

Hemophagocytic lymphohistiocytosis (HLH) is an uncommon condition, which can result either from a primary genetic abnormality affecting children or secondary to various conditions like malignancy or infection predominantly in adults. HLH is associated with immune dysregulation, resulting in an uncontrolled overproduction and infiltration of lymphocytes and histiocytes. The infiltration predominantly involves liver, spleen, lymph nodes, and central nervous system. Neuroimaging features on magnetic resonance imaging are highly nonspecific and variable. The most typical findings include periventricular white matter hyperintensities and diffuse atrophy. Ring or nodular enhancing or nonenhancing focal parenchymal lesions may be seen. Here, we present three pediatric cases of primary HLH with a wide spectrum of imaging findings involving cerebral and cerebellar cortex, white matter, deep gray matter, and brain stem. The findings in these patients range from small nonenhancing hemorrhagic lesions and enhancing small lesions to ill-defined mass with mass effect and midline shift. Lesions in deep gray matter including thalamus, basal ganglia, and also brain stem in HLH are rarely described in literature. Early diagnosis of HLH and timely management can improve the course of the disease.

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.

Approaching hemophagocytic lymphohistiocytosis.

Hemophagocytic Lymphohistiocytosis (HLH) is a rare clinical condition characterized by sustained but ineffective immune system activation, leading to severe and systemic hyperinflammation. It may occur as a genetic or sporadic condition, often triggered by an infection. The multifaceted pathogenesis results in a wide range of non-specific signs and symptoms, hampering early recognition. Despite a great improvement in terms of survival in the last decades, a considerable proportion of patients with HLH still die from progressive disease. Thus, prompt diagnosis and treatment are crucial for survival. Faced with the complexity and the heterogeneity of syndrome, expert consultation is recommended to correctly interpret clinical, functional and genetic findings and address therapeutic decisions. Cytofluorimetric and genetic analysis should be performed in reference laboratories. Genetic analysis is mandatory to confirm familial hemophagocytic lymphohistiocytosis (FHL) and Next Generation Sequencing is increasingly adopted to extend the spectrum of genetic predisposition to HLH, though its results should be critically discussed with specialists. In this review, we critically revise the reported laboratory tools for the diagnosis of HLH, in order to outline a comprehensive and widely available workup that allows to reduce the time between the clinical suspicion of HLH and its final diagnosis.

Hemophagocytic lymphohistiocytosis in inflammatory bowel disease: a nationwide analysis.

Hemophagocytic lymphohistiocytosis (HLH) is a rare but life-threatening immune dysregulation disease. Patients with inflammatory bowel disease (IBD) can become profoundly immunocompromised due to immunosuppressive therapy, hence increasing the risk of viral infections that can trigger HLH. However, data on the association between IBD and HLH remains limited. We used data from the National Inpatient Sample (2012-2019) utilizing International Classification of Diseases (ICD)-9 or ICD-10 codes to identify individuals with IBD, either Crohn's disease (CD) or ulcerative colitis (UC), and HLH. The primary outcome was to compare the prevalence of HLH among patients with IBD with those without IBD. Secondary outcomes included in-hospital mortality, mean hospital length of stay, and description of HLH-associated triggers in IBD patients. A total of 513,322 hospitalizations included a diagnosis of IBD, 188,297 had UC and 325,025 had CD. Compared to the general population, patients with IBD were older (median age of 52 vs. 49years, p < 0.05), more likely to be male, and of Asian/Pacific Islander descent, and had a higher median household income. There was also a higher prevalence of liver disease, autoimmune diseases, tobacco abuse, and hypothyroidism (all had p-value of < 0.001) in IBD patients. There were 94 hospitalizations identified with a diagnosis of HLH in IBD patients. Compared to patients without IBD, patients with IBD had increased odds of developing HLH (0.02% vs 0.01%, p-value < 0.001). After adjusting for various demographic characteristics, co-morbidities, and HLH-related conditions, IBD was an independent predictor for developing HLH (adjusted OR, 2.3; 95% CI, 1.847-2.866, p-value of < 0.001). There was no statistical difference between CD and UC in the odds of developing HLH. Compared to IBD patients without HLH, patients with IBD and HLH had a lower mean age at diagnosis (38 vs 52, p-value of < 0.001), higher in-hospital mortality (14.9% vs 1.5%, p-value of < 0.001), and longer mean hospital length of stay (days) (17 vs 5.4, p-value of < 0.001). Prevalence of different HLH-associated illnesses was identified in HLH patient's discharge data. Lymphoma was the most common associated malignancy (18.1%) and cytomegalovirus infection was the most common associated infection (16.0%). Our population-based study suggests that IBD is independently associated with developing HLH. Early recognition of IBD patients presenting with features suggestive of HLH is warranted to aide early diagnosis and aggressive treatment.

