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BACKGROUND: Ganciclovir/valganciclovir is currently indicated during the first 6 months of life in symptomatic children with congenital cytomegalovirus (CMV) infection. However, this treatment may have the potential to induce mitochondrial toxicity due to off-target inhibition of DNA-polymerases. Similar anti-HIV drugs have been associated with mitochondrial toxicity but this has never been explored in CMV. OBJECTIVE: To determine the potential mitochondrial toxicity profile at the genetic, functional and biogenesis level in peripheral blood mononuclear cells from a cohort of newborns and infants with symptomatic congenital CMV infection (treated with valganciclovir, untreated and uninfected controls). DESIGN: Longitudinal, observational and controlled study. SETTING AND PATIENTS: Subjects were recruited at the tertiary referral Hospital Sant Joan de Déu and experiments were conducted at IDIBAPS-Hospital Clínic of Barcelona, Spain. CMV-infected newborns underwent comprehensive monthly clinical follow-up. METHODS: Mitochondrial parameters, audiometry and neurological assessment were measured at baseline, 3-6 and 12 months after inclusion in the study. The Kruskal-Wallis test for k-independent samples and Friedman tests for repeated measurements were applied. RESULTS: Complex IV, citrate synthase enzymatic activities and mtDNA remained preserved in congenital CMV-infected infants treated with valganciclovir compared with controls (p>0.05 in all cases). CONCLUSIONS: No evidence of mitochondrial toxicity was found in infants treated with valganciclovir for congenital CMV.

BACKGROUND: Understanding the role of children in SARS-CoV-2 transmission is critical to guide decision-making for schools in the pandemic. We aimed to describe the transmission of SARS-CoV-2 among children and adult staff in summer schools. METHODS: During July 2020 we prospectively recruited children and adult staff attending summer schools in Barcelona who had SARS-CoV-2 infection. Primary SARS-CoV-2 infections were identified through: (1) surveillance program in 22 summer schools' of 1905 participants, involving weekly saliva sampling for SARS-CoV-2 RT-PCR during 2-5 weeks; (2)cases identified through the Catalonian Health Surveillance System of children diagnosed with SARS-CoV-2 infection by nasopharyngeal RT-PCR. All centres followed prevention protocols: bubble groups, hand washing, facemasks and conducting activities mostly outdoors. Contacts of a primary case within the same bubble were evaluated by nasopharyngeal RT-PCR. Secondary attack rates and effective reproduction number in summer schools(R*) were calculated. RESULTS: Among the over 2000 repeatedly screened participants, 30children and 9adults were identified as primary cases. A total of 253 close contacts of these primary cases were studied (median 9 (IQR 5-10) for each primary case), among which twelve new cases (4.7%) were positive for SARS-CoV-2. The R* was 0.3, whereas the contemporary rate in the general population from the same areas in Barcelona was 1.9. CONCLUSIONS: The transmission rate of SARS-CoV-2 infection among children attending school-like facilities under strict prevention measures was lower than that reported for the general population. This suggests that under preventive measures schools are unlikely amplifiers of SARS-CoV-2 transmission and supports current recommendations for school opening.

OBJECTIVES: To assess the performance of interferon-gamma release assays (IGRAs) in the differential diagnosis between Mycobacterium avium complex (MAC) and tuberculosis (TB) in children affected with subacute/chronic submandibular/cervical lymphadenitis. STUDY DESIGN: Multicenter observational study comparing children with microbiologically confirmed MAC lymphadenitis from the European NontuberculouS MycoBacterial Lymphadenitis in childrEn study with children with TB lymphadenitis from the Spanish Network for the Study of Pediatric TB database. RESULTS: Overall, 78 patients with MAC and 34 with TB lymphadenitis were included. Among MAC cases, 44 out of 74 (59.5%) had positive tuberculin skin test (TST) results at the 5-mm cut-off, compared with 32 out of 33 (97%) TB cases (P

Infectious diseases occur worldwide with great frequency in both adults and children, causing 350,000 deaths in 2017, according to the latest World Health Organization reports. Both infections and their treatments trigger mitochondrial interactions at multiple levels: (i) incorporation of damaged or mutated proteins into the complexes of the electron transport chain; (ii) impact on mitochondrial genome (depletion, deletions and point mutations) and mitochondrial dynamics (fusion and fission); (iii) membrane potential impairment; (iv) apoptotic regulation; and (v) generation of reactive oxygen species, among others. Such alterations may result in serious adverse clinical events with considerable impact on the quality of life of the children and could even cause death. Herein, we use a systematic review to explore the association between mitochondrial alterations in paediatric infections including human immunodeficiency virus, cytomegalovirus, herpes viruses, various forms of hepatitis, adenovirus, T-cell lymphotropic virus and influenza. We analyse how these paediatric viral infectious processes may cause mitochondrial deterioration in this especially vulnerable population, with consideration for the principal aspects of research and diagnosis leading to improved disease understanding, management and surveillance.

WHAT IS KNOWN AND OBJECTIVE: Therapeutic alternatives to simplify antiretroviral therapy (ART) in HIV-infected children are needed. We report our experience with abacavir(ABC)/lamivudine(3TC) individualized dose compounded capsules (IDCC). COMMENT: We present a prospective case series of HIV-infected children who did not weigh enough to receive the adult fixed-dose combination including ABC/3TC 600mg/300mg, and were treated with weight-adapted ABC/3TC IDCC in Barcelona, Spain. Thirteen patients (12 girls) received ABC/3TC IDCC for a median(IQR) time of 30(17-54) months. No significant changes were observed in CD4 cell counts, weight or height z-scores over time. Suppression of viral replication was maintained in 7 patients with undetectable viremia at baseline. Another 5 patients achieved viral suppression with ABC/3TC IDCC-based ART, while one non-adherent girl did not. No adverse events related to ABC/3TC IDCC were observed. WHAT IS NEW AND CONCLUSION: Despite small numbers, the long-term use of ABC/3TC IDCC was feasible, safe, and effective in the treatment of HIV-infected children.

