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Abstract 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.
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INTRODUCTION: Epstein-Barr virus (EBV) infection, with a global prevalence exceeding 95%, typically manifests in children as infectious mononucleosis. However, clinical practice frequently encounters diverse atypical presentations characterized by multisystem involvement, often resulting in an unfavorable clinical course. Our objective is to describe the clinical manifestations and results of EBV infection in a tertiary pediatric hospital in Mexico. METHOD: An observational, transversal, retrospective, and descriptive study that included a systematic review of medical records (2012-2022) of patients under 18 years of age with detectable EBV particles in peripheral blood. RESULTS: The study included 26 patients with a median age of 5 years and a male predominance of 53.8%. Predominant symptoms were fever (85%) and lymphadenopathy (35%). Sixty-five percent had severe and atypical manifestations, including pneumonia and hepatic, hematologic-oncologic, and autoimmune diseases. Anemia, thrombocytopenia and leukopenia were common, with lymphocytosis in 19% of cases. The median EBV viral load was 2816 copies/mL (range: 555-355,500 copies/mL). Four deaths related to EBV infection were reported. Viral load in these cases also varied widely from 594 to 121,000 copies/mL. Supportive care was administered to 85% of patients, while others received antiviral treatment, steroids, and rituximab. CONCLUSION: Atypical manifestations were common, especially in children with multisystem involvement. EBV should be considered as a potential contributor to a diverse spectrum of clinical presentations, emphasizing the need for comprehensive evaluation and awareness in clinical diagnosis.
INTRODUCCIÓN: La infección por el virus de Epstein-Barr (VEB) tiene una prevalencia mundial superior al 95%. Se considera que en los niños se manifiesta principalmente como mononucleosis infecciosa; sin embargo, en la práctica clínica, a menudo encontramos numerosas manifestaciones atípicas con compromiso multisistémico que llevan a un curso desfavorable. Nuestro objetivo es describir las manifestaciones clínicas y los resultados de la infección por VEB en un hospital pediátrico de tercer nivel en México. MÉTODO: Estudio observacional, transversal, retrospectivo y descriptivo, en el cual se revisaron sistemáticamente los expedientes médicos de pacientes menores de 18 años con una detección positiva de partículas de VEB en sangre periférica en el periodo 2012-2022. RESULTADOS: Se incluyeron 26 pacientes con una mediana de edad de 5 años y predominio de varones (53.8%). El 65% presentaron manifestaciones graves y atípicas, incluyendo enfermedades respiratorias, hepáticas, hematooncológicas y autoinmunitarias. Los síntomas más frecuentes fueron fiebre (85%) y linfadenopatía (35%). El 54% presentaron manifestaciones atípicas, incluyendo linfohistiocitosis hemofagocítica, neumonía y neoplasia. La anemia, la trombocitopenia y la leucocitopenia fueron comunes, mientras que el 19% presentaron linfocitosis. La media de la carga viral fue de 2816 copias/ml (555-355,500). Se informaron cuatro muertes atribuidas a la infección por VEB, con valores de carga viral de 594 a 121,000 copias/ml. El 85% de los pacientes recibieron solo tratamiento sintomático, mientras que otros recibieron antivirales, esteroides y rituximab. CONCLUSIÓN: Las manifestaciones atípicas se observaron comúnmente, en especial en niños con compromiso multisistémico. El VEB debe considerarse como un potencial factor contribuyente en el diagnóstico de una amplia gama de manifestaciones clínicas.
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Infecções por Vírus Epstein-Barr , Centros de Atenção Terciária , Humanos , México/epidemiologia , Masculino , Feminino , Infecções por Vírus Epstein-Barr/epidemiologia , Infecções por Vírus Epstein-Barr/diagnóstico , Criança , Estudos Retrospectivos , Pré-Escolar , Adolescente , Lactente , Estudos Transversais , Carga Viral , Hospitalização/estatística & dados numéricos , Herpesvirus Humano 4/isolamento & purificação , Herpesvirus Humano 4/genética , Febre/virologia , Linfadenopatia/virologiaRESUMO
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.
