Clinical significance and different strategies for re-elevation of plasma EBV-DNA during treatment in pediatric EBV-associated hemophagocytic lymphohistiocytosis.

OBJECTIVE: Monitoring the disease status of Epstein-Barr virus (EBV)-related hemophagocytic lymphohistiocytosis (HLH) patients is crucial. This study aimed to investigate the different strategies and outcomes of patients with EBV-HLH and re-elevated EBV-DNA. METHOD: A retrospective analysis was conducted on 20 patients diagnosed with EBV-HLH. Clinical features, laboratory tests, treatments, plasma EBV-DNA levels, and outcomes were assessed. Three cases were highlighted for detailed analysis. RESULTS: Nine of the 20 patients had a re-elevation of EBV-DNA during treatment, and 55.5 % (5/9) experienced relapses. Patients with persistently positive plasma EBV-DNA (n = 4) and those with re-elevated EBV-DNA after conversion (n = 9) showed a significantly higher relapse rate compared to those with persistently negative EBV-HLH (n = 7) (p < 0.05). Among the highlighted cases, Case 1 exhibited plasma EBV-DNA re-elevation after four weeks of treatment without relapse, maintaining stability with the original treatment regimen, and eventually, his plasma EBV-DNA turned negative. In Case 2, plasma EBV-DNA was elevated again with a recurrence of HLH after L-DEP. Consequently, she underwent allogeneic hematopoietic stem cell transplantation and eventually achieved complete remission (CR) with negative plasma EBV-DNA. Case 3 experienced plasma EBV-DNA re-elevation after L-DEP but remained in CR, discontinuing chemotherapy without relapse. CONCLUSION: The re-elevation of plasma EBV-DNA during EBV-HLH treatment poses challenges in determining disease status and treatment strategies. Optimal management decisions require a combination of the level of elevated EBV-DNA, the intensity of hyperinflammation, and the patient's immune function.

Variation of Diagnostic Approaches and Treatment Practices for Hemophagocytic Lymphohistiocytosis/Macrophage Activation Syndrome Among Pediatric Subspecialists.

OBJECTIVE: To assess the diagnostic and treatment practices among a variety of subspecialists at pediatric institutions in the US. STUDY DESIGN: Using a web-based survey, we assessed the consultation, diagnostic, and treatment preferences of providers from the different pediatric subspecialties who care for pediatric patients with hemophagocytic lymphohistiocytosis (HLH)/macrophage activating syndrome (MAS). Domains included demographics, provider training level and specialty, experience and comfort level with the diagnosis and treatment of HLH/MAS, and institutional approaches toward the diagnosis and management of HLH/MAS. Participants also were given 2 case scenarios: one describing Epstein-Barr virus-associated HLH and another describing an underlying rheumatologic condition with MAS. RESULTS: Of 263 respondents, 23%, 29%, 39%, and 7% identified as hematology/oncology, rheumatology, general pediatrics/critical care/hospitalist, and allergy/immunology, respectively. For Epstein-Barr virus/HLH, hematology/oncology was the preferred first consultant by most respondents other than rheumatologists, of whom only 47% agreed. For MAS, 92% of respondents from all specialties favored a rheumatology consultation. Preferred diagnostic tests varied by subspecialty, with hematology/oncology more likely than rheumatology to order an infectious workup, natural killer cell function, soluble interleukin-2 receptor, bone marrow biopsy, and genetic testing. First-line therapy also varied, with hematology/oncology preferring dexamethasone and etoposide and rheumatology more often preferring methylprednisolone and anakinra. One-half of respondents were unaware of institutional algorithms for diagnosis and treatment of HLH/MAS. Most (85.6%) favored the development of treatment algorithms for HLH/MAS, and 90% supported a multidisciplinary approach. CONCLUSIONS: Current consulting patterns, diagnostic workup, and treatment approaches of HLH/MAS vary by specialty, highlighting the need for standardized management algorithms and institutional multidisciplinary HLH/MAS teams.

Case Report: Visceral Leishmaniasis and Hemophagocytic Lymphohistiocytosis: Three Clinical Cases, Three Different Patterns.

