Criteria For Hemophagocytic Lymphohistiocytosis Research Articles

97. Hemophagocytic Lymphohistiocytosis in Disseminated Histoplasmosis: an Overlooked Diagnosis

Abstract Background Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening syndrome involving pathologic excitation of the immune system. Disseminated histoplasmosis (DH) is a known trigger of HLH. However, the prevalence of HLH in DH is not known. Limited data exist on risk factors and outcomes. The goals of this study are to determine the prevalence of HLH among participants with DH, identify risk factors for HLH in this population, and describe the treatment and outcomes of people with DH and HLH. Methods We retrospectively identified 110 cases of DH at our institution from 2014 to 2022. The diagnosis of DH required culture of Histoplasma capsulatum from a non-pulmonary site, or non-pulmonary tissue histopathology with yeast identifiable as Histoplasma, or a combination of clinical abnormalities consistent with DH plus detection of Histoplasma antigen in urine or blood (MiraVista Diagnostics). Established HLH-04 criteria defined HLH. Continuous variables are presented as medians with interquartile ranges. Categorical variables are compared with Fisher’s exact test or Mann-Whitney U test. We used odds ratios to identify potential predictors of HLH. P values < 0.05 were considered significant. Results Among 110 participants with DH, 22 met criteria for HLH (Table 1). In the subset who were hospitalized, 23.7% (22/93) had HLH. Compared to participants without HLH, the HLH cohort was more likely to have serum ferritin above the limit of quantification (LOQ) ( > 15,000 ng/ml), urine Histoplasma antigen above the LOQ ( > 19 ng/mL), serum beta-D-glucan (BDG) above the LOQ ( > 500 pg/mL), and more likely to be treated in the ICU (Table 2). There was no significant difference in HIV/AIDS status, race, sex, or in-hospital death/transition to hospice. All 22 participants identified with HLH received liposomal amphotericin B. 2 participants with HLH received etoposide, and 1 received IVIG. Conclusion Nearly a quarter of participants with DH admitted to our hospital had HLH. This is likely an underestimate because most were not assessed for every HLH criterion. Serum ferritin > 15,000 ng/ml, urine Histoplasma antigen above the LOQ, and serum BDG above the LOQ should prompt investigation for HLH. Further studies are needed to assess optimal treatment strategies in this population. Disclosures All Authors: No reported disclosures

Multicenter validation of secondary hemophagocytic lymphohistiocytosis diagnostic criteria.

Five fulfilled hemophagocytic lymphohistiocytosis (HLH)-2004 criteria, and the HScore are widely used and recommended by international expert consensus to diagnose secondary HLH. Both diagnostic scores have never been validated in heterogeneous patient cohorts of secondary HLH patients. We aimed to systematically optimize and validate diagnostic criteria of secondary HLH using a multicenter approach. We developed optimized criteria in our cohort of critically ill patients as a first step. We next validated these new criteria together with the original and modified HLH-2004 criteria as well as the HScore using original data of 13 published cohorts, which were identified by a systematic literature search. The best performing HLH diagnostic criteria sets over all 13 validation cohorts were the original HLH-2004 criteria with a decreased cut-off (cut-off 4, mean sensitivity 86.5%, mean specificity 86.1%), followed by the revised HLH-2004 criteria (natural killer cell activity removed; cut-off 4, mean sensitivity 83.8%, mean specificity 87.8%) and the HScore (cut-off 169, mean sensitivity 82.4%, mean specificity 87.6%). Our newly developed HLH diagnostic criteria showed inferior performance. Ferritin ≥500µg/L had 94.0% mean sensitivity over all cohorts. In this first multicenter validation study, four fulfilled HLH-2004 criteria and an HScore of 169 were suitable to diagnose secondary HLH, which will lead to rapid diagnosis and improved patient outcomes. Ferritin proved as a reliable HLH screening marker. Our results should be taken into account in clinical recommendations and in designing new studies.

