Longitudinal Trends in HIV-1 Subtypes and Drug Resistance in Children from Argentina over a 15-Year Period (2006-2021).

Background: Human immunodeficiency virus (HIV) drug resistance is a major cause of treatment failure in children and adolescents infected with the virus. Objectives: The objectives of the study are to investigate HIV drug resistance (HIVDR) in patients who attended a referral care center in Argentina over a 15-year period and to compare mutational patterns between HIV-1 polsequences characterized as B or BF recombinants. Methods: Individual resistance-associated mutations (RAMs) (to protease and reverse transcriptase inhibitors) were identified according to IAS-USA guidelines in 374 HIV-1-infected children and adolescents. HIV-1 subtype was characterized by phylogenetic and recombination analysis using MEGA5.1 and Simplot. Poisson linear regression was used to model the dynamics of the RAMs over time. Results: The prevalence of RAMs to protease inhibitors (R2 = 0.52, p = 0.0012) and nucleoside reverse transcriptase inhibitors (R2 = 0.30, p = 0.0225) decreased over time. HIVDR to non-nucleoside reverse transcriptase inhibitors remained moderate to high, ranging between 33% and 76%. BF recombinants showed a higher frequency of thymidine analog mutation 1 RAMs profile and I54V mutation. Conclusion: In Argentina, HIVDR observed in children and adolescents has decreased over the past 15 years, regardless of the viral subtype. (REV INVEST CLIN. 2024;76(1):29-36).

Variable antiviral activity of islatravir against M184I/V mutant HIV-1 selected during antiretroviral therapy.

BACKGROUND: Islatravir is a new antiretroviral drug that inhibits the reverse transcriptase (RT) of HIV-1 through multiple mechanisms. It is proposed to be used in combination with doravirine, a new NNRTI. M184V/I mutations have been shown to reduce the in vitro antiviral activity of islatravir, but their effect when pre-selected during ART has not been investigated. METHODS: HIV-1 rt sequences were obtained from four individuals of the Garrahan HIV cohort prior to, or during virological failure to ART. HIV-1 infectious molecular clones were constructed on an NL4-3 backbone, and infectious viruses were produced by transfection of 293T cells. Fold-changes in IC50 were calculated for each mutant versus the NL4-3 WT. HIV-1 phenotypic drug resistance was tested in vitro against NRTIs and NNRTIs. RESULTS: In all the cases, M184I/V, either alone or in the presence of other mutations, was associated with reduced susceptibility to islatravir, abacavir and lamivudine. Viruses carrying M184V/I showed variable levels of resistance to islatravir (4.8 to 33.8-fold). The greatest reduction in susceptibility was observed for viruses carrying the mutations M184V + V106I (33.8-fold resistance) or M184V + I142V (25.2-fold resistance). For NNRTIs, the presence of V106I alone did not affect susceptibility to doravirine or etravirine, but showed a modest reduction in susceptibility to efavirenz (6-fold). Susceptibility to doravirine was slightly reduced only for one of the mutants carrying V106I in combination with Y181C and M184V. CONCLUSIONS: Mutations and polymorphisms selected in vivo together with M184V/I depend on the viral genetic context and on ART history, and could affect the efficacy of islatravir once available for use in the clinic.

Nucleoside/nucleotide reverse transcriptase inhibitor sparing regimen with once daily integrase inhibitor plus boosted darunavir is non-inferior to standard of care in virologically-suppressed children and adolescents living with HIV - Week 48 results of the randomised SMILE Penta-17-ANRS 152 clinical trial.

Background: Integrase inhibitor (INSTI) with boosted darunavir (DRV/r), a regimen with a high-resistance barrier, avoiding NRTI toxicities, might be a switching option in children living with HIV (CLWHIV). Methods: SMILE is a randomised non-inferiority trial evaluating safety and antiviral efficacy of once-daily INSTI + DRV/r vs. continuing on current standard-of-care (SOC) triple ART (2NRTI + boosted PI/NNRTI) in virologically-suppressed CLWHIV aged 6-18 years. The primary outcome is the proportion with confirmed HIV-RNA ≥50 copies/mL by week 48, estimated by Kaplan-Meier method. Non-inferiority margin was 10%. Registration number for SMILE are: ISRCTN11193709, NCT #: NCT02383108. Findings: Between 10th June 2016 and 30th August 2019, 318 participants were enrolled from Africa 53%, Europe 24%, Thailand 15% and Latin America 8%, 158 INSTI + DRV/r [153 Dolutegravir (DTG); 5 Elvitegravir (EVG)], 160 SOC. Median (range) age was 14.7 years (7.6-18.0); CD4 count 782 cells/mm3 (227-1647); 61% female. Median follow-up was 64.3 weeks with no loss to follow-up. By 48 weeks, 8 INSTI + DRV/r vs. 12 SOC had confirmed HIV-RNA ≥50 copies/mL; difference (INSTI + DRV/r-SOC) -2.5% (95% CI: -7.6, 2.5%), showing non-inferiority. No major PI or INSTI resistance mutations were observed. There were no differences in safety between arms. By week 48, difference (INSTI + DRV/r-SOC) in mean CD4 count change from baseline was -48.3 cells/mm3 (95% CI: -93.4, -3.2; p = 0.036). Difference (INSTI + DRV/r-SOC) in mean HDL change from baseline was -4.1 mg/dL (95% CI: -6.7, -1.4; p = 0.003). Weight and Body Mass Index (BMI) increased more in INSTI + DRV/r than SOC [difference: 1.97 kg (95% CI: 1.1, 2.9; p < 0.001), 0.66 kg/m2 (95% CI: 0.3, 1.0; p < 0.001)]. Interpretation: In virologically-suppressed children, switching to INSTI + DRV/r was non-inferior virologically, with similar safety profile, to continuing SOC. Small but significant differences in CD4, HDL-cholesterol, weight and BMI were observed between INSTI + DRV/r vs. SOC although clinical relevance needs further investigation. SMILE data corroborate adult findings and provide evidence for this NRTI-sparing regimen for children and adolescents. Funding: Fondazione Penta Onlus, Gilead, Janssen, INSERM/ANRS and UK MRC. ViiV-Healthcare provided Dolutegravir.