Visceral leishmaniasis (VL) is a neglected tropical disease with more than 30,000 cases annually reported worldwide. In Brazil, about 3,700 cases are annually reported. The VL clinical presentation is variable, from asymptomatic to severe cases with a high risk of death. We reported three cases of VL with clinical sign similarities but distinct development. All cases had bone marrow hemophagocytosis and hemophagocytic lymphohistiocytosis (HLH) criteria. HLH is a rare condition that may have secondary causes, including infectious and parasitic diseases, like VL. The delayed recognition of the secondary HLH (sHLH) association to VL may cause unfavorable outcomes and death.

Diagnostic and therapeutic caveats in Griscelli syndrome.

Griscelli syndrome (GS) is a rare autosomal recessive disease with characteristic pigment distribution, and there are currently 3 types according to the underlying genetic defect and clinical features. We present the case of a girl born from consanguineous parents who presented with predominant neurologic symptoms, silvery hair and granulomatous skin lesions. Cerebral magnetic resonance revealed diffuse white matter lesions, and central nervous system (CNS) lymphocytic infiltration was suspected. The patient underwent haematopoietic stem cell transplantation with graft failure and autologous reconstitution. She developed elevated liver enzyme with a cholestatic pattern. Multiple liver biopsies revealed centrilobular cholestasis and unspecific portal inflammation that improved with immunomodulatory treatment. She was revealed to have an impaired cytotoxicity in NK cells and a decreased expression of RAB27A. However, no variants were found in the gene. All types of GS present with pigment dilution and irregular pigment clumps that can be seen through light microscopy in hair and skin biopsy. Dermic granulomas and immunodeficiency with infectious and HLH predisposition have been described in GS type 2 (GS2). Neurologic alterations might be seen in GS type 1 (GS1) and GS type 2 (GS2), due to different mechanisms. GS1 presents with neurologic impairment secondary to myosin Va role in neuronal development and synapsis. Meanwhile, GS2 can present with neurologic impairment secondary to SNC HLH. Clinical features and cytotoxicity might aid in differentiating GS1 and GS2, especially since treatment differs.

Haploidentical Stem Cell Transplant with Post-Transplant Cyclophosphamide in Pediatric Hemophagocytic Lymphohistiocytosis.

PURPOSE: Primary hemophagocytic lymphohistiocytosis is a severe and uncommon disease affecting pediatric patients. Genetic abnormalities have been related to altered apoptosis and exaggerated inflammatory reactions. Chemoimmunotherapy and stem cell transplantation are treatment options, but transplant is the only curative treatment. Here we aim to describe the treatment with hematopoietic stem cell transplantation with a novel strategy and the outcomes. METHODS: An observational, descriptive, case series study was performed in pediatric patients of two high complexity medical centers in Colombia. Data was collected retrospectively between 2015 and 2020. RESULTS: We describe five pediatric cases with a diagnosis of primary hemophagocytic lymphohistiocytosis. All were treated with replete-cell haploidentical hematopoietic stem transplantation, reduced-intensity conditioning, and post-transplant cyclophosphamide, in two high-complexity centers in Colombia. All patients are alive, and one is receiving management for chronic graft-versus-host disease. CONCLUSION: To the best of our knowledge, there are few reports in the literature with this strategy, promising a possible alternative when there are no other donor options.

Utilidad de la Determinación de CD25 Soluble en Pacientes con sospecha de Síndrome de Activación Macrofágica / Usefulness of the determination of soluble CD25 in patients with suspected macrophage activation syndrome

El síndrome de activación macrofágica (SAM) presenta criterios clínicos y de laboratorio establecidos. Presentamos el caso de un adolescente varón con debut de Lupus eritematoso generalizado pediátrico grave, donde su manifestación principal fue un SAM y el receptor de interleucina 2 soluble en suero (IL-2rs) o CD25 soluble (CD25s) aumentado resultó clave en la confirmación diagnóstica, en el tratamiento y pronóstico de su enfermedad. Sin embargo, este receptor de citocinas no se mide habitualmente en la práctica clínica.

