Safety of standardised treatments for haematologic malignancies as regards to testicular endocrine function in children and teenagers.

STUDY QUESTION: Does standardised treatments used in children and adolescents with haematologic malignancies, including acute lymphoblastic (ALL) or myeloid leukaemia (AML) and non-Hodgkin lymphoma (NHL), affect endocrine function of the developing testes? SUMMARY ANSWER: Therapy of haematologic malignancies do not provoke an overt damage of Sertoli and Leydig cell populations, as revealed by normal levels of anti-Müllerian hormone (AMH) and testosterone, but a mild primary testicular dysfunction may be observed, compensated by moderate gonadotropin elevation, during pubertal development. WHAT IS KNOWN ALREADY: Evidence exists on the deleterious effect that chemotherapy and radiotherapy have on germ cells, and some attention has been given to the effects on Leydig and Sertoli cells of the adult gonads, but information is virtually non-existent on the effects of oncologic treatment on testicular somatic cell components during childhood and adolescence. STUDY DESIGN, SIZE, DURATION: A retrospective, analytical, observational study included 97 boys with haematological malignancies followed at two tertiary paediatric public hospitals in Buenos Aires, Argentina, between 2002 and 2015. PARTICIPANTS/MATERIALS, SETTING, METHODS: Clinical records of males aged 1-18 years, referred with the diagnoses of ALL, AML or NHL for the assessment of gonadal function, were eligible. We assessed serum levels of AMH and FSH as biomarkers of Sertoli cell endocrine function and testosterone and LH as biomarkers of Leydig cell function. MAIN RESULTS AND THE ROLE OF CHANCE: All hormone levels were normal in the large majority of patients until early pubertal development. From Tanner stage G3 onwards, while serum AMH and testosterone kept within the normal ranges, gonadotropins reached mildly to moderately elevated values in up to 35.9% of the cases, indicating a compensated Sertoli and/or Leydig cell dysfunction, which generally did not require hormone replacement therapy. LIMITATIONS, REASONS FOR CAUTION: Serum inhibin B determination and semen analysis were not available for most patients; therefore, we could not conclude on potential fertility impairment or identify whether primary Sertoli cell dysfunction resulted in secondary depleted spermatogenesis or whether primary germ cell damage impacted Sertoli cell function. WIDER IMPLICATIONS OF THE FINDINGS: The regimens used in the treatment of boys and adolescents with ALL, AML or NHL in the past two decades seem relatively safe for endocrine testicular function; nonetheless, a mild primary testicular endocrine dysfunction may be observed, usually compensated by slightly elevated gonadotropin secretion by the pituitary in adolescents, and not requiring hormone replacement therapy. No clinically relevant risk factor, such as severity of the disease or treatment protocol, could be identified in association with the compensated endocrine dysfunction. STUDY FUNDING/COMPETING INTEREST(S): This work was partially funded by grants PIP 11220130100687 of Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET) and PICT 2016-0993 of Fondo para la Investigación Científica y Tecnológica (FONCYT), Argentina. R.A.R., R.P.G. and P.B. have received honoraria from CONICET (Argentina) for technology services using the AMH ELISA. L.A.A. is part-time employee of CSL Behring Argentina. The other authors have no conflicts of interest to disclose.

Haemophilia care in Latin America: Assessment and perspectives.

INTRODUCTION: The study is the first application of the Principles of Haemophilia Care for Europe (PHCE) in other regions of the world, specifically in Latin America. OBJECTIVE: To identify strengths in the care of haemophilia, and the aspects that should be improved. METHODS: The information was obtained through a questionnaire designed according to the PHCE and answered by specialists in mid-2016. The countries included were as follows: Argentina, Brazil, Chile, Colombia, Costa Rica, El Salvador, Mexico, Panama, Dominican Republic and Venezuela. RESULTS: In most countries, there is a central organization for haemophilia care supported by local groups. The existence of a national registry of people with haemophilia (PWH) was verified in eight countries. Centres of integrated care are located in large cities. In the majority of countries, there was no evidence of the participation of multiple actors in the decision-making. The supply of factor concentrates presents constraints, although it is reported as adequate in half of the countries. In most countries, home treatment is available under special conditions. In most countries, there are restrictions on the use of prophylaxis. The coordination of specialized and emergency services depends on each centre. Unrestricted treatment of inhibitors is performed in most countries. In all countries, there are human resources training programmes; however, clinical and health services researches are not widely developed. CONCLUSION: The study identifies the initial situation of principles of care, as well as the alternatives that must be implemented to achieve improvements in the quality of life of PWH in the region.