An Unusual Case of Hemophagocytic Lymphohistiocytosis Associated with Mycobacterium chimaera or Large-Cell Neuroendocrine Carcinoma

Hemophagocytic lymphohistiocytosis (HLH) is a rare and very dangerous condition characterized by abnormal activation of the immune system, causing hemophagocytosis, inflammation, and potentially widespread organ damage. The primary (genetic) form, caused by mutations affecting lymphocyte cytotoxicity, is most commonly seen in children. Secondary HLH is commonly associated with infections, malignancies, and rheumatologic disorders. Most current information on diagnosis and treatment is based on pediatric populations. HLH is a disease that should be diagnosed and treated promptly, otherwise it is fatal. Treatment is directed at treating the triggering disorder, along with symptomatic treatment with dexamethasone and etoposide. We present a 56-year-old patient who was admitted with worsening weakness, exertional dyspnea, dry and nonproductive cough, and a 5-pound weight loss associated with loss of appetite. This is among the rare disorders that are not commonly encountered in day-to-day practice. Our differential diagnoses were broad, including infection, such as visceral leishmaniasis, atypical/tuberculous mycobacteria, histoplasmosis, Ehrlichia, Bartonella, Brucella, Adenovirus, disseminated herpes simplex virus (HSV), hematological-like Langerhans cell histiocytosis, or multicentric Castleman disease; drug reaction, such as drug rash with eosinophilia and systemic symptoms (DRESS); and metabolic disorder, including Wolman's disease (infantile lysosomal acid lipase deficiency) or Gaucher's disease. Based on our investigations as described in our case report, it was narrowed down to hemophagocytic lymphohistiocytosis and COVID-19. Two COVID-19 tests were negative. His lab abnormalities and diagnostic testing revealed hemophagocytic lymphohistiocytosis. He was empirically started on antibiotics and dexamethasone, to be continued for 2 weeks then tapered if the patient showed continued improvement. Dexamethasone was tapered over 8 weeks. He improved on just one of the Food and Drug Administration (FDA)-approved medications, proving that treatment should be tailored to the patient. In addition, in this case study, we included the background, etiology, pathogenesis, diagnosis, management, and prognosis of HLH.

Combination of gemcitabine, pegaspargase, etoposide, and dexamethasone (GPED) in treatment of advanced extranodal NK/T-cell lymphoma.

Combination of gemcitabine, pegaspargase, etoposide, and dexamethasone (GPED) in treatment of advanced extranodal NK/T-cell lymphoma.

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.

Hemophagocytic Lymphohistiocytosis: an Under-recognized and Life-threatening Condition.

Diagnosis of hemophagocytic lymphohistiocytosis is a challenge in Nepal because of limited resources and the high prevalence of tropical febrile illness mimicking hemophagocytic lymphohistiocytosis. We retrospectively reviewed medical records of 21 patients who were diagnosed with hemophagocytic lymphohistiocytosis from 2010 to 2015 at a single center in Nepal. Two patients had a mutation in their perforin gene and underwent successful haploidentical stem cell transplantation. Marrow hemophagocytosis was found only in 57% of the patients. Five patients had hematological malignancy and were treated with disease-specific chemotherapy. Seven patients developed hemophagocytic lymphohistiocytosis secondary to an infection, including visceral leishmaniasis, scrub typhus, and Epstein Barr virus. EBV-associated hemophagocytic lymphohistiocytosis was refractory to hemophagocytic lymphohistiocytosis 94 protocol, including the addition of rituximab. Malignancy and infection-associated hemophagocytic lymphohistiocytosis was more common. The most common clinical presentations included fever, splenomegaly, hyponatremia, liver function derangement, hyperfibrinogenemia, hyperferritinemia, and cytopenia. With a mortality of 29% in our study cohort, hemophagocytic lymphohistiocytosis should be considered a lethal disease, and clinicians should maintain a high index of suspicion to diagnose this disease. Keywords: Hemophagocytic lymphohistiocytosis; infection; malignancy.

