Atherosclerosis in HIV infected children and adolescents : related physiopatholgycal factors

Tesis inédita de la Universidad Complutense de Madrid, Facultad de Medicina, Departamento de Pediatría, leída el 03-04-2014Entre otras patologías asociadas al envejecimiento prematuro, se ha descrito en pacientes infectados por el VIH un aumento de enfermedad arteriosclerótica a una edad relativamente joven. A pesar de ser foco de intensa investigación, las causas del aumento del riesgo cardiovascular en esta población no se conocen con exactitud, debido probablemente a que se trata de un proceso multifactorial. Actualmente existen diferentes métodos no invasivos que permiten evaluar el desarrollo de enfermedad cardiovascular, tales como la medición del engrosamiento de las capas íntima y media arterial (grosor íntima media - GIM), que pueden verse complementados por la determinación de múltiples biomarcadores. En la actualidad, disponer de herramientas que permitan identificar a los sujetos con mayor riesgo de presentar complicaciones asociadas resulta prioritario especialmente en la población única de pacientes con infección de transmisión vertical, con el fin de establecer medidas preventivas que podrían resultar en una mayor calidad de vida y una mejora en la esperanza de vida. En este contexto, los objetivos principales de esta Memoria son:1) Analizar los valores de las GIM en una cohorte de niños y adolescentes infectados por el VIH, en comparación con controles sanos.2) Investigar los posibles factores (clínicos, epidemiológicos, inmunovirológicos e inflamatorios) asociados con un aumento del GIM.3) Analizar la funcionalidad de las lipoproteinas de alta densidad en el contexto de lainfección por el VIH, y su posible papel en el desarrollo de enfermedad cardiovascular.4) Identificar posibles marcadores de complicaciones no asociadas a SIDA en esta población.Se diseñó un estudio multicéntrico, observacional, prospectivo, en el que se incluyeron, entre junio y diciembre de 2011, niños y adultos jóvenes en seguimiento en los hospitales que integran la Cohorte de Madrid de niños y adolescentes infectados por el VIH, así como controles sanos de características comparables. Se determinó el GIM mediante ecografía, y se extrajeron muestras de sangre para determinar perfil lípidico, insulina, glucosa y biomarcadores inflamatorios y cardíacos [PCR, interleucina 6 , mieloperoxidasa , ligando CD40, molécula de adhesión vascular soluble ( sVCAM ), proteína quimio atrayente de monocitos (MCP- 1), P-selectina y CD14 soluble]. La expresión de marcadores de activación y senescencia en células T se midieron por citometría de flujo. En un subgrupo de pacientes, se estudió la función anti-inflamatoria de las lipoproteínas de alta densidad (HDL). En resumen, los resultados recogidos en esta Memoria demuestran que los sujetos infectados por el VIH de forma perinatal presentan aterosclerosis carotidea precoz, en comparación con controles no infectados. Las técnicas ecográficas no invasivas resultan seguras y bien toleradas y permiten el estudio de enfermedad vascular subclínica en población pediátrica. Los niños y adolescentes infectados por el VIH presentan niveles más altos de activación y senescencia inmune, a menudo relacionados con la presencia de carga viral detectable. En ausencia de medidas preventivas específicas, lograr la supresión viral y un adecuado control de las alteraciones metabólicas asociadas al TAR deben ser una prioridad en el manejo de estos pacientes, con el fin de prevenir las enfermedades cardiovasculares en el futuro. La inversión del cociente CD4/CD8 podría permitir identificar a los sujetos en situación de riesgo, y por tanto éste debe ser un marcador a considerar en cuanto al diseño de estrategias orientadas al diagnóstico y tratamiento de los fenómenos de inflamación y activación inmune, en la búsqueda de una mayor calidad y esperanza de vida en la población de pacientes infectados por el VIH por transmisión vertical.Depto. de Salud Pública y Materno - InfantilFac. de MedicinaTRUEunpu