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Linfo-Histiocitose Hemofagocítica , Esplenectomia , Linfo-Histiocitose Hemofagocítica/cirurgia , Linfo-Histiocitose Hemofagocítica/diagnóstico , Humanos , Masculino , Adulto , Esplenectomia/métodosRESUMO
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.
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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
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.
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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 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.
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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
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.
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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.
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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.
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COVID-19 , Ciclosporinas , Linfo-Histiocitose Hemofagocítica , Masculino , Adulto , Humanos , Pessoa de Meia-Idade , Linfo-Histiocitose Hemofagocítica/diagnóstico , Linfo-Histiocitose Hemofagocítica/tratamento farmacológico , Linfo-Histiocitose Hemofagocítica/etiologia , COVID-19/complicações , Etoposídeo/uso terapêutico , Medula Óssea , FebreRESUMO
Abstract Introduction Hemophagocytic lymphohistiocytosis (HLH) is a rare clinical laboratory condition with high mortality rates, resulting from ineffective overactivation of the immune system. Data in the Brazilian literature is scarce, contributing to the challenge in standardizing conducts and performing an early diagnosis of HLH. Objective To describe the clinical, laboratory, and evolutionary findings on HLH patients treated at a pediatric hospital. Methods This is an observational, cross-sectional and retrospective study on children diagnosed with HLH, hospitalized between 2009 and 2019. The diagnostic criteria were those described in the Histiocyte Society protocol. The authors evaluated HLH patient laboratory tests, myelograms and bone marrow biopsies, clinical characteristics and therapy. Results Twenty-three patients were included, 52.2% of whom were males. The age at diagnosis ranged from one to one hundred and eighty months. Four cases were classified as Primary HLH and nineteen, as Secondary HLH. The main triggers were infections and rheumatological diseases. All children had bicytopenia, and 95.4% had hyperferritinemia. Nineteen patients had liver dysfunction, sixteen had neurological disorders and fourteen had kidney injury. Pulmonary involvement was seen in 61.9%, acting as a worse prognosis for death (p= 0.01). Nine patients underwent the immuno-chemotherapy protocol proposed in the HLH 2004. The time to confirm the diagnosis varied from five to eighty days. The lethality found was 56.3%. Conclusions The present study is the most extensive retrospective exclusively pediatric study published in Brazil to date. Despite the limitations, it was possible to demonstrate the importance of discussing HLH as a pediatric emergency.
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Humanos , Masculino , Feminino , Linfo-Histiocitose Hemofagocítica , PediatriaRESUMO
Introduction: Pediatric inflammatory multisystem syndrome temporally associated with SARS-CoV-2 (PIMS-TS) is a systemic hyperinflammatory disease that occurs in a small number of children after being infected with SARS-CoV-2. Macrophage activation syndrome, an aggressive condition characterized by the excessive inflammation and activation of well-differentiated macrophages, has been shown to occur in patients infected by SARS-CoV-2. Considering the clinical and pathophysiological similarities between these diseases, our main objective was to determine whether gene polymorphisms associated with macrophage activation syndrome were also present in patients with PIMS-TS. Methods: DNA from 10 pediatric patients with PIMS-TS (case group) and ten COVID-19 patients without PIMS-TS (control group) were genotyped by Real-time PCR analysis (TaqMan®) for single nucleotide polymorphisms (SNP) in four genes associated with macrophage activation syndrome: perforin 1 (PRF1), granzyme B (GZMB), syntaxin 11 (STX11), and syntaxin binding protein 2 (STXBP2). The SNP analysis was performed using the additive, dominant, and recessive models. Results: A significantly higher frequency of an SNP (C wild allele in rs6573910) in the GZMB gene was observed in both the additive and dominant models in the PIMS-TS group than controls. A borderline significant difference was also observed for the G allele in rs7764017 of the STX11 gene in the PIMS-TS group in the additive model. Conclusions: This study indicated the presence of two polymorphisms in genes associated with macrophage activation syndrome (GZMB and STX11) in patients who developed PIMS-TS. If the presence of these SNPs is validated in a larger number of PIMS-TS cases, they can be used as potential biomarkers for early identification of pediatric patients with a higher probability of developing PIMS-TS associated with SARS-CoV-2 infection.