Macrophage activation syndrome (MAS) presents established clinical and laboratory criteria. We present the case of a male adolescent with the onset of severe pediatric systemic Lupus erythematosus, manifested mainly by MAS and how a laboratory marker, serum soluble interleukin-2 receptor (IL-2rs) or altered soluble CD25(CD25s), played a key role in treatment and prognosis of the disease. However, this cytokine receptor is rarely measured in clinical practice.

Cytomegalovirus and disseminated histoplasmosis-related hemophagocytic lymphohistiocytosis syndrome in an HIV-patient late presenter with IRIS: a case report.

BACKGROUND: Hemophagocytic lymphohistiocytosis syndrome (HLS) is an immune-mediated life-threatening disease considered as a medical emergency, with a potentially fatal multisystem inflammatory outcome. We present a patient that developed HLS and was able to be diagnosed efficiently with the help of an academic research institute of immunology. CASE PRESENTATION: A 21 years old male Mexican with human immunodeficiency virus (HIV), late presenter; who developed cytomegalovirus (CMV) infection and a disseminated histoplasmosis-related HLS, as part of an immune reconstitution inflammatory syndrome (IRIS). The patient required a long course of corticotherapy, intravenous immunoglobulin and massive transfusions (more than 10 units in 24 h, and a total of 83 units), besides amphotericin-B and ganciclovir treatment. An academic research institute of immunology aided in the accurate diagnosis of HLS with the implementation of tests not available within the hospital, thus improving the care provided to the patient. The patient recovered, was discharged, and continue to improve. CONCLUSION: The objective of this report is to highlight the importance of having multidisciplinary support, including basic medical sciences groups providing specific tests that are sometimes very difficult to get, which provides a benefit to patients in the well-aimed diagnosis as part of applied translational medicine.

Hemophagocytic lymphohistiocytosis as a presentation of inflammatory bowel disease / Linfohistiocitosis hemofagocítica como presentación de la enfermedad inflamatoria intestinal

Abstract Background: Hemophagocytic lymphohistiocytosis (HLH) is considered a medical emergency that should be recognized in patients with fever, splenomegaly, and progressive deterioration of the general condition. Laboratory findings include cytopenia, hypertriglyceridemia, hypofibrinogenemia, and hyperferritinemia. For HLH diagnosis, it is essential, although not mandatory, to perform a bone marrow biopsy. Given its nature, secondary causes of HLH should be sought, mainly infections, hemato-oncological disorders, autoimmune diseases, and auto-inflammatory conditions. Case report: We present the case of a female adolescent who presented with fever and lower gastrointestinal bleeding. Upon admission, acute liver failure and pancytopenia were documented. A bone marrow aspirate was performed, which revealed hemophagocytosis; other tests confirmed HLH diagnosis. During the diagnostic approach, inflammatory bowel disease was diagnosed. The patient received first-line treatment with an adequate response. Conclusions: Inflammatory bowel disease can be considered a cause of secondary HLH, particularly in patients with suggestive symptoms, such as digestive bleeding in the absence of other secondary causes of HLH.

Resumen Introducción: La linfohistiocitosis hemofagocítica (LHH) es considerada una urgencia médica que debe reconocerse en pacientes con deterioro progresivo del estado general, fiebre, pancitopenia y esplenomegalia. Los hallazgos de laboratorio incluyen citopenia, hipertrigliceridemia, hipofibrinogenemia e hiperferritinemia. Para su diagnóstico es importante, aunque no obligatoria, la realización de aspirado de médula ósea. Dada su naturaleza, se deben buscar causas secundarias de LHH, principalmente enfermedades infecciosas, hematooncológicas, autoinmunitarias y autoinflamatorias. Caso clínico: Se presenta el caso de una adolescente que inició con fiebre y sangrado digestivo bajo. A su ingreso, se documentó falla hepática aguda y pancitopenia. Se realizó aspirado de médula ósea y se encontró hemofagocitocis; el resto de los exámenes concluyeron LHH. Durante su abordaje se diagnosticó enfermedad inflamatoria intestinal. La paciente recibió tratamiento de primera línea con adecuada respuesta. Conclusiones: La enfermedad inflamatoria intestinal puede considerarse como una causa secundaria de LHH, en particular en pacientes con clínica sugestiva, como es el sangrado digestivo, en ausencia de otras causas secundarias de LHH.