Skeletal involvement in Gaucher disease: An observational multicenter study of prognostic factors in the Argentine Gaucher disease patients.

Patients with Gaucher type 1 (GD1) throughout Argentina were enrolled in the Argentine bone project to evaluate bone disease and its determinants. We focused on presence and predictors of bone lesions (BL) and their relationship to therapeutic goals (TG) with timing and dose of enzyme replacement therapy (ERT). A total of 124 patients on ERT were enrolled in a multi-center study. All six TG were achieved by 82% of patients: 70.1% for bone pain and 91.1% for bone crisis. However, despite the fact that bone TGs were achieved, residual bone disease was present in 108 patients on ERT (87%) at time 0. 16% of patients showed new irreversible BL (bone infarcts and avascular osteonecrosis) despite ERT, suggesting that they appeared during ERT or were not detected at the moment of diagnosis. We observed 5 prognostic factors that predicted a higher probability of being free of bone disease: optimal ERT compliance; early diagnosis; timely initiation of therapy; ERT initiation dose ≥45 UI/kg/EOW; and the absence of history of splenectomy. Skeletal involvement was classified into 4 major phenotypic groups according to BL: group 1 (12.9%) without BL; group 2 (28.2%) with reversible BL; group 3 (41.9%) with reversible BL and irreversible chronic BL; and group 4 (16.9%) with acute irreversible BL. Our study identifies prognostic factors for achieving best therapeutic outcomes, introduces new risk stratification for patients and suggests the need for a redefinition of bone TG. Am. J. Hematol. 91:E448-E453, 2016. © 2016 Wiley Periodicals, Inc.

Hb Wilde and Hb Patagonia: two novel elongated beta-globin variants causing dominant beta-thalassemia.

We describe here the molecular and hematological characteristics of novel frameshift mutations in exon 2 of the HBB gene (in heterozygous state) found in two Argentinean pediatric patients with dominant ß-thalassemia-like features. In Hb Wilde, HBB:c.270_273delTGAG(p.Glu90Cysfs*67), we detected the deletion of the third base of the codon 89 (T) and the codon 90 (GAG), whereas in Hb Patagonia, HBB:c.296_297dupGT(p.Asp99Trpfs*59), the frameshift mutation was due to a duplication of a 'GT' dinucleotide after the second base of codon 98 (GTG). The Hb Patagonia and Hb Wilde mutations would result in elongated ß-globin chains with modified C-terminal sequences and a total of 155 and 157 amino acids residues, respectively. Based on bioinformatics and structural analysis, as well as protein modeling, we predict that the elongated ß-globins would affect the formation of the αß dimers and their stability, which would further support the mechanism for the observed clinical features in both patients.

Epstein-Barr virus (EBV) association and latency profile in pediatric Burkitt's lymphoma: experience of a single institution in Argentina.

The aim of this study is to characterize EBV expression and latency pattern in pediatric Burkitt's lymphoma in a single institution in Argentina. EBV-encoded RNA or protein was analyzed in 27 patients. EBERs was expressed in 37% of patients (29% of immunocompetent and 100% of immunosuppressed patients). EBV-positive cases were observed exclusively in patients younger than 5 years old. EBV association with immunocompetent patients exhibits the sporadic pattern in region under study, while its presence in patients infected with HIV was higher than described previously. EBV latency I profile was present in most of the patients, except for two immunosuppressed patients who displayed LMP1 expression.

Testicular dysfunction at diagnosis in children and teenagers with haematopoietic malignancies improves after initial chemotherapy.