Infectious diseases occur worldwide with great frequency in both adults and children. Both infections and their treatments trigger mitochondrial interactions at multiple levels: (i) incorporation of damaged or mutated proteins to the complexes of the electron transport chain, (ii) mitochondrial genome (depletion, deletions, and point mutations) and mitochondrial dynamics (fusion and fission), (iii) membrane potential, (iv) apoptotic regulation, (v) generation of reactive oxygen species, among others. Such alterations may result in serious adverse clinical events with great impact on children's quality of life, even resulting in death. As such, bacterial agents are frequently associated with loss of mitochondrial membrane potential and cytochrome c release, ultimately leading to mitochondrial apoptosis by activation of caspases-3 and -9. Using Rayyan QCRI software for systematic reviews, we explore the association between mitochondrial alterations and pediatric infections including (i) bacterial: M. tuberculosis, E. cloacae, P. mirabilis, E. coli, S. enterica, S. aureus, S. pneumoniae, N. meningitidis and (ii) parasitic: P. falciparum. We analyze how these pediatric infections and their treatments may lead to mitochondrial deterioration in this especially vulnerable population, with the intention of improving both the understanding of these diseases and their management in clinical practice.

BACKGROUND: We aimed to assess the postnatal pattern of cardiovascular remodeling associated with intrauterine exposure to maternal HIV and antiretroviral treatment (ART). METHODS: Prospective cohort including 34 HIV-exposed uninfected (HEU) infants and 53 non-HIV-exposed infants were evaluated from fetal life up to 6 months postnatally. A cardiovascular evaluation was performed including echocardiography, blood pressure, and carotid intima media thickness (cIMT) measurement. RESULTS: ART regimens during pregnancy included 2 nucleoside reverse transcriptase inhibitors (Abacavir + Lamivudine (32.4%), Emtricitabine + Tenofovir (41.2%), and Zidovudine + Lamivudine (20.6%)). At 6 months of age, HIV-exposed uninfected infants showed thicker myocardial walls (septal wall thickness mean 5.02 mm (SD 0.85) vs 3.98 mm (0.86); P < .001), relative systolic dysfunction with decreased mitral ring displacement (8.57 mm (2.03) vs 10.34 mm (1.84); P = .002), and decreased tricuspid S' (9.71 cm/s (1.94) vs 11.54 cm/s (2.07); P = .003) together with relative diastolic dysfunction showed by prolonged left isovolumic relaxation time (58.57 ms (13.79) vs 47.94 (7.39); P < .001). Vascular assessment showed significantly higher systolic and diastolic blood pressure (102 mmHg (16.1) vs 80 mmHg (13.9); P < .001 and 64 mmHg (14.4) vs 55 mmHg (10.2); P = .045 respectively), with 50% of HIV-exposed children meeting criteria for hypertension vs 3.77% of the non-HIV-exposed group (P < .001) and thicker mean cIMT in the HIV-exposed group (0.62 µm (0.09) vs 0.51 µm (0.09); P = .015). CONCLUSIONS: Subclinical cardiac impairment together with higher blood pressure and thicker cIMT were observed in HIV-exposed infants at 6 months of age. Half of them presented hypertension. Our findings support a possible increased cardiovascular risk in HIV uninfected infants exposed in utero to ART.

Introduction: We aimed to describe antimicrobial use (AU) and quality of prescriptions (QP) in a 28-bed medical-surgical PICU of a European referral children's hospital during 2019. Methods: AU data were expressed as days-of-therapy (DOT) over 100 days-present (DP) and as length-of-treatment (LOT). QP was based on monthly cross-sectional point-prevalence surveys. Length-of-stay (LOS), readmission rates (RR), and mortality rates (MR) were also collected. Results: PICU AU accounted for 13.5% of the global hospital AU; the median PICU density of AU was 1.4 (IQR 1.3-1.5) times higher than that of the rest of the hospital areas. Antibacterials represented 88.5% of the overall AU, cefazolin and amoxicillin-clavulanate being the most used drugs. A high QP rate was observed (149/168 optimal, 88.9%), with room for improvement in prophylactic regimens and de-escalation of broad-spectrum regimens. LOT, LOS, RR, and MR remained stable. Conclusions: PICU AU represented a major portion of the global hospital AU. Despite high QP rates, prophylactic and broad-spectrum antibiotic regimens were optimizable. (C) 2021 Sociedad Espanola de Enfermedades Infecciosas y Microbiologia Clinica. Published by Elsevier Espana, S.L.U. All rights reserved.

INTRODUCTION: After the introduction of combination antiretroviral treatment, (ART) mortality in HIV-infected patients has dramatically decreased. However, it is still high in patients at risk, as adolescents transitioning to adult care (AC) without virologic control. The aim of this study was to characterize mortality and comorbidities of perinatally infected HIV (PHIV) patients after transition to AC. METHODS: A multicenter retrospective study from patients included in the CoRISpe-FARO Spanish cohort was conducted. PHIV patients who died after transition to AC between 2009 and 2019 were included. Clinical, immunovirologic characteristics, treatments received, comorbidities and causes of death were described. RESULTS: Among 401 PHIV patients, 14 died (3.5%). All were Spanish, 11/14 (78.6%) women. The median age at diagnosis was 1.5 years (interquartile range [IQR] 0.5-3.9), at transfer to AC was 18 years [16.1-19.9] and at death was 25.8 years [23.6-27.1]. In pediatric units [pediatric care (PC)], CD4+ nadir was 85 cells/µL [IQR 9.7-248.5] and 6/14 patients were classified as C-clinical stage. During AC, all patients were on C-clinical stage and CD4+ nadir dropped to 11.5 cells/µL [4.5-43.3]. cART adherence was extremely poor: in PC, 8/14 patients registered voluntary treatment interruptions; only one had undetectable VL at transition. In AC, 12/14 patients stopped treatment 2 or more periods of time. All deaths were related to advanced HIV disease. Mental health disorders were observed in 7/14 (50%). Main complications described: recurrent bacterial infections (57.1%), wasting syndrome (42.9%), esophageal candidiasis (28.6%) and Pneumocystis jirovecii pneumonia (28.6%). Four women had 11 pregnancies; 5 children were born (none infected). CONCLUSIONS: Young adults PHIV infected who transition to AC without virologic suppression or proven ability to adhere to ART are at high risk of mortality. Mortality was noted as a consequence of advanced HIV disease, frequent mental health problems and poor adherence to ART.

