RESUMO
BACKGROUND: Hemophagocytic lymphohistiocytosis (HLH) is characterized by uncontrolled activation of inflammatory cells and an exaggerated release of cytokines. It can be triggered by different factors, including viruses, such as dengue. The objective of this study was to characterize the clinical and laboratory profiles of children with severe dengue and HLH, and to identify the risk factors for this clinical complication. METHODS: An analytical study was conducted in children with severe dengue who were treated in an intensive care unit between January 2019 and March 2020. Clinical and laboratory factors were compared between patients with and without HLH. RESULTS: HLH represented 13.4% (15/112) of children with severe dengue. Patients with HLH had a long-lasting fever (10.1 vs. 5.8 days; P = 0.012), low hemoglobin levels (7.6 vs. 10.8 g/dL; P = 0.000) and high aspartate aminotransferase values (4443 vs. 1061 U/L; P = 0.002), alanine transaminase (1433 vs. 487 U/L; P = 0.004), partial thromboplastin time (80.6 vs. 51.8 seconds; P = 0.010), prothrombin time (23.5 vs. 19.6 seconds; P = 0.024), triglycerides (333.7 vs. 223.2 mg/dL; P = 0.005), lactate dehydrogenase (4209 vs. 1947 U/L; P = 0.006), soluble CD25 (3488 vs. 1026 pg/mL; P = 0.014), and presented with higher frequency of myocarditis (66.7% vs. 38.3%; P = 0.048), hepatitis (5.3% vs. 1.3%; P = 0.014), bacterial coinfection (73.3% vs. 26.7%; P = 0.010) and fatal outcome (26% vs. 5%; P = 0.037). CONCLUSIONS: HLH is a serious life-threatening clinical complication of dengue virus infection that must be considered, particularly during outbreaks.
Assuntos
Linfo-Histiocitose Hemofagocítica , Dengue Grave , Humanos , Criança , Dengue Grave/complicações , Dengue Grave/epidemiologia , Linfo-Histiocitose Hemofagocítica/epidemiologia , Linfo-Histiocitose Hemofagocítica/tratamento farmacológico , Colômbia/epidemiologia , Estudos Retrospectivos , Surtos de DoençasRESUMO
OBJECTIVES: To investigate the prevalence of hemophagocytic lymphohistiocytosis (HLH) syndrome in pediatric acute liver failure (PALF) of infancy and assess the diagnostic role of rapid immunologic tests, genotype/phenotype correlations, and clinical outcomes. STUDY DESIGN: We retrospectively analyzed 78 children with PALF aged <24 months referred over almost 2 decades. The studied patients with a phenotype of HLH syndrome had a comprehensive immunologic workup, including additional genetic analysis for primary immunologic causes. RESULTS: Thirty of the 78 children had the HLH phenotype and underwent genetic assessment, which demonstrated positive findings in 19 (63.3%), including 9 (30%) with biallelic primary HLH mutations and 10 (33.3%) with heterozygous mutations and/or polymorphisms. The most common form of primary HLH was familial hemophagocytic lymphohistiocytosis (FHL)-2, diagnosed in 6 children, 4 of whom had a c.50delT (p.Leu17ArgfsTer34) mutation in the PRF1 gene. Three patients with primary HLH received genetic diagnoses of FHL-3, Griscelli syndrome, and LRBA (lipopolysaccharide-responsive vesicle trafficking, beach- and anchor-containing) protein deficiency. Overall mortality in the series was 52.6% (10 of 19), and mortality in children with a documented biallelic pathogenic HLH mutation (ie, primary HLH) was 66.6% (6 of 9). Two children underwent liver transplantation, and 4 children underwent emergency hematopoietic stem cell transplantation; all but 1 child survived medium term. CONCLUSIONS: Primary HLH can be diagnosed retrospectively in approximately one-third of infants with indeterminate PALF (iPALF) who meet the clinical criteria for HLH, often leading to their death. The most common HLH type in iPALF is FHL-2, caused by biallelic mutations in PRF-1. The clinical relevance of observed heterozygous mutations and variants of uncertain significance requires further investigation. Prompt hematopoietic stem cell transplantation could be life-saving in infants who survive the liver injury.
