José Tomás Ramos Amador

Impact of highly active antiretroviral therapy on the morbidity and mortality in Spanish human immunodeficiency virus-infected children.

Background. Highly active antiretroviral therapy (HAART) slows the progression of HIV disease and lowers mortality and morbidity in adults. The impact on the disease course in children has not been still completely elucidated. Furthermore the effect of HAART on organ-specific complications of HIV is unknown. Objectives. To assess the effect of HAART on the progression of HIV infection, mortality, organ-specific complications, number of infections and hospitalizations in HIV-1-infected children. Patients and methods. Records of HIV-1-infected children were reviewed in a large referral pediatric hospital. Patients were divided into three groups: children who did not receive antiretroviral therapy (Group 1); children who received mono- or bitherapy (Group 2); and patients who received HAART (Group 3). Endpoints analyzed were progression to AIDS and mortality among AIDS patients and overall. Results. One hundred seven children have been evaluated. Actuarial survival at 5 years of age was 33% in Groups 1 and 2 compared with 100% in Group 3 (P < 0.01). At 5 years of age, the proportion of children progressing to AIDS was 76% in Groups 1 and 2, compared with 26% in Group 3 (P < 0.01). At 5 years of follow-up, there were 45 cases of organ-specific complications in patients without HAART. No children without organ-specific complications when HAART was started have developed them after 5 years (P < 0.01). In patients without HAART there were 9 cases of lymphoid interstitial pneumonia, and there was none in Group 3 (P < 0.01). The incidence rates of infections and hospitalizations were 2.83 and 0.52 per patient-year, respectively, in children who did not receive HAART and 0.75 and 0.17 when they were managed with HAART (relative risk, 0.26 and 0.32). Conclusions. HAART is associated with a marked decline in the progression to AIDS, improved survival in HIV-1-infected children, reduced incidence of infections and hospitalizations and decreased incidence of some organ-specific complications of HIV.

Outcome of protease inhibitor substitution with nevirapine in HIV-1 infected children

BackgroundProtease inhibitors (PIs) have been associated with metabolic complications. There is a trend to switch to simpler therapy to improve these disturbances. We report a case-series describing the effects in metabolic abnormalities in seven HIV-infected children, previously treated with protease inhibitor (PI) after switching to nevirapine.MethodsSeven children with stable PI-containing regimen and a long lasting HIV-1 RNA < 50 copies/ml were switched to nevirapine. All patients were naïve to non nucleoside reverse transcriptase inhibitor. PIs were switched to nevirapine. Preentry nucleoside reverse transcriptase inhibitors were maintained. The substitution of PIs with nevirapine was made when the patient showed hyperlipidemia or lipodystrophy or the physician and/or the patients willingness to simplify. Clinical, laboratory data and anthropometric parameters were assessed every 3 months. Dual-energy X-Ray absorptiometry scans (DXA) was performed at baseline and at 12 months.ResultsSeven HIV-infected children were enrolled. Median age: 130 months (99,177). Median baseline CD4%: 32%. All had HIV-1 RNA < 50 copies/ml. Median length of preentry PI-therapy was 47 months (28, 91). Median age at the beginning of nevirapine was 120 months (99,177). Median decrease in cholesterol in 7.2 mmol/L was observed (P = 0.09), from baseline to 12 months. HDL-cholesterol increased in 5.1 mmol/L (P = 0.03) throughout the study period. No significant changes were observed in DXA with regard to body fat, but changes in total body bone mineral content and lean body content were significant. CD4% remained stable. All patients but one maintained viral load < 50 copies/ml at 12 months. The patient with virologic failure referred bad adherence. Children referred to take medication more easily.ConclusionPI substitution with nevirapine improved lipid profile in our patients, although this strategy did not show significant changes in body fat or lipodystrophy.