BACKGROUND: Congenital cytomegalovirus (cCMV) infection is the most frequent mother-to-child transmitted infection worldwide and a prevalent cause of neonatal disease and long-term morbidity. The kidney is a target organ for CMV, which replicates in renal tubules and is excreted in large quantities in urine for years in children with cCMV infection. Nonetheless, kidney disease has rarely been reported in cCMV-infected patients. OBJECTIVE: We aimed to describe the available data on renal involvement in patients with cCMV infection at the pathologic, functional, anatomical, and/or clinical levels. METHODS: A systematic search was performed in the MEDLINE/PubMed, SCOPUS, and Cochrane databases. Studies describing any renal involvement in fetuses or neonates aged =3 weeks at diagnosis of microbiologically confirmed cCMV infection were eligible. RESULTS: Twenty-four articles were included, with a very low level of evidence. Pathologic findings in autopsy studies universally described CMV typical inclusion bodies in tubular cells. No functional studies were identified. cCMV infection was not associated with an increased risk of kidney malformations. Congenital nephrotic syndrome was the most common clinical condition associated with cCMV, but a causal relationship cannot be established. CONCLUSIONS: Typical pathological features of cCMV infection are very common in renal tissue, but they do not seem to entail significant consequences at the anatomical or clinical levels.

BACKGROUND: The emergence of Zika virus (ZIKV) represents a threat with consequences on maternal and children's health. We aimed to assess the clinical and epidemiological characteristics of pregnant women returning from ZIKV affected areas, and the effects of maternal ZIKV infection on birth outcomes and children's health. METHODS: This was a hospital-based prospective observational study conducted at the Hospital Clínic of Barcelona and Hospital Sant Joan de Déu, Barcelona, Spain, from January 2016 to February 2020. RESULTS: One hundred and ninety-five pregnant women who had travelled to ZIKV affected areas during pregnancy were recruited. Four women (2.1%) had a confirmed ZIKV infection, 40 women (20.5%) a probable infection, and 151 (77.4%) were negative for ZIKV. Among the ZIKV confirmed cases, a pregnant woman suffered a miscarriage, highly plausible to be associated with ZIKV infection. Brain cysts and microcalcifications were detected in 7% of fetuses or infants from women with confirmed or probable ZIKV infection. Neurodevelopmental delay in the language function was found in 33.3% out of the 21 children evaluated. CONCLUSIONS: These findings contribute to the understanding of ZIKV prevalence estimates, and the impact of maternal ZIKV infection on pregnancy outcomes and children's health. Results highlight the importance of long-term surveillance in pregnant travellers and their children.

HIV co-infection has been suggested to play a deleterious role on the pathogenesis of liver fibrosis among vertically HCV-infected children. The aim of this study was to describe the longitudinal evolution of vertically acquired HIV/HCV co-infection in youths, in comparison with HCV infection alone. This was a retrospective, multicentre study including vertically HIV/HCV-co-infected patients and age- and sex-matched vertically HCV-mono-infected patients. Progression to advanced liver fibrosis, defined as F3 or more by elastography or METAVIR biopsy staging, and response to treatment were compared by means of univariate and multivariate regression analyses and Cox regression models. Sixty-seven co-infected patients were compared with 67 matched HCV-mono-infected patients. No progression to advanced liver disease was observed during the first decade. At a median age of 20.0 [19.0, 22.0] years, 26.7% co-infected vs 20% mono-infected had progressed to advanced fibrosis (P = .617). Peg-IFN/RBV for HCV treatment was given to 37.9% vs 86.6% (P-value

BACKGROUND/OBJECTIVE: Currently, there is no validated treatment for fetal cytomegalovirus (CMV). Two studies suggest that high-dose maternal valacyclovir decreases fetal viral load and improves outcomes in moderately-symptomatic fetuses. We offered valacyclovir in cases of fetal infection lacking ultrasound abnormalities or with non-severe infection. Maternal tolerability, fetal outcome and newborn blood viral load were evaluated in pregnancies of mothers receiving valacyclovir. STUDY DESIGN: We performed a case series including 8 pregnancies with fetal CMV classified as unaffected/mildly-moderately affected. Mothers received valacyclovir (8 g/24h) from fetal infection diagnosis to delivery. Standard newborn evaluation was performed, and viremia was determined in the first 48 h of life and compared according to length of maternal treatment and presence/absence of prenatal anomalies. RESULTS: Valacyclovir was administered at a median gestational age of 26.5 weeks (23.8-33.1) in 3 cases without fetal abnormalities, and 5 with mild/moderate abnormalities. Three were 3 first trimester primary infections, one non-primary infection, and in 4 the type of infection was unknown. Valacyclovir was well-tolerated. Fetal features did not progress. Three newborns were asymptomatic, and one was severely affected (bilateral chorioretinitis). The median newborn viral load (IQR) was 502 IU/mL (231-191781) with lower levels when maternal treatment was administered =10 weeks, and in cases without fetal abnormalities [median 234 IU/mL (228-711) vs. 4061 (292-510500) p = .18; and 234 IU/mL (228-379500) vs. 711 IU/mL (292-4061) p = .65, respectively], these differences being non-significant. CONCLUSIONS: Fetal CMV lesions remained stable with high-dose maternal valacyclovir. Newborn viral load was unchanged despite treatment duration and fetal/neonatal abnormalities. SUMMARY: Fetal cytomegalovirus lesions remained stable with high-dose maternal valacyclovir. Newborn viral load was unchanged despite treatment duration and fetal/newborn abnormalities.

BACKGROUND: Fidaxomicin, a narrow-spectrum antibiotic approved for Clostridioides (Clostridium) difficile infection (CDI) in adults, is associated with lower rates of recurrence than vancomycin; however, pediatric data are limited. This multicenter, investigator-blind, phase 3, parallel-group trial assessed the safety and efficacy of fidaxomicin in children. METHODS: Patients aged

We investigated the impact of baseline tuberculin skin tests (TSTs) and preventive isoniazid chemoprophylaxis on subsequent QuantiFERON-TB Gold In-Tube (QFT-GIT) assays performed after a 10- to 12-week window period in 114 children

Direct-acting antivirals (DAAs) for HCV treatment have improved tolerance and efficacy among adults, but experience in vertical transmission is scarce. In our vertically HIV/HCV co-infected youth cohort of 58 patients, DAA achieved excellent rates of cure among naïve and pretreated individuals. Treating vertically infected seems important as 29.6% displayed advanced fibrosis at treatment initiation.