Griscelli syndrome: a diagnostic challenge of a rare disease: a case report

Introduction: Griscelli syndrome (GS) is a rare autosomal recessive genetic disorder that primarily manifests as hair and skin hypopigmentation, with three types differentiated by their specific genetic defects as well as by their clinical features. Clinically, GS type 1 is characterized by early neurological alterations, while GS type 2 is characterized by immunodeficiency and could present with neurological symptoms, and type 3 is characterized by a chromosomal anomaly without a specific clinical profile besides hypopigmentation. This article details the challenges faced in the diagnosis of a patient with GS who presents with neurological symptoms followed by immunological deficits. Case presentation: A 7-month-old female presented with complaints of developmental delay following an otitis media infection. Upon examination, she exhibited signs of psychomotor developmental regression and had pale bronze skin and silvery-gray hair, as well as hepatosplenomegaly. The examination of her hair shaft revealed a pattern consistent with GS. During her hospitalization, the patient developed an intermittent fever and signs of hemophagocytic lymphohistiocytosis (HLH). She subsequently developed recurrent seizures treated with phenytoin and Aciclovir. Shortly she succumbed to respiratory distress syndrome and multisystem failure. Discussion: The presence of HLH confirms the type of GS. However, in some cases, the HLH criteria could not be fulfilled, presenting a diagnostic challenge. Conclusion: The genetic examination is the only way to differentiate GS type 1 from type 2. However, when it is not available, the presence of specific symptoms and features may assist in the classification. Furthermore, treatments should be administered when GS type 2 is suspected since they have the potential to improve life quality through treating HLH, delaying and altering the neurological symptoms.

Hemophagocytic Lymphohistiocytosis: Clinical Characteristics and Diagnostic Prediction Model

To investigate the clinical characteristics of patients with hemophagocytic lymphohistiocytosis (HLH) and quantify the diagnostic value of various indexes in patients with elevated soluble interleukin-2 receptor (sCD25), so as to construct a diagnostic prediction model of HLH. The clinical characteristics of 121 patients with elevated sCD25 (≥2 400 U/ml) in the Third Affiliated Hospital of Sun Yat-Sen University were analyzed retrospectively. The patients were divided into HLH group and non-HLH group according to the diagnostic criteria of HLH. The patients with HLH were divided into infection group, tumor group, macrophage activation syndrome (MAS) group and unknown etiology group according to their etiology. The basic data and treatment of the patients were collected for univariate and multivariate logistic analysis to establish a diagnostic prediction model of HLH. Among the 121 enrolled patients with elevated sCD25, 68 were diagnosed as HLH. The proportion of patients using vasopressors, the incidence rate of disseminated intravascular coagulation (DIC), and the HScore in the HLH group were higher than those in the non-HLH group (P < 0.05). Hepatomegaly, splenomegaly, and hemophagocytosis were more common in HLH patients(P < 0.05). Compared with the patients in non-HLH group, patients in HLH group had lower levels of neutrophils, platelets, fibrinogen, IgG, and IgM, while the levels of triglycerides, ferritin (FER), sCD25, serum glutamic oxaloacetic transaminase (SGOT), alkaline phosphatase (ALP), total bilirubin (TBil), lactate dehydrogenase (LDH), and D-dimer were higher (P < 0.05). In subgroup analysis, the level of sCD25 in tumor group was higher than that in infection group. The level of sCD25/ferritin in tumor group was higher than that in infection group and MAS group. Compared with HLH patients in the tumor group, the procalcitonin (PCT) level, proportion of patients using vasopressors, positive rate of hemophagocytosis, and incidence rate of DIC were all higher in the infection group, and the differences were statistically significant (P < 0.05). The results of multivariate analysis showed that fever, splenomegaly, hemophagocytosis, cytopenias, IgM, M.sCD25 [multiple of sCD25 detection value relative to the diagnostic threshold (2400 U/ml)], fibrinogen, and triglycerides were independent predictive factors for HLH (P < 0.05).The diagnostic prediction model H constructed based on temperature, splenomegaly, hemophagocytosis, cytopenias, IgM, M.sCD25, fibrinogen, triglycerides showed good predictive accuracy. The optimal cutoff value of H was 39.45, the sensitivity of the model was 94.12%, the specificity was 83.02%. sCD25, sCD25/FER, PCT, hemophagocytosis, hemodynamic instability and DIC could help to distinguish the underlying etiology of HLH. The prediction model H has high discrimination and calibration, which could be used as a relatively accurate clinical diagnostic tool for HLH.

Autopsy findings from patients diagnosed with COVID-19 demonstrate unique morphological patterns in bone marrow and lymph node

AimsThe identification of haemophagocytosis in bone marrow (BM) is recurrently identified in patients with severe COVID-19. These initial COVID-19 autopsy studies have afforded valuable insight into the pathophysiology of this...

Early Infantile Hemophagocytic Lymphohistiocytosis Masquerading as Late-onset Sepsis: A Case Report with Review of the Literature

