Paediatric European Network for Treatment of AIDS (PENTA) guidelines for treatment of paediatric HIV-1 infection 2015: optimizing health in preparation for adult life.

The 2015 Paediatric European Network for Treatment of AIDS (PENTA) guidelines provide practical recommendations on the management of HIV-1 infection in children in Europe and are an update to those published in 2009. Aims of treatment have progressed significantly over the last decade, moving far beyond limitation of short-term morbidity and mortality to optimizing health status for adult life and minimizing the impact of chronic HIV infection on immune system development and health in general. Additionally, there is a greater need for increased awareness and minimization of long-term drug toxicity. The main updates to the previous guidelines include: an increase in the number of indications for antiretroviral therapy (ART) at all ages (higher CD4 thresholds for consideration of ART initiation and additional clinical indications), revised guidance on first- and second-line ART recommendations, including more recently available drug classes, expanded guidance on management of coinfections (including tuberculosis, hepatitis B and hepatitis C) and additional emphasis on the needs of adolescents as they approach transition to adult services. There is a new section on the current ART 'pipeline' of drug development, a comprehensive summary table of currently recommended ART with dosing recommendations. Differences between PENTA and current US and World Health Organization guidelines are highlighted and explained.

Higher rates of triple-class virological failure in perinatally HIV-infected teenagers compared with heterosexually infected young adults in Europe.

OBJECTIVES: The aim of the study was to determine the time to, and risk factors for, triple-class virological failure (TCVF) across age groups for children and adolescents with perinatally acquired HIV infection and older adolescents and adults with heterosexually acquired HIV infection. METHODS: We analysed individual patient data from cohorts in the Collaboration of Observational HIV Epidemiological Research Europe (COHERE). A total of 5972 participants starting antiretroviral therapy (ART) from 1998, aged < 20 years at the start of ART for those with perinatal infection and 15-29 years for those with heterosexual infection, with ART containing at least two nucleoside reverse transcriptase inhibitors (NRTIs) and a nonnucleoside reverse transcriptase inhibitor (NNRTI) or a boosted protease inhibitor (bPI), were followed from ART initiation until the most recent viral load (VL) measurement. Virological failure of a drug was defined as VL > 500 HIV-1 RNA copies/mL despite ≥ 4 months of use. TCVF was defined as cumulative failure of two NRTIs, an NNRTI and a bPI. RESULTS: The median number of weeks between diagnosis and the start of ART was higher in participants with perinatal HIV infection compared with participants with heterosexually acquired HIV infection overall [17 (interquartile range (IQR) 4-111) vs. 8 (IQR 2-38) weeks, respectively], and highest in perinatally infected participants aged 10-14 years [49 (IQR 9-267) weeks]. The cumulative proportion with TCVF 5 years after starting ART was 9.6% [95% confidence interval (CI) 7.0-12.3%] in participants with perinatally acquired infection and 4.7% (95% CI 3.9-5.5%) in participants with heterosexually acquired infection, and highest in perinatally infected participants aged 10-14 years when starting ART (27.7%; 95% CI 13.2-42.1%). Across all participants, significant predictors of TCVF were those with perinatal HIV aged 10-14 years, African origin, pre-ART AIDS, NNRTI-based initial regimens, higher pre-ART viral load and lower pre-ART CD4. CONCLUSIONS: The results suggest a beneficial effect of starting ART before adolescence, and starting young people on boosted PIs, to maximize treatment response during this transitional stage of development.

[Griscelli-Prunieras syndrome: report of two cases]. / Síndrome de Griscelli-Prunieras: a propósito de dos casos.

Griscelli-Prunieras syndrome (GS) is a rare autosomal recessive disorder characterized by partial albinism. His pathogenic mechanism is associated with defects in the packaging of melanin and other cellular proteins. GS is classified into 3 types based on the genetic and molecular features. Mutations in the genes which cause GS are known. We report two first cases described in Spain who presented a silver-gray sheen of the hair and a severe immune disorder. They were studied for mutations principally related to this syndrome. Two patients showed the Rab27a mutation (frequently associated with GS2). The natural disorder evolution differs considerably among the various forms, so a genetic study is essential in GS to achieve the most accurate prognosis and treatment possible.

European shortage of purified protein derivative and its impact on tuberculosis screening practices.