OBJECTIVES: To evaluate the results of the first 24 months of a postprescription review with feedback-based antimicrobial stewardship program in a European referral children's hospital. STUDY DESIGN: We performed a pre-post study comparing antimicrobial use between the control (2015-2016) and the intervention periods (2017-2018) expressed in days of therapy/100 days present. Quality of prescriptions was evaluated by quarterly cross-sectional point-prevalence surveys. Length of stay, readmission rates, in-hospital mortality rates, cost of systemic antimicrobial agents, and antimicrobial resistance rates were included as complementary outcomes. RESULTS: Total antimicrobial use and antibacterial use significantly decreased during the intervention period (P = .002 and P = .001 respectively), and total antifungal use remained stable. A significant decline in parenteral antimicrobial use was also observed (P

Data for a total of 57 patients vertically coinfected with human immunodeficiency virus (HIV)/hepatitis C virus (HCV) and 365 HIV-monoinfected patients were compared until their transition to adult care. No differences regarding the dynamics of CD4 and/or CD8 T-cell counts during childhood were found. The coexistence of HCV does not increase the risk of disease progression in vertically HIV-infected patients.

Background: Enterovirus-A71 causes outbreaks of brainstem encephalitis, ranging from self-limited disease to acute flaccid paralysis. The aim of this study was to assess the role of cerebrospinal fluid (CSF) neopterin as a biomarker of disease severity in children with enterovirus-related brainstem encephalitis. Methods: A descriptive, prospective cohort study was conducted from April 2016 to March 2017 in a tertiary hospital. Pediatric patients with a diagnosis of brainstem encephalitis with or without myelitis due to enterovirus infection were enrolled. The final study group comprised a convenience sample including all patients with sufficient CSF volume for neopterin determination. The major variables considered in estimating the severity were the diagnosis of encephalomyelitis, the presence of lesions and extensive lesions on brain and spinal magnetic resonance imaging (MRI), hospital stay length greater than seven days, and sequelae at day 30. Results: Of 60 patients, CSF neopterin could be measured in 36. Median age was 26 months (interquartile range: 19 to 32). Thirty-three were diagnosed with brainstem encephalitis and three with encephalomyelitis. Enterovirus-A71 was the only identified genotype (25 of 25). CSF neopterin levels were elevated (>61 nmol/L) in 33 of 36 (92%), with a median of 347 nmol/L (interquartile range: 204 to 525). CSF neopterin was useful to distinguish patients with lesions on MRI (area under the receiver operating characteristic curve = 0.76; P = 0.02) and extensive lesions (area under the receiver operating characteristic curve = 0.76; P = 0.04). Conclusions: This study suggests an association between CSF neopterin levels and the presence of inflammatory lesions on MRI. (C) 2019 Elsevier Inc. All rights reserved.

BACKGROUND: Detection of cytomegalovirus (CMV) DNA by real-time polymerase chain reaction (rt-PCR) in dried blood spots (DBSs) collected for newborn screening has been assessed for retrospective diagnosis of congenital CMV (cCMV) infection, with variable results (sensitivities ranging from 34% to 100%). We aimed to assess the accuracy of this technique in Spain in a large patient series. METHODS: Ambispective, multicenter study including patients with confirmed cCMV from the Spanish Registry of cCMV patients. cCMV was established on the presence of CMV DNA in any body fluid, by positive culture findings or by molecular techniques during the first 2 weeks of life. Children in whom cCMV had been excluded were used as negative controls. Neonatal DBS samples were collected from both groups. The presence of CMV DNA was assessed by rt-PCR (RealStar CMV, Altona, Germany) in a central laboratory. RESULTS: One-hundred three patients and 81 controls from 10 hospitals were included. The performance of CMV DNA determination in DBS for the diagnosis of cCMV was as follows (95% confidence interval): sensitivity 0.56 (0.47-0.65), specificity 0.98 (0.91-0.99), positive likelihood ratio 22.81 (5.74-90.58) and negative likelihood ratio 0.45 (0.36-0.56). Sensitivity increased with the birth viral load (bVL) log category. In cCMV patients, lower bVL was the single variable associated with a negative DBS rt-PCR result (P = 0.017). CONCLUSIONS: The sensitivity of CMV rt-PCR in DBS in our series was low and correlated with the bVL. Thus, a negative DBS result would not rule out cCMV infection, especially in patients with a low viremia level at birth.

BACKGROUND: Congenital cytomegalovirus infection (CMVc) affects 0.7%-6% of recent births. Among its clinical manifestations are low weight and length at birth. OBJECTIVE: Describe the growth patterns of children with CMVc in their early years. METHODS: Observational, multicenter study of patients with CMVc. Anthropometric data were collected during the first 2 years of life and compared with World Health Organization standards. RESULTS: Anthropometric characteristics of 383 children with CMVc were studied, of which 198 (51%) were symptomatic at birth. At birth, 9% were small for gestational age (SGA) in terms of their weight and length and 17% had microcephaly. At 24 ± 3 months, 10% had a weight and length =2 SD, and 13% a head circumference =2 SD. Of those who were SGA at birth, at 24 ± 3 months >20% remained at =2 SD of their weight and length. Conversely, 75% of children with low weight or length at 24 ± 3 had not been SGA at birth. 20% of infants with microcephaly at birth remained with microcephaly, and 10% of those without microcephaly developed it at 24 ± 3 months. The average growth rate in length and weight was normal. Patients who were symptomatic at birth, premature and with motor and neurocognitive impairment had a significantly higher risk of low weight and length at 24 ± 3 months. CONCLUSION: Around 10% of children with CMVc are at =2 SD in weight, length and head circumference at 24 ± 3 months. The lack of adequate growth is associated with symptoms at birth, prematurity and motor and neurocognitive impairment. Growth impairment could be incorporated into the symptomatic spectrum of CMVc.