Nutritional Supplementation to Increase Influenza Vaccine Response in Children Living With HIV: A Pilot Clinical Trial

Final results of this work have been presented at the following meetings: 36rd Annual Meeting of the European Society for Pediatric Infectious Diseases (ESPID 2018), Malmö, Sweden, 28th May-June 2nd, 2018. (Ref. ESP18-0517).Aims: Vaccine response is poor among children living with HIV. The gut microbiota has been identified as a potential target to improve vaccine immunogenicity, but data are scarce in the context of HIV infection. Methods: Pilot, double-blind, randomized placebo-controlled trial in which 24 HIV-infected children were randomized to receive a mixture of symbiotics, omega-3/6 fatty acids, and amino acids or placebo for 4 weeks, each in combination with ART, and were then immunized against influenza. Vaccine response and safety of the nutritional supplementation were the primary outcomes. Results: Eighteen HIV-infected children completed the follow-up period (mean age 11.5 ± 4.14 years, 61% female). The nutritional supplement was safe but did not enhance the response to the influenza vaccine. A 4-fold rise in antibody titers was obtained in only 37.5% of participants in the intervention arm vs. 40% in the placebo. No immunological or inflammatory predictors of vaccine response were identified. Conclusions: In this exploratory study, a 4-week course of symbiotics did not increase influenza vaccine immunogenicity in HIV-infected children. Larger studies are warranted to address the potential of modulating the microbiome in children living with HIV.This work was funded by the Instituto de Salud Carlos III-Fondos FEDER (grant number CB21/17/00025), Acción Estratégica en Salud (PI13/0422, PI17/01283, PI18/00154, and PI18CIII/00009). TS and SS-V have been funded by the Instituto de Salud Carlos III-Fondos FEDER (BA21/00022 and BA21/00017). The funding bodies did not have a role in the design or conduct of the study, the analysis and interpretation of the results, and the writing of the report or the decision to publish. The authors would like to particularly acknowledge all the children and adolescents as well as their families for their participation in this study. They acknowledge the Spanish Pediatric HIV infection Group CORISPE and the Pediatric HIV BioBank integrated in the Spanish AIDS Research Network and collaborating Centers [supported by the Instituto de Salud Carlos III, Spanish Health Ministry (Grant n◦ RD06/0006/0035)] for its collaboration and cession of clinical information and samples used in this work. Nutricion Médica S.L., manufactured and packaged the nutritional product under investigation. Final results of this work have been presented at the following meetings: 36rd Annual Meeting of the European Society for Pediatric Infectious Diseases (ESPID 2018), Malmö, Sweden, 28th May-June 2nd, 2018. (Ref. ESP18-0517).S

Nutritional Supplementation to Increase Influenza Vaccine Response in Children Living With HIV: A Pilot Clinical Trial

AimsVaccine response is poor among children living with HIV. The gut microbiota has been identified as a potential target to improve vaccine immunogenicity, but data are scarce in the context of HIV infection.MethodsPilot, double-blind, randomized placebo-controlled trial in which 24 HIV-infected children were randomized to receive a mixture of symbiotics, omega-3/6 fatty acids, and amino acids or placebo for 4 weeks, each in combination with ART, and were then immunized against influenza. Vaccine response and safety of the nutritional supplementation were the primary outcomes.ResultsEighteen HIV-infected children completed the follow-up period (mean age 11.5 ± 4.14 years, 61% female). The nutritional supplement was safe but did not enhance the response to the influenza vaccine. A 4-fold rise in antibody titers was obtained in only 37.5% of participants in the intervention arm vs. 40% in the placebo. No immunological or inflammatory predictors of vaccine response were identified.ConclusionsIn this exploratory study, a 4-week course of symbiotics did not increase influenza vaccine immunogenicity in HIV-infected children. Larger studies are warranted to address the potential of modulating the microbiome in children living with HIV