Background: Hemophagocytic lymphohistiocytosis (HLH) is a condition due to uncontrolled overactivation of macrophages, cytotoxic T cells, and natural killer cells creating a cytokine storm, characterized by multiorgan involvement. Familial HLH (fHLH) is due to genetic defects and presents early in life. There are only a few reports of neonatal onset of fHLH. Clinical Description: A 40-days-old male baby, born at 36 weeks of gestation, presented with fever, abdominal distension, poor feeding, lethargy, seizures. He had metabolic acidosis, respiratory failure, hepatosplenomegaly and bicytopenia, with a deranged coagulation profile. Management and Outcome: Treatment was started as per sepsis with meningitis with disseminated coagulation profile. All cultures were sterile, bacterial and fungal polymerase chain reaction were negative, but the baby deteriorated rapidly to shock. As the baby fulfilled the HLH criteria, he was started on intravenous immunoglobulin, methylprednisolone, and immunomodulator anakinra while sending sample for whole-exome sequencing for primary HLH. However, the baby succumbed to the illness. Whole-exome sequencing revealed a perforin-1 gene defect which confirmed primary HLH type 2. Conclusion: This report creates awareness that a primary genetic HLH may mimic early infantile sepsis. The rapidly progressive course in an otherwise healthy, breast-fed baby, with no setting of sepsis, and absence of infective etiology, should raise a suspicion of this underlying potentially fatal condition.

A fatal case of hemophagocytic lymphohistiocytosis in an elderly male

We present a case of an 87-year-old male with hemophagocytic lymphohistiocytosis (HLH). Hemophagocytic lymphohistiocytosis is a life-threatening disorder characterized by dysregulated immune activity leading to end-organ damage. Hematologic malignancies appear to be the main cause of secondary HLH. Diagnostic criteria include fever, cytopenia, splenomegaly, hypertriglyceridemia, hypofibrinogenemia, a ferritin level greater than 500 ng/mL, low NK-cell activity, and elevated sIL2Ra levels greater than or equal to 2400 U/mL. Five out of eight of the criteria are necessary to establish a diagnosis of HLH. Our patient met five out of eight diagnostic criteria for HLH (fever, cytopenia, splenomegaly, hypertriglyceridemia, and ferritin level greater than 500 ng/mL). Bone marrow aspirate revealed hemophagocytosis. Bone marrow biopsy revealed marginal zone B cell lymphoma, which is presumed to be the underlying cause of his condition. Due to poor functional status, the patient was a poor candidate for curative treatment, and the family chose not to pursue this route. The patient was treated with Decadron 20 mg intravenous (IV) push daily until he ultimately died, likely due to respiratory failure due to heart failure (HF).

Markers of hemophagocytic lymphohistiocytosis are associated with survival in critically ill patients

Abstract Funding Acknowledgements Type of funding sources: Foundation. Main funding source(s): This work was supported by the Association for the Promotion of Research on Arteriosclerosis, Thrombosis and Vascular Biology (ATVB) and the Ludwig Boltzmann Cluster for Cardiovascular Research Background/Introduction Patients admitted to the intensive care unit (ICU) often show systemic immune dysregulation paired with significantly increased inflammatory activity. Haemophagocytic lymphohistiocytosis (HLH) represents a rare syndrome characterized by fever, inflammation, cytopenia, and organ dysfunction. Inappropriate survival of cytotoxic T cells as well as histiocytes triggers cytokine storm, accompanied by the occurrence of hemophagocytosis and multi-organ failure. prevalence of HLH in critical illness continues to be a topic of discussion but most certainly remains underreported. This circumstance often leads to delays in the necessary immunosuppressive therapy due to difficulty in early diagnosis. Purpose In the present study, we aimed to illuminate the prospective value of the individual HLH criteria in a cohort of critically ill patients. Although the prevalence of this syndrome might be low, isolated markers of HLH could help to assess the extent of inflammatory activation and further be of use in predicting the outcome of patients admitted to the ICU. Methods This was a prospective, observational cohort study. 176 consecutive patients admitted to a cardiac ICU were included over the course of one year. Available HLH criteria were recorded except for biopsy samples of bone marrow and measurements of low or absent natural killer cell activity. For soluble CD25 (sCD25) a specific ELISA kit was used according to the manufacturer's instructions. Results The median age was 67.51 years (IQR: 57.50-77.41) and 38.64% of the included patients were female. The total 30-day mortality was calculated to be 25.57% and positivity for two or more criteria of HLH was found to be associated with depicted mortality (p = 0.033). Analyzing the individual parameters, only sCD25 was found to be a predictor of death within the first 30 days (p &amp;lt; 0.001). The combination of triglycerides and fibrinogen did not predict outcomes. However, low fibrinogen values were found to possess prognostic merit in regard to mortality (p= 0.019). In multivariate analysis, both sCD25 and fibrinogen remained a significant predictor of 30-day survival after adjustment for age, sex, and BMI (sCD25 p &amp;lt; 0.001, fibrinogen p = 0.042). Finally, the addition of fibrinogen was able to improve the prognostic value of the SAPS II score significantly (ROC curve, SAPS II – AUC: 0.790, SAPS II &amp; fibrinogen – AUC: 0.827, p = 0.045). Conclusion We provided evidence for the prognostic value of certain markers of HLH in critically ill patients. Positivity for two or more criteria was found to be associated with an increased 30-day mortality. Moreover, sCD25 and fibrinogen independently predicted outcomes in multivariate analysis after adjustment for age, sex, and BMI. The addition of fibrinogen was able to improve the prognostic properties of the SAPS II score.Figure 1Figure 2

Hemophagocytic lymphohistiocytosis in pregnancy-a case report.

Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening condition that is a rare occurrence in pregnancy and can be elusive in its diagnosis thereby delaying treatment. We report the case of a 30-year-old female patient at 36 weeks of pregnancy who presented with a persistent fever that did not respond to antibiotics. After we investigated her thoroughly, considering the persistent fever, we performed a bone marrow biopsy as part of the workup for prolonged pyrexia. We diagnosed her with HLH secondary to cytomegalovirus pneumonia. As her laboratory investigations fulfilled the criteria for HLH we treated her with the appropriate therapy using a multidisciplinary approach, resulting in her complete recovery. HLH should be considered a potential differential diagnosis in pregnant patients complaining of persistent fever, cytopenia, or declining clinical condition despite delivery of the baby.

Hemophagocytic lymphohistiocytosis in Egyptian children: diagnosis, treatment challenges, and outcome

ABSTRACT Background Hemophagocyticlymphohistiocytosis (HLH) is a spectrum of immune activation which could be genetically determined, or secondary to an underlying illness. Our aim was to present the clinico-genetic aspects of HLH among Egyptian children and to evaluate the patterns of reactivation and outcome with illustrations of overlap manifestations. Research designand methods We retrospectively collected the data of 55 patients with HLH, registered at Ain Shams University Children’s Hospital,Cairo, Egypt. Results Median age at diagnosis was 19 months (range 2–180), 33 patients (60%) fulfilled the diagnostic HLH criteria at presentation. Fourteen (25.45%) patients had secondary HLH, 15 (27.27%) patients had genetically documented familial HLH (11 had variants in UNC13D gene and one in PRF1 gene), 3 had Griscelli and Chediak-Higashi syndromes. Sixteen patients (29.1%) had reactivations, 8 (50%) of them had molecularly confirmed HLH. We report the death of 40 patients, the median duration from the diagnosis to death of 5 months mostly due to disease activity. Conclusions This study confirms that the nonspecific signs and symptoms of HLH are challenging. Genetic testing, though expensive and sophisticated, is integral for the diagnosis. The difficulty in finding non-related donors for stem cell transplantation and the early reactivations are the causes of the inferior outcome.

Hemophagocytic lymphohistiocytosis-a rare life threatening association with scrub typhus: case report

Scrub typhus is an important cause of acute febrile illness and one of the re-emerging infectious diseases in India particularly in southern Rajasthan. Hemophagocytic lympho-histiocytosis (HLH) results from an uncontrolled and ineffective hyperinflammatory response to a variety of triggers. HLH is further subdivided into primary and secondary type. We present a case of Scrub typhus which presented with multiple organ dysfunction syndrome (MODS) and secondary HLH which is a rare entity. A 9-month-old male child presented with high grade fever with encephalopathy. Examination showed hepatosplenomegaly, cervical Lymph adenopathy with eschar mark visible on abdomen. Scrub typhus was suspected on clinical grounds and further investigations were done. Serological diagnosis was strongly positive for scrub typhus. Initially, child did not respond to doxycycline, so further investigations were done to rule out HLH which fits into criteria of secondary HLH as per the revised HLH 2004 protocol. In view of secondary HLH and MODS methylprednisolone was added to treatment. Child responded to steroids and there was complete recovery. Scrub typhus patient with progressive MODS, in spite of appropriate antimicrobial therapy should raise the suspicion of secondary HLH which is rare but life-threatening condition and steroids plays an important role in the management of this condition.

The History of Macrophage Activation Syndrome in Autoimmune Diseases.