Assuntos
Falência Hepática Aguda , Linfo-Histiocitose Hemofagocítica , Humanos , Linfo-Histiocitose Hemofagocítica/complicações , Linfo-Histiocitose Hemofagocítica/diagnóstico , Linfo-Histiocitose Hemofagocítica/epidemiologia , Perforina/genética , Estudos Retrospectivos , Prevalência , Mutação , Falência Hepática Aguda/diagnóstico , Falência Hepática Aguda/epidemiologia , Falência Hepática Aguda/etiologia , Proteínas Adaptadoras de Transdução de Sinal/genéticaRESUMO
BACKGROUND: Hemophagocytic lymphohistiocytosis (HLH) is an exaggerated inflammatory reaction secondary to a host's inadequate immune response causing a self-perpetuating loop of altered regulation. Signs and symptoms of HLH are compatible with other common diseases and are nonspecific. Underdiagnosis makes it difficult to estimate the real incidence of HLH, especially in developing countries. METHODS: Retrospective, descriptive study of pediatric patients admitted to a high-complexity institution in Cali, Colombia between 2012 and 2019 with HLH diagnosis. Medical history review to complete an electronic database and a secondary, descriptive analysis was carried out. The study was approved by the Institutional Ethics Committee. RESULTS: Twenty-one patients were included. 52.4 % of the population was male with a median age of 9.3 years [IQR (3.0-13.7 years)]. More than half of patients (66.6 %) had viral disease at diagnosis, the most frequent being Epstein-Barr Virus (EBV) (52.3 %) and dengue (14.3 %). Three patients had confirmed gene mutations (G6PC3, XIAP, and UNC13D). 95 % of the patients were treated with the HLH 2004 protocol, half of them received incomplete protocol with intravenous immunoglobulin (IVIG) and/or systemic steroids, while the other half received the complete protocol including etoposide and cyclosporine. More than three-fourths (76.2 %) required admission to an ICU with a median stay of 14 days [IQR (11-37 days)] and a median hospital stay of 30 days [IQR (18-93 days)]. 14.3 % (n = 3) of patients died. CONCLUSIONS: HLH is a complex disease that requires multidisciplinary management with secondary HLH due to EBV infection being a common cause. There is increasing awareness of HLH diagnosis in developing countries such as Colombia which can offer earlier treatment options and better outcomes.
Assuntos
Infecções por Vírus Epstein-Barr , Linfo-Histiocitose Hemofagocítica , Adolescente , Criança , Pré-Escolar , Países em Desenvolvimento , Infecções por Vírus Epstein-Barr/complicações , Infecções por Vírus Epstein-Barr/diagnóstico , Infecções por Vírus Epstein-Barr/epidemiologia , Feminino , Herpesvirus Humano 4/genética , Humanos , Linfo-Histiocitose Hemofagocítica/diagnóstico , Linfo-Histiocitose Hemofagocítica/epidemiologia , Linfo-Histiocitose Hemofagocítica/etiologia , Masculino , Estudos RetrospectivosRESUMO
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.