Effect of a nutritional intervention on the intestinal microbiota of vertically HIV-infected children: The pediabiota study

This article belongs to the Special Issue Role of Prebiotics and Probiotics in Health and Disease.[Aims]: The gut microbiota exerts a critical influence in the immune system. The gut microbiota of human virus immunodeficiency (HIV)-infected children remains barely explored. We aimed to characterize the fecal microbiota in vertically HIV-infected children and to explore the effects of its modulation with a symbiotic nutritional intervention.[Methods]: A pilot, double blind, randomized placebo-controlled study including HIV-infected children who were randomized to receive a nutritional supplementation including prebiotics and probiotics or placebo for four weeks. HIV-uninfected siblings were recruited as controls. The V3–V4 region of the 16S rRNA gene was sequenced in fecal samples.[Results]: 22 HIV-infected children on antiretroviral therapy (ART) and with viral load (VL) <50/mL completed the follow-up period. Mean age was 11.4 ± 3.4 years, eight (32%) were male. Their microbiota showed reduced alpha diversity compared to controls and distinct beta diversity at the genus level (Adonis p = 0.042). Patients showed decreased abundance of commensals Faecalibacterium and an increase in Prevotella, Akkermansia and Escherichia. The nutritional intervention shaped the microbiota towards the control group, without a clear directionality.[Conclusions]: Vertical HIV infection is characterized by changes in gut microbiota structure, distinct at the compositional level from the findings reported in adults. A short nutritional intervention attenuated bacterial dysbiosis, without clear changes at the community level.[Summary]: In a group of 24 vertically HIV-infected children, in comparison to 11 uninfected controls, intestinal dysbiosis was observed despite effective ART. Although not fully effective to restore the microbiota, a short intervention with pre/probiotics attenuated bacterial dysbiosis.This work was funded by the Instituto de Salud Carlos III, Acción Estratégica en Salud (PI13/0422, ICI14/00207, PI17/01283, and PI18/00042) and by an agreement between the Instituto de Salud Carlos III and the Fundación Asociación Española contra el Cáncer within the ERANET TRANSCAN-2 program, grant number AC17/00022. CoRISpe is integrated in the Spanish AIDS Research Network (RIS), supported by the Instituto de Salud Carlos III (Grant nº RD06/0006/0034 and nº RD06/0006/0035). TS was funded by a 2014 Research Fellowship Award from the European Society of Pediatric Infectious Diseases (ESPID) and is now funded by the Spanish Ministry of Science and Innovation- Instituto de Salud Carlos III and Fondos FEDER (Contratos Juan Rodés R16/00021). Nutricion Médica NM, SL, manufactured and packaged the nutritional product under investigation.Peer reviewe

Targeting the Gut Microbiota of Vertically HIV-Infected Children to Decrease Inflammation and Immunoactivation: A Pilot Clinical Trial

Aims: Children with HIV exhibit chronic inflammation and immune dysfunction despite antiretroviral therapy (ART). Strategies targeting persistent inflammation are needed to improve health in people living with HIV. The gut microbiota likely interacts with the immune system, but the clinical implications of modulating the dysbiosis by nutritional supplementation are unclear. Methods: Pilot, double-blind, randomized placebo-controlled trial in which 24 HIV-infected on ART were randomized to supplementation with a daily mixture of symbiotics, omega-3/6 fatty acids and amino acids, or placebo four weeks, in combination with ART. We analyzed inflammatory markers and T-cell activation changes and their correlations with shifts in fecal microbiota. Results: Twenty-four HIV-infected children were recruited and randomized to receive a symbiotic nutritional supplement or placebo. Mean age was 12 ± 3.9 years, 62.5% were female. All were on ART and had HIV RNA < 50/mL. We did not detect changes in inflammatory (IL-6, IL-7, IP-10), microbial translocation (sCD14), mucosal integrity markers (IFABP, zonulin) or the kynurenine to tryptophan ratio, or changes in markers of the adaptive immune response in relation to the intervention. However, we found correlations between several key bacteria and the assessed inflammatory and immunological parameters, supporting a role of the microbiota in immune modulation in children with HIV. Conclusions: In this exploratory study, a four-week nutritional supplementation had no significant effects in terms of decreasing inflammation, microbial translocation, or T-cell activation in HIV-infected children. However, the correlations found support the interaction between gut microbiota and the immune system