SETTING: In June 2014, we became aware that shortages of purified protein derivative (PPD), the test substance used for the tuberculin skin test (TST), had occurred in several European health care institutions providing care for children with tuberculosis (TB). OBJECTIVE: To establish the extent of the shortage, a survey was performed. DESIGN: Survey conducted over a 1-month period (June-July 2014) among members of the Paediatric Tuberculosis Network European Trials Group (ptbnet). RESULTS: Thirty-five physicians from 23 European countries contributed data. The most commonly used PPD product was RT23 (Statens Serum Institut; n = 22, 63%). Twenty-one (60%) participants reported that their institution was experiencing a PPD shortage. The majority (n = 17, 81%) of those reporting a shortage were using RT23. Thirteen (37%) participants reported changes in screening practices resulting from the shortage, including sourcing PPD from alternative manufacturers, restricting remaining supplies to patients at greatest risk or replacing TST by an interferon-gamma release assay. CONCLUSIONS: The data show that a PPD shortage occurred in 2014, affecting multiple European countries. The shortage resulted in changes in TB screening capabilities and practices, potentially compromising both patient care as well as public health efforts. Appropriate actions to prevent future PPD shortages should be explored urgently by public health agencies and key stakeholders.

Factors associated with severity in invasive community-acquired Staphylococcus aureus infections in children: a prospective European multicentre study.

Staphylococcus aureus is the main pathogen responsible for bone and joint infections worldwide and is also capable of causing pneumonia and other invasive severe diseases. Panton-Valentine leukocidin (PVL) and methicillin-resistant S. aureus (MRSA) have been studied as factors related with severity in these infections. The aims of this study were to describe invasive community-acquired S. aureus (CA-SA) infections and to analyse factors related to severity of disease. Paediatric patients (aged 0-16 years) who had a CA-SA invasive infection were prospectively recruited from 13 centres in 7 European countries. Demographic, clinical and microbiological data were collected. Severe infection was defined as invasive infection leading to death or admission to intensive care due to haemodynamic instability or respiratory failure. A total of 152 children (88 boys) were included. The median age was 7.2 years (interquartile range, 1.3-11.9). Twenty-six (17%) of the 152 patients had a severe infection, including 3 deaths (2%). Prevalence of PVL-positive CA-SA infections was 18.6%, and 7.8% of the isolates were MRSA. The multivariate analysis identified pneumonia (adjusted odds ratio (aOR) 13.39 (95% confidence interval (CI) 4.11-43.56); p 0.008), leukopenia at admission (<3000/mm(3)) (aOR 18.3 (95% CI 1.3-259.9); p 0.03) and PVL-positive infections (aOR 4.69 (95% CI 1.39-15.81); p 0.01) as the only factors independently associated with severe outcome. There were no differences in MRSA prevalence between severe and nonsevere cases (aOR 4.30 (95% CI 0.68- 28.95); p 0.13). Our results show that in European children, PVL is associated with more severe infections, regardless of methicillin resistance.

[Spanish Society for Pediatric Infectious Diseases guidelines on tuberculosis in pregnant women and neonates (i): Epidemiology and diagnosis. Congenital tuberculosis]. / Guía de la Sociedad Española de Infectología Pediátrica sobre tuberculosis en la embarazada y el recién nacido (I): epidemiología y diagnóstico. Tuberculosis congénita.

Tuberculosis (TB) screening in pregnancy using tuberculin skin test (TST) is recommended in case of symptoms of TB disease, close contact with a patient with infectious TB, or high risk of developing active disease. The new interferon gamma release assay (IGRA) tests are recommended in BCG-vaccinated pregnant women with positive TST and no known risk factors for TB, and in those immunocompromised, with clinical suspicion of TB but negative TST. TB diagnosis is difficult due to the non-specific symptoms, the increased frequency of extrapulmonary disease, the delay in radiological examinations, and the high rate of tuberculin anergy. Neonatal TB can be acquired in utero (congenital TB), or through airborne transmission after delivery (postnatal TB). Congenital TB is extremely rare and does not cause fetal malformations. It may be evident at birth, although it usually presents after the second week of life. In newborns with no family history of TB, the disease should be considered in cases of miliary pneumonia, hepatosplenomegaly with focal lesions, or lymphocytic meningitis with hypoglycorrhachia, especially in those born to immigrants from high TB-burden countries. TST is usually negative, and IGRAs have lower sensitivity than in older children. However, the yield of acid-fast smear and culture is higher, mostly in congenital TB. Molecular diagnosis techniques enable early diagnosis and detection of drug resistance mutations. There is a substantial risk of disseminated disease and death.

