Hemophagocytic Lymphohistiocytosis Research Articles

Ophthalmic artery ischemia in hemophagocytic lymphohistiocytosis: A case report and review of current literature

Introduction: This case report describes the ocular manifestations of hemophagocytic lymphohistiocytosis in a 35-year-old male with suspected Adult-onset Still’s Disease. Documented ocular presentations of hemophagocytic lymphohistiocytosis are variable, and the pathophysiology remains unclear. A complete review of the current literature suggests that posterior segment findings, including retinal and vitreous hemorrhage, are most common. Case Report: Here we describe the first published case of bilateral combined choroidal and retinal ischemia in a patient with ocular hemophagocytic lymphohistiocytosis. This is suggestive of complete ophthalmic artery occlusion driving proliferative retinopathy. Mechanistic hypotheses include anemia, thrombocytopenia, coagulopathy, and histiocytic infiltration. Conclusion: In this case, pre-retinal hemorrhage, retinal hemorrhage, and vitreous hemorrhage were treated with panretinal photocoagulation, pars plana vitrectomy, and bevacizumab at different stages in each eye. Unusually for ocular hemophagocytic lymphohistiocytosis, the patient developed a unilateral tractional retinal detachment, later thought to be due to early administration bevacizumab prior to vitrectomy in the left eye. Final visual acuity in this patient remains poor, and worse in the left eye. We therefore suggest early vitrectomy to maintain adequate views of the fundus before bevacizumab or panretinal photocoagulation in this patient cohort.

Cotrimoxazole-related risk of haemophagocytic lymphohistiocytosis

Cotrimoxazole-related risk of haemophagocytic lymphohistiocytosis

Highly sensitive detection of Epstein-Barr virus-infected cells by EBER flow FISH.

When Epstein-Barr virus (EBV) infection is suspected, identification of infected cells is important to understand the pathogenesis, determinine the treatment strategy, and predict the prognosis. We used the PrimeFlow™ RNA Assay Kit with a probe to detect EBV-encoded small RNAs (EBERs) and multiple surface markers, to identify EBV-infected cells by flow cytometry. We analyzed a total of 24 patients [11 with chronic active EBV disease (CAEBV), 3 with hydroa vacciniforme lymphoproliferative disorder, 2 with X-linked lymphoproliferative disease type 1 (XLP1), 2 with EBV-associated hemophagocytic lymphohistiocytosis, and 6 with posttransplant lymphoproliferative disorder (PTLD)]. We compared infected cells using conventional quantitative PCR methods and confirmed that infected cell types were identical in most patients. Patients with CAEBV had widespread infection in T and NK cells, but a small amount of B cells were also infected, and infection in patients with XLP1 and PTLD was not limited to B cells. EBV-associated diseases are believed to be complex pathologies caused by EBV infecting a variety of cells other than B cells. We also demonstrated that infected cells were positive for HLA-DR in patients with CAEBV. EBER flow FISH can identify EBV-infected cells with high sensitivity and is useful for elucidating the pathogenesis.

Pregnancy-Associated Onset of Adult-Onset Still's Disease

Objective: This study aims to elucidate the clinical manifestations, diagnostic challenges, and management strategies of Adult-Onset Still’s Disease (AOSD) during pregnancy, leveraging a case series overview and a detailed case report from our center. Study Design: A comprehensive review of 21 published case reports on AOSD diagnosed during pregnancy was conducted, alongside a detailed case report of a patient diagnosed and managed at our center. This study emphasizes the importance of recognizing AOSD in pregnant patients, outlines the therapeutic challenges encountered, and discusses the potential complications arising from the disease and its treatment. Results: The onset of AOSD during pregnancy predominantly occurs in the first or second trimester, with a polycyclic disease course observed in the majority of cases. Management primarily involves corticosteroids and immunosuppressive medications. The case report highlights the complex interplay between AOSD, Hemophagocytic Lymphohistiocytosis (HLH), and pregnancy, illustrating a multidisciplinary approach to management that ensured favorable maternal and fetal outcomes despite the significant challenges. Conclusion: AOSD presents unique diagnostic and therapeutic challenges during pregnancy, requiring careful consideration of maternal and fetal health. Early diagnosis, a multidisciplinary approach to care, and judicious use of immunosuppressive therapy are critical for managing AOSD flares and associate

Septic arthritis caused by gout progressed to sepsis and hemophagocytic syndrome

Septic arthritis caused by gout progressed to sepsis and hemophagocytic syndrome

Clinical characteristics and outcomes of acute liver failure in neonates: a retrospective cohort in China.