In 1979, it became recognized in the literature that what we call hemophagocytic lymphohistiocytosis (HLH) was a nonmalignant disease of histiocytes. Subsequently a familial form and a secondary form of HLH were differentiated. When HLH is secondary to an autoimmune disease, rheumatologists refer to this entity as macrophage activation syndrome (MAS) to differentiate it from HLH itself. Although the first cases of MAS likely appeared in the literature in the 1970s, it was not until 1985 that the term activated macrophages was used to describe patients with systemic juvenile idiopathic arthritis (sJIA) complicated by MAS and the term macrophage activation syndrome first appeared in the title of a paper in 1993.MAS is one of the many types of secondary HLH and should not be confused with primary HLH. Experience has taught that MAS secondary to different autoimmune diseases is not equal. In the 30years since initial description in patients with sJIA, the clinical spectrum, diseases associated with MAS, therapy, and understanding the pathogenesis have all made significant gains. The diagnostic/classification criteria for MAS secondary to sJIA, SLE, RA, and KD differ based on the different laboratory abnormalities associated with each (Ahn et al., J Rheumatol 44:996-1003, 2017; Han et al., Ann Rheum Dis 75:e44, 2016; Ravelli et al., Ann Rheum Dis 75:481-489, 2016; Borgia et al., Arthritis Rheumatol 70:616-624, 2018). These examples include the thrombocytosis associated with sJIA, a chronic generalized activation of the immune system, leading to elevations of fibrinogen and sIL-2R, low platelet count associated with SLE, and more acute inflammation associated with KD. Therefore, individual diagnostic criteria are required, and they all differ from the diagnostic criteria for HLH, which are based on a previously non-activated immune system (Ahn et al., J Rheumatol 44:996-1003, 2017; Han et al., Ann Rheum Dis 75:e44, 2016; Ravelli et al., Ann Rheum Dis 75:481-489, 2016; Borgia et al., Arthritis Rheumatol 70:616-624, 2018; Henter et al., Pediatr Blood Cancer 48:124-131, 2007). This helps to explain why the HLH diagnostic criteria do not perform well in MAS.The initial treatment remains high-dose steroids and IVIG followed by the use of a calcineurin inhibitor for resistant cases. IVIG can be used if there is a concern about malignancy to wait for appropriate investigations or with steroids. Interluekin-1 inhibition is now the next therapy if there is a failure to respond to steroids and calcineurin inhibitors. Advances in understanding the mechanisms leading to MAS, which has been greatly aided by the use of mouse models of MAS and advances in genome sequencing, offer a bright future for more specific therapies. More recent therapies are directed to specific cytokines involved in the pathogenesis of MAS and can lead to decreases in the morbidity and mortality associated with MAS. These include therapies directed to inhibiting the JAK/STAT pathway and/or specific cytokines, interleukin-18 and gamma interferon, which are currently being studied in MAS. These more specific therapies may obviate the need for nonspecific immunosuppressive therapies including high-dose prolonged steroids, calcineurin inhibitors, and etoposide.

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.

Clinical and Pathological Characteristics of Severe EBV Infection in Japanese Children; a Disease Spectrum from Acute Liver Failure to Hemophagocytic Lymphohistiocytosis

Abstract Background Epstein-Barr virus (EBV) is a ubiquitous herpesvirus known as a cause of infectious mononucleosis (IM). While most EBV infection is mild and self-limited, severe EBV diseases such as severe IM, EBV-associated hemophagocytic lymphohistiocytosis (HLH) and EBV-associated acute liver failure (ALF) may occur on rare occasions. Interestingly, the severe EBV disease with ALF may occasionally present with overlapping features of HLH; however, it remains unknown if the presence or absence of HLH reflects a distinctive underlying pathophysiology of EBV infection. To investigate the clinical and pathological characteristics of EBV-associated ALF among children, we conducted a single-center, retrospective study at the largest tertiary children’s hospital in Japan. Methods We enrolled children under 18 years old who required medical management in the intensive care unit due to primary EBV infection between January 2010 and April 2021. Patients with underlying immunodeficiencies and other medical conditions were excluded. Clinical data, type of EBV-infected cell lineage, and pathological exam were reviewed. Fourteen patients with EBV-associated ALF were identified in the initial screening, and two were excluded (due to underlying medical conditions). Thus, the details of 12 patients were further analyzed. Five patients fulfilled the criteria for HLH, while seven presented as isolated ALF only. Results The most common symptoms of these patients include fever (92%), vomiting (58%), and consciousness disturbance (100%). EBV loads were higher when HLH co-existed (median 2,700 copies/μg of DNA vs. 130,000 copies/μg of DNA, p = 0.01). Identification of EBV-infected cells revealed that the most common cell type was CD8+T cells (8/12, 80%), followed by CD3+T cells (1/12, 10%), and CD19+ cells (2/12, 20%). EBV infected in both CD8+T and CD19+ cells in one case and EBV-infected cells were not identified in two cases. In addition, an increase of activated CD8+ T cells (CD3+CD8+HLA-DR+) was observed in both HLH and ALF cases. Among 12 patients with ALF, seven patients underwent life-saving liver transplantation (LT) due to ALF. Of five patients with ALF+HLH, all patients received corticosteroid, four received cyclosporin or etoposide, and one underwent hematopoietic stem cell transplantation (HSCT). Overall mortality is 17% (2/12 patients), and both patients were complicated with HLH. Conclusion This study suggests that HLH and ALF can be an indistinguishable spectrum of severe EBV disease, and the underlying pathogenesis may be associated with the unusual type of EBV-infected cells. Hence, the identification of EBV-infected cells should be considered to guide the diagnosis and treatment. Our study also revealed that LT and cytotoxic anti-inflammatory therapy effectively treated patients with EBV-associated ALF with or without HLH, given the high mortality (&amp;gt;70%) of this disease spectrum. Further studies investigating EBV-associated ALF pathology are warranted to determine optimal management.