[Spanish Society for Pediatric Infectious Diseases guidelines on tuberculosis in pregnant women and neonates (ii): Prophylaxis and treatment]. / Guía de la Sociedad Española de Infectología Pediátrica sobre tuberculosis en la embarazada y el recién nacido (ii): profilaxis y tratamiento.

In pregnant women who have been exposed to tuberculosis (TB), primary isoniazid prophylaxis is only recommended in cases of immunosuppression, chronic medical conditions or obstetric risk factors, and close and sustained contact with a patient with infectious TB. Isoniazid prophylaxis for latent tuberculosis infection (LTBI) is recommended in women who have close contact with an infectious TB patient or have risk factors for progression to active disease. Otherwise, it should be delayed until at least three weeks after delivery. Treatment of TB disease during pregnancy is the same as for the general adult population. Infants born to mothers with disseminated or extrapulmonary TB in pregnancy, with active TB at delivery, or with postnatal exposure to TB, should undergo a complete diagnostic evaluation. Primary isoniazid prophylaxis for at least 12 weeks is recommended for those with negative diagnostic tests and no evidence of disease. Repeated negative diagnostic tests are mandatory before interrupting prophylaxis. Isoniazid for 9 months is recommended in LTBI. Treatment of neonatal TB disease is similar to that of older children, but should be maintained for at least 9 months. Respiratory isolation is recommended in congenital TB, and in postnatal TB with positive gastric or bronchial aspirate acid-fast smears. Separation of mother and infant is only necessary when the mother has received treatment for less than 2 weeks, is sputum smear-positive, or has drug-resistant TB. Breastfeeding is not contraindicated, and in case of mother-infant separation expressed breast milk feeding is recommended.

[Course and treatment of progressive subacute encephalopathy caused by human immunodeficiency virus in children. The value of Botulinum toxin]. / Evolución y tratamiento de la encefalopatía subaguda progresiva por virus de inmunodeficiencia humana en el niño. Utilidad de la toxina botulínica.

INTRODUCTION: Progressive subacute encephalopathy due to human immunodeficiency virus (PSE-HIV) is an important cause of morbidity and mortality in perinatal HIV infection. Although current combined antiretroviral therapies do manage to check its progression, they often give rise to severe motor sequelae that are similar to the spastic infantile cerebral palsy resulting from other aetiologies. We present the case reports of four preschool age children suffering from this pathology who have benefited from long term treatment with botulinum toxin type A (BTA). CASE REPORTS: Four patients suffering from early onset PSE HIV, who responded well to combined antiviral therapies, and who had severe motor sequelae (two cases of tetraparesis and two spastic dysplegias), with no cognitive disorders. The multidisciplinary treatment of their motor disorder included six monthly sessions of muscular injections of BTA in the usual doses, with good results from the functional point of view and with no significant side effects. DISCUSSION: PSE-HIV is defined by one of the following criteria: acquired microcephalus, retarded neurological development or symmetrical motor involvement. It constitutes one of the most frequent diagnostic criteria of AIDS in patients infected by vertical transmission. An early diagnosis and treatment are fundamental for the patient's prognosis. Severe motor sequelae in the form of spastic infantile cerebral palsy are frequent. In our experience treatment of the spasticity associated to this entity with BTA has proved to be useful and safe, with a clear improvement in gait functionality.

[Cerebral venous thrombosis in a girl carrier of the prothrombin gene mutation 20210G--> A treated by local fibrinolysis of the superior sagittal sinus]. / Trombosis venosa cerebral en niña portadora de la mutación 20210G--> A del gen de la protrombina, tratada mediante fibrinólisis local del seno sagital superior.

CASE REPORT: Girl, aged 4, without antecedents who was admitted to our hospital for drowsiness and progressive sensorial depression. Within 24 hours the clinical picture deteriorated with partial seizures of the right hand side of the body and right hemiparesis. A brain CAT scan showed a left temporoparietal parenchymatous haematoma with collapse of the left lateral ventricle and moderate obliteration of the basal cisterns. MR angiography and cerebral arteriography displayed images that were compatible with thrombosis of the superior sagittal, the left transverse and the sigmoid sinuses. The patient was heterozygotic for the G A mutation in position 20210 of the prothrombin gene, which is linked with a high risk of thrombosis. She was given heparin intravenously, but continued to display endocranial hypertension and tissue ischemia with partial response to hyperosmolar agents and barbituric coma. She was therefore submitted to selective catheterization of the superior sagittal sinus and continuous local fibrinolysis with urokinase for 72 hours. The outcome was satisfactory, with repermeabilisation of the thrombosed sinuses and a good clinical response with no complications. At present the patient has functional paresis of the right hand and receives treatment with oral anticoagulants. CONCLUSIONS: We advocate the use of early local fibrinolytic treatment with urokinase in children affected by thrombosis of the venous sinuses who do not respond to treatment with sodium heparin. We consider it necessary to include the molecular study of the G20210A mutation of the prothrombin gene in screening for prothrombotic risk factors in small children

[Neurofibromatosis type 2 as a result of a de novo mutation: a case report]. / Neurofibromatosis tipo 2 por mutación de novo. A propósito de un caso.