Assuntos
Leishmaniose Visceral/complicações , Leishmaniose Visceral/diagnóstico , Leishmaniose Visceral/tratamento farmacológico , Linfo-Histiocitose Hemofagocítica/diagnóstico , Linfo-Histiocitose Hemofagocítica/etiologia , Linfo-Histiocitose Hemofagocítica/terapia , Adulto , Anfotericina B/uso terapêutico , Antiprotozoários/uso terapêutico , Brasil/epidemiologia , Evolução Fatal , Feminino , Humanos , Imunoglobulinas/uso terapêutico , Leishmaniose Visceral/epidemiologia , Linfo-Histiocitose Hemofagocítica/epidemiologia , Masculino , Metilprednisolona/uso terapêutico , Doenças Negligenciadas/complicações , Doenças Negligenciadas/diagnóstico , Doenças Negligenciadas/tratamento farmacológico , Doenças Negligenciadas/epidemiologia , Resultado do Tratamento , Adulto JovemRESUMO
Introduction: Leishmaniasis is a tropical and subtropical disease highly reported in Southeast Asia, East Africa, Latin America, and the Mediterranean basin, with an incidence of two million new cases by year and 500,000 cases of visceral leishmaniasis. One of the more severe and rare complications of visceral leishmaniasis is hemophagocytic lymphohistiocytosis. Objective: To describe the clinical characteristics of hemophagocytic lymphohistiocytosis associated with visceral leishmaniasis Methods: We performed a literature review based on the case reports indexed in MEDLINE/PubMed. Results: Twenty-five cases were included; 52 percent under two years of age. All cases presented splenomegaly and 84 percent hepatomegaly. Cytopenias were described in all patients: 100 prcent thrombocytopenia, 96 percent anemia, and 84 percent leukopenia or neutropenia. Hypertriglyceridemia and hypofibrinogenemia were found in 68 percent and 32 percent, respectively, and hyperferritinemia in 80 percent. Additionally, hemophagocytosis was documented in 84 percent, with Leishmania detection in 92 percent. All patients were treated against Leishmania: 80% with liposomal amphotericin B. regarding the treatment for hemophagocytic lymphohistiocytosis; corticosteroid were used in 36 percent, endovenous immunoglobulin in 28 percent, cyclosporine in 28 prcent and etoposide in 16 percent The complications reported included gastrointestinal hemorrhage (8 percent), disseminated intravascular coagulation (8 percent), autoimmune hemolytic anemia (12 percent), multiple-organ dysfunction/septic shock (12 prcent), petechial rash (16 percent), and four patients deceased. Variables such as fever (p=0.031), hemoglobin level (p=0.031), platelet count (p=0.0048), and ferritin (p=0.0072) were associated with mortality Conclusions: During visceral leishmaniasis, the hemophagocytic syndrome is a rare condition that mainly affects pediatric patients, but with excellent outcomes using liposomal amphotericin B. However, there is a lack of strong evidence to make a recommendation(AU)
Introducción: La leishmaniasis es una enfermedad tropical y subtropical con una elevada incidencia, dos millones de casos nuevos por año y 500 000 de leishmaniasis visceral. La linfohistiocitosis hemofagocítica es una complicación grave y rara de la leishmaniasis visceral. Objetivo: Describir las características clínicas de la linfohistiocitosis hemofagocítica asociada con leishmaniasis visceral. Métodos: Se realizó una revisión bibliográfica basada en los informes de casos indexados en MEDLINE/PubMed. Se identificaron 34 publicaciones; después de analizarlas en función de los criterios de inclusión se trabajó con 22 trabajos. Resultados: En los trabajos incluidos se informaron 25 casos; el 52 por ciento fueron pacientes menores de 2 años. Todos presentaron esplenomegalia y 84 por ciento hepatomegalia. Se describieron citopenias en todos los pacientes: 100 por ciento trombocitopenia, 96 por ciento anemia y 84 por ciento leucopenia o neutropenia. Se encontró hipertrigliceridemia e hipofibrinogenemia en 68 por ciento y 32 por ciento, respectivamente, e hiperferritinemia en 80 por ciento. Todos los pacientes fueron tratados contra leishmania, 80 por ciento con anfotericina B liposomal. Las complicaciones incluyeron: hemorragia gastrointestinal, coagulación intravascular diseminada, anemia hemolítica autoinmune, falla multiorgánica/shock séptico, erupción petequial y cuatro pacientes fallecieron. Conclusiones: En la leishmaniasis visceral, el síndrome hemofagocítico es una afección poco frecuente que afecta principalmente a pacientes pediátricos. Para el tratamiento, usando la anfotericina B liposomal se obtienen excelentes resultados; sin embargo, la evidencia es insuficiente para hacer una recomendación(AU)