Introduction: Hematopoietic malignancies are the most frequent type of cancer in childhood. Recent advances in cancer treatment have significantly improved survival until adulthood. There is an extensive literature on the effects of cancer treatment on the gonadal axis in adult survivors of childhood cancer mainly focused on sperm production, but scarce information exists on the immediate impact of cancer and its treatment in boys. Objectives: In this work, we determined the status of the hypothalamic-pituitary-testicular (HPT) axis function at diagnosis and the immediate impact of chemotherapy at the start of treatment in children and adolescents with hematopoietic malignancies. Subjects and methods: In a prospective study of 94 boys and adolescents with acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML) or non-Hodgkin lymphoma (NHL), we determined serum AMH, inhibin B and FSH to assess the gonadotrophin-Sertoli cell component of the HPT axis, and testosterone and LH to evaluate the gonadotrophin-Leydig cell component, at diagnosis and after 3 months of chemotherapy. Secondarily, the general health state was evaluated. Results: In prepubertal boys, at diagnosis, AMH, inhibin B and FSH were lower compared to the reference population, reflecting an FSH-Sertoli cell axis dysfunction. After 3 months of chemotherapy, all hormone concentrations increased. At pubertal age, at diagnosis, AMH and inhibin B were lower compared to the reference population for Tanner stage, with inappropriately normal FSH, suggesting a primary Sertoli cell dysfunction with insufficient gonadotrophin compensation. The LH-Leydig cell axis was mildly disrupted. After 3 months of chemotherapy, inhibin B and AMH were unchanged while median FSH levels rose to values that exceeded the reference range, indicating a significant impairment of Sertoli cell function. Testosterone normalized concomitantly with an abnormal LH elevation reflecting a compensated Leydig cell impairment. General health biomarkers were impaired at diagnosis and improved after 3 months. Conclusion: The HPT axis function is impaired in boys with hematopoietic malignancies before the initiation of chemotherapy. There is a primary testicular dysfunction and a concomitant functional central hypogonadism that could be due to an impaired overall health. The HPT axis function improves during the initial 3 months of chemotherapy concomitantly with the general health state. However, in pubertal boys the dysfunction persists as shown by elevated gonadotropin levels after 3 months.

Treatment and outcome of childhood cerebral sinovenous thrombosis.

OBJECTIVE: To test our hypothesis that anticoagulation is associated with better neurologic outcomes in childhood cerebral sinovenous thrombosis (CSVT), we analyzed treatment and outcomes in a population of 410 children from the International Pediatric Stroke Study (IPSS). METHODS: We included patients enrolled in the IPSS registry with a diagnosis of CSVT at age >28 days with radiologic confirmation, in isolation or with concomitant arterial ischemic stroke. The primary outcome was the neurologic status at discharge. We defined unfavorable outcome as severe neurologic impairment or death at discharge. The Pediatric Stroke Outcome Measure was used for long-term outcome in those with follow-up. Predictors of anticoagulation use and outcome were analyzed by logistic regression. RESULTS: Most children (95%) had identifiable risk factors, and 82% received anticoagulation. Shift analysis demonstrated better outcomes at discharge in children who were anticoagulated, and this persisted with longer-term outcomes. In multivariable analysis, anticoagulation was significantly associated with favorable outcomes (adjusted odds ratio [aOR] unfavorable 0.32, p = 0.007) whereas infarct was associated with unfavorable outcome (aOR unfavorable 6.71, p < 0.001). The trauma/intracranial surgery was associated with a lower odds of anticoagulation use (aOR 0.14, p < 0.001). CONCLUSIONS: Within the IPSS registry, children with risk factors of trauma or intracranial surgery were less likely to receive anticoagulation for CSVT. Anticoagulation was associated with a lower odds of severe neurologic impairment or death at hospital discharge, but this finding is limited and needs further confirmation in randomized, controlled, prospective studies.

Outcome of Infants Younger Than 1 Year With Acute Lymphoblastic Leukemia Treated With the Interfant-06 Protocol: Results From an International Phase III Randomized Study.