Inter-Rater Variability in the Evaluation of Lung Ultrasound in Videos Acquired from COVID-19 Patients

12 páginas, 7 figuras, 1 tablaLung ultrasound (LUS) allows for the detection of a series of manifestations of COVID-19, such as B-lines and consolidations. The objective of this work was to study the inter-rater reliability (IRR) when detecting signs associated with COVID-19 in the LUS, as well as the performance of the test in a longitudinal or transverse orientation. Thirty-three physicians with advanced experience in LUS independently evaluated ultrasound videos previously acquired using the ULTRACOV system on 20 patients with confirmed COVID-19. For each patient, 24 videos of 3 s were acquired (using 12 positions with the probe in longitudinal and transverse orientations). The physicians had no information about the patients or other previous evaluations. The score assigned to each acquisition followed the convention applied in previous studies. A substantial IRR was found in the cases of normal LUS (κ = 0.74), with only a fair IRR for the presence of individual B-lines (κ = 0.36) and for confluent B-lines occupying 50% (κ = 0.50). No statistically significant differences between the longitudinal and transverse scans were found. The IRR for LUS of COVID-19 patients may benefit from more standardized clinical protocols.This research was partially funded by CDTI (Spanish acronym: Centre for Industrial Tech- nological Development), funding number COI-20201153. Partially supported by the Google Cloud Research Credits program with the funding number GCP19980904, by the project RTI2018-099118- A-I00 founded by MCIU/AEI/FEDER UE and by the European Commission–NextGenerationEU, through CSIC’s Global Health Platform (PTI Salud Global)

Viruses and Mycoplasma pneumoniae are the main etiological agents of community-acquired pneumonia in hospitalized pediatric patients in Spain

[Objectives]: To describe the etiology of community-acquired pneumonia (CAP) in hospitalized children in Spain and analyze the predictors of the etiology.[Hypothesis]: The different etiological groups of pediatric CAP are associated with different clinical, radiographic, and analytical data.[Design]: Observational, multicenter, and prospective study.[Patient selection]: This study included children aged 1 month to 17 years with CAP, who were hospitalized between April 2012 and May 2019.[Methods]: An extensive microbiological workup was performed. The clinical, radiographic, and analytical parameters were analyzed for three etiological groups.[Results]: Among the 495 children included, at least one causative pathogen was identified in 262 (52.9%): pathogenic viruses in 155/262 (59.2%); atypical bacteria (AB), mainly Mycoplasma pneumonia, in 84/262 (32.1%); and typical bacteria (TyB) in 40/262 (15.3%). Consolidation was observed in 89/138 (64.5%) patients with viral CAP, 74/84 (88.1%) with CAP caused by AB, and 40/40 (100%) with CAP caused by TyB. Para-pneumonic pleural effusion (PPE) was observed in 112/495 (22.6%) patients, of which 61/112 (54.5%) presented a likely causative pathogen: viruses in 12/61 (19.7%); AB in 23/61 (37.7%); and TyB in 26/61 (42.6%). Viral etiology was significantly frequent in young patients and in those with low oxygen saturation, wheezing, no consolidation, and high lymphocyte counts. CAP patients with AB as the etiological agent had a significantly longer and less serious course as compared to those with other causative pathogens.[Conclusions]: Viruses and M. pneumoniae are the main causes of pediatric CAP in Spain. Wheezing, young age, and no consolidation on radiographs are indicative of viral etiology. Viruses and AB can also cause PPE. Since only a few cases can be directly attributed to TyB, the indications for antibiotics must be carefully considered in each patient.Instituto de Investigación Hospital 12 de Octubre (i+12), Grant/Award Number: AY191212‐1; Instituto de Salud Carlos III (Ministry of Economy, Industry and Competitiveness) and co‐funded by the European Regional Development Funds, Grant/Award Number: Project PI17/01458; Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Grant/Award Number: PCAPE 2011_0025 Register 320/11; Research Project of Universidad Europea de Madrid, Grant/Award Number: 2017/UEM03Peer reviewe