Assuntos
Humanos , Masculino , Feminino , Recém-Nascido , Lactente , Pré-Escolar , Anfotericina B/uso terapêutico , Linfo-Histiocitose Hemofagocítica/epidemiologia , Doenças Negligenciadas/epidemiologia , Leishmaniose Visceral/diagnóstico , Leishmaniose Visceral/epidemiologiaRESUMO
Introduction: Haemophagocytic Lymphohistiocytosis (HLH), during HIV infection is a rare complication with a poor prognosis. There are few data on HLH within the Amazon region. The objective was to describe epidemiological, clinical and therapeutic features of HIV-related HLH in French Guiana. Methods: A retrospective analysis of adult HIV patients at Cayenne hospital with HLH between 2012 and 2015. A diagnosis of HLH was given if the patient presented at least 3 of 8 criteria of the HLH-2004 classification. Results: Fourteen cases of HLH were tallied during the study period. The mean age was 46 years with a sex ratio of 1.8. The most frequent etiology of HLH was an associated infection (12/14). Confirmed disseminated histoplasmosis, was found in 10 of 14 cases, and it was suspected in 2 other cases. The CD4 count was below 200/mm3 in 13/14 cases. An HIV viral load >100,000 copies/ml was observed in 13/14 cases. An early treatment with liposomal amphotericin B was initiated in 12/14 cases. The outcome was favorable in 12/14 of all cases and in 10/12 cases involving histoplasmosis. Case fatality was 2/14 among all cases (14.3%) et 1/10 among confirmed disseminated histoplasmosis with HLH (10%). During the study period 1 in 5 cases of known HIV-associated disseminated histoplasmosis in French Guiana was HLH. Conclusion: Histoplasmosis was the most frequent etiology associated with HLH in HIV-infected patients in French Guiana. The prognosis of HLH remains severe. However, a probabilistic empirical first line treatment with liposomal amphotericin B seemed to have a favorable impact on patient survival.
Assuntos
Infecções por HIV , Histoplasmose , Linfo-Histiocitose Hemofagocítica , Adulto , Guiana Francesa , Infecções por HIV/complicações , Histoplasmose/complicações , Histoplasmose/diagnóstico , Histoplasmose/tratamento farmacológico , Hospitais , Humanos , Linfo-Histiocitose Hemofagocítica/diagnóstico , Linfo-Histiocitose Hemofagocítica/epidemiologia , Pessoa de Meia-Idade , Estudos RetrospectivosRESUMO
BACKGROUND: The hemophagocytic syndrome is a serious complication of several systemic illnesses. OBJECTIVE: To define the characteristics of the hemophagocytic syndrome at a pediatric specialty hospital in Tuxtla Gutiérrez, Chiapas, Mexico; incidences, underdiagnosis and overdiagnosis, associated conditions, treatment, and prognosis were included. METHODS: 214 cases of probable hemophagocytic syndrome that were seen between January 2011 and May 2019 were analyzed. 26 patients diagnosed with hemophagocytic syndrome and 188 cases with suspicion of this entity and/or ferritin > 500 ug/L were included. The cases that met four or more criteria of the HFS (Histiocyte Society, 2004) were included in this study. RESULTS: Thirty-five cases were validated (fourteen were previously diagnosed, nine had suspicion, and twelve had ferritin > 500 µg/L). Neither twelve out of 26 of the cases that were previously diagnosed (46.2 % overdiagnosed). Of the 35 validated cases, 21 hadn't been diagnosed (60 % underdiagnosed) met the diagnostic criteria of the HFS. The annual occurrence was of 2.0/1000 egresses. The Epstein-Barr virus was involved in 42 % of the cases. The overall mortality was of 80 %. CONCLUSIONS: Hemophagocytic syndrome had been significantly underdiagnosed and overdiagnosed at the analyzed hospital. The clinical features allow early suspicion, diagnosis, and treatment. Specific and non-specific illnesses that were associated to hemophagocytic syndrome were identified.