PURPOSE: Infant acute lymphoblastic leukemia (ALL) is characterized by KMT2A (MLL) gene rearrangements and coexpression of myeloid markers. The Interfant-06 study, comprising 18 national and international study groups, tested whether myeloid-style consolidation chemotherapy is superior to lymphoid style, the role of stem-cell transplantation (SCT), and which factors had independent prognostic value. MATERIALS AND METHODS: Three risk groups were defined: low risk (LR): KMT2A germline; high risk (HR): KMT2A-rearranged and older than 6 months with WBC count 300 × 109/L or more or a poor prednisone response; and medium risk (MR): all other KMT2A-rearranged cases. Patients in the MR and HR groups were randomly assigned to receive the lymphoid course low-dose cytosine arabinoside [araC], 6-mercaptopurine, cyclophosphamide (IB) or experimental myeloid courses, namely araC, daunorubicin, etoposide (ADE) and mitoxantrone, araC, etoposide (MAE). RESULTS: A total of 651 infants were included, with 6-year event-free survival (EFS) and overall survival of 46.1% (SE, 2.1) and 58.2% (SE, 2.0). In West European/North American groups, 6-year EFS and overall survival were 49.4% (SE, 2.5) and 62.1% (SE, 2.4), which were 10% to 12% higher than in other countries. The 6-year probability of disease-free survival was comparable for the randomized arms (ADE+MAE 39.3% [SE 4.0; n = 169] v IB 36.8% [SE, 3.9; n = 161]; log-rank P = .47). The 6-year EFS rate of patients in the HR group was 20.9% (SE, 3.4) with the intention to undergo SCT; only 46% of them received SCT, because many had early events. KMT2A rearrangement was the strongest prognostic factor for EFS, followed by age, WBC count, and prednisone response. CONCLUSION: Early intensification with postinduction myeloid-type chemotherapy courses did not significantly improve outcome for infant ALL compared with the lymphoid-type course IB. Outcome for infant ALL in Interfant-06 did not improve compared with that in Interfant-99.

Clinical consequences of interrupting enzyme replacement therapy in children with type 1 Gaucher disease.

OBJECTIVE: To document the effects of interrupting enzyme replacement therapy (ERT) for at least 1 year in a group of children with type 1 Gaucher disease. STUDY DESIGN: All children with type 1 Gaucher disease who were treated at 2 pediatric centers and who were required to suspend ERT for at least 1 year were studied before, during, and after treatment interruption. Hemoglobin and platelet levels, organomegaly, growth, and bone manifestations were monitored. RESULTS: Five of 32 children experienced treatment interruptions. Before ERT, all children had splenomegaly, 4 children had hepatomegaly, 4 children had growth retardation, 3 children had skeletal manifestations, 3 children had thrombocytopenia, and 1 child had anemia. After 1 to 7 years of ERT, all children were growing normally, none had skeletal manifestations, organomegaly had decreased or disappeared, and hematologic features had improved. After 15 to 36 months of ERT interruption, splenomegaly recurred or worsened in all children, hepatomegaly and hematologic features recurred or worsened in 4 children, serious bone manifestations developed in 4 children, and 3 children experienced growth retardation. After at least 11 months of resumed ERT in 4 children, 2 had hepatomegaly, 2 had splenomegaly, and all had persistent skeletal manifestations. CONCLUSION: Interruption of ERT in children with type 1 Gaucher disease should be avoided because it can cause recurrent organomegaly, growth delays, and skeletal manifestations that do not resolve after treatment reinstatement.

Assessment of Epstein-Barr virus association with pediatric non-hodgkin lymphoma in immunocompetent and in immunocompromised patients in Argentina.

CONTEXT: Epstein-Barr virus (EBV) has been classically associated with 3 malignancies, Burkitt lymphoma, B-cell lymphoproliferative syndromes, and nasopharyngeal carcinoma, and more recently with Hodgkin disease, T-cell lymphomas, and gastric and breast carcinomas, as well as with leiomyosarcoma and leiomyoma associated with immunosuppression. OBJECTIVE: To compare EBV expression in Argentine tumor samples with those reported elsewhere, we analyzed EBV expression in an Argentine pediatric population with non-Hodgkin lymphoma and correlated these results with clinical course and outcome. METHODS: We studied EBV presence by latent membrane protein-1 protein labeling by immunohistochemistry, by in situ hybridization, and by polymerase chain reaction for Epstein-Barr-encoded RNAs (EBERs) in formalin-fixed and paraffin-embedded non-Hodgkin lymphoma tissue samples (collected retrospectively) from 32 pediatric patients at Ricardo Gutiérrez Children's Hospital from 1993 to 2000. RESULTS: Eight out of the 32 (25%) non-Hodgkin lymphoma cases showed latent membrane protein-1 and EBERs by in situ hybridization positive staining in tumor cells. Among EBERs and latent membrane protein-1-positive cases, there were 5 immunocompromised patients, with either human immunodeficiency virus infection or primary immunodeficiency. The EBERs in situ hybridization results were confirmed by EBERs polymerase chain reaction in good-quality DNA from 11 samples, with 3 proving positive and 8 negative. CONCLUSIONS: The association of EBV with non-Hodgkin lymphoma in the Argentine pediatric population was low (25%), and this figure rose to 100% when only the immunocompromised patients subgroup was considered, confirming that the virus is probably a cofactor in the lymphomagenesis of some but not all pediatric non-Hodgkin lymphoma. So far, no differences in clinical outcome are discernible between EBV-positive and EBV-negative non-Hodgkin lymphoma patients.