Introdução: A síndrome multissistêmica inflamatória pediátrica temporariamente associada ao SARS-CoV-2 (SIMP-TS) é uma doença hiperinflamatória sistêmica que ocorre em um pequeno número de crianças após serem infectadas pelo SARS-CoV-2. A síndrome de ativação de macrófagos (SAM), uma condição agressiva caracterizada pela inflamação excessiva e ativação de macrófagos bem diferenciados, demonstrou ocorrer em pacientes infectados por SARS-CoV-2. Considerando as semelhanças clínicas e fisiopatológicas entre essas doenças, neste estudo o nosso principal objetivo foi determinar se polimorfismos gênicos associados à SAM também estavam presentes em pacientes com SIMP-TS. Métodos: DNA de dez pacientes pediátricos com SIMP (grupo caso) e dez pacientes COVID-19 sem SIMP (grupo controle) foram genotipados por análise de PCR em tempo real (tecnologia TaqMan®) para polimorfismos de nucleotídeo único (SNPs) em quatro genes selecionados associados com SAM: perforina 1 (PRF1), granzima B (GZMB), sintaxina 11 (STX11) e proteína de ligação de sintaxina 2 (STXBP2). A análise dos SNPs foi realizada utilizando o modelo aditivo, dominante e recessivo. Resultados: Uma frequência significativamente maior de um SNP (alelo selvagem C em rs6573910) no gene GZMB foi observada pelos modelos aditivo e dominante no grupo SIMP quando comparado aos controles. Além disso, uma significância limítrofe foi observada para o alelo G em rs7764017 do gene STX11 no grupo SIMP pelo modelo aditivo. Conclusões: Nosso estudo indicou a presença de dois polimorfismos em genes associados à SAM (GZMB e STX11) em pacientes que desenvolveram SIMP-TS. Uma vez validada a presença desses SNPs em um número maior de casos de SIMP-TS, eles podem ser usados como potenciais biomarcadores para a identificação precoce de pacientes pediátricos com maior probabilidade de desenvolver SIMP-TS associado à infecção por SARS-CoV-2.
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Humanos , Pré-Escolar , CriançaRESUMO
A síndrome hemofagocítica é determinada por desregulação do sistema imunológico, caracterizada por ativação excessiva de macrófagos, resultando em fagocitose de células sanguíneas normais no fígado, baço e medula óssea. Pode ser primária (genética) ou secundária (adquirida). Em adultos quase sempre é secundária, tendo infecções, neoplasias e doenças autoimunes como frequentes desencadeadores. Entre as principais manifestações da síndrome estão febre prolongada e hepatoesplenomegalia. O diagnóstico até o momento é confirmado pelo achado de hemofagocitose em biópsia de medula óssea. Entretanto, é descrito que a biópsia de medula óssea é normal nos primeiros dias de manifestações da síndrome. O presente relato tem como objetivo mostrar a observação de hemofagocitose em cultura de células de sangue periférico de paciente de 29 anos precedendo a hemofagocitose em biópsia de medula óssea. A paciente apresentava diferentes infecções, com grave comprometimento do estado geral e sem melhora com o tratamento das infecções. O achado laboratorial permitiu o tratamento precoce da síndrome hemofagocítica e a melhora da paciente. No presente relato a técnica utilizada está descrita detalhadamente para que possa ser reproduzida, além de ser apresentada uma revisão não sistemática da literatura sobre a síndrome.
Hemophagocytic syndrome, which is caused by dysregulation of the immune system, is characterized by excessive macrophage activation, resulting in phagocytosis of normal blood cells in the liver, spleen, and bone marrow. It can be primary (genetic) or secondary (acquired). In adults, it is almost always secondary, with infections, neoplasms, and autoimmune diseases as frequent triggers. The main manifestations of this syndrome are prolonged fever and hepatosplenomegaly. Currently, diagnosis is confirmed through finding hemophagocytosis in a bone marrow biopsy. However, it has been reported that bone marrow biopsy results are still normal on the first day the syndrome manifests. Here we report observing hemophagocytosis in cultured peripheral blood cells from a 29-year-old patient prior to finding hemophagocytosis in bone marrow biopsy. The patient had various infections and a poor general condition, which did not improve after treating the infections. The laboratory findings allowed early treatment of hemophagocytic syndrome and the patient improved. We describe our technique in detail so it can be reproduced, and we provide a non-systematic review of the literature on the syndrome.