Immune checkpoint inhibitor-related haemophagocytic lymphohistiocytosis in a patient with non-small cell lung carcinoma.

Hemophagocytic lymphohistiocytosis (HLH) has been reported as a rare complication of immune checkpoint inhibitors (ICI); however, ICI-related HLH is a life-threatening and comparatively late adverse event. Early diagnosis is critical, and it should be included in the differential diagnosis especially in patients with cytopenia with fever and hyperferritinaemia.

Soluble interleukin-2 receptor in pediatric patients investigated for hemophagocytic lymphohistiocytosis: A single-center, 10-year-long experience

Introduction/Objective Hemophagocytic lymphohistiocytosis (HLH) is a severe hyperinflammatory condition characterized by fever, splenomegaly, and cytopenias. Diagnosis of HLH requires at least five of the eight criteria set by the Histiocyte Society and poses a significant challenge to physicians. HLH-2004 criteria include measurement of plasma levels of soluble receptor for interleukin-2 (sIL-2R), an invaluable tool in the diagnosis of HLH, particularly because it can be measured swiftly and inexpensively. Methods We retrospectively analyzed medical records of 45 pediatric patients (28 boys and 17 girls, median age 8.1 years) who were investigated for suspected HLH in University Children?s Hospital in Belgrade, during the period from 2012 to 2022. Results Ten children were diagnosed with HLH, while 35 did not have HLH. All 10 HLH patients had secondary HLH: eight suffered from infection or inflammatory condition, one from an autoimmune disease, and one from malignancy. Level of sIL-2R was above the HLH-2004 cutoff value of 2400 IU/ml in 9/10 patients with HLH (sensitivity 90%) and 9/35 of patients who did not have HLH (specificity 74.2%). Conclusion Soluble IL-2 receptor measurement is valuable in children suspected to have HLH. Sensitivity and specificity of this analysis can be further improved by strict patient selection and a comprehensive diagnostic approach.

222: DKA? THINK AGAIN: AN INTERESTING CASE OF HLH

Introduction: Hemophagocytic lymphohistiocytosis (HLH) is an aggressive, life-threatening syndrome of abnormal immune activation that leads to multiorgan dysfunction and death if not diagnosed and treated. Several genetic defects and causative factors have been implicated in the pathogenesis however, presentation with diabetic ketoacidosis (DKA) is uncommon. Description: A 10-year-old male with no past medical history presented to the emergency room for altered mental status, three-day history of nausea and vomiting, and one-day history of abdominal pain and decreased urine output. On exam, the patient was hypothermic, tachycardic, obtunded, and Kussmaul breathing. Initial blood work was consistent with DKA. On hospital day two, while patient’s mental status improved, it had not returned to baseline, and he began having low grade fevers. The patient progressively developed evidence of multiorgan dysfunction with pancytopenia, acute liver failure, hypoxic respiratory failure, coagulopathy, and a hyperinflammatory state including a ferritin level of 1783 ng/mL. The patient’s mental status worsened. Computerized tomography of the brain showed no acute intracranial process; chest radiograph showed evidence of right sided pleural effusion. On day four, patient was transferred to an outside hospital for liver transplant evaluation. The patient subsequently developed evidence of depressed cardiovascular function with an ejection fraction of 38% as well as coronary artery ectasia. Laboratory results were notable for positive GAD Abs consistent with type 1 diabetes mellitus. The patient was found to have diminished natural killer cell function consistent with a diagnosis of HLH. The patient received intravenous immunoglobin, methylprednisolone, and canakinumab as treatment for his HLH. The patient had gradual improvement in his clinical condition and laboratory findings and was discharged home. Discussion: Although the patient initially presented with DKA, he subsequently developed laboratory and physical findings consistent with HLH in addition to his newly diagnosed type 1 diabetes. This case highlights the nonspecific, varied presentation and rapidly progressive nature of HLH. It is important to maintain a broad differential in patients with disease processes that do not respond as expected to treatment.