Guías de Vacunación en Huéspedes Especiales / Guidelines for the Vaccination of Special Hosts

Los niños con alteración de su sistema inmunológico son más vulnerables ante las infecciones que el resto de la población. Una de las formas de protegerlos de infecciones graves es a través de la vacunación, deben ser correctamente evaluados al planear los esquemas a fin de establecer los riesgos vs. los beneficios que implican inmunizarlos. El rol del médico pediatra y del médico especialista trabajando en equipo es fundamental, para que puedan beneficiarse con vacunas y esquemas especiales que requieran por su patología de base. Una protección óptima de estos pacientes incluye además la adecuada inmunización de los convivientes y del equipo médico tratante. La inmunización de los huéspedes especiales es una situación clínica compleja que requiere un análisis exhaustivo personalizado en cada caso, debido a las diferentes características de estos pacientes con enfermedades crónicas y/o inmunosuprimidos, los diversos grupos y muchos tipos de terapias inmunosupresoras que se están desarrollando y utilizando en un número cada vez mayor. Es fundamental el trabajo en equipo del médico especialista y el pediatra de cabecera para lograr el mejor control de las enfermedades inmunoprevenibles en estos pacientes de tan alta complejidad

Children with weakened immune systems are more vulnerable to infections than the rest of the population. One of the ways to protect them against serious infections is vaccination; they must be correctly evaluated when planning schedules in order to define the risks versus the benefits involved by their immunization. The role of pediatricians and medical specialists working as a team is fundamental, so that patients can benefit from vaccines and special schedules that they may require due to their underlying pathologies. Optimal protection of these patients also includes the adequate immunization of household members and their treating medical teams. The immunization of special hosts is a complex clinical situation that requires an exhaustive personalized case-by-case analysis, due to the different characteristics of these patients who have chronic diseases and / or are immunosuppressed, the various groups and many types of immunosuppressive therapies that are being developed and increasingly used. The teamwork of specialists and family pediatricians is essential to achieve the best control of immuno-preventable diseases in these highly complex patients

Peripheral venous thrombosis in children and adolescents with adipsic hypernatremia secondary to hypothalamic tumors.

OBJECTIVE: To determine the clinical presentation and laboratory follow-up in patients with the syndrome of adipsic hypernatremia complicated with a peripheral thrombosis event. METHODS: Report of 3 patients (6-19 years old) with chronic hypernatremia with sustained difficulties to normalize their serum osmolality levels. RESULTS: During post-surgical management the 3 patients developed a peripheral venous thrombotic event as a complication of their chronic hyperosmolality. CONCLUSIONS: Chronic hypernatremia in patients with prolonged immobilization is associated with an increased risk for development of deep venous thrombosis.

Transplante hematopoyetico alogenico con celulas progenitoras extraidas de la sangre periferica / Allogenic hematopoietic transplantation with peripheral blood progenitor cells