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Humanos , Feminino , Adulto , HIVRESUMO
We describe a patient with HIV who presented with hemophagocytic lymphohistiocytosis and nonspecific abdominal imaging findings. He was diagnosed with visceral leishmaniasis via bone marrow biopsy and treated in the hospital with amphotericin B infusions. Despite pharmacologic interventions, including amphotericin and miltefosine in addition to antiretroviral therapy, our patient experienced multiple relapses and a challenging clinical course.
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INTRODUCTION: Hemophagocytic lymphohistiocytosis (HLH) is a rare clinical laboratory condition with high mortality rates, resulting from ineffective overactivation of the immune system. Data in the Brazilian literature is scarce, contributing to the challenge in standardizing conducts and performing an early diagnosis of HLH. OBJECTIVE: To describe the clinical, laboratory, and evolutionary findings on HLH patients treated at a pediatric hospital. METHODS: This is an observational, cross-sectional and retrospective study on children diagnosed with HLH, hospitalized between 2009 and 2019. The diagnostic criteria were those described in the Histiocyte Society protocol. The authors evaluated HLH patient laboratory tests, myelograms and bone marrow biopsies, clinical characteristics and therapy. RESULTS: Twenty-three patients were included, 52.2% of whom were males. The age at diagnosis ranged from one to one hundred and eighty months. Four cases were classified as Primary HLH and nineteen, as Secondary HLH. The main triggers were infections and rheumatological diseases. All children had bicytopenia, and 95.4% had hyperferritinemia. Nineteen patients had liver dysfunction, sixteen had neurological disorders and fourteen had kidney injury. Pulmonary involvement was seen in 61.9%, acting as a worse prognosis for death (p = 0.01). Nine patients underwent the immuno-chemotherapy protocol proposed in the HLH 2004. The time to confirm the diagnosis varied from five to eighty days. The lethality found was 56.3%. CONCLUSIONS: The present study is the most extensive retrospective exclusively pediatric study published in Brazil to date. Despite the limitations, it was possible to demonstrate the importance of discussing HLH as a pediatric emergency.
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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.
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Infecções por Vírus Epstein-Barr , Linfo-Histiocitose Hemofagocítica , Síndrome de Ativação Macrofágica , Pediatria , Humanos , Criança , Linfo-Histiocitose Hemofagocítica/diagnóstico , Linfo-Histiocitose Hemofagocítica/terapia , Síndrome de Ativação Macrofágica/diagnóstico , Síndrome de Ativação Macrofágica/terapia , Infecções por Vírus Epstein-Barr/complicações , Infecções por Vírus Epstein-Barr/diagnóstico , Infecções por Vírus Epstein-Barr/terapia , Herpesvirus Humano 4RESUMO
ABSTRACT Introduction: Hemophagocytic lymphohistiocytosis comprises a systemic hyperactivation of macrophages that requires prompt recognition of symptoms and early treatment. Objective and Method: In this context, we described clinical and laboratory characteristics, therapeutic modality and outcome of 21 patients with HLH treated at a pediatric oncology hospital between January 2000 and February 2019. Results: HLH mainly affected females, fever was the most frequent clinical sign and hyperferritinemia was the most prevalent laboratory abnormality. All patients were admitted to the intensive care unit (ICU) at some point. Fifteen (71.4%) patients presented resolution criteria and eight (53.3%) of them presented reactivation. The mortality rate was 57.1% and the mean time between diagnosis and death was 9.98 months. The 5-year overall survival (OS) was 36.7%. We observed a significant difference in prognosis associated with reactivation of HLH. These patients demonstrated an estimated 5-year OS of 25%, while all patients that did not reactivate were alive until the end of the follow-up. Conclusion: In conclusion, HLH is a rare disease with a high mortality rate, especially in patients with disease reactivation and those with familial- or immunodeficiency-associated forms, which makes early recognition and genetic testing crucial for appropriate management and prompt SCT indication.