Compassionate Use of Emapalumab in Children with Life-Threatening Disorders: Real-World Data

Introduction: Life threatening hyperinflammation occurs in hemophagocytic lymphohistiocytosis (HLH) and during acute rejection of hematopoietic stem cell (HSC) grafts. Both conditions reflect acute activation of the immune system, in part due to overproduction of proinflammatory cytokines, particularly interferon gamma (IFNγ). Emapalumab, a fully human monoclonal antibody that binds to IFNγ, is approved by the FDA for refractory or recurrent primary HLH (pHLH) or in patients intolerant to conventional therapy. Off-label use of emapalumab has been reported for treatment of secondary HLH (sHLH) and for HSC graft rejection. The European Medicines Agency did not approve emapalumab for the treatment of HLH and many other regulatory authorities, including the Israeli Ministry of Health, have yet to approve emapalumab for clinical use. Pending such regulatory approval, emapalumab is available in Israel exclusively though the Managed Access Request Program (MAP) on a compassionate basis sponsored by Sobi (Swedish Orphan Biovitrum AB,Reg. no. 556038-9321). Experience that accumulates through on- and off-label use of emapalumab obtained via MAP enriches the knowledge base regarding the uses of this drug in the real-world clinical setting. Methods: We summarized the data of patients receiving emapalumab at our tertiary pediatric center. The medication was received after application to the MAP sponsored by Sobi International with import approval of the Israel Ministry of Health on a named-patient basis. Results: Seven patients (Pt) aged 2.5 months-17.5 years were treated with emapalumab between 3/2020-6/2023. Patients 1-5 fulfilled HLH-2004 diagnostic criteria. Indications for the use of emapalumab included treatment of HLH in a newborn with severe hepatotoxicity after treatment with the standard HLH-94 protocol (Pt. 3), treatment of acute graft rejection with recurrence of HLH in a patient with pHLH (Pt.1), secondary HSC graft failure and disease relapse in a child with pHLH (Pt. 4), sHLH with multi-organ failure (MOF) requiring extracorporeal membrane oxygenation (ECMO) (Pts 2&amp;5) and HSC primary graft rejection with suspected 2 nd rejection (Pts.6&amp;7). Table 1 summarizes the clinical characteristics of all cases. The patient outcomes were closely related to their clinical status at treatment initiation. Pt.3 was able to reach remission and successfully bridge to SCT without complications after only 4 doses of VP-16 with continuation therapy using only dexamethasone and emapalumab. Pt.4, who experienced relapsed pHLH with concomitant HSC graft loss, attained complete remission with emapalumab, dexamethasone and IVIG, facilitating a successful second HSC graft. Pt. 1 expired after initial graft failure, severe sepsis and relapse of pHLH. Pts. 2&amp;5, despite showing improvement of their HLH criteria after treatment with emapalumab, succumbed to MOF that was already present when they were referred to our center for ECMO support. Following unsuccessful emapalumab treatment for primary graft rejection, Pts. 6&amp;7 underwent successful 2 nd HSC transplants with early emapalumab treatment for suspected re-rejection. Conclusions: Emapalumab is a safe, effective, and well tolerated treatment for various HLH scenarios, and for similar hyper-inflammatory medical conditions. Administration of emapalumab early in the disease course is likely to be more effective as compared to administration of the drug when MOF has occurred or when the HSC graft has already been rejected. Since these diseases are life-threatening, eliminating delays in procurement of emapalumab is essential to expedite treatment before irreversible organ failure ensues.

Neonatal Hemophagocytic Lymphohistiocytosis: Scoping Review and Analysis of 205 Cases