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.

Factors Associated with in-Hospital Mortality in Patients with Hemophagocytic Lymphohistiocytosis: A 5-Year Analysis from the National Inpatient Sample

Background: Haemophagocytic lymphohistiocytosis (HLH) is an aggressive, life-threatening syndrome caused by a robust and excessive immune response leading to multi-organ failure. HLH can be due to a myriad of etiologies that range from primary disorders related to genetic defects or secondary to infections, autoimmune conditions, malignancies, etc. HLH has been broadly recognized in the pediatric population. Most of the clinical guidelines and evidence are based on this population; thus, more literature is needed amongst the adult population, especially on what factors increase mortality. Therefore, our study aims to evaluate factors associated with mortality in HLH Among Hospitalized Patients in the US using a Large Nation-wide Database. Methods: We performed a retrospective survey analysis of the National Inpatient Sample (NIS) using ICD10-CM and PCS codes to identify adult patients hospitalized with a primary or secondary diagnosis of HLH between October 2015 and December 2019. We compared patients who survived the illness as a control group versus patients who died during the hospitalization. A comparison was done between demographic variables including age, race, sex, median income, among other factors. Data regarding past medical history was also included. The most common causes of HLH were queried and compared between the two groups. Lastly, we performed a final comparison between multiple inpatient complications and outcomes between the two groups. We used qui-square and fisher exact test for categorical variables and student t-test or Mann-Whitney U test for continuous variables. All analysis was done using R studio utilizing the survey package. Results: Data from 8,660 admissions with HLH were included, of which 21% of patients died during the hospitalization. Patients with HLH who died tended to be males (61%), slightly older at age 53 years, and a higher percentage of white patients (55%), though not statistically significant than those who did not die. On the other hand, increased mortality was associated with hematological malignancies (37% vs 24%, p<0.05), baseline chronic kidney, heart, and liver disease. Additionally, these patients were also more likely to develop renal failure, non-septic shock, and pneumonia. Interestingly, patients with rheumatological disorders had statistically lower deaths (13% vs 17% p<0.05). Patients in the lowest percentile of income had the highest percentage of deaths at 30% and the highest percentile of income had a lower percentage of deaths at 22%. The length of inpatient stay was significantly longer in patients who died (18 vs 14 days, p<0.05). In terms of location, larger academic hospitals had higher mortality (77% vs 71%, p=0.02), with no difference between regions. Conclusions: This nationwide data analysis demonstrates the high mortality rates that persist in patients with HLH. Our study contributes to the growing literature on HLH, an intricate and complex topic that is not yet fully understood. Increased attention should be placed on the older population with pre-existent co-morbidities as well as patients with hematological malignancies and low socioeconomic status who are at potentially higher risk of death, to elucidate the mechanisms leading to poor outcomes and potential treatments of this condition. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

The Decisive Role of Pronounced Hyperferritinemia for Diagnosis and Prognosis in the Spectrum of Hematological Disorders