BACKGROUND: Available data to assess the optimal diagnostic approach in infants and preschool children at risk of tuberculosis (TB) are limited. METHODS: We conducted a prospective observational study in children younger than 5 years undergoing assessment with both tuberculin skin tests (TST) and QuantiFERON-TB Gold In-Tube (QFT-GIT) assays at 2 tertiary TB units in Barcelona, Spain. RESULTS: A total of 383 children were included. One of 304 participants considered uninfected developed active TB during follow-up {median [interquartile range (IQR)]: 47 [30; 48] months}, compared with none of 40 participants with latent TB infection [follow-up since completion of anti-TB treatment: 42 (32; 45) months]. Overall test agreement between TST and QFT-GIT was moderate (? = 0.551), but very good in children screened after TB contact (? = 0.801) and in Bacillus Calmette-Guérin (BCG)-unvaccinated children (? = 0.816). Discordant results (16.8%, all TST+/QFT-GIT-) were mainly observed in new-entrant screening and in BCG-vaccinated children. Children with indeterminate QFT-GIT results were on average younger than those with determinate results (median age: 12 vs. 30 months; P < 0.001). The sensitivity of TSTs and QFT-GIT assays in children with confirmed active TB was 100% (95% confidence interval: 79.4%-100%) and 93.7% (95% confidence interval: 69.8%-99.8%), respectively. In patients with latent TB infection or active TB, there was no correlation between age and antigen-stimulated interferon-? responses (r = -0.044; P = 0.714). CONCLUSIONS: In young BCG-unvaccinated children with recent TB contact, a dual testing strategy using TST and QFT-GIT in parallel may not be necessary. However, TST+/QFT-GIT- discordance is common, and it remains uncertain if this constellation indicates TB infection or not. In active TB, QFT-GIT assays do not perform better than TSTs.

Introduction: Mother-to-child transmission (MTCT) is relevant in the global epidemiology of human immunodeficiency virus (HIV), as it represents the main route of infection in children. The study objectives were to determine the rate of HIV-MTCT and its epidemiological trend between the Spanish-born and immigrant population in Catalonia in the period 2000-2014. Methods: A prospective observational study of mother-child pairs exposed to HIV, treated in 12 hospitals in Catalonia in the period 2000-2014. HIV-MTCT rate was estimated using a Bayesian logistic regression model. R and WinBUGS statistical software were used. Results: The analysis included 909 pregnant women, 1,009 pregnancies, and 1,032 children. Data on maternal origin was obtained in 79.4% of women, of whom 32.7% were immigrants, with 53.0% of these from sub-Saharan Africa. The overall HIV-MTCT rate was 1.4% (14/1,023; 95% CI; 0.8-2.3). The risk of MTCT-HIV was 10-fold lower in women with good virological control (P=.01), which was achieved by two-thirds of them. The proportion of immigrants was significantly higher in the period 2008-2014 (P

Normal procalcitonin (PCT) levels have been reported in adult pulmonary tuberculosis (TB) but have not been previously investigated in children. We aimed to assess PCT levels at diagnosis of TB in young children in a low-burden setting. In a cross-sectional observational study in a referral pediatric center in Barcelona (Spain), we assessed the value of PCT and other inflammatory markers (leucocyte counts, C-reactive protein, and erythrocyte sedimentation rate) in the diagnosis of TB in pre-school children (< 6 years at diagnosis, n = 45), as compared with two control groups (pneumococcal pneumonia, n = 25; and healthy controls, n = 49). Normal PCT levels were observed at diagnosis of TB in most cases, while C-reactive protein values and leucocyte counts were slightly elevated when compared to healthy controls. All three inflammatory biomarkers were significantly higher in children with pneumococcal pneumonia. CONCLUSIONS: In our study, PCT was not a useful diagnostic test for TB in young children. In a low-burden TB setting, PCT may be of some value in distinguishing pulmonary TB from pneumococcal pneumonia. What is Known: • Diagnosis of pediatric tuberculosis on clinical evidence is difficult, particularly in infants and small children. • Studies in adults with tuberculosis have mostly reported normal procalcitonin levels at diagnosis. What is New: • In pre-scholars with tuberculosis, erythrocyte sedimentation rate and white blood cell counts were higher than in healthy controls, but procalcitonin was not. • Procalcitonin may be useful in the differential diagnosis of intrathoracic tuberculosis and pneumococcal pneumonia.

Vertical human immunodeficiency virus (HIV) infection has decreased in industrialized countries in recent decades, but there are no studies on the mechanisms of HIV transmission among infected children in Spain. Our aim was to study the characteristics and trends of diagnoses of vertically HIV-infected children in Spain from 2004 to 2013.Vertically HIV-infected children were selected if they were diagnosed from 2004 to 2013, were aged 0 to 18 years old, and were included in the Cohort of the Spanish Pediatric HIV Network (CoRISpe). Demographic, clinical, immunological, and virological data at diagnosis were obtained. The rate of diagnoses of vertically HIV-infected children was calculated as the number of cases per 100,000 inhabitants. Obstetric data of mothers of Spanish children and prophylaxis at childbirth and postpartum were obtained.A total of 218 HIV-infected children were included in the study. Of this sample, 182 children (83.5%) were perinatally HIV infected, and 125 out of those 182 children (68.7%) were born in Spain. The vertically HIV-infected Spanish children were diagnosed earlier and were in better clinical and immunological condition at diagnosis than were foreign children. The rate of vertically HIV-infected children declined from 0.09 in 2004 to 0.03 in 2013 due to the decrease in the rate of children born in Spain (0.08 in 2004 vs 0.01 in 2013). A total of 60 out of 107 mothers (56.1%) of Spanish children were diagnosed at or after childbirth. However, this number declined between 2004 and 2013.The rate of new HIV diagnoses of vertically HIV-infected children decreased significantly between 2004 and 2013 from 0.09 to 0.03 per 100,000 inhabitants.