Hemophagocytic lymphohistiocytosis as a presentation of inflammatory bowel disease.

Background: Hemophagocytic lymphohistiocytosis (HLH) is considered a medical emergency that should be recognized in patients with fever, splenomegaly, and progressive deterioration of the general condition. Laboratory findings include cytopenia, hypertriglyceridemia, hypofibrinogenemia, and hyperferritinemia. For HLH diagnosis, it is essential, although not mandatory, to perform a bone marrow biopsy. Given its nature, secondary causes of HLH should be sought, mainly infections, hemato-oncological disorders, autoimmune diseases, and auto-inflammatory conditions. Case report: We present the case of a female adolescent who presented with fever and lower gastrointestinal bleeding. Upon admission, acute liver failure and pancytopenia were documented. A bone marrow aspirate was performed, which revealed hemophagocytosis; other tests confirmed HLH diagnosis. During the diagnostic approach, inflammatory bowel disease was diagnosed. The patient received first-line treatment with an adequate response. Conclusions: Inflammatory bowel disease can be considered a cause of secondary HLH, particularly in patients with suggestive symptoms, such as digestive bleeding in the absence of other secondary causes of HLH.

Introducción: La linfohistiocitosis hemofagocítica (LHH) es considerada una urgencia médica que debe reconocerse en pacientes con deterioro progresivo del estado general, fiebre, pancitopenia y esplenomegalia. Los hallazgos de laboratorio incluyen citopenia, hipertrigliceridemia, hipofibrinogenemia e hiperferritinemia. Para su diagnóstico es importante, aunque no obligatoria, la realización de aspirado de médula ósea. Dada su naturaleza, se deben buscar causas secundarias de LHH, principalmente enfermedades infecciosas, hematooncológicas, autoinmunitarias y autoinflamatorias. Caso clínico: Se presenta el caso de una adolescente que inició con fiebre y sangrado digestivo bajo. A su ingreso, se documentó falla hepática aguda y pancitopenia. Se realizó aspirado de médula ósea y se encontró hemofagocitocis; el resto de los exámenes concluyeron LHH. Durante su abordaje se diagnosticó enfermedad inflamatoria intestinal. La paciente recibió tratamiento de primera línea con adecuada respuesta. Conclusiones: La enfermedad inflamatoria intestinal puede considerarse como una causa secundaria de LHH, en particular en pacientes con clínica sugestiva, como es el sangrado digestivo, en ausencia de otras causas secundarias de LHH.

Hemophagocytic lymphohistiocytosis secondary to visceral leishmaniasis in an endemic area in the north of Minas Gerais, Brazil.

INTRODUCTION: Visceral leishmaniasis (VL) is an ill-studied disease that is endemic to several regions of Brazil. It is often complicated by hemophagocytic lymphohistiocytosis (HLH), a potentially fatal disorder resulting from excessive non-malignant activation/proliferation of T lymphocytes and macrophages. Considering the overlapping clinical and laboratory characteristics of these diseases, diagnosing HLH is a challenge. Therefore, tracking the association between VL and HLH is necessary in endemic areas. Although HLH can be inapparent and resolve with antileishmanicides, this may not always occur. HLH causes high lethality; therefore, immunosuppressive therapy should be instituted immediately in order to avoid a fatal outcome. METHODS: We described the epidemiological, clinical, laboratory, and therapeutic profile of this association in a region of Brazil endemic for VL. RESULTS: We presented 39 patients with this association in a retrospective cohort of 258 children who were admitted from January 2012 to June 2017. Of the 39 patients, 31 were from urban areas (79.5%), and 21 (53%) were males. The mean age and weight were 2.86 (2.08) years and 14.03 (5.96) kg, respectively. The main symptoms were fever (100%), hepatosplenomegaly (100%), pallor of the skin and mucosa (82.5%), edema (38.5%), bleeding (25%), and jaundice (7.5%). Hemophagocytosis was identified in 16/37 (43.24%) patients, and direct examination revealed that 26/37 (70.27%) patients were positive for VL. The patients were treated as recommended by the Ministry of Health. CONCLUSIONS: It was observed that HLH is a common complication in endemic areas, and its diagnosis must consider the overlapping of clinical characteristics and pancytopenia.