Background Ferritin is an iron storage protein that can also be elevated in serum by various inflammatory pathologic states. Hyperferritinemia is defined as ferritin levels ≥500 ng/mL and is mainly related to hemophagocytic lymphohistiocytosis (HLH) when seen in association with hematologic abnormalities. However, its prevalence in the general population has been reported as high as 13%, and its diagnostic and prognostic role has not been determined among the different hematologic disease subgroups, nor for different levels besides extreme hyperferritinemia (ferritin levels ≥10,000 ng/mL). Our aim was to describe the hematologic etiologies for hyperferritinemia and define the impact over diagnosis and clinical outcomes of different ferritin values within the 500 ng/mL and 15,000 ng/mL range. Methods This was a retrospective single-center study that included all consecutive cases of hyperferritinemia according to our laboratory records between January 2015 and December 2019. A total of 6602 cases were identified. After excluding cases with incomplete medical records or redundant ferritin measurements, more than one measurement within six months, 3193 cases were included. Chi-squared test and Kruskal-Wallis ANOVA tests were performed to demonstrate differences between categorical and quantitative variables, respectively. ROC curves were used to analyze the diagnostic performance of our tests. Survival analyses were carried out with Kaplan-Meier curves. All statistical analyses were carried out by IBM SPSS version 26. Results After non-HIV infection (26.1%; n=832), hematologic disease was the second most common etiology at 23.5% (n=749) within the cohort. The median age for this group was 50 years (17-95), and the median ferritin level was 1,133.3 ng/mL (500-15,000). Hematologic diagnoses were grouped into four categories: hematologic malignancy (60%), iron overload (26%), hemolytic anemia (7%), and HLH (7%). Median serum ferritin was higher in patients with HLH (6,717.5 ng/mL) when compared to other subgroups (p<0.01). Additional baseline characteristics are shown in Table 1. With a cut-off of >3,000 ng/ml (pronounced hyperferritinemia), ferritin level as a diagnostic test for HLH had a sensitivity of 75%, specificity of 87.8%, an area under the curve (AUC) of 0.814, positive predictive value (PPV) of 31.5%, and negative predictive value (NPV) of 97.9%. The same cutoff value in all 3,193 episodes of hyperferritinemia had similar results (sensitivity of 75%, specificity of 92.5%, AUC of 0.837, PPV of 14.1%, NPV of 99.6%). There was no association between pronounced hyperferritinemia and hematologic malignancy, iron overload, or hemolytic anemia. Overall survival (OS) at six months was 79.6% (n=596). When stratified per hematologic diagnosis, OS was 55.8% (n=29) for HLH, 76.4% (n=344) for hematologic malignancy, 89.8% (n=176) for iron overload, and 92.2% (n=47) for hemolytic anemia (p<0.01). On univariate analysis, pronounced hyperferritinemia was related to an increased mortality in patients with hematologic malignancy (p<0.01) and iron overload (p<0.01). There was no association between pronounced hyperferritinemia and mortality for HLH or hemolytic anemia (Figure 1). Conclusion To our knowledge, this is the first study to analyze the impact of hyperferritinemia in patients with diverse hematologic diagnoses. Our findings suggest that a cut-off value of >3000 ng/mL has a high NPV to exclude the diagnosis of HLH, within other differential diagnoses. Regarding prognosis, besides HLH, where clinical outcomes are known to be poor, pronounced hyperferritinemia can be useful in identifying patients with a higher risk of early mortality within the hematologic malignancy and iron overload subgroups. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Incidence and Factors Associated with Hemophagocytic Lymphohistiocytosis Among Hospitalized Patients in the US Using a Large Nation-Wide Database

Background Hemophagocytic lymphohistiocytosis (HLH) is a rare and life-threatening condition triggered by an excessive inflammatory response leading to multiorgan failure with high mortality rates. Early diagnosis and treatment are imperative for survival. However, the diversity in etiologies and clinical presentations make it very challenging to diagnose. HLH has been widely described in the pediatric population. While it is being increasingly recognized in adults, the current knowledge of epidemiological characteristics is limited. The aim of our study is to evaluate the incidence and factors associated with HLH among hospitalized patients in the US using a large nationwide database. Methods We performed a retrospective analysis with the National Inpatient Sample (NIS) using ICD10-CM and PCS codes to identify adult patients hospitalized with a primary or secondary diagnosis of HLH between October 2015 and December 2019. We described patient characteristics including location, charges, length of stay (LOS), associated diagnosis, and inpatient complication variables. We used R studio survey package to analyze survey data included in the NIS to account for the sampling weight and obtain accurate estimates of the included population. Lastly, we included a graph to describe the annual trend of HLH admissions and mortality. Results Data from 8,660 admissions with HLH were included, of which 1785 (21%) patients died during the hospitalization. Patients with HLH tended to be males (56%), with a mean age of 48 years, fifty five percent of the population were white, 17% black, 15% Hispanic, and 7.3% Asian. Associated diagnosis included DLBCL (9.1%), other Non-Hodgkin lymphoma (4.3%), Hodgkin lymphoma (3.8%), Leukemia (4.2%), NK-Cell lymphoma (2%), Viral infections (11.56%), fungal infections (17.85%), bacterial infections (1.16%), and rheumatological disorders (18.51%). Most patients were hospitalized in larger hospitals (74%). A higher percentage of patients were admitted in the South (34%), followed by West (23%), Northeast (22%), and Midwest (20%), with a mean hospitalization cost of $ 251,283. An increasing trend was noted in admissions for HLH. However, the mortality rate has remained stable, despite the recent approval of the interferon-gamma monoclonal antibody emapalumab-lzsg in November of 2018. Conclusions HLH in adults is an increasingly identified disorder that remains a challenging and critical condition. This nationwide data analysis demonstrates its geographical distribution and the persistently high mortality associated with it. Further studies are needed to improve early diagnosis, help understand its pathophysiology to identify patients at risk, and allow for improved treatment. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