Neonatal acute liver failure (NALF), as a rare disease with high mortality, has limited relevant literature reports in China. We attempted to analyze a NALF cohort to improve the prognosis of this disease. We included all patients diagnosed with NALF at our institution between 2016 and 2021 and retrospectively reviewed their electronic records. NALF was defined as an INR ≥ 2.0 due to liver disease 28days after birth. Comparisons were made according to etiology and outcome. The Kaplan-Meier method was used to estimate survival. Fifty-eight patients were included in this study. Etiologies included hypoxic/ischemic injury (29.3%), infection (27.6%), gestational alloimmune liver disease with neonatal hemochromatosis (GALD-NH) (10.3%), inherited metabolic diseases (5.2%), hemophagocytic lymphohistiocytosis (1.7%), other etiologies (12.1%), and unidentified causes (13.8%). Enteroviruses constituted 87.5% of the viral infections, whereas herpes simplex virus accounted for no infections. The median INR was significantly lower in the infection group than in the GALD-NH group (P < 0.05 for multiple comparisons). At the last follow-up, none of the patients had undergone liver transplantation, and the overall mortality rate was 50%. Liver function completely recovered in 31% of the patients, all of whom survived. The overall median survival time was 48days; 26days for hypoxic/ischemic injury and 43days for GALD-NH. The incidence of cholestasis was significantly greater among surviving patients (P = 0.018). Conclusion: Hypoxic/ischemic injury and infection are the predominant etiologies of NALF in China. The overall prognosis of NALF is poor, but its short-term prognosis is determined by the etiology. What is Known: • Neonatal acute liver failure (NALF) is a rare disorder with limited cohort studies, especially in China. • Gestational alloimmune liver disease, viral infections (especially herpes simplex virus), metabolic diseases and ischemic insults are common etiologies of NALF, which are significantly different from other populations. • There are no reliable biochemical markers to predict the outcome of NALF. What is New: • In this first report on a Chinese NALF cohort, we demonstrate that hypoxic/ischemic injury and infection (excluding herpes simplex virus) are the predominant etiologies of NALF. • The overall prognosis of NALF is poor, and its etiology determines the short-term outcome.

Infections associated with haemophagocytic syndrome: A case report of a rare coexistence with common infections

Infection-associated haemophagocytic syndrome (IAHS) is exceptional in typhoid and tuberculosis co-infections. We encountered a 50-year-old man with a history of pacemaker implantation who was previously treated for typhoid fever and currently presented with a chronic fever and shortness of breath. Initial laboratory tests revealed pancytopenia. A bone marrow aspiration was performed. However, due to cardiac problems, a bone marrow biopsy could not be performed. A bone marrow aspirate was submitted for cell block preparation. The cytology of the bone marrow aspirate revealed hemophagocytosis, which was initially presumed to be secondary to typhoid. Subsequently, cell block preparation of the bone marrow aspirate exhibited numerous granulomas with necrosis suggestive of tuberculosis. The patient was successfully treated with anti-tuberculosis drugs, steroids, and antibiotics. This case highlighted an association between IAHS and a common tropical illness. The usefulness of an aspirate cell block in the absence of biopsy and the potential existence of tuberculosis, especially in tuberculosis-endemic countries is to be noted.

Hemophagocytic Lymphohistiocytosis Secondary to Dengue Fever in a Pediatric Patient: A Case Report

Hemophagocytic Lymphohistiocytosis Secondary to Dengue Fever in a Pediatric Patient: A Case Report

Combined Use of Emapalumab With Ruxolitinib and Dexamethasone as an Effective Treatment for Epstein-Barr Virus-Associated Hemophagocytic Lymphohistiocytosis Complicated With Multiorgan Damage and Severe Infection.

