Extended half-life recombinant factor VIII treatment of hemophilia A in Brazil: an expert consensus statement

Introduction Treatment of hemophilia A in Brazil is offered to all patients at no cost. However, several unmet medical needs exist. Method In this study, we applied the Delphi method to discuss with seven hemophilia A specialists the challenges that patients and the health system face regarding hemophilia A treatment and opportunities for improvement. Results A consensus was obtained regarding the number of weekly infusions and patient adherence to treatment. The bleeding profile, unfavourable pharmacokinetics (PKs), low adherence and high daily activity were patient profiles that would benefit from using the extended half-life (EHL) recombinant factor VIII (rFVIII). The advantages of treatment with the EHL rFVIII were the lower number of infusions per week, which could increase patient adherence and decrease the risk of bleeds, due to a more constant plasma level, a lower value. Additionally, the EHL rFVIII could improve quality of life, especially in patients with high daily activity, such as adolescents and young adults. The panelists mentioned that EHL rFVIII, if available, could be offered first to the priority group (adolescents between 12 and 19 years old), followed by adults (20 to 64 years old) and elderly people (over 65 years old). Conclusion In summary, the EHL rFVIII offers the optimal prophylaxis by decreasing the dose frequency, increasing the treatment adherence and improving the QoL, without compromising safety and efficacy.

Clinical observation on uterine and breast development in girls with Turner syndrome with the estrogen hormone replacement therapy / 中国实用儿科杂志

OBJECTIVE: To research an appropriate estrogen therapy for in the pubertal development in Turner syndrome(TS)achievedbyestradiolvalerate.METHODS: In 57 TS girls of no spontaneous puberty or puberty arrest,we retrospectively studied pubertalstageanduterinedimensionduringtheestrogenreplacementtherapy.Datafrompatientrecordswascollected,described thepubertaldevelopingprocedure,and compared in groups which grouped by estrogen dosage to detect an appropriate dosage andthatcanleadabetterbreastanduterinedevelopment.RESULTS: The median age at start of puberty induction was 15.00 years,witharangeof11.5-21.0 years.(1)Breast development:Breast development to Tanner stage B2 was achieved in 0.29(0.25-0.33)years,stage B3 in 0.75(0.46,1.08)years,stage B4 in 2.20(0.92,3.08)years and B5 in 3.67(1.71,4.44)years.(2)Uterine development:The uterine volume and length in TS girls before treatment was 0.51(0.14,0.86)ml and 1.89(1.23,2.18)cm. We groupedthepatientsofTannerstageB2 ingroupsofestrogendosage≤0.5 mg/dand>0.5 mg/d and the uterine dimension and weightshowednodifference.Whenthepatientsweregroupedasgroupsofdosage<1.0 mg/d and group of dosage≥1.0 mg/d in stageB3,the uterine indexes in lower dosage group were less than group with larger dosage. When they were grouped as groups ofdosage<1.5 mg/d and ≥1.5 mg/d,the uterine volume 6.96(3.15-11.00)ml in lower dosage group was smaller than that in group withlargerdosage.CONCLUSION: During estrogen treatment in TS girls,normal breast development can be achieved. In a clinical setting,the uterine volume and length under pubertal induction developed properly with the breast stages progressing. when the breastdevelopedtostageB2,the uterine development was more dependable on estrogen. We recommend a low daily beginning estrogendosageuntilstageB2,which can be increased gradually after B2 to speed up the uterine development.

Tratamiento de la púrpura fulminans neonatal. Reporte de caso y revisión de la literatura / Treatment for neonatal fulminans purpura. Case report and literature review

Resumen La púrpura fulminans (PF) neonatal es un estado de hipercoagulabilidad poco frecuente pero grave. Su presentación clínica es súbita con lesiones purpúricas-necróticas que pueden dejar secuelas permanentes o incluso tener una evolución fatal. Se caracteriza por trombosis en la microcirculación de la piel acompañada de hemorragia perivascular. Los sitios más afectados son las extremidades pélvicas, torácicas o las zonas de presión. La alteración funcional más común es el defecto de la proteína с que fisiológicamente regula la coagulación, el defecto puede ser de causa primaria o secundaria. Caso clínico: Recién nacido varón con 8 días de vida extrauterina que presenta súbitamente rechazo a la vía oral, irritabilidad y fiebre de 39 °С. Dos días después es hospitalizado por deshidratación y rechazo a la vía oral. Al ingreso no se documentó fiebre o foco infeccioso. A las 24 horas presentó lesiones purpúricas-necróticas en el pie derecho. Se realizó un ultrasonido Doppler que confirmó trombosis venosa y arterial. Los dímeros Deran positivos. Se dio tratamiento con plasma fresco congelado (PFC), anticoagulante y antiplaquetario con buena respuesta. Conclusión: La PF es un estado protrombótico grave que requiere un diagnóstico y tratamiento oportunos para mejorar el pronostico.