INTRODUCTION: Adolescents may present with adult-type pulmonary tuberculosis (TB), including cavity disease in upper lobes and smear-positive sputum, which involves a significant transmission risk for social and family contacts. PATIENTS AND METHODS: A retrospective (2007-2012) observational study of a case series of TB was conducted in children and adolescents (12 years at diagnosis are compared. RESULTS: The series consisted of 124 patients (56.5% males, median age: 4.0 years). In half of the cases, the patient was of immigrant origina and TB was diagnosed after clinical-radiological suspicion, intra-thoracic disease being the most common (91.9%). Cultures yielded positive results in one third of cases (37.9%) and isolates were sensitive to oral first-line anti-TB agents in 100%. Median (interquartile range) duration of treatment was 6 (6-9) months, directly observed therapy was needed in 10 patients, and there was a satisfactory outcome after treatment in 98.4%. Among adolescents, TB was more prevalent in females (63.2%) and immigrant patients (68.4%), comorbidity at diagnosis and lung cavity forms were more common, and the source case was identified only in 21.1% of the patients. CONCLUSION: Adult-type pulmonary TB is common among adolescents, may be associated with underlying medical conditions, and is often diagnosed late, posing a significant transmission risk to the community.

Administration of antiretroviral drugs to individuals exposed to, but not infected by, HIV has been shown to reduce the risk of transmission. The efficacy of pre-exposure prophylaxis (PrEP) makes it obligatory to include it in an integral program of prevention of HIV transmission, together with other measures, such as use of the condom, training, counseling, and appropriate treatment of infected individuals. In this document, the AIDS Study Group (GeSIDA) of the Spanish Society of Infectious Diseases and Clinical Microbiology (Sociedad Española de Enfermedades Infecciosas y Microbiología Clínica [SEIMC]) provides its views on this important subject. The available evidence on the usefulness of PrEP in the prevention of transmission of HIV is presented, and the components that should make up a PrEP program and whose development and implementation are feasible in Spain are set out.

OBJECTIVE: Several pieces of evidence indicate that HIV-infected adults undergo premature aging. The effect of HIV and antiretroviral therapy (ART) exposure on the aging process of HIV-infected children may be more deleterious since their immune system coevolves from birth with HIV. DESIGN: Seventy-one HIV-infected (HIV+), 65 HIV-exposed-uninfected (HEU), and 56 HIV-unexposed-uninfected (HUU) children, all aged 0-5 years, were studied for biological aging and immune senescence. METHODS: Telomere length and T-cell receptor rearrangement excision circle levels were quantified in peripheral blood cells by real-time PCR. CD4 and CD8 cells were analysed for differentiation, senescence, and activation/exhaustion markers by flow cytometry. RESULTS: Telomere lengths were significantly shorter in HIV+ than in HEU and HUU children (overall, P < 0.001 adjusted for age); HIV+ ART-naive (42%) children had shorter telomere length compared with children on ART (P = 0.003 adjusted for age). T-cell receptor rearrangement excision circle levels and CD8 recent thymic emigrant cells (CD45RACD31) were significantly lower in the HIV+ than in control groups (overall, P = 0.025 and P = 0.005, respectively). Percentages of senescent (CD28CD57), activated (CD38HLA-DR), and exhausted (PD1) CD8 cells were significantly higher in HIV+ than in HEU and HUU children (P = 0.004, P < 0.001, and P < 0.001, respectively). Within the CD4 cell subset, the percentage of senescent cells did not differ between HIV+ and controls, but programmed cell death receptor-1 expression was upregulated in the former. CONCLUSIONS: HIV-infected children exhibit premature biological aging with accelerated immune senescence, which particularly affects the CD8 cell subset. HIV infection per se seems to influence the aging process, rather than exposure to ART for prophylaxis or treatment.

To assess the safety and efficacy of rilpivirine in combination with emtricitabine and tenofovir (RPV/FTC/TDF) as a once-daily single-tablet regimen (STR) in HIV-1-infected children and adolescents we performed a multicenter case series study of HIV-1-infected patients. Inclusion criteria were initiation of therapy with RPV/FTC/TDF before the age of 18. Patients were divided into undetectable viral load (uVL) group, HIV-1 RNA < 20 copies/mL on stable combined antiretroviral therapy (cART), and detectable viral load (dVL) group, HIV-1 RNA = 20 copies/mL at RPV/FTC/TDF initiation. Patients were monitored from the date of RPV/FTC/TDF initiation until June 30, 2015, RPV/FTC/TDF discontinuation or failure to follow-up. Seventeen patients (8 in uVL and 9 in dVL group) with age between 11.6 and 17.6 were included. Reasons for switching were toxicity (n = 4) and simplification (n = 4) in uVL; viral failure (n = 8) and cART initiation (n = 1) in the dVL group. After a median follow-up of 90 (uVL) and 40 weeks (dVL), 7/8 (86%) patients maintained and 8/9 (89%) achieved and maintained HIV-1 suppression. Median CD4 count increased from 542 to 780/µL (uVL, P = 0.069) and 480 to 830/µL (dVL, P = 0.051). Five patients (2 in uVL and 3 in dVL) improved their immunological status from moderate to no immunosuppression. Serum lipid profiles improved in both groups; cholesterol dropped significantly in the dVL group (P = 0.008). Grade 1 laboratory adverse events (AEs) were observed in 3 patients. No clinical AEs occurred. Adherence was complete in 9 patients (5 in uVL and 4 in dVL); 1 adolescent interrupted treatment. Once-daily STR with RPV/FTC/TDF may be a safe and effective choice in selected HIV-1-infected adolescents and children.

Maternal combined antiretroviral therapy (cART) successfully prevents HIV mother-to-child transmission but also causes hematological toxicity in the HIV-exposed uninfected (HEU) infant. We performed a single-center prospective observational study. Hematological toxicity during the first year of life (at 3 and 6 weeks, and 3, 6, and 12 months) was compared between HEU infants born in two different time periods: P1 (2000-2001) and P2 (2007-2013). Mother-infant pairs in P1 (n = 55) and P2 (n = 48) mainly differed in maternal ethnic origin, HIV route of transmission, and cART regimens. Anemia and neutropenia were both less common in P2 than P1, albeit not significantly. Earlier normalization of red blood cell mean corpuscular volume levels in P2 infants suggests that current cART maternal regimens and shorter neonatal prophylaxis are less toxic. Leukocyte, lymphocyte, and platelet counts remained within normal values during follow-up, without differences between groups. CONCLUSION: New cART regimens have had very little impact on the hematological toxicity in HEU infants. WHAT IS KNOWN: • Antiretroviral drugs during pregnancy and the neonatal period very effectively prevent mother-to-child transmission of HIV infection. • Hematological toxicity has been widely reported among HIV-exposed uninfected children. What is New: • In HIV-exposed uninfected children, hematological toxicity is still mainly caused by exposure to zidovudine. • New antiretroviral drugs have very little impact on hematological toxicity among HIV-exposed uninfected children.