Anti-interferon-γ monoclonal antibody emapalumab and JAK1/2 inhibitors ruxolitinib have been widely reported for the treatment of hemophagocytic lymphohistiocytosis (HLH) recently. These targeted drugs have fewer side effects and may provide new options for patients with HLH who are refractory to previous treatment or intolerant to chemotherapy. Herein, we reported a case of Epstein-Barr virus-related HLH, which did not respond well to HLH-94 plus ruxolitinib and developed severe fungal infection. The disease was successfully controlled after a combination therapy of emapalumab, ruxolitinib, and dexamethasone.

Heterogeneity of macrophage activation syndrome and treatment progression

Macrophage activation syndrome (MAS) is a rare complication of autoimmune inflammatory rheumatic diseases (AIIRD) characterized by a progressive and life-threatening condition with features including cytokine storm and hemophagocytosis. Predisposing factors are typically associated with microbial infections, genetic factors (distinct from typical genetically related hemophagocytic lymphohistiocytosis (HLH)), and inappropriate immune system overactivation. Clinical features include unremitting fever, generalized rash, hepatosplenomegaly, lymphadenopathy, anemia, worsening liver function, and neurological involvement. MAS can occur in various AIIRDs, including but not limited to systemic juvenile idiopathic arthritis (sJIA), adult-onset Still’s disease (AOSD), systemic lupus erythematosus (SLE), Kawasaki disease (KD), juvenile dermatomyositis (JDM), rheumatoid arthritis (RA), and Sjögren’s syndrome (SS), etc. Although progress has been made in understanding the pathogenesis and treatment of MAS, it is important to recognize the differences between different diseases and the various treatment options available. This article summarizes the cell types and cytokines involved in MAS-related diseases, the heterogeneity, and treatment options, while also comparing it to genetically related HLH.

Clinical Characteristics, Prognostic Factors and Outcomes of Paediatric Patients with Haemophagocytic Lymphohistiocytosis

Objective: Haemophagocytic lymphohistiocytosis (HLH) is a multi-system autoimmune disorder. The objective of this study was to find out the clinical characteristics and prognosis of paediatric patients with Haemophagocytic Lymphohistiocytosis. Study Design and setting: Cross sectional study conducted at Pak Emirates Military Hospital, Rawalpindi from July 2021 to June 2023.   Methodology: Children with diagnosis of HLH were assessed by including patients who were aged = 13 years during hospitalization. All the patients who had not been diagnosed by using the HLH-2004 criteria were disqualified. Relevant findings were noted by evaluating records pertinent to physical examination, radiology and laboratory markers. Prognosis was assessed by determining the underlying clinical aetiology and whether patient-related factors modulated the overall life expectancy.   Results: A total of 32 patient records were evaluated. Mean age at diagnosis was 44.3 ± 39.1 months (Range: 1-132 months) with majority being males [n=23 (71.9%)]. The common clinical characteristics included fever [n=29 (90.6%)], lymphadenopathy [n=27 (84.4%)], splenomegaly [n=23 (71.9%)] and hepatomegaly [n=23 (71.9%)]. Serum ferritin, bilirubin, ALT, AST, and LDH were also raised. All patients were followed for a mean period of 12 months and 18 (56.3%) children failed to survive. Negative prognostic indicators included severe anaemia (p=0.001), neutropenia (p=0.007), thrombocytopenia (p=0.033), and hyperferritinemia (p&lt;0.001). Elevation of liver enzymes (ALT: p&lt;0.001; AST: p=0.031), serum bilirubin (p=0.037), and LDH (p&lt;0.001) also indicated worse disease prognosis.   Conclusion: HLH in childhood is a potentially life-threatening disease and carries a significant association with deranged liver function

Population Pharmacokinetics of the Anti-Interferon-Gamma Monoclonal Antibody Emapalumab: An Updated Analysis.