Background: Hemophagocytic lymphohistiocytosis (HLH) is a syndrome of pathologic immune activation and uncontrolled inflammation. Neonatal HLH (nHLH), defined as HLH that presents in the first month of life, is clinically devastating. nHLH is estimated to comprise 10% of familial HLH (fHLH) diagnoses. There have been few, large descriptive studies of nHLH. Objectives: The primary objective of this study was to perform a scoping review and descriptive analysis of published cases of nHLH. The secondary objective of this study was to assess the reporting quality of published nHLH cases. Methods: A comprehensive literature database search was performed. Cases of HLH were eligible for inclusion if clinical analysis was performed at age &amp;lt; 30 days. As many as 70 variables were extracted from each case. Frequencies and percentages of variables reported per case in the articles included were provided. Qualitative variables were summarized by frequency and percentage. Quantitative variables which were not approximately normally distributed were summarized with median and interquartile range (IQR). Results: 544 studies were assessed for eligibility. Studies were excluded if they did not discuss nHLH (n=280), aggregated nHLH patient data with all ages (n=83), provided insufficient detail and/or data describing nHLH (n=28), and for other reasons (n=8).205 cases of nHLH from 142 articles were included. Cases were published from 31 countries from 1985-2023. Primary presenting features included fever (38.1%, n=67/176), organomegaly (11.9%, n=21/176) respiratory distress (11.4%, n=20/176), jaundice (4.5%, n=8/176), and signs of bleeding (3.4%, n-6/176). Symptoms began in utero in 20 patients (n=20/161). The median age of symptom onset was day of life (DOL) 3 (IQR: 0-14) (n=141). Median age at diagnosis was DOL 15 (IQR: 6-27) (n=87). The median time from initial evaluation to initiation of HLH therapy was 8 days (IQR: 3-14) (n=53). The frequency of HLH criteria and criteria median values are summarized in Table 1. The median number of diagnostic criteria met by patients were 5/8 (IQR: 4, 6). CNS manifestations were reported in 62.7% of cases (n=64/102). Skin manifestations were reported in 75.4% of cases (n=52/69). Liver injury (67.9%, n=91/134) and/or liver failure (23.9%, n=32/134) were common. Infections were reported in 46.7% of patients (n=70/150). Causes of nHLH included familial/inherited disease (46.8%, n=96/205), infection (26%, n=53), macrophage activation syndrome (2.9%, n=6), primary immunodeficiency (2.9%, n=6), inborn error of metabolism (2.4%, n=5), and malignancy (2%, n=4). Diagnosis was made using clinical and laboratory features (82.4%, n=169/205), gene panel (16.1%, n=33/205), sanger sequencing (1.0%, n=2/205), and ultra-rapid whole genome sequencing (0.5%, n=1/205). Genetic causes of fHLH included mutations in PRF1, STX11, STXBP2, UNC13D, NOCAR-H, and XIAP. The majority of patients (62.7%, n=121/193) died within the period of reporting. The estimated median survival time from nHLH onset of symptoms was 83 days. Only 4.4% (n=9/205) of studies reported complete data to calculate an H-score. Studies reported discernable values for HLH diagnostic variables at the following frequencies: temperature (71.7%), organomegaly (82.9%), hemoglobin (69.3%), thrombocytopenia (82.4%), neutrophils (55.1%), fibrinogen (64.4%), triglycerides (5.5%), hemophagocytosis (73.2%), ferritin (71.2%), low/absent NK cell activity (33.2%), and sIL2R (29.3%). Other clinically relevant variables such as the presence or absence of skin manifestations (33.7%), and CNS manifestations (49.8%) frequently went unreported. There were many cases that made a categorical description of a lab value (e.g., thrombocytopenia) without providing an absolute value (e.g., platelets level). Conclusions: This is the largest aggregated study of nHLH presentations, diagnostic criteria, clinical trajectory, and etiologic diagnoses. Neurologic, dermatologic, and hepatic manifestations occur in the neonatal population. Current reports of nHLH suggest a grim prognosis. Future publications containing data on nHLH should report all clinically relevant variables. Studies looking at multiple patients in aggregate should provide supplemental information with detailed nHLH cases.

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.

Spectrum of Hemophagocytosis in Bone Marrow Aspirates: Experience from a Tertiary Care Hospital in North India.

Hemophagocytosis refers to the engulfment of hematopoietic cells by histiocytes. It can be seen in various conditions but is usually reported in the setting of hemophagocytic lymphohistiocytosis (HLH). Optimal interpretation of hemophagocytosis in the bone marrow in relation to the underlying disease significantly contributes to correct patient management. The present study was done to identify the spectrum of conditions associated with hemophagocytosis in the bone marrow aspirates and grade the degree of hemophagocytosis. This retrospective observational study included all the bone marrow aspirates showing hemophagocytosis, identified over a period of 5 years (January 2015 to January 2020). Two pathologists independently reviewed bone marrow slides. Hemophagocytosis was graded as mild, moderate, or severe by observing the number of histiocytes showing hemophagocytosis per 500 nucleated cells. Eighty-eight patients showing hemophagocytosis in the bone marrow aspirate smear were included in the study. The most common cause of hemophagocytosis was infection (18%). There were 4 (5%) cases of HLH. Grade 1 (mild) hemophagocytosis was seen in 25 (29%) cases followed by Grade 2 (moderate) in 53 (60%) cases and Grade 3 (severe) in 10 (11%) cases. Fever was the most common clinical symptom present in 45 (51%) cases. Hemophagocytosis in bone marrow aspirates is a common and under-reported finding. It is not only seen in cases of HLH but also in infections and other conditions. Documenting hemophagocytosis, even in the absence of fulfilled HLH criteria, is vital to explain cytopenias.