BACKGROUND: Renal disease is a leading cause of morbidity in HIV-infected adults in the highly active antiretroviral therapy (HAART) era. Cystatin C has been proposed as a more sensitive marker of renal function, but it may be affected by ongoing inflammation. We aimed to study the cystatin C levels in a cohort of HIV-infected pediatric patients at 3 Spanish centers. METHODS: This is a multicenter cross-sectional observational study. Renal function was assessed by means of first morning urine protein/creatinine and albumin/creatinine ratios and creatinine-estimated glomerular filtration rates (GFRs), together with the following inflammation markers: cystatin C, reactive C protein, ß-2-microglobulin and 25(OH)-vitamin D levels. A control group of healthy children and adolescents was used. RESULTS: Eighty-three patients (51 females, median age: 13.3 years; 32 males, median age: 13.6 years) and 44 controls (24 females, median age: 12.2 years; 20 males, median age: 10.9 years) were included. Among the former, mean CD4 cell count was 860/mm, 29(35%) patients had a previous AIDS diagnosis, 73(88%) were on HAART and HIV viremia was undetectable in 61(73%). No differences in cystatin C levels were observed between the 2 groups. In HIV-infected patients, cystatin C levels correlated with GFR (r = -0.27; P = 0.01), age at first HAART (r = -0.21; P = 0.05), and ß-2-microglobulin (r = 0.569; P < 0.01). In multivariate analysis, lower GFR (P = 0.014) and higher ß-2-microglobulin levels (P = 0.001) remained as independent risk factors for higher cystatin C values. CONCLUSIONS: Cystatin C values were associated with GFR and ß-2-microglobulin. Cystatin C may be useful as a marker of renal function in HIV-infected pediatric patients, independently of ongoing inflammation or viremia.

Isoniazid exposure causes dose-dependent pyridoxine deficiency. Recently, the recommended dosage of isoniazid in children was increased from 5 (4-6) to 10 (10-15) mg/kg/day. We aimed to analyze longitudinally pyridoxine levels in a cohort of previously healthy children and adolescents treated with isoniazid. Mild symptom-free pyridoxine deficiency was observed in 4/75 (5.6%) and 3/40 (7.5%) at baseline and at 3-month follow-up, respectively. Classical age-related risk factors identified patients at risk of pyridoxine deficiency. Our preliminary results support current recommendations regarding pyridoxine supplementation in healthy children.

Background: Metabolic syndrome (MetS) is considered an independent risk factor for developing cardiovascular disease. It is well known that the prevalence of metabolic disorders have increased in pediatric HIV-infected children. The objective of this study is to assess the prevalence and characteristics of MetS in HIV-infected children and adolescents in Spain. Methods: A cross-sectional multicenter study in 152 patients from the pediatric cohort of the Spanish AIDS Research Network (CoRISpe) was performed. MetS was defined according to the new International Diabetes Federation (IDF) diagnostic criteria and the modified National Cholesterol Education Program Adult Treatment Panel III (NCEP-ATP III) criteria. Measurements included anthropometry, waist circumference, blood pressure, fasting lipids, glucose and insulin and lipodystrophy assessment. Demographic, clinical, immunological, virological and antiretroviral therapy data were obtained from the Network database. Results: An abnormally low high-density lipoprotein-cholesterol level was the most prevalent disturbance (21.05%) found. Three patients met IDF criteria for MetS (1.97%), and MetS was significantly associated with lipohypertrophy (P=0.029) in the analysis. When the modified NCEP-ATP III criteria were used, the prevalence of MetS was 5.92% (9 patients), and MetS was significantly associated with Tanner stage >= 2 (P= 0.041), lipohypertrophy (P= 0.001) and higher Z scores for weight and body mass index (P= 0.002 and P< 0.001). Insulin resistance was observed in 17 patients (11.18%) and was associated with MetS (as per the modified NCEP-ATP III criteria) (P=0.03) and lower high-density lipoprotein-cholesterol values (P=0.036). Conclusions: The prevalence of MetS in our cohort was 1.97% or 5.92%, depending on the diagnostic criteria used. MetS should be actively assessed, particularly in children who show lipohypertrophy.

BACKGROUND: The use of nevirapine in HIV-infected pregnant women is discouraged due to its potential to cause hepatotoxicity. There is limited information available on the toxicity in non-HIV infected newborn exposed to this drug during pregnancy. The aim of the study is to determine the extent of hepatotoxicity in the newborn exposed to nevirapine and HIV during pregnancy. METHODS: A cross-sectional, observational, multicenter study was conducted on a cohort of healthy infants born to HIV-infected mothers, in whom the first determination of alanine aminotransferase (ALT), before 6weeks of age, was collected. Patients were allocated to 2groups according to exposure to nevirapine during pregnancy. Hepatotoxicity was rated according to the AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events (DAIDS). RESULTS: This study included 160newborns from 159pregnancies (88exposed to nevirapine-based regimens and 71 exposed to protease inhibitors-based therapies). No cases of hepatotoxicity were observed according to the DAIDS Table for Grading. Two cases of ALT above normal values (2.8%; 95%CI: 0.3-9.8%) were observed in patients not exposed to nevirapine, and one case (1.1%; 95%CI: 0.0-6.1%) in the group exposed to nevirapine (P=.585). CONCLUSION: The lack of differences between groups suggests that highly active antiretroviral treatment regimens including nevirapine administered during pregnancy do not involve a higher risk of liver disease compared to other treatment combinations.