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Humanos , Masculino , Feminino , Linfo-Histiocitose Hemofagocítica , Síndrome de Ativação Macrofágica , Síndrome da Liberação de Citocina , HiperferritinemiaRESUMO
Hemophagocytic lymphohistiocytosis (HLH) is a disorder that occurs due to unsuitable monocyte activation in a variety of infections. In human immunodeficiency virus (HIV) infections, patients with advanced immunossupression associated with opportunistic infections are at increased risk of developing HLH. We describe a clinical case of a 33-year-old male student diagnosed with HIV who was hospitalized for investigation of asthenia and dyspnea, accompanied by adynamia, decreased motor force in the left leg, dysphagia, and dysfluency. His general condition was regular, he was pale, feverish, and had normal cardiac and pulmonary auscultation. Physical examination revealed ulcerated lesions in the perianal region and hepatosplenomegaly without palpable lymph node enlargement. Laboratory parameters showed pancytopenia, a slight increase in liver function accompanied by high lactate dehydrogenase, and hiperferritinemia. The initial diagnosis was disseminated histoplasmosis, thus amphotericin B deoxycholate was empirically prescribed while waiting on myeloculture and blood cultures for fungi and mycobacteria. Other clinical procedures were blood transfusion, resumption of antiretroviral therapy (ART) and secondary prophylaxis. Myeloculture blood cultures of fungi and mycobacteria were negative. Patient evolved well in relation to the initial complaints and showed partial clinical and laboratory improvement. However, 23 days after hospitalization, he developed a febrile episode accompanied by chills and a convulsive crisis. The patient was transferred to the intensive unit care and developed septic shock and respiratory failure. He died 25 days after the onset of the condition. After the postmortem examination, histopathology revealed countless rounded fungal structures compatible with Histoplasma sp., which were observed in the peripancreatic lymph node, liver, and spleen, in addition to hemophagocytosis in the splenic parenchyma. We thus conclude that when the patient met criteria for HLH, such as fever, hepatosplenomegaly, hiperferritinemia, and pancytopenia, the evolution was fast due to the aggressive and rapidly fatal nature of HLH, despite anti-fungal and corticoid treatment. Therefore, this case report reinforces the need to consider hemophagocytic syndrome in patients with HIV and disseminated histoplasmosis, especially where histoplasmosis is highly endemic, in order for the treatment be started early when there is high clinical suspicion.
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COVID-19 is a viral disease associated with an intense inflammatory response. Macrophage Activation Syndrome (MAS), the complication present in secondary hemophagocytic lymphohistiocytosis (sHLH), shares many clinical aspects observed in COVID-19 patients, and investigating the cytolytic function of the responsible cells for the first line of the immune response is important. Formalin-fixed paraffin-embedded lung tissue samples obtained by post mortem necropsy were accessed for three groups (COVID-19, H1N1, and CONTROL). Polymorphisms in MAS cytolytic pathway (PRF1; STX11; STXBP2; UNC13D and GZMB) were selected and genotyping by TaqMan® assays (Thermo Fisher Scientific, MA, USA) using Real-Time PCR (Applied Biosystems, MA USA). Moreover, immunohistochemistry staining was performed with a monoclonal antibody against perforin, CD8+ and CD57+ proteins. Histopathological analysis showed high perforin tissue expression in the COVID-19 group; CD8+ was high in the H1N1 group and CD57+ in the CONTROL group. An association could be observed in two genes related to the cytolytic pathway (PRF1 rs885822 G/A and STXBP2 rs2303115 G/A). Furthermore, PRF1 rs350947132 was associated with increased immune tissue expression for perforin in the COVID-19 group. The genotype approach could help identify patients that are more susceptible, and for this reason, our results showed that perforin and SNPs in the PRF1 gene can be involved in this critical pathway in the context of COVID-19.