Emapalumab is a fully human monoclonal antibody that targets free and receptor-bound interferon-gamma (IFNγ), neutralizing its biological activity. IFNγ levels differ by orders of magnitude between patients with primary hemophagocytic lymphohistiocytosis (HLH) and macrophage activation syndrome (MAS; a form of secondary HLH) in systemic juvenile idiopathic arthritis (sJIA). Therefore, this study aimed to develop a population pharmacokinetic model for emapalumab across a patient population with a wide range of total (free and emapalumab-bound) IFNγ levels using observations from patients with primary HLH or MAS in sJIA in clinical trials. Pharmacokinetic data were pooled (n = 58; 2709 observations) from studies enrolling patients administered emapalumab for primary HLH or MAS in sJIA. Patients with primary HLH were administered emapalumab 1mg/kg (potentially increasing to 3, 6, and up to 10mg/kg based on clinical response) every 3days. Patients with MAS in sJIA were administered emapalumab 6mg/kg, followed by 3mg/kg every 3days until day 15 and twice weekly until day 28. An earlier population PK model was re-parameterized using this data. The final model for emapalumab comprised a 2-compartment model with first-order elimination. Emapalumab clearance remains constant when the total IFNγ concentration (free and emapalumab-bound) is < ~ 10,000pg/ml but increases proportionally to total IFNγ concentration above this threshold. Emapalumab clearance was estimated to be 0.00218, 0.00308, 0.00623 and 0.01718 l/h at total serum IFNγ concentrations of 103, 104, 105 and 106pg/ml, respectively, with corresponding terminal half-lives of 19.2, 13.8, 7.18 and 3.12days for a 1-year-old patient weighing 10kg with primary HLH. The median terminal half-life for emapalumab in patients with MAS in sJIA was estimated to be 24.0 (range, 6.13-32.4)days, which is similar to observations in healthy volunteers. Emapalumab pharmacokinetics in patients with primary HLH and MAS in sJIA were described by a two-compartment model with fixed allometric exponents and an age-related effect. Differences in total IFNγ levels between patients with primary HLH and MAS may affect emapalumab pharmacokinetics, suggesting that each indication may require different dosing to rapidly control hyperinflammation. Clinicaltrials.gov identifiers: NCT01818492, NCT03311854 and NCT02069899.

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.

85 Navigating the Gray Area: Borderline Hemophagocytic Lymphohistiocytosis Criteria and Dilemmas in Diagnosis and Treatment – A Case Report

85 Navigating the Gray Area: Borderline Hemophagocytic Lymphohistiocytosis Criteria and Dilemmas in Diagnosis and Treatment – A Case Report

166 PRF1-Related Isolated CNS Hemophagocytic Lymphohistiocytosis Successfully Treated with Ruxolitinib Monotherapy

166 PRF1-Related Isolated CNS Hemophagocytic Lymphohistiocytosis Successfully Treated with Ruxolitinib Monotherapy

Single-Cell Transcriptomic Analysis of Epstein-Barr Virus-Associated Hemophagocytic Lymphohistiocytosis.

Epstein-Barr virus (EBV) infection can lead to infectious mononucleosis (EBV-IM) and, more rarely, EBV-associated hemophagocytic lymphohistiocytosis (EBV-HLH), which is characterized by a life-threatening hyperinflammatory cytokine storm with immune dysregulation. Interferon-gamma (IFNγ) has been identified as a critical mediator for primary HLH; however, the detailed role of IFNγ and other cytokines in EBV-HLH is not fully understood. In this study, we used single-cell RNA sequencing to characterize the immune landscape of EBV-HLH and compared it with EBV-IM. Three pediatric patients with EBV-HLH with different backgrounds,one with X-linked lymphoproliferative syndrome type 1 (XLP1), two with chronic active EBV disease (CAEBV), and two patients with EBV-IM were enrolled. The TUBA1B + STMN1 + CD8 + T cell cluster, a responsive proliferating cluster with rich mRNA detection, was explicitly observed in EBV-IM, and the upregulation of SH2D1A-the gene responsible for XLP1-was localized in this cluster. This proliferative cluster was scarcely observed in EBV-HLH cases. In EBV-HLH cases with CAEBV, upregulation of LAG3 was observed in EBV-infected cells, which may be associated with an impaired response by CD8 + T cells. Additionally, genes involved in type I interferon (IFN) signaling were commonly upregulated in each cell fraction of EBV-HLH, and activation of type II IFN signaling was observed in CD4 + T cells, natural killer cells, and monocytes but not in CD8 + T cells in EBV-HLH. In conclusion, impaired responsive proliferation of CD8 + T cells and upregulation of type I IFN signaling were commonly observed in EBV-HLH cases, regardless of the patients' background, indicating the key features of EBV-HLH.