Adult-onset CLIPPERS with systemic Hemophagocytic Lymphohistiocytosis related to PRFN1 mutation: A case report. (P4-5.032)

<h3>Objective:</h3> NA <h3>Background:</h3> Recently, in a cohort of patients presenting with chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS), one third exhibited familial hemophagocytic lymphohistiocytosis (HLH) gene mutations. As none of them displayed systemic signs of HLH, implication of these mutations in the pathophysiology of CLIPPERS remains to be established. <h3>Design/Methods:</h3> In a patient with CLIPPERS features, genetic analysis of genes implicated in familial HLH was performed, and systemic HLH criteria were searched. <h3>Results:</h3> A 43-year-old man, with a medical history of macrophagic activation syndrome of unknown origin, presented with clinical and radiological features of CLIPPERS. Genetic analysis revealed a <i>PRFN1</i> mutation, and ancillary tests showed multiple mediastino-hilar lymph nodes on PET scan. Nodal biopsy showed a lymphohistiocytic infiltrate together with aggregates of histiocytes resembling loose granulomas. Evolution was favorable under steroid sparring therapy with Infliximab and Methotrexate. <h3>Conclusions:</h3> We describe the first case of adult-onset CLIPPERS accompanied by systemic HLH in the setting of <i>PRFN1</i> mutation. Interestingly, histological findings in lymph nodes match with those described in brain biopsy of CLIPPERS patients. Thus, we speculate that CLIPPERS features in mutated patients might be a central nervous system (CNS) expression of HLH. The CNS-restricted manifestations in some mutated patients could be due to other genetic and/or environmental factors. The genetic diagnosis of these patients is needed to better describe their phenotype and propose the appropriate treatment. <b>Disclosure:</b> Dr. Lemarchant has nothing to disclose. The institution of Dr. De Saint Basile-Chazelas has received research support from LHF espoir: patient association. Helene Zephir has received personal compensation in the range of $0-$499 for serving as a Consultant for BIogen Idec. Helene Zephir has received personal compensation in the range of $0-$499 for serving as a Consultant for novartis. Helene Zephir has received personal compensation in the range of $0-$499 for serving as a Consultant for BMS. Helene Zephir has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Alexion. Julie Boucher has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Sanofi. Julie Boucher has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Merck. Julie Boucher has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Biogen. Julie Boucher has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Merck. Julie Boucher has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Novartis . Julie Boucher has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Sanofi. Guillaume Taieb has nothing to disclose.

A Three-Step Screening Procedure for Early Identification of Children at High Risk of Hemophagocytic Lymphohistiocytosis.

The first step in diagnosing hemophagocytic lymphohistiocytosis (HLH) is to suspect its presence and then order the appropriate diagnostic tests. The development of screening procedures for HLH could facilitate early diagnosis. In this study, we evaluated the utility of fever, splenomegaly, and cytopenias as screening criteria for identifying pediatric HLH at an early stage, built a screening model using commonly measured laboratory parameters, and developed a step-wise screening procedure for pediatric HLH. The medical records of 83,965 pediatric inpatients, including 160 patients with HLH, were collected retrospectively. The utility of fever, splenomegaly, hemoglobin level, and platelet and neutrophil counts at hospital admission as screening criteria for HLH was evaluated. For HLH patients who might be missed by screening based on the presence of fever, splenomegaly, and cytopenias, a screening model using common laboratory parameters was developed. Following that, a three-step screening procedure was then developed. The criteria of cytopenias affecting two or more lineages plus fever or splenomegaly had a sensitivity of 51.9% and a specificity of 98.4% for identifying HLH in pediatric inpatients. Our screening score model comprises six parameters: splenomegaly, platelet count, neutrophil count, albumin level, total bile acid level, and lactate dehydrogenase level. The use of the validation set had a sensitivity of 87.0% and a specificity of 90.6%. A three-step screening procedure has been developed: Step 1: Is fever or splenomegaly present? (Yes: risk for HLH should be considered, go to Step 2; No: less likely HLH); Step 2: Are cytopenias affecting at least two lineages? (Yes: consider HLH; No: go to Step 3); Step 3: Calculate the screening score. Is the sum of the score greater than 37? (Yes: consider HLH; No: less likely HLH). The overall sensitivity and specificity of the three-step screening procedure were 91.9% and 94.4%, respectively. A significant proportion of pediatric HLH patients present at the hospital without having all three symptoms: fever, splenomegaly, and cytopenias. Our three-step screening procedure, utilizing commonly available clinical and laboratory parameters, can effectively identify pediatric patients who may be at high risk for HLH.