A Review of Current and Emerging Therapeutic Options for Hemophagocytic Lymphohistiocytosis.

To provide an overview of clinical sequelae and emerging treatment options for hemophagocytic lymphohistiocytosis (HLH). A literature search was conducted using the search terms "hemophagocytic lymphohistiocytosis," "hemophagocytic syndrome," "macrophage activation syndrome," and "treatment" on Ovid and PubMed from January 1, 2017, through September 28, 2022. Relevant clinical trials, meta-analyses, case reports, review articles, package inserts, and guidelines to identify current and emerging therapeutic options for the management of HLH. Genetic disorders and secondary causes may trigger HLH in both children and adults. Notable improvements in the diagnosis of HLH were seen with implementation of the HLH-2004 standard diagnostic criteria; however, timely and accurate identification of HLH remain significant barriers to optimal management. Multiagent immunochemotherapy are the backbone of aggressive therapy for acutely ill patients with HLH. The global coronavirus 2019 (COVID-19) pandemic and emerging immune effector cell therapies have served to highlight the concerns with immune dysregulation and subsequent HLH precipitation. Without prompt identification and treatment, HLH can be fatal. Historically, the clinician's armamentarium for managing HLH was sparse, with etoposide-based protocols serving as the standard of care. Relapsed or refractory disease portends a poor prognosis and requires additional treatment options. Second- or subsequent-line options now include hematopoietic stem cell transplantation, emapalumab, alemtuzumab, anakinra, ruxolitinib, and tocilizumab. Improvements in diagnostic methods and novel immunosuppressive treatment strategies, including noncytotoxic immunochemotherapy, have transformed the therapeutic landscape. Unfortunately, many unanswered questions remain. Additional studies are required to optimize dosing, schedules, treatment sequences, and indications for novel treatment options.

Clinical characteristics and risk factors for 90-day overall survival among 204 adult patients with secondary hemophagocytic lymphohistiocytosis: Experience from a single-center retrospective study.

ObjectivesTo describe the clinical characteristics of secondary hemophagocytic lymphohistiocytosis (HLH) among adult patients, investigate its risk factors for 90-day overall survival (OS) from diagnosis, and establish a new prognostic model applicable to adult patients with secondary HLH.MethodsWe conducted a retrospective cohort study of 204 adult patients with secondary HLH, between January 2010 and December 2020. All patients met at least five HLH-2004 criteria. Clinical features, laboratory results, treatments, and clinical outcomes of the patients were reviewed. Prognostic factors associated with 90-day overall survival from diagnosis were screened using Cox proportional hazard models.ResultsThe most common trigger was malignancy (61.3%). Multivariate analysis showed that age, coagulopathy, levels of hemoglobin, aspartate aminotransferase (AST), lactate dehydrogenase (LDH), creatinine, ferritin, and prothrombin time (PT) were independent prognostic factors for 90-day OS from the diagnosis of HLH. Based on the above risk factors, the patients were further divided into two groups: low-risk (≤4 risk factors) and high-risk (>4 risk factors), with overall 90-day survival rates of 82.7 and 28.1%, respectively (P < 0.001).ConclusionPatients with older age, coagulopathy, lower hemoglobin, and AST levels, elevated LDH, creatinine and ferritin levels, and prolonged PT tended to have a worse prognosis. Moreover, our prognostic model provides the possibility of forecasting the clinical outcome of adult secondary HLH patients, although a larger sample, multicenter, randomized controlled clinical study is needed to verify the accuracy of the prognostic model.