Antecedentes: El síndrome hemofagocítico es una complicación grave que se observa en diversos padecimientos sistémicos. Objetivo: Conocer las características del síndrome hemofagocítico en el Hospital de Especialidades Pediátricas de Tuxtla Gutiérrez, Chiapas, México; se incluyó incidencia, subdiagnóstico y sobrediagnóstico, padecimientos asociados, tratamiento y pronóstico. Métodos: Se analizaron 214 casos probables de síndrome hemofagocítico atendidos entre enero de 2011 y mayo de 2019. Se incluyeron 26 pacientes con diagnóstico de síndrome hemofagocítico y 188 en los que se sospechaba esta entidad o con ferritina > 500 µg/L. Los casos en los que se cumplieron cuatro o más criterios de la Sociedad del Histiocito fueron incluidos en el estudio. Resultados: Se validaron 35 casos (14 con diagnóstico previo, nueve con sospecha y 12 con ferritina > 500 µg/L). No cumplieron con los criterios de la Sociedad del Histiocito, 12 casos diagnosticados previamente (sobrediagnóstico de 46.2 %). De los 35 validados, 21 no habían sido diagnosticados (subdiagnóstico de 60 %). La incidencia anual fue de 2.0/1000 egresos. El virus Epstein-Barr estuvo involucrado en 42 % de los casos. La mortalidad representó 80 %. Conclusiones: El síndrome hemofagocítico fue subdiagnosticado y sobrediagnosticado en el hospital estudiado. Las características clínicas permiten sospecharlo, diagnosticarlo y tratarlo oportunamente. Se identificaron padecimientos específicos y no específicos asociados a síndrome hemofagocítico.
Assuntos
Infecções por Vírus Epstein-Barr , Linfo-Histiocitose Hemofagocítica , Criança , Herpesvirus Humano 4 , Hospitais , Humanos , Linfo-Histiocitose Hemofagocítica/diagnóstico , Linfo-Histiocitose Hemofagocítica/epidemiologia , Uso Excessivo dos Serviços de SaúdeRESUMO
Various infectious diseases can hyper-stimulate the immune system, causing hemophagocytic syndrome (HPS). Little is known regarding the accuracy of diagnostic criteria and epidemiological triggering factors in the acquired immunodeficiency syndrome (AIDS) setting. We investigated the major infectious disease triggers of HPS in patients living with human immunodeficiency virus (HIV)/AIDS and determined the accuracy of bone marrow aspiration (BMA). The inclusion criteria were (i) confirmed HIV diagnosis, (ii) bone marrow aspiration, and (iii) a minimum of four HPS criteria. Patients were further classified into those with four presumed HPS criteria, or ≥ 5 confirmed criteria. The disease triggers, accuracy of bone marrow aspiration, and prognosis markers were examined. Presumed HPS was observed in 15/36 patients (41%), and confirmed HPS in 58% (n = 21). The major etiological triggers were infection with Mycobacterium (34%), Cytomegalovirus (14%), Cryptococcus neoformans (11%), and hematological or tumoral disease (11%). BMA demonstrated 93% specificity on screening diagnosis (odds ratio [OR] 12.7, 95% confidence interval [CI] 1.4-115.1, P = 0.01). Ferritin > 5000 ng/mL correlated with probability of death in univariate analysis (OR 6.00, 95% CI 1.33-27.05, P = 0.02). Ferritin performance as test of death probability presented area under the curve as 0.74 (95% CI 0.56-0.91, P = 0.016). However, neither cluster of differentiation for lymphocyte count nor HIV viral load correlated with patient deaths. Mycobacterium spp. and Cytomegalovirus were the main factors triggering HPS, followed by Cryptococcus neoformans, and hematological and tumoral diseases. High ferritin levels were associated with increased death probability. High specificity was noted with BMA.
