RESUMO
Background: Hemophagocytic syndrome or hemophagocytic lymphohistiocytosis (HL) is an immune hyperactivation of multifactorial etiology, characterized by excessive activation of lymphocytes and macrophages, as well as numerous pro-inflammatory cytokines. It has a non-specific and highly variable clinical presentation, with splenomegaly being one of the clinical manifestations. Due to its nature, it can manifest during childhood or adult life, which is why it is a disease of diagnostic and therapeutic complexity. Clinical case: 38-year-old male patient without comorbidities, who presented with abdominal pain, choluria, fever > 38 °C and diaphoresis of more than 10 days of evolution. A bone marrow aspirate was performed as part of the diagnostic approach with data compatible with hemophagocytosis and cytopenias. The immunosuppressive management did not show the expected response, which is why an open splenectomy was performed as the last therapeutic option with adequate hematological control. A documentary review of the disease was carried out, and of the therapeutic options, emphasizing surgical management in case of refractoriness to medical treatment. Conclusions: Splenectomy increases the overall survival rate and the time free of HL progression, even though there are still no studies to determine with certainty the ideal time to perform a splenectomy in patients with pancytopenia without splenomegaly who suffer from hemophagocytic syndrome.
Introducción: el síndrome hemofagocítico o linfohistiocitosis hemofagocítica (LH) es una hiperactivación inmune de etiología multifactorial, caracterizada por activación excesiva de linfocitos y macrófagos, así como por numerosas citocinas proinflamatorias. Tiene una presentación clínica poco específica y muy variable, y la esplenomegalia es una de las manifestaciones clínicas. Debido a su naturaleza puede manifestarse durante la infancia o la vida adulta, por lo que es una enfermedad de complejidad diagnóstica y terapéutica. Caso clínico: paciente del sexo masculino de 38 años sin comorbilidades, quien presentó dolor abdominal, coluria, fiebre > 38 °C y diaforesis de más de 10 días de evolución. Se le hizo aspirado de médula ósea como parte del abordaje diagnóstico con datos compatibles con hemofagocitosis y citopenias. El manejo inmunosupresor no mostró la respuesta esperada, por lo que se hizo esplenectomía abierta como última opción terapéutica con adecuado control hematológico. Se hizo una revisión documental de la enfermedad y de las opciones terapéuticas con énfasis en el manejo quirúrgico en caso de refractariedad al tratamiento médico. Conclusiones: la esplenectomía aumenta la tasa de supervivencia general y el tiempo libre de progresión de la LH, aunque no hay todavía estudios para determinar con certeza el tiempo ideal para hacer una esplenectomía en pacientes con pancitopenia sin esplenomegalia que padezcan síndrome hemofagocítico.
Assuntos
Linfo-Histiocitose Hemofagocítica , Esplenectomia , Linfo-Histiocitose Hemofagocítica/cirurgia , Linfo-Histiocitose Hemofagocítica/diagnóstico , Humanos , Masculino , Adulto , Esplenectomia/métodosRESUMO
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.
Assuntos
DNA Viral , Infecções por Vírus Epstein-Barr , Herpesvirus Humano 4 , Linfo-Histiocitose Hemofagocítica , Recidiva , Humanos , Linfo-Histiocitose Hemofagocítica/terapia , Linfo-Histiocitose Hemofagocítica/sangue , Linfo-Histiocitose Hemofagocítica/virologia , Estudos Retrospectivos , Masculino , Infecções por Vírus Epstein-Barr/sangue , Infecções por Vírus Epstein-Barr/complicações , Infecções por Vírus Epstein-Barr/terapia , Feminino , DNA Viral/sangue , Pré-Escolar , Criança , Herpesvirus Humano 4/genética , Herpesvirus Humano 4/isolamento & purificação , Lactente , Adolescente , Resultado do Tratamento , Relevância ClínicaRESUMO
Hemophagocytic lymphohistiocytosis (HLH) is a rare genetic hyperinflammatory syndrome that occurs early in life. Macrophage activation syndrome (MAS) usually refers to a secondary form of HLH associated with autoimmunity, although there are other causes of secondary HLH, such as infections and malignancy. In this article, we reviewed the concepts, epidemiology, clinical and laboratory features, diagnosis, differential diagnosis, prognosis, and treatment of HLH and MAS. We also reviewed the presence of MAS in the most common autoimmune diseases that affect children. Both are severe diseases that require prompt diagnosis and treatment to avoid morbidity and mortality.