Hemophagocytic lymphohistiocytosis secondary to visceral leishmaniasis in an endemic area in the north of Minas Gerais, Brazil

Abstract INTRODUCTION Visceral leishmaniasis (VL) is an ill-studied disease that is endemic to several regions of Brazil. It is often complicated by hemophagocytic lymphohistiocytosis (HLH), a potentially fatal disorder resulting from excessive non-malignant activation/proliferation of T lymphocytes and macrophages. Considering the overlapping clinical and laboratory characteristics of these diseases, diagnosing HLH is a challenge. Therefore, tracking the association between VL and HLH is necessary in endemic areas. Although HLH can be inapparent and resolve with antileishmanicides, this may not always occur. HLH causes high lethality; therefore, immunosuppressive therapy should be instituted immediately in order to avoid a fatal outcome. METHODS: We described the epidemiological, clinical, laboratory, and therapeutic profile of this association in a region of Brazil endemic for VL. RESULTS We presented 39 patients with this association in a retrospective cohort of 258 children who were admitted from January 2012 to June 2017. Of the 39 patients, 31 were from urban areas (79.5%), and 21 (53%) were males. The mean age and weight were 2.86 (2.08) years and 14.03 (5.96) kg, respectively. The main symptoms were fever (100%), hepatosplenomegaly (100%), pallor of the skin and mucosa (82.5%), edema (38.5%), bleeding (25%), and jaundice (7.5%). Hemophagocytosis was identified in 16/37 (43.24%) patients, and direct examination revealed that 26/37 (70.27%) patients were positive for VL. The patients were treated as recommended by the Ministry of Health. CONCLUSIONS It was observed that HLH is a common complication in endemic areas, and its diagnosis must consider the overlapping of clinical characteristics and pancytopenia.

Pulmonary Alveolar Proteinosis in Association with Secondary Hemophagocytic Lymphohistiocytosis.

Pulmonary alveolar proteinosis (PAP) is a rare diffuse lung disease in the pediatric population. There are currently few cases documenting hemophagocytic lymphohistiocytosis as a cause for secondary PAP. We describe an ex-preterm child with secondary hemophagocytic lymphohistiocytosis, complicated by PAP and hypoxemic respiratory failure.

Linfo-histiocitose hematofagocítica: relato de caso e revisão da literatura / Hemophagocytic lymphohistiocytosis: case report and literature review

A linfo-histiocitose hematofagocítica é uma síndrome pouco comum, caracterizada por descontrolada ativação e proliferação imunopatológica, levando a evidências clínicas e laboratoriais de inflamação extrema. Pode ser causada primariamente por mutações genéticas (linfo-histiocitose hematofagocítica familiar) ou secundariamente, por uma condição esporádica (linfo--histiocitose hematofagocítica adquirida), como infecções e malignidades.O objetivo deste trabalho foi chamar a atenção para a hinfo-histiocitose hematofagocítica em sua forma secundária (adquirida), com discussão de relato de caso e breve revisão da literatura. Em razão da forma secundária da linfo-histiocitose hematofagocítica ser rara e letal, pouco difundida no meio médico-acadêmico, ter apresentação variável e possuir testes que exigem tempo necessário para o diagnóstico, ela constitui desafio para a realização do diagnóstico precoce e do pronto início da imunoquimioterapia necessária à sobrevivência. O tratamento é complicado por curso clínico dinâmico, alto risco de morbidade e recorrência da doença. O prognóstico geralmente é muito ruim, com evolução potencialmente letal em curto período de tempo se não tratada.

Hemophagocytic Lymphohistiocytosis (HLH) is an uncommon syndrome, characterized by uncontrolled immunopathologic activation and proliferation, leading to clinical and laboratory evidence of severe inflammation. It can be primarily caused by genetic mutations (familial HLH), or secondarily, by a sporadic condition (acquired HLH), such as an infection or malignancy. The purpose of the study is to draw the attention to hematophagocytic Lymphohistiocytosis in its secondary (acquired) form, discussing a case report and briefly reviewing the literature. Because the secondary form of hematophagocytic lymphohistiocytosis is rare and lethal, and poorly widespread in the medical-academic area, with variable appearance, and requiring time-consuming diagnostic tests, it represents a challenge for getting an early diagnosis, and immediately starting immunochemotherapy necessary for survival. Treatment is complicated by the dynamic clinical course, high morbidity risk and recurrence. The prognosis is generally very poor, with potentially fatal outcomes in short time if not treated.