Assuntos
Síndrome da Imunodeficiência Adquirida , Linfo-Histiocitose Hemofagocítica , Síndrome da Imunodeficiência Adquirida/epidemiologia , Síndrome da Imunodeficiência Adquirida/microbiologia , Síndrome da Imunodeficiência Adquirida/patologia , Síndrome da Imunodeficiência Adquirida/virologia , Adulto , Medula Óssea/metabolismo , Medula Óssea/microbiologia , Medula Óssea/patologia , Medula Óssea/virologia , Criptococose/epidemiologia , Criptococose/microbiologia , Criptococose/patologia , Criptococose/virologia , Cryptococcus neoformans , Citomegalovirus , Infecções por Citomegalovirus/epidemiologia , Infecções por Citomegalovirus/microbiologia , Infecções por Citomegalovirus/patologia , Infecções por Citomegalovirus/virologia , Feminino , HIV-1 , Humanos , Linfo-Histiocitose Hemofagocítica/epidemiologia , Linfo-Histiocitose Hemofagocítica/microbiologia , Linfo-Histiocitose Hemofagocítica/patologia , Linfo-Histiocitose Hemofagocítica/virologia , Masculino , Mycobacterium , Infecções por Mycobacterium/epidemiologia , Infecções por Mycobacterium/microbiologia , Infecções por Mycobacterium/patologia , Infecções por Mycobacterium/virologia , Estudos RetrospectivosRESUMO
BACKGROUND: Hemophagocytic lymphohistiocytosis (HLH) is a rare, potentially fatal disorder characterized by fever, pancytopenia, hepatosplenomegaly, and increased serum ferritin. HLH is being increasingly reported as a complication of dengue, a common tropical acute febrile illness. METHODOLOGY/PRINCIPAL FINDINGS: After a cluster of pediatric dengue-associated HLH patients was identified during the 2012-2013 dengue epidemic in Puerto Rico, active surveillance and a case-control investigation was conducted at four referral hospitals to determine the incidence of HLH in children and identify risk factors for HLH following dengue. Patients with dengue-associated HLH (cases) were matched by month of illness onset and admission hospital to dengue patients that did not develop HLH (controls). During 2008-2013, a total of 33 HLH patients were identified, of which 22 (67%) were associated with dengue and 1 died (dengue-associated HLH case-fatality rate: 4.5%). Two patients with dengue-associated HLH had illness onset in 2009, none had illness onset during the 2010 dengue epidemic, and 20 had illness onset during the 2012-2013 epidemic. Frequency of infection with either dengue virus (DENV)-1 or DENV-4 did not differ between cases and controls. Cases were younger than controls (median age: 1 vs. 13 years, p < 0.01), were hospitalized longer (18 vs. 5 days, p < 0.01), and were admitted more frequently to pediatric intensive care units (100% vs. 16%, p < 0.01). Cases had co-infection (18.2% vs. 4.5%, p = 0.04), recent influenza-like illness (54.5% vs. 25.0%, p = 0.01), and longer duration of fever (7 vs. 5 days; p < 0.01). Cases were more likely to have lymphadenopathy, hepatomegaly, splenomegaly, anemia, and elevated liver transaminases (p ≤ 0.02). CONCLUSIONS/SIGNIFICANCE: During this cluster of dengue-associated HLH cases that was temporally associated with the 2012-2013 epidemic, most patients with dengue-associated HLH were infants and had higher morbidity than dengue inpatients. Physicians throughout the tropics should be aware of HLH as a potential complication of dengue, particularly in patients with anemia and severe liver injury.