Worldwide, the benefits of combined antiretroviral (ARV) therapy in morbidity and mortality due to perinatally acquired human immunodeficiency virus infection are beyond question and outweigh the toxicity these drugs have been associated with in HIV-infected children and adolescents to date. In puberty, abnormal body fat distribution is stigmatizating and leads to low adherence to ARV treatment. The other metabolic comorbidities (mitochondrial toxicity, dyslipidemias, insulin resistance and low bone mineral density) and renal toxicity, albeit nonsymptomatic in most children, are increasingly being reported and potentially put this population at risk for early cardiovascular or cerebrovascular atherosclerotic disease, diabetes, pathologic fractures or premature renal failure in the third and fourth decades of life. Evidence from available studies is limited because of methodological limitations and also because of several HIV-unrelated factors influencing, to some degree, the development of these conditions. Current recommendations for the prevention, diagnosis, monitoring and treatment of metabolic and renal adverse effects in HIV-children and adolescents are based on adult studies, observational pediatric studies and experts' consensus. Healthy lifestyle habits (regarding diet, exercise and refraining from toxic substances) and wise use of ARV options are the only preventive tools for the majority of patients. Should abnormal findings arise, switches in one or more ARV drugs have proved useful. Specific therapies are also available for some of these comorbidities, although the experience in the pediatric age is still very scarce. We aim to summarize the epidemiological, clinical and therapeutic aspects of metabolic and renal adverse effects in vertically HIV-infected children and adolescents.

BACKGROUND: During the last decades remarkable scientific advances have been made toward the prevention of HIV mother-to-child transmission, in particular in developed nations. The aim of this review was to analyze the latest findings and available international recommendations on the prevention of HIV mother-to-child transmission in high-income countries. METHODS: We performed a literature search of the Cochrane Library, MEDLINE by PubMed and EMBASE from database inception through June 2014, using the following terms: HIV, mother-to-child transmission and mother-to-child-transmission prevention. All types of articles in the English language were included. US and available European guidelines were searched and included in the analysis. RESULTS: One hundred fifty articles were selected for inclusion in this review. CONCLUSIONS: Global epidemiology of HIV infection is rapidly evolving, in particular in high-resource countries. The interpretation of clinical and epidemiological studies is crucial for the development of evidence-based recommendations to guide the management of HIV mother-to-child transmission. Although significant progress has been made, heterogeneity between countries in specific interventions still exists, which may address future research.

This is a cross-sectional study of 15 aviremic chronic HIV-infected children revealing no differences in immune activation (IA; HLA-DRCD38 CD4 and CD8 T cells, and sCD14) and microbial translocation (MT; lipopolysaccharides (LPS) and 16S rDNA) among HIV-infected patients under combined antiretroviral treatment (cART; n = 10) or ritonavir-boosted protease inhibitor monotherapy (mtPI/rtv; n = 5). In both cases, IA and MT were lower in healthy control children (n = 32). This observational study suggests that ritonavir boosted protease inhibitor monotherapy (mtPI/rtv) is not associated with an increased state of IA or MT as compared with children receiving cART.

BACKGROUND: Combination antiretroviral therapy (cART) generally suppresses the replication of the human immunodeficiency virus type 1 (HIV-1) but does not cure the infection, because proviruses persist in stable latent reservoirs. It has been proposed that low-level proviral reservoirs might predict longer virologic control after discontinuation of treatment. Our objective was to evaluate the impact of very early initiation of cART and temporary treatment interruption on the size of the latent HIV-1 reservoir in vertically infected children. METHODS: This retrospective study included 23 perinatally HIV-1-infected children who initiated very early treatment within 12 weeks after birth (n = 14), or early treatment between week 12 and 1 year (n = 9). We measured the proviral reservoir (CD4(+) T-cell-associated HIV-1 DNA) in blood samples collected beyond the first year of sustained virologic suppression. RESULTS: There is a strong positive correlation between the time to initiation of cART and the size of the proviral reservoir. Children who initiated cART within the first 12 weeks of life showed a proviral reservoir 6-fold smaller than children initiating cART beyond this time (P < .01). Rapid virologic control after initiation of cART also limits the size of the viral reservoir. However, patients who underwent transient treatment interruptions showed a dramatic increase in the size of the viral reservoir after discontinuation. CONCLUSIONS: Initiation of cART during the first 12 weeks of life in perinatally HIV-1-infected children limits the size of the viral reservoir. Treatment interruptions should be undertaken with caution, as they might lead to fast and irreversible replenishment of the viral reservoir.

BACKGROUND: Adult patients receiving anti-TNFa drugs are at increased risk of tuberculosis (TB), but studies in pediatric populations are limited, and the best strategy for latent tuberculosis infection (LTBI) screening in this population remains controversial. We describe the prevalence of LTBI prior to anti-TNFa therapy and the long-term follow-up after biological treatment initiation in a cohort of children and adolescents. METHODS: Cohort observational study in children and adolescents receiving anti-TNFa agents in a tertiary-care pediatric hospital. LTBI was ruled out prior to the implementation of anti-TNFa drugs by tuberculin skin test (TST), and, from March 2012 on, QuantiFERON Gold-In Tube test (QTF-G). During anti-TNFa treatment, patients were evaluated every 6 months for TB with history and physical examination. TST/QTF-G were not repeated unless signs or symptoms consistent with TB arose or there was proven TB contact. RESULTS: The final cohort consisted of 221 patients (56.1% female; 261 treatments), of whom 51.7%/30.0%/17.3% were treated with etanercept/adalimumab/infliximab, respectively, for a variety of rheumatic diseases (75.6%), inflammatory bowel disease (20.8%), and inflammatory eye diseases (3.6%). The median (IQR) age at diagnosis of the primary condition was 6.8 years (2.7-11.0) and the duration of the disease before implementing the anti-TNFa agent was 1.8 years (0.6-4.2). LTBI was diagnosed in 3 adolescent girls (prevalence rate: 1.4%; 95% CI: 0.4-4.2) affected with juvenile idiopathic arthritis: TST tested positive in only 1, while QTF-G was positive in all cases (including 2 patients already on etanercept). They all received antiTB chemoprophylaxis and were later (re)treated with etanercept for 24-29 months, without incidences. No incident cases of TB disease were observed during the follow-up period under anti-TNFa treatment of 641 patients-year, with a median (IQR) time per patient of 2.3 years (1.4-4.3). CONCLUSIONS: In our study, the prevalence of LTBI (1.4%) was similar to that reported in population screening studies in Spain; no incident cases of TB disease were observed. In low-burden TB settings, initial screening for TB in children prior to anti-TNFa treatment should include both TST and an IGRA test, but systematic repetition of LTBI immunodiagnostic tests seems unnecessary in the absence of symptoms or known TB contact.