Abstract Neonatal Purpura Fulminans (PF) is an infrequent hypercoagulable state but very severe. Its clinical manifestation is sudden with purpuric-necrotic injuries. It can leave permanent sequels oreven have a fatal evolution. It is characterized by thrombosis in the skin's microcirculation, accompanied with perivascular hemorrhage. The most affected areas are the pelvic and thoracic limbs, and pressure zones. The most common molecular alteration is the protein с defect, which physiologically regulates coagulation; the defect can be of a primary or secondary cause. Case report: A male newborn with 8 days of extrauterine life suddenly presents oral rejection, irritability and a 39° с fever. Two days later, he was hospitalized for dehydration and oral rejection. He didn't show signs of fever or infection at the time of his admission. Twenty-four hours after his entry, he presented purpuric-necrotic injuries in the right foot, hence, he was diagnosed with purpura fulminans. D-dimer studies and doppler ultrasound were taken. They confirmed venous and arterial thrombosis. The treatment was initiated with fresh frozen plasma, an anticoagulant and an antiplatelet, with a good response. Conclusion: PF is a serious hypercoagulable state that requires an early diagnosis and therapy to improve the outcome.

Tratamiento sustitutivo en la insuficiencia suprarrenal crónica / Replacement treatment for chronic adrenal failure

La insuficiencia suprarrenal crónica es una enfermedad que se caracteriza por el déficit de las hormonas de la corteza adrenal. Necesita tratamiento sustitutivo de por vida para lograr suplir ese déficit y así poder desarrollar una vida normal y con calidad. Para el éxito del tratamiento sustitutivo es muy importante conocer sus pautas y variantes, lo que resulta un arma en el trabajo diario de los galenos. Conocer las tendencias actuales resulta algo imprescindible, por lo que el propósito del siguiente trabajo es revisar las diferentes variantes del tratamiento que se pueden usar en este grupo de enfermos(AU)

Chronic adrenal failure is a disease characterized by shortage of adrenal cortex hormones. It requires lifelong replacement treatment to overcome this shortage in order to enjoy quality normal life. For the replacement treatment to be successful, it is very important to learn about its guidelines and variants, which is a useful tool in the daily work of physicians. Knowing the present trends is indispensable; therefore, the objective of this paper was to review the different treatment variants that may be used in this group of patients(AU)

Normativas de diagnóstico y tratamiento del déficit de alfa-1 antitripsina / Guidelines on Diagnosis and Treatment of Alpha-1 Antitrypsin Deficiency

El déficit de alfa-1 antitripsina (AAT) es una condición hereditaria rara y raramente diagnosticada en todo el mundo, incluida Argentina. El infradiagnóstico es fundamentalmente debido a que muchos médicos desconocen su existencia, diagnóstico y tratamiento. Por ello, la Asociación Argentina de Medicina Respiratoria encomendó a un grupo de expertos la elaboración de la presente normativa. La AAT es una glicoproteína secretada por el hígado, muy abundante en sangre, tejidos y fluidos corporales, cuya función principal consiste en inhibir la elastasa del neutrófilo y otras serin proteasas, confiriendo al suero humano más del 90% de su capacidad antiproteasa. El déficit de AAT deriva de mutaciones del gen de la SERPINA1, y se manifiesta clínicamente por enfisema pulmonar, cirrosis hepática y, con menor frecuencia, por paniculitis, vasculitis sistémicas y posiblemente otras enfermedades. El déficit grave de AAT afecta mayoritariamente a individuos de raza caucasiana y tiene su máxima prevalencia (1:2.000-1:5.000 individuos) en el norte, oeste y centro de Europa. En EEUU y Canadá, la prevalencia es de 1: 5.000-10.000, y es 5 veces menor en países latinoamericanos, incluida Argentina, donde se estima que puede haber unos 18.000 individuos con genotipos deficientes graves SZ y ZZ, la inmensa mayoría sin diagnosticar. Sospechar la enfermedad resulta clave para medir la concentración sérica de AAT y completar el diagnóstico con la determinación del fenotipo o genotipo ante concentraciones bajas. La detección de casos permite la puesta en práctica del consejo genético, el chequeo de familiares consanguíneos y, en casos seleccionados, la aplicación de terapia sustitutiva.