Assuntos
Doenças Autoimunes , Linfo-Histiocitose Hemofagocítica , Síndrome de Ativação Macrofágica , Criança , Humanos , Síndrome de Ativação Macrofágica/diagnóstico , Síndrome de Ativação Macrofágica/etiologia , Linfo-Histiocitose Hemofagocítica/diagnóstico , Linfo-Histiocitose Hemofagocítica/complicações , Doenças Autoimunes/complicações , Diagnóstico DiferencialRESUMO
Hemophagocytic lymphohistiocytosis (HLH) is a rare condition characterized by a hyperinflammatory state secondary to dysregulated immune activity with multisystem involvement. HLH may be primary or hereditary, or triggered by various diseases. Mortality without a timely treatment reaches 50% of the cases. Here we describe the case of a 1-year and 8-month-old female patient with a recent diagnosis of human immunodeficiency virus infection in the AIDS stage. She was hospitalized for assessment and initiation of antiretroviral therapy during which she developed multiple intercurrent infectious and immune conditions. Two episodes of hemophagocytic lymphohistiocytosis in the setting of uncontrolled acquired immunodeficiency and opportunistic co-infections stand out. The objective of this case report is to highlight the importance of suspecting HLH for a relevant diagnosis and treatment.
La linfohistiocitosis hemofagocítica (LHH) es una entidad rara que se caracteriza por un estado hiperinflamatorio secundario a la activación desregulada del sistema inmune con compromiso multisistémico. Puede ser primaria o hereditaria, o estar desencadenada por diversas enfermedades. La mortalidad sin tratamiento oportuno es del 50 % de los casos. Se presenta el caso de una paciente de 1 año y 8 meses con diagnóstico reciente de infección por virus de inmunodeficiencia humana en estadio sida. Cursó internación para estudio e inicio de tratamiento antirretroviral durante la cual presentó múltiples intercurrencias infectológicas e inmunológicas. Se destacan dos episodios de linfohistiocitosis hemofagocítica en contexto de inmunodeficiencia adquirida no controlada y coinfecciones oportunistas. El objetivo de este reporte es destacar la importancia de la sospecha de LHH para un diagnóstico y tratamiento pertinente.
Assuntos
Coinfecção , Infecções por HIV , Linfo-Histiocitose Hemofagocítica , Humanos , Linfo-Histiocitose Hemofagocítica/diagnóstico , Linfo-Histiocitose Hemofagocítica/etiologia , Feminino , Infecções por HIV/complicações , Infecções por HIV/tratamento farmacológico , Lactente , Infecções Oportunistas Relacionadas com a AIDS/diagnósticoRESUMO
NSG-SGM3 and NOG-EXL mice combine severe immunodeficiency with transgenic expression of human myeloid stimulatory cytokines, resulting in marked expansion of myeloid populations upon humanization with CD34+ hematopoietic stem cells (HSCs). Humanized NSG-SGM3 mice typically develop a lethal macrophage activation syndrome and mast cell hyperplasia that limit their use in long-term studies (e.g., humanization followed by tumor xenotransplantation). It is currently unclear to what extent humanized NOG-EXL mice suffer from the same condition observed in humanized NSG-SGM3 mice. We compared the effects of human CD34+ HSC engraftment in these two strains in an orthotopic patient-derived glioblastoma model. NSG-SGM3 mice humanized in-house were compared to NOG-EXL mice humanized in-house and commercially available humanized NOG-EXL mice. Mice were euthanized at humane or study endpoints, and complete pathological assessments were performed. A semiquantitative multiparametric clinicopathological scoring system was developed to characterize chimeric myeloid cell hyperactivation (MCH) syndrome. NSG-SGM3 mice were euthanized at 16 weeks after humanization because of severe deterioration of clinical conditions. Humanized NOG-EXL mice survived to the study endpoint at 22 weeks after humanization and showed less-severe MCH phenotypes than NSG-SGM3 mice. Major differences included the lack of mast cell expansion and limited tissue/organ involvement in NOG-EXL mice compared to NSG-SGM3 mice. Engraftment of human lymphocytes, assessed by immunohistochemistry, was similar in the two strains. The longer survival and decreased MCH phenotype severity in NOG-EXL mice enabled their use in a tumor xenotransplantation study. The NOG-EXL model is better suited than the NSG-SGM3 model for immuno-oncology studies requiring long-term survival after humanization.
Assuntos
Antígenos CD34 , Transplante de Células-Tronco Hematopoéticas , Células-Tronco Hematopoéticas , Camundongos Transgênicos , Células Mieloides , Animais , Camundongos , Humanos , Células-Tronco Hematopoéticas/patologia , Antígenos CD34/metabolismo , Células Mieloides/patologia , Fenótipo , Modelos Animais de DoençasRESUMO
Abstract Hemophagocytic lymphohistiocytosis (HLH) is a rare genetic hyperinflammatory syndrome that occurs early in life. Macrophage activation syndrome (MAS) usually refers to a secondary form of HLH associated with autoimmunity, although there are other causes of secondary HLH, such as infections and malignancy. In this article, we reviewed the concepts, epidemiology, clinical and laboratory features, diagnosis, differential diagnosis, prognosis, and treatment of HLH and MAS. We also reviewed the presence of MAS in the most common autoimmune diseases that affect children. Both are severe diseases that require prompt diagnosis and treatment to avoid morbidity and mortality.