Cinquenta y tres pacientes (ptes) recibieron transplante alogénico con células progenitoras extraídas de la sangre periférica (PSP); 25 ptes eran mujeres y 28 varones. La edad media del grupo fue de 20 años, (rango 2-550. Los diagnósticos fueron leucemia mieloide aguda (LMA) en 16 ptes, leucemia linfoblástica aguda (LLA) en 15, leucemia mieloide crónica (LMC) en primera fase crónica en 12, aplasia medular en 4, síndrome mielodisplásico en 3 y Enfermedad de Hodgkin en recaída luego de trasplante autólogo, talasemia mayor y síndrome de Hunter en 1 caso, respectivamente. Los acondicionamientos fueron en 38 ptes radioterapia corporal total 1200 cGy y ciclofosfamida 120 mg/kg EV; en 10 ptes busulfán 16 mg/kg y ciclosfosfamida 120 mg/kg EV, 3 ptes radioterapia linfoide total (RLT) y ciclosfosfamida, 2 ptes con otros agentes quimioterápicos. Los PSP se infundieron a través de un catéter sin ningún tipo de manipulación. La profilaxis de injerto vs huésped (EICH) se realizó con ciclosporina y metotrexato. Los donantes fueron familiares con HLA compatibles 6/6 y un caso 5/6 de los antígenos. Previo a la extración de PSP, recibieron G-DSF (filgrastim) 10 mug/kg/día sc. Cuatro días. El quinto día se realizó la féresis, en los primeros treinta casos se hizo la extracción adicional de médula ósea. Las medias de CD34, CD3, CD4, CD8, CD56, CD19 (cel x 10(6)/kg de peso) 4.12; 4.59; 2.57; 1.9; 0.55 y 0.68 respectivamente. La mediana de recuperación de nuetrófilos > 500 se obtuvo el día = 11 y de plaquetas > 20000, + 13. El tiempo de internación fue de 26 días (18-39) y la media de días con antibióticos parenterales fue de 12.2 días (5-45). La mortalidad relacionada al trasplante fue del 15 por ciento. EICH aguda se observó en el 43.4 por ciento de los ptes, con sólo 5 ptes con EICH aguda grado III o IV. En 43 ptes se pudo evaluar la aparición de EICH crónica con un tiempo medio de seguimiento de 18 meses (4-39). En la presente experiencia el trasplante de PSP alogénicos mantuvo una aceptable incidencia de EICH crónica; dados los recientes informes de aumento de esta complicación, parece lógico desaconsejar el uso de PSP en patología no maligna en la que no importaría la potencia del efecto injerto versus leucemia.

Lupus eritematoso sistémico de inicio juvenil: detección de enfermedad vascular y factores de riesgo asociados / Childhood onset systemic lupus erythematous detection of vascular disease and associated risk factors

Durante las dos últimas décadas, se ha comunicado una alta tasa de mortalidad por enfermedad cardiovascular en pacientes con lupus eritematoso sistémico (LES), relacionada con la presencia de aterosclerosis prematura y enfermedad arterial coronaria. Objetivos: 1) determinar la prevalencia de anormalidades de la perfusión miocárdica en pacientes juveniles con LES, 2) determinar la frecuencia de aterosclerosis carotídea subclínica, 3)analizar los factores de riesgo asociados a ellas. Métodos: se incluyeron en forma consecutiva pacientes con LES (ACRï82) de inicio juvenil. Se analizaron variables clínicoserológicas y terapéuticas, puntuación de SLEDAI, antecedente de enfermedad coronaria, presencia de nefritis, hipertensión y factores de riesgo asociados con el desarrollo de aterosclerosis. En todos los pacientes, se realizó SPECT gatillada, electrocardiograma y ecocardiograma bidimensional. El engrosamiento carotídeo intimal-medial (CIM) fue medido a través de ecografía bidimensional modo B en pacientes y controles sanos apareados por sexo y edad. Análisis estadístico: se utilizó la prueba de ji2, la prueba t de Student y el análisis de regresión logística. Resultados: Fueron evaluados 38 pacientes con LES de comienzo juvenil, con una edad media al estudio de 16,2 años (DE3,8), y un tiempo medio de duración de la enfermedad de 48,9 meses (DE36). Todos los pacientes se hallaban libres de síntomas cardiológicos al momento del estudio. Diez (26,8 por ciento) presentaron anormalidades de la perfusión miocárdica; en 6, la isquemia fue significativa. Ocho de 34 (23,5) por ciento tenían un CIM mayor que los controles (0,57 mm vs 0,43; p= 0,0003). A pesar de que la proteinuria en rango nefrótico y la hipertensión fueron más frecuentes en pacientes con CIM patológico (p= 0,03), en el modelo de análisis multivariado, se halló que la duración de la enfermedad y la hiperfibrinogenemia fueron los únicos factores de riesgo asociados a anormalidades de la perfusión y aterosclerosis carotídea (OR 1,1 y 6,6, respectivamente, p= 0,03). Conclusión: la aterosclerosis subclínica y la enfermedad coronaria son un hallazgo y una complicación frecuentes en pacientes juveniles con LES