PFAPA syndrome in siblings. Is there a genetic background

Abstract“PFAPA syndrome” is an autoinflammatory entity composed of periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis. There have been many reports of children with the disease, but only occasionally have been described in siblings, and no specific genetic mutation has been determined yet. Corticosteroids are the mainstay in the treatment of the acute attacks. The role of surgery in long-term follow-up (tonsillectomy with or without adenoidectomy) is controversial. We report two brothers affected with the syndrome, in whom corticosteroids as the only treatment led to an improvement. A genetic work-up was performed, making very unlikely other possible syndromes of recurrent fever. Conclusion: PFAPA syndrome is the most common recurrent periodic fever disorder described in childhood. Its genetic background has not been elucidated yet. Our contribution with two siblings affected with PFAPA syndrome further support the genetic basis for the entity.

Características maternas en una cohorte de gestantes con infección por el VIH-1

Fundamento y objetivo Como prevencion de la transmision vertical del virus de la inmunodeficiencia humana (VIH-1) destaca la administracion de farmacos antirretrovirales durante el embarazo y el parto, asi como al recien nacido. Sin embargo, hay pocos datos acerca de la seguridad de este tratamiento y son precisos estudios de seguimiento de un gran numero de gestantes para estudiar este aspecto, asi como la transmision vertical y las tendencias epidemiologicas en esta poblacion. En este trabajo se presentan las caracteristicas maternas de la cohorte. Pacientes y metodo Se ha realizado un estudio observacional, multicentrico y colaborativo en la cohorte de gestantes seropositivas y sus hijos (666 y 686 casos, respectivamente) nacidos en el periodo de estudio (desde enero o mayo de 2000 hasta el 31 de diciembre de 2003). Resultados La mayoria de las gestantes se infecto por transmision heterosexual (54%), se encontraba en el estadio A de la infeccion por el VIH (71%) y recibio tratamiento antirretroviral de gran actividad (74%) durante el embarazo. La proporcion de efectos adversos al tratamiento fue del 7%; entre ellos destaco la anemia asociada al tratamiento con zidovudina. Encontramos 6 casos de transmision vertical entre los 686 ninos nacidos (0,8%; intervalo de confianza del 95%, 0,3-1,8). Conclusiones La mayoria de las pacientes recibio tratamiento antirretroviral de gran actividad, con una buena tolerancia y una baja tasa de efectos adversos. La tasa de transmision vertical fue muy baja, sin que superara el 1%. Es preciso prestar atencion a fenomenos como la coinfeccion por el virus de la hepatitis C, posibles efectos secundarios graves, como la hepatotoxicidad, y trastornos del embarazo mas frecuentes en esta poblacion, como la prematuridad y la diabetes gestacional.

Estimación de la prevalencia de infección por VIH-1 en la embarazada y efectividad de la zidovudina administrada durante la gestación en la prevención de la transmisión vertical

Fundamento : A pesar de la eficacia probada de la zidovudina (ZDV) administrada a la embarazada enla disminucion de la transmision vertical del VIH-1, existen importantes dudas sobre la efectividad yel cumplimiento en la practica clinica. Los objetivos han sido determinar la efectividad de la ZDV duranteel embarazo a las mujeres con infeccion por VIH en la reduccion de la transmision vertical (TV)y analizar la tendencia en el tiempo de la prevalencia de infeccion y de los casos identificados precozmente. Pacientes Y Metodos : Se han seleccionado los pares de madres/hijos seguidos prospectivamente desdeel nacimiento, en el periodo comprendido entre el 1 de enero de 1987 y el 30 de octubre de 1997.Se ha considerado infectado al nino con anticuerpos positivos a partir de los 18 meses, o al menos 2determinaciones mediante reaccion en cadena de la polimerasa (PCR) positivas en los primeros 3 mesesde vida. Resultados : Se han identificado 229 madres y 248 ninos. Se administro ZDV a 34 madres en el embarazocon una media (DE) de 4,7 (3,1) meses. El valor medio de CD4 fue de 465 (261) celulas ×10 6 /l. Las unicas variables asociadas con un mayor riesgo de transmision fueron el tiempo de roturade bolsa (mediana en transmisoras 6 h, mediana en no transmisoras 1,04 h; p = 0,023) y el tratamientocon ZDV. De las madres tratadas durante el embarazo solo un nino resulto infectado (TV2,9%), frente a 37 ninos en las no tratadas (TV 17,5%) (p = 0,029; odds ratio [OR]: 0,14; intervalode confianza [IC] del 95%: 0,07-0,92). La prevalencia estimada de infeccion por VIH-1 en mujeresgestantes en nuestra area se situa en torno al 0,39% (IC del 95%: 0,34-0,45). En los primeros 5anos del periodo de estudio, 14 ninos (9,7%) fueron identificados como seropositivos despues del periodoneonatal, en comparacion a solo 3 a partir de 1992 (p = 0,034). Conclusiones : En este estudio, la prevalencia estimada de infeccion por VIH-1 en mujeres embarazadases elevada. El tratamiento con ZDV durante el embarazo se asocia a una disminucion en la transmisionvertical del VIH-1. Es posible que la disponibilidad de esta medida haya contribuido a la mayoridentificacion de las embarazadas seropositivas observada en el tiempo.