RESUMO
While SARS-CoV-2 infection causes a mild disease in most children, SARS-CoV-2 infection may be lethal in a few of them. In the defense against SARS-CoV-2, type I interferons are key players, and several studies have identified a defective or neutralized interferon response as the cause of overwhelming viral infection. However, inappropriate, untimely, or excessive interferon production may also be detrimental to the host. Here, we describe two patients with STAT1 gain-of-function (GOF), a known type I interferonopathy, who died of COVID-19. Whole-exome sequencing and interferon-gamma-activated sequence (GAS) and interferon-sensitive responsive element (ISRE) reporter assay were performed to identify and characterize STAT1 variants. Patient 1 developed hemophagocytic lymphohistiocytosis (HLH) in the context of COVID-19 infection and died in less than a week at the age of 4 years. Patient 2 developed a high fever, cough, and hypoxemia and succumbed to COVID-19 pneumonia at the age of 5 years. Two heterozygous missense variants, p.E563Q and p.K344E, in STAT1 were identified. Functional validation by reporter assay and immunoblot confirmed that both variants are gain-of-function (GOF). GOF variants transiently expressing cells exhibited enhanced upregulation of downstream genes, including ISG15, MX1, and OAS1, in response to IFN-α stimulation. A catastrophic course with HLH or acute respiratory failure is thought to be associated with inappropriate immunoregulatory mechanisms to handle SARS-CoV-2 in STAT1 GOF. While most patients with inborn errors of immunity who developed COVID-19 seem to handle it well, these cases suggest that patients with STAT1-GOF might be at risk of developing fatal complications due to SARS-CoV-2.
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COVID-19 , Interferon Tipo I , Criança , Pré-Escolar , Humanos , COVID-19/genética , Mutação com Ganho de Função , Interferon-alfa/genética , SARS-CoV-2/metabolismo , Fator de Transcrição STAT1/genética , Fator de Transcrição STAT1/metabolismoRESUMO
Background: Dengue fever is a mosquito-borne infectious disease endemic in over 100 countries around the world. Among the complications that dengue can cause the Hemophagocytic Lymphohistiocytosis is one of great concern for its severity and complex diagnosis. Case report: Hereby we document a case of this disease expressed on a previously healthy 6-year-old female patient whose dengue infection was so severe that needed intensive care management with vasoactive drugs and diuretics. After a short period of wellness began newly with fever, pancytopenia, hepatitis, and inflammatory response symptoms. Conclusions: A Dengue associated Hemophagocytic Lymphohistiocytosis syndrome was suspected and treated with intravenous corticosteroids on a 3-day scheme at no signs of malignancy with excellent response. The health care professionals must know about this not novel entity in order to reach an efficient diagnosis and treatment mostly, but not only, those in tropical and sub-tropical regions of the word were dengue virus is endemic.
Antecedentes: La fiebre por dengue es una enfermedad infecciosa transmitida por mosquitos, endémica en más de 100 países alrededor del mundo. La Linfohistiocitosis Hemofagocítica, dentro de las complicaciones que puede ocasionar el dengue, es una de las más preocupantes por su complejidad diagnostica y gravedad. Reporte de caso: Femenino de 6 años de edad, previamente sana, cuya infección por dengue fue tan grave que requirió manejo en cuidados intensivos. Después de un breve período de bienestar recrudeció la fiebre, además de pancitopenia, hepatitis y síntomas de respuesta inflamatoria. Conclusiones: Se sospechó síndrome de Linfohistiocitosis Hemofagocítica asociada a Dengue y se trató con corticoides intravenosos en un esquema de 3 días con excelente respuesta. Los profesionales de la salud deben conocer esta entidad no novedosa para poder llegar a un diagnóstico y tratamiento eficaz en su mayoría, pero no solo, en las regiones tropicales y subtropicales del mundo donde el virus del dengue es endémico.
Assuntos
Dengue , Hepatite , Linfo-Histiocitose Hemofagocítica , Feminino , Humanos , Criança , Linfo-Histiocitose Hemofagocítica/etiologia , Hepatite/complicações , Dengue/complicaçõesRESUMO
The case of a 57-year-old male patient with jaundice, high-grade fever, and upper abdominal pain who was recovering from a mild coronavirus disease-19 (COVID-19) infection is reported. Laboratory analysis showed liver injury with high levels of AST and ALT, as well as an elevated serum ferritin level. The patient underwent a bone marrow biopsy which showed features of hemophagocytic lymphohistiocytosis (HLH), a systemic syndrome caused by immune activation. The patient was successfully treated with etoposide and dexamethasone and kept on maintenance therapy with cyclosporine, with resolution of the HLH. The discussion highlights that COVID-19 infection may cause liver injury, and in severe cases, patients may develop HLH as a cause for liver injury. The incidence of HLH in adults with severe COVID-19 infection is estimated to be lower than 5%. The association between HLH and COVID-19 infection has been studied due to immunological hyperactivation. Signs such as persistent high fever, hepatosplenomegaly, and progressive pancytopenia should raise suspicion for the diagnosis of overlapping HLH. A specific approach using steroids and etoposide, followed by maintenance therapy with cyclosporine, is proposed in the HLH-94 protocol as the mainstay of treatment. It is suggested that HLH should be suspected in patients with laboratory signs of liver injury following COVID-19 infection, especially in patients with high-grade fever and a history of rheumatic conditions.