Dengue-Associated Hemophagocytic Lymphohistiocytosis: A Narrative Review of Its Identification and Treatment.

Dengue's lack of specific treatments beyond supportive care prompts a focus on uncovering additional pathophysiological factors. Dengue-associated hemophagocytic lymphohistiocytosis (HLH), characterized by dysregulated macrophage activation and cytokine storm, remains underexplored despite its potential to worsen disease severity and mortality. While rare, dengue-associated HLH disproportionately affects severe cases, significantly impacting mortality rates. To mitigate high mortality, early identification and familiarity with dengue-associated HLH are imperative for prompt treatment by clinicians. This narrative review therefore aims to examine the current clinical and therapeutic knowledge on dengue-associated HLH, and act as a resource for clinicians to improve their management of HLH associated with severe dengue. Dengue-associated HLH should be considered for all cases of severe dengue and may be suspected based on the presence of prolonged or recurrent fever for >7 days, or anemia without intravascular hemolysis or massive bleeding. Diagnosis relies on fulfilling at least five of the eight HLH-2004 criteria. Treatment predominantly involves short courses (3-4 days) of high-dose steroids (e.g., dexamethasone 10 mg/m2), with additional therapies considered in more severe presentations. Notably, outcomes can be favorable with steroid therapy alone.

[L-DEP regimen salvage therapy for refractory primary hemophagocytic lymphohistiocytosis triggered by Epstein-Barr virus infection in 4 children].

Objective: To analyze the efficacy and safety of the L-DEP regimen (asparaginase, liposome doxorubicin, etoposide and methylprednisolone) as a salvage therapy for the refractory primary hemophagocytic lymphohistocytosis triggered by Epstein-Barr virus infection (EBV-pHLH) in children. Methods: In this retrospective case study, clinical and laboratory data before and after L-DEP regimen of 4 children diagnosed with EBV-pHLH in Beijing Children's hospital between January 2016 and June 2022 were collected, and the efficacy and safety of L-DEP regimen for the treatment of EBV-pHLH were analyzed. Results: Among 4 patients, there were 3 females and 1 male with the age ranged from 0.8 to 7.0 years. Two of them showed compound heterozygous mutations of PRF1, one with a heterozygous mutation of UNC13D, one homozygous mutation of ITK. Before the L-DEP therapy, all of them had anemia and a soaring level of soluble CD25, 3 patients had neutropenia and thrombopenia, 3 patients had a high level of ferritin, 3 patients had hypofibrinogenemia and 1 patient had hypertriglyceridemia. After receiving 1 or 2 cycles of L-DEP treatment, three achieved remission, including complete remission (1 case) and partial remission (2 cases), and the other one had no remission. The levels of blood cell counts, soluble CD25, triglyceride, fibrinogen and albumin were recovered gradually in 3 patients who got remission. All four patients underwent hematopoietic stem cell transplantation (HSCT) after L-DEP regimen, and three survived. All patients had no severe chemotherapy related complications. The main side effects were bone marrow suppression, infection and pancreatitis, which recovered after appropriate treatments, apart from one who died from severe infection after urgent HSCT. Conclusion: L-DEP regimen could be served as an effective and safe salvage treatment for refractory pediatric EBV-pHLH, and also provide an opportunity for patients to receive HSCT.

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.

A Case Series of Hemophagocytic Lymphohistiocytosis: An Atypical Presentation of Visceral Leishmaniasis

A Case Series of Hemophagocytic Lymphohistiocytosis: An Atypical Presentation of Visceral Leishmaniasis