Síndrome PFAPA: Estudio de 10 casos

BACKGROUND AND OBJECTIVES «PFAPA syndrome» is an autoinflammatory entity consisting of periodic fever, aphthous stomatitis, pharyngitis and cervical adenitis. Its etiology is unknown although a dysregulation in the control of the autoinflammatory response seems to play a role. Although a genetic origin is suspected, no specific mutation has been determined yet. Corticosteroids are the mainstay of the treatment during the acute attacks. However, in long-term follow-up the role of tonsillectomy is controversial. PATIENTS AND METHODS A retrospective study of the pediatric cases diagnosed with the PFAPA syndrome was performed in our center during the last 4 years. RESULTS Ten patients were diagnosed with the syndrome who received corticosteroids as the only treatment with improvement and favourable prognosis. CONCLUSION PFAPA syndrome is the most common periodic fever disorder described in childhood whose genetic background has not been yet clarified. Our contribution with 10 patients further supports the common existence of this entity and the need to keep it in mind when having recurrent fevers.

Por qué micafungina puede ser de elección en el paciente pediátrico

: Micafungin is an echinocandin approved by the European Medicines Evaluation Agency for the treatment of invasive candidiasis in children, including premature infants born before 29 weeks of pregnancy, and as prophylaxis in children undergoing hematopoietic stem-cell transplantation or patients at risk of prolonged neutropenia. This drug has good activity in several Candida spp., including those resistant to fluconazole. Although micafungin is active against Aspergillus spp., it has been used mainly in combination therapy for invasive aspergillosis. There is ample information on the use of micafungin in children, including neonates, and this drug is the only echinocandin approved for use in infants aged less than 3 months. The efficacy, pharmacokinetics and safety of micafungin have been evaluated in phase II and III clinical trials in children, in which its efficacy and safety were demonstrated in comparison with liposomal amphotericin B and fluconazole. The pharmacokinetic profile of micafungin in children allows once daily intravenous administration, with greater clearance than in adults, and consequently pediatric doses are relatively higher. The most appropriate dose in children weighing less than 40 kg is 2 mg/kg/day in the treatment of invasive candidiasis and 1 mg/kg/day as prophylaxis in children undergoing hematopoietic stem-cell transplantation. Doses in neonates should be higher. In premature infants, the most appropriate doses to achieve levels in the brain parenchyma are 7 mg/kg/day and 10 mg/kg/day in those weighing more and less than 1,000 g, respectively. Micafungin has few drug-drug interactions and an acceptable safety profile. Withdrawal of this drug due to adverse effects is rare, although transaminase monitoring is recommended during treatment, as well as evaluation of the risk-benefit balance in patients with liver disease or concomitant administration of hepatotoxic drugs.Micafungin is an echinocandin approved by the European Medicines Evaluation Agency for the treatment of invasive candidiasis in children, including premature infants born before 29 weeks of pregnancy, and as prophylaxis in children undergoing hematopoietic stem-cell transplantation or patients at risk of prolonged neutropenia. This drug has good activity in several Candida spp., including those resistant to fluconazole. Although micafungin is active against Aspergillus spp., it has been used mainly in combination therapy for invasive aspergillosis. There is ample information on the use of micafungin in children, including neonates, and this drug is the only echinocandin approved for use in infants aged less than 3 months. The efficacy, pharmacokinetics and safety of micafungin have been evaluated in phase II and III clinical trials in children, in which its efficacy and safety were demonstrated in comparison with liposomal amphotericin B and fluconazole. The pharmacokinetic profile of micafungin in children allows once daily intravenous administration, with greater clearance than in adults, and consequently pediatric doses are relatively higher. The most appropriate dose in children weighing less than 40 kg is 2 