The alpha-1 antitrypsin (AAT) deficiency is a rare hereditary condition which is rarely diagnosed in the world, including Argentina. Underdiagnosis is mainly due to lack of knowledge of its diagnosis and treatment by many physicians. For this reason, the Argentine Association of Respiratory Medicine convened a group of experts to develop the present guidelines. AAT is a glycoprotein secreted by the liver; it reaches high levels in blood, body tissues and fluids. Its main function is to inhibit the neutrophil elastase and other serum proteases providing 90% of human serine antiprotease activity. The AAT deficiency is produced by mutations of the SERPINA1 gene. Its clinical manifestations are pulmonary emphysema, liver cirrhosis, and less often panniculitis, systemic vasculitis and possibly other conditions. The severe AAT deficiency affects mainly Caucasian individuals. The highest prevalence, ranging from 1 in 2000 to 1 in 5000 population is observed in northern, western and central Europe. In the USA and Canada, the prevalence varies from 1 in 5000 to 1 in 10000 population. It is 5 times less frequent in Latin American countries. It is estimated that in Argentina there may be 18000 cases with severe deficiency of SZ y ZZ genotypes, most of them undiagnosed. It is crucial to suspect the disease in order to measure the serum AAT concentration, and, if the concentrations are low, to confirm the diagnosis with the phenotype or genotype determinations. Case detection allows genetic advice, control of blood-related relatives and in selected cases, replacement therapy.

Home infusion program for Fabry disease: experience with agalsidase alfa in Argentina / Programa de infusión domiciliaria para la enfermedad de Fabry: experiencia con agalsidasa alfa en la Argentina

Fabry disease is an X-linked lysosomal storage disorder caused by inherited deficiency of the enzyme α-galactosidase A. Enzyme replacement treatment using agalsidase alfa significantly reduces pain, improves cardiac function and quality of life, and slows renal deterioration. Nevertheless, it is a life-long treatment which requires regular intravenous infusions and entails a great burden for patients. Our objective was to evaluate retrospectively the safety and tolerability of the home infusion of agalsidase alfa in patients with Fabry disease in Argentina. We evaluated all the patients with Fabry disease who received home infusion with agalsidase alfa 0.2 mg/kg between January 2005 and June 2011. The program included 87 patients; 51 males (mean age: 30 years) and 36 females (mean age: 34 years). A total of 5229 infusions (mean: 59 per patient; range: 1-150) were administered. A total of 5 adverse reactions were seen in 5 patients (5.7% of patients and 0.9% of the total number of infusions). All were mild in severity and resolved by reducing the rate of infusion and by using antihistaminics. All these 5 patients were positive for IgG antibodies, but none of them presented IgE antibodies and none suffered an anaphylactic shock. In our group 18 patients were switched from agalsidase beta to agalsidase alfa without complications. Home infusion with agalsidase alfa is safe, well tolerated and is associated to high compliance.

La enfermedad de Fabry es un trastorno de almacenamiento lisosomal hereditario ligado al cromosoma X ocasionado por el déficit de la enzima alfa galactosidasa A. La terapia de reemplazo enzimático utilizando agalsidasa alfa reduce significativamente el dolor, mejora la función cardíaca y la calidad de vida y enlentece el deterioro renal. Sin embargo, es un tratamiento de por vida que requiere infusiones intravenosas regulares y supone una gran carga para los pacientes. Nuestro objetivo fue evaluar retrospectivamente la tolerabilidad y la seguridad del procedimiento de infusión domiciliaria de agalsidasa alfa en pacientes con enfermedad de Fabry en Argentina. Evaluamos a todos los pacientes con enfermedad de Fabry que recibieron infusiones domiciliarias de 0.2 mg/kg de agalsidasa alfa entre enero del 2005 y junio del 2011. El programa incluyó 87 pacientes; 51 hombres (edad media: 30 años) y 36 mujeres (edad media: 34 años). Se administraron un total de 5229 infusiones (media: 59 por paciente; rango: 1-50). Se observaron un total de 5 reacciones adversas en 5 pacientes (5.7% de los pacientes y 0.9 % del número total de infusiones). Todas fueron de gravedad leve y se resolvieron reduciendo la velocidad de la infusión o usando antihistamínicos. Los 5 pacientes fueron positivos para anticuerpos IgG, pero ninguno presentó anticuerpos IgE o sufrió un shock anafiláctico. En nuestro grupo, 18 pacientes fueron cambiados de agalsidasa beta a agalsidasa alfa sin complicaciones. La infusión domiciliaria de agalsidasa alfa es segura, bien tolerada y logra una alta adherencia al tratamiento.