INTRODUCTION: Neurofibromatosis type 2 is a dominant autosomic hereditary disease which courses with distinct tumours of the central nervous system and scant cutaneous manifestations. The increased knowledge of the natural history and the genetics of NF 2 acquired over the past few years has shown that clinical onset possibly occurs during the paediatric age and an early diagnosis of these patients can be decisive in the final outcome. CLINICAL CASE: A 12 year old girl who visited the clinic because of a month old presentation of cervical tumour, otalgia and dysphonia. Exploration revealed signs of cranial nerve disorder and the magnetic resonance (MR) showed bilateral schwannomas of the eighth cranial nerves. The extension study showed ocular, auditory, troncoencephalic and cervical spinal cord disorders. The patient died three months after hospital admission. The genetic study showed a de novo mutation in the NF 2 gene (chromosome 22q12). DISCUSSION: The identification of the various mutations that cause NF 2 has enabled the early diagnosis of the patient s relatives. However, there are still patients who have not been confirmed genetically. Furthermore, de novo mutations are not predictable. NF 2 diagnosis is still clinical. In the last few years, two disease phenotypes have been defined: mild and moderate/serious, which is associated with an early onset and de novo mutations. The high incidence rate of cataracts and other associated tumours, such as those affecting paraspinal and cutaneous areas together with meningiomas, which up until now could have gone unnoticed, has also been observed. Clinical onset in the paediatric age is more frequent than was expected and shows distinct and subtle symptoms.

[Recommendations issued by the Spanish Society of Pediatric Infectious Diseases for the follow-up of the child exposed to the human immunodeficiency virus and to antiretroviral drugs during pregnancy and the neonatal period]. / Recomendaciones de la Sociedad Española de Infectología Pediátrica para el seguimiento del niño expuesto al virus de la inmunodeficiencia humana y a fármacos antirretrovirales durante el embarazo y el periodo neonatal.

Human immunodeficiency virus vertical transmission in developed countries has dramatically decreased to less than 2% over the last 15 years due to the consecutive implementation of different prophylactic measures, including the use of antiretrovirals, elective cesarean section and refraining from breastfeeding. The follow-up of these otherwise healthy children is, by far, the most common situation related to HIV infection that general pediatricians currently face in routine clinical care in Spain. These recommendations issued by the Spanish Society of Pediatric Infectious Diseases attempt to summarize the main aspects of this follow-up, including birth management, type of feeding, neonatal antiretroviral prophylaxis, HIV infection diagnosis, common early comorbidities, short- and mid-term toxicities, vaccination and other prophylactic measures and long-term follow-up.

Low prevalence of invasive bacterial infection in febrile infants under 3 months of age with enterovirus infection.

Infants under 3 months of age with fever without source (FWS) generally undergo a full, invasive septic evaluation to exclude invasive bacterial infection (IBI). Enterovirus (EV) infections are mostly banal and self-limiting and show a high prevalence rate at this age. We aimed to investigate the prevalence of IBI in EV-infected and uninfected infants under 3 months of age with FWS. This was a prospective observational cohort study of infants aged <90 days who were admitted because of FWS. As per protocol, blood and urine analysis and culture were obtained in all cases, and RNA EV from blood and/or cerebrospinal fluid samples was determined by real-time PCR. Three hundred and eighty-one previously healthy infants with FWS were included. EV infection was diagnosed in 64 children (16.8%; 95% confidence interval, 13.2-20.9%) and showed an uneventful evolution in all cases. Laboratory markers of infection were consistently lower in EV-infected patients; only one case of IBI (1.6%) was observed in an EV-infected patient as compared with 25.2% in EV-negative infants (p <0.001). Intravenous antibiotic use and length of stay were no different in EV-infected and uninfected patients. In our study, febrile infants (<90 days) diagnosed with EV infection showed a low risk of IBI when compared with uninfected patients. The systematic investigation of EV infection in young infants with FWS may allow a more conservative approach to the management of these patients. Further studies on this diagnostic approach are needed.