mg/kg/day in the treatment of invasive candidiasis and 1 mg/kg/day as prophylaxis in children undergoing hematopoietic stem-cell transplantation. Doses in neonates should be higher. In premature infants, the most appropriate doses to achieve levels in the brain parenchyma are 7 mg/kg/day and 10 mg/kg/day in those weighing more and less than 1,000 g, respectively. Micafungin has few drug-drug interactions and an acceptable safety profile. Withdrawal of this drug due to adverse effects is rare, although transaminase monitoring is recommended during treatment, as well as evaluation of the risk-benefit balance in patients with liver disease or concomitant administration of hepatotoxic drugs.Resumen La micafungina es una equinocandina aprobada por la European Medicines Agency como tratamiento de la candidiasis invasora en ninos, incluidos grandes prematuros, y como profilaxis en ninos sometidos a trasplante de progenitores hematopoyeticos (TPH), o en quienes se prevea una duracion prolongada de la neutropenia. Tiene buena actividad sobre diferentes especies de Candida spp., incluidas las resistentes a fluconazol. Aunque tiene actividad sobre Aspergillus spp., se ha utilizado sobre todo en terapia de combinacion en aspergilosis invasoras. Se dispone de una amplia informacion del uso de micafungina en ninos, incluidos neonatos, siendo la unica equinocandina aprobada en menores de 3 meses. Se ha evaluado su eficacia, farmacocinetica y seguridad en ensayos en fases II y III en ninos, en los que ha demostrado su eficacia y seguridad en estudios comparativos con anfotericina B liposomal y fluconazol. Micafungina tiene un perfil farmacocinetico en ninos que permite su dosificacion intravenosa 1 vez al dia, con un aclaramiento aumentado respecto al adulto, por lo que las dosis pediatricas son relativamente mas altas. La dosis mas apropiada en ninos menores de 40 kg es de 2 mg/kg/dia como tratamiento de candidiasis invasora y de 1 mg/kg/dia como profilaxis en ninos sometidos a TPH. En neonatos las dosis deben ser superiores. En prematuros, las dosis mas apropiadas para alcanzar valores en parenquima cerebral deberian ser de 7 mg/kg/dia y de 10 mg/kg en mayores y menores de 1.000 g, respectivamente. Tiene escasas interacciones medicamentosas y un aceptable perfil de seguridad, siendo rara la retirada de la medicacion por efectos adversos, si bien se recomienda la monitorizacion de las transaminasas durante el tratamiento, y la valoracion del riesgo-beneficio en pacientes con hepatopatia o administracion conjunta de agentes hepatotoxicos.

Actualización del tratamiento de la tuberculosis en niños

Tuberculosis (TB) is the most important infectious disease all over the world, with a high morbidity and mortality. Pediatric tuberculosis has been a neglected epidemic, due to the difficulties in assessing its global impact, reduced incidence and lower infectivity compared to adults. In 2015, the WHO reported 1 million cases of paediatric TB and 169,000 deaths. In Europe, the emergence of MDR TB is a major concern, representing 16% of the new diagnosis in Eastern Europe. In 2014, it was estimated that about 219,000 children were infected by MDR-TB-strains in Europe, and 2,120 developed the disease. Spain is the Western European country with more paediatric cases, with an incidence 4.3/100,000 inhabitants in 2014. Paediatric tuberculosis mortality in Spain is rare, but extra-pulmonary disease is associated with significant complications. The prevalence of paediatric drug resistant TB in Spain is over 4%, higher than the estimated incidence in adult population, representing mayor difficulties for therapeutic intervention. These data reveal that paediatric TB is still a Public Health priority in our country. The difficulties in diagnosis and the lack of optimal paediatric drug formulations are the major challenges for controlling the childhoods tuberculosis epidemic. A group of national paeditric TB experts has reviewed the international guidelines and the most recent evidences, and has established new recommendations for the management of paediatric TB contacts, latent infection and active TB disease, especially focused in drug resistant cases. This document replaces the former national guidelines from the Spanish Society for Pediatric Infectios Diseases, although the prior recommendations on the diagnosis remain valid.