Hemophagocytic lymphohistiocytosis: a case series of a Brazilian institution

Objective: To describe the clinical and laboratory presentation of hemophagocytic lymphohistiocytosis in children treated at a referral institution. Methods: A retrospective descriptive study was carried out of seven children diagnosed with hemophagocytic lymphohistiocytosis between 2010 and 2012. The criteria for diagnosis were those proposed by the Histiocyte Society. When indicated, immunochemotherapy was prescribed according to the HLH94 and HLH2004 protocols of the Histiocyte Society. Results: The patients' ages at diagnosis ranged from one month to nine years. All patients had splenomegaly, fever, anemia, thrombocytopenia, hyperferritinemia and hypertriglyceridemia. Bone marrow hemophagocytosis was detected in six patients. In six cases, infectious diseases triggered the syndrome. In two cases, associated with visceral leishmaniasis, remission was achieved after treatment of the underlying infection. Three patients, who had Epstein–Barr-related hemophagocytic lymphohistiocytosis, required treatment with immunochemotherapy. They are alive and in remission; one patient had symptoms of juvenile rheumatoid arthritis and another, who was suspected of having primary hemophagocytic lymphohistiocytosis, entered into remission after bone marrow transplantation. Two deaths (28.6%) occurred in patients with suspected primary hemophagocytic lymphohistiocytosis; one whose clinical picture was triggered by cytomegalovirus infection did not respond to immunochemotherapy and the other died before any specific treatment was provided. Conclusion: As reported before, hemophagocytic lymphohistiocytosis has a multifaceted presentation with nonspecific signs and symptoms. In secondary forms, remission may be achieved by treating the underlying disease. In the primary forms, remission may be achieved with immunochemotherapy, but bone marrow transplantation is required for cure...

Haemophagocytic syndrome in a liver transplant patient during treatment with Telaprevir.

Haemophagocytic syndrome (HS) is a rare disease that is often fatal despite treatment. HS is characterized by fevers, lymphadenopathy, hepatosplenomegaly, cytopenias and hyperferritinaemia due to deregulated activation and proliferation of macrophages, leading to uncontrolled phagocytosis of platelets, erythrocytes, lymphocytes, and their hematopoietic precursors throughout the reticuloendothelial system. Mycobacterium tuberculosis-associated HS is a rare and underdiagnosed association with only 39 cases reported. We describe a case of HS associated with disseminated Mycobacterium tuberculosis in the setting of post-liver transplantation anti-hepatitis C therapy with pegylated interferon (pegIFN), ribavirin (RBV) and telaprevir (TVR). Despite the delay in the etiologic diagnosis, the patient was treated properly with corticosteroids, cyclosporine and tuberculostatic agents. It is unknown whether telaprevir, a drug that only recently has been started off-label in liver transplant recipients, may have contributed to the development of the HS. Unfortunately, as in many reported cases of HS, the outcome was unfavourable resulting in the death of the patient.

[Hemophagocytic syndrome. Current concepts]. / Síndrome hemofagocítico. Conceptos actuales.

Hemophagocytic lymphohistiocytosis is a syndrome characterized by pathological immune activation that may occur as either a primary a familial disorder (associated with genetic mutations), or as a sporadic condition, associated to infections, malignancies or autoimmune diseases. The clinical picture is characterized by a disproportionate inflammation that causes fever, cytopenias, splenomegaly, bone marrow hemophagocytosis, hypertriglyceridemia and hypofibrinogenemia. Syndrome-related mortality is high, so it is important to maintain a high index of suspicion and start early treatment with immunochemotherapy and bone marrow transplantation in primary and refractory cases. In this article, we review the clinical manifestations, pathology, diagnosis and treatment of these patients.