Time to Switch to Second-line Antiretroviral Therapy in Children With Human Immunodeficiency Virus in Europe and Thailand.

Background: Data on durability of first-line antiretroviral therapy (ART) in children with human immunodeficiency virus (HIV) are limited. We assessed time to switch to second-line therapy in 16 European countries and Thailand. Methods: Children aged <18 years initiating combination ART (≥2 nucleoside reverse transcriptase inhibitors [NRTIs] plus nonnucleoside reverse transcriptase inhibitor [NNRTI] or boosted protease inhibitor [PI]) were included. Switch to second-line was defined as (i) change across drug class (PI to NNRTI or vice versa) or within PI class plus change of ≥1 NRTI; (ii) change from single to dual PI; or (iii) addition of a new drug class. Cumulative incidence of switch was calculated with death and loss to follow-up as competing risks. Results: Of 3668 children included, median age at ART initiation was 6.1 (interquartile range (IQR), 1.7-10.5) years. Initial regimens were 32% PI based, 34% nevirapine (NVP) based, and 33% efavirenz based. Median duration of follow-up was 5.4 (IQR, 2.9-8.3) years. Cumulative incidence of switch at 5 years was 21% (95% confidence interval, 20%-23%), with significant regional variations. Median time to switch was 30 (IQR, 16-58) months; two-thirds of switches were related to treatment failure. In multivariable analysis, older age, severe immunosuppression and higher viral load (VL) at ART start, and NVP-based initial regimens were associated with increased risk of switch. Conclusions: One in 5 children switched to a second-line regimen by 5 years of ART, with two-thirds failure related. Advanced HIV, older age, and NVP-based regimens were associated with increased risk of switch

Effect of a Nutritional Intervention on the Intestinal Microbiota of Vertically HIV-Infected Children: The Pediabiota Study

Aims: The gut microbiota exerts a critical influence in the immune system. The gut microbiota of human virus immunodeficiency (HIV)-infected children remains barely explored. We aimed to characterize the fecal microbiota in vertically HIV-infected children and to explore the effects of its modulation with a symbiotic nutritional intervention. Methods: a pilot, double blind, randomized placebo-controlled study including HIV-infected children who were randomized to receive a nutritional supplementation including prebiotics and probiotics or placebo for four weeks. HIV-uninfected siblings were recruited as controls. The V3&ndash;V4 region of the 16S rRNA gene was sequenced in fecal samples. Results: 22 HIV-infected children on antiretroviral therapy (ART) and with viral load (VL) &lt;50/mL completed the follow-up period. Mean age was 11.4 &plusmn; 3.4 years, eight (32%) were male. Their microbiota showed reduced alpha diversity compared to controls and distinct beta diversity at the genus level (Adonis p = 0.042). Patients showed decreased abundance of commensals Faecalibacterium and an increase in Prevotella, Akkermansia and Escherichia. The nutritional intervention shaped the microbiota towards the control group, without a clear directionality. Conclusions: Vertical HIV infection is characterized by changes in gut microbiota structure, distinct at the compositional level from the findings reported in adults. A short nutritional intervention attenuated bacterial dysbiosis, without clear changes at the community level. Summary: In a group of 24 vertically HIV-infected children, in comparison to 11 uninfected controls, intestinal dysbiosis was observed despite effective ART. Although not fully effective to restore the microbiota, a short intervention with pre/probiotics attenuated bacterial dysbiosis