Seroprevalencia y transmisión vertical de enfermedad de Chagas en una cohorte de gestantes latinoamericanas en un hospital terciario de Madrid

BACKGROUND Chagas disease, caused by Trypanosoma cruzi (T. cruzi), is endemic in Latin-America and is emerging in Spain due to immigration. The vertical transmission rate is around 5%. A routine prenatal screening with serology of all pregnant women from endemic areas is recommended to identify infected newborns, allowing early treatment and cure. OBJECTIVE The aim of this study was to estimate the prevalence of positive Chagas serology in a cohort of pregnant women from Latin-America and its vertical transmission. PATIENTS AND METHODS An observational, prospective, follow-up study was conducted on women with positive serology to T. cruzi, as well as their newborns, from January 2013 to April 2015. Congenital Chagas was ruled out using a PCR technique at birth and at 1 month, and with serology at 9-12 months old. A child was considered infected when PCR was positive, and uninfected when PCR was negative, and/or it had a negative serology. RESULTS Screening was performed on 1244 pregnant women from Latin-America, and there were positive results in 40 (prevalence 3.2%, 95% CI: 2.4-4.4%), with 85% of them from Bolivia. There was only one infected newborn (rate of vertical transmission 2.8% (95% CI: 0-15%)), who had a positive PCR at birth. Relative studies enabled an 8-year-old sister with an asymptomatic disease to be diagnosed and treated. Both were treated successfully with benznidazole (later the PCR and serology were negative). CONCLUSION Screening during pregnancy in Latin-American women helped to detect those with Chagas disease. The rate of vertical transmission was 2.8%, in keeping with literature. Screening led to the detection and treatment of previously unidentified familial cases.

Safety of darunavir and atazanavir in HIV-infected children in Europe and Thailand

BACKGROUND Surveillance for mid- and long-term antiretroviral therapy (ART) toxicity in children is important for informing treatment guidelines. We assessed the safety of darunavir (DRV) and atazanavir (ATV), commonly used as second-line protease inhibitors following lopinavir/ritonavir, in Europe and Thailand. METHODS Cohorts contributed individual patient data on adverse events (AE) in those aged <18 years taking DRV and ATV, respectively, to 02/2014. Rates of Division of AIDS (DAIDS) grade ≥3 laboratory AEs were calculated. RESULTS Of 431 patients on DRV and 372 on ATV, 317 (74%) and 301 (81%), respectively, had weight and dose data available, of whom 56 (18%) and 33 (9%) took the drugs at a non-approved age or dose. Median age at DRV and ATV start was 14.8 years (IQR 12.8-16.1) and 13.5 years (11.4-15.2); 43% and 26% had received ≥8 ART drugs previously. Overall rates of grade ≥3 AEs for absolute neutrophils, total cholesterol, triglycerides, pancreatic amylase, lipase and alanine aminotransferase (ALT) were ≤3/100 person-years (PY) on approved doses of both drugs, but 66/100 PY (95% CI 52, 84) for bilirubin after <12 months on ATV declining to 32/100 PY (95% CI 23, 44) after >24 months. Five serious drug-related clinical AEs were reported in four patients on ATV (one discontinued) and three in three patients on DRV (all discontinued), and did not substantially differ in those on approved compared to non-approved doses. Proportions on the drugs at last follow-up were 89% (383/431) for DRV and 81% (301/372) for ATV (including 73/92 with grade ≥3 hyperbilirubinaemia). CONCLUSIONS AEs were few in number and comparable for the two drugs, with the exception of high rates of hyperbilirubinaemia for ATV; few patients discontinued due to toxicity.