Treatment of infections in patients with primary immunodeficiency disease / 中国小儿急救医学

Primary immunodeficiency disease (PID) is a heterogeneous group of congenital disorders of the immune system.The impaired immune response is caused by defect of immune active cells and moleculars,which results in increased susceptibility to pathogens.Recurrent infection is the predominant presenting complaint for patients with PID.Early diagnosis,immunoglobulin replacement therapy,antimicrobial treatment,haematopoietic stem cell transplantation and gene therapy,genetic conselling and prenatal diagnosis will help to prevent and control infections in patients with PID.In addition,we should strengthen the education of paediatricians,improve awareness about PID and collaboration across different centers to advance the diagnosis and management of PID in China and save the life of patients at the maximum limit.

Progress in Turner syndrome / 国际儿科学杂志

Turner Syndrome is a sex chromosome disease associated with loss of an entire sex chromosome or a portion of the X chromosome containing the tip of its short arm.The common clinical features are short stature,cardiovascular disease and gonadal dysgenesis.Short stature is due to the impaired response to endogenous GH and SHOX ( short-stature homeobox ) haploinsufficiency.Congenital heart disease and coronary heart disease,especially the aortic aneurysm,made higher mortality in Turner syndrome.Treatment for short stature are GH and treatment for gonadal dysgenesis is gonadal hormone replacement.New studies demonstrated that adult height could be maximized if GH therapy begun at a young age with early,ultra-low-dose estrogen in girls with Turner syndrome.

The Effectiveness of Short-Term Sequential Combined Hormonal Replacement Therapy Augmentation of Selective Serotonin Reuptake Inhibitor in Postmenopausal Women with Depression: Pilot Study / 대한정신약물학회지

OBJECTIVES: Estrogen may be useful to manage depression. Some studies have suggested that treatment using antidepressant medications augmented with estrogen can be more effective than using antidepressant medication alone. However, data about the estrogen augmentation of selective serotonin reuptake inhibitor (SSRI) medication is insufficient. We investigated the effect of hormonal replacement treatment (HRT) as an augmentation in postmenopausal women with depression who were already being treated with SSRIs. METHODS: This was an 8-week prospective, open trial study. The subjects were 13 patients who met the DSM-IV criteria for major depressive disorder or dysthymia. The menses of all subjects had ceased for at least one year, and all subjects had serum levels of follicular stimulating hormone (FSH) greater than 40 mIU/mL. All subjects were already taking sertraline (50-150 mg) or paroxetine (20-30 mg); during the study they received sequential combined hormone replacement treatment (1.25 mg estrogen +5 mg medroxyprogesterone). Subjects continued their SSRI medication at their original dosages throughout the 8-week study. Mood and anxiety symptoms were measured with the Beck Depression Inventory (BDI) and the State-Trait Anxiety Inventory (STAI). Menopause-related symptoms were assessed using the Women's Health Questionnaire (WHQ). Overall clinical symptoms were also assessed using the Symptom Checklist 90-Revised (SCL-90-R). Serum levels of luteinizing hormone (LH), FSH, prolactin, estradiol, and progesterone were measured. Measurements were conducted at three times: baseline, four weeks, and endpoint. RESULTS: The subjects' mean age was 53.54+/-5.38 years and mean postmenopausal duration was 4.46+/-3.67 years. During the HRT, BDI and Trait Anxiety Inventory scores decreased significantly. On the WHQ subscales, scores for somatic symptoms, vasomotor symptoms, sexual behavior, and sleep problems were significantly improved. Hormonal levels of LH, FSH, and estradiol changed significantly. Menopausal duration was significantly correlated with changes in each assessment: somatic symptoms (r=-0.583, p=0.037), anxiety symptoms (r=-0.623, 0.023), WHQ depressive symptoms (r=-0.586, p=0.035), depression (r=-0.584, p=0.036), global severity index (r=-0.642, p=0.018), and positive symptom distress index (r=-0.592, p=0.033) of SCL-90-R. CONCLUSION: The results suggest that HRT may augment the antidepressant response to SSRIs in postmenopausal women with depression. The treatment effect of augmentation by HRT seems to be influenced by menopausal duration. Therefore, further controlled studies should be conducted to test estrogen augmentation of antidepressants, dependent on the duration of menopause.