Shock séptico en niños con bacteriemia por Staphylococcus aureus de la comunidad en un hospital pediátrico de alta complejidad

Introducción: La información disponible sobre los factores de riesgo para el desarrollo de shock séptico es escasa, especialmente en población pediátrica. Objetivo: Describir las características epidemiológicas y clínicas de los niños con bacteriemia adquirida en la comunidad por Staphylococcus aureus y comparar las características de los pacientes con y sin shock séptico. Pacientes y Métodos: Estudio de cohorte retrospectivo. Criterios de inclusión: niños entre 30 días y 16 años de edad, internados en el Hospital de Pediatría Juan P. Garrahan entre enero de 2017 y diciembre de 2019 por infecciones adquiridas en la comunidad con desarrollo de S. aureus en hemocultivos. Criterios de exclusión: antecedente de internación dentro de los 3 meses previos al ingreso, vivir en una comunidad cerrada, presencia de catéter de larga permanencia, dispositivos intraventriculares o intraperitoneales. Análisis estadístico: STATA 16. Resultados: Se incluyeron 142 niños. 21 niños (15%) presentaron shock séptico. En el análisis multivariado, se asociaron con shock séptico, la bacteriemia persistente (OR 7,15; IC95% 4,39-23,81; p: 0,001) y el foco secundario de infección (OR 6,72; IC 95% 2,02-22,2; p 0,002). La mortalidad relacionada con la infección fue 3,5% (5 pacientes). Conclusiones: El shock séptico se asoció con la bacteriemia persistente y la presencia de focos secundarios de infección.

Background: Available information about risk factors for the development of septic shock is scarce, especially in the pediatric population. Aim: To describe the epidemiological and clinical characteristics of children with community-acquired Staphylococcus aureus bacteremia and to compare the characteristics of children with and without septic shock. Methods: Retrospective cohort study. Inclusion criteria: Children between 30 days and 16 years old, hospitalized in the Juan P. Garrahan Pediatric Hospital between January 2017 and December 2019 for community-acquired infections with S. aureus isolation in blood cultures. Exclusion criteria: History of hospitalization within 3 months prior to admission, living in a closed community, presence of long-term catheter, intraventricular or intraperitoneal devices. Statistical analysis: STATA 16. Results: 142 children were included. 21 children (15%) experienced septic shock. On multivariate analysis, persistent bacteremia (OR 7.15, 95% CI 4.39-23.81, p: 0.001) and secondary focus of infection (OR 6.72, 95% CI 2.02-22.2, p 0.002) were associated with septic shock. The infection-related mortality rate was 3.5% (5 patients). Conclusions: Septic shock was associated with persistent bacteremia and the presence of secondary foci of infection.

Comparison of SARS-CoV-2 viral load in asymptomatic and symptomatic children attended in a referral public pediatric hospital in Argentina / Comparación de la carga viral de SARS-CoV-2 en niños asintomáticos y sintomáticos atendidos en un hospital pediátrico público de referencia en Argentina

Abstract At present, different reports have shown that children reach similar SARS-CoV-2 viral load (VL) levels compared to adults; however, the impact of VL on children remains ambiguous when asymptomatic versus symptomatic cases are compared. Thus, the aim of this study was to assess VL at the time of diagnosis in asymptomatic and symptomatic SARS-CoV-2 infected children. VL analysis was retrospectively carried out from nasopharyngeal swabs on 82 SARS-CoV-2 infected children, from March to October 2020. Of the 82 children, 31 were asymptomatic. Symptomatic patients had significantly higher VL values compared to asymptomatic ones (median = 7.41 vs4.35 log10 copies/ml, respectively). Notwithstanding, 8 out of 31 asymptomatic children had high VL levels, overlapping levels observed above the first quartile in the symptomatic group. Analysis of different age groups revealed that median VL values were higher in the symptomatic groups, although there was only a significant difference in children younger than 5 years of age. On the other hand, there was no significant difference between the VL values from the 82 SARS-CoV-2 infected children according to age, sex, underlying disease, symptoms or severity of COVID-19 related disease. This study emphasizes the importance of VL analysis in SARS-CoV-2 infected children, who could contribute to viral spread in the community. This concern could be extended to healthcare workers, who are in contact with children.

Resumen Diferentes informes han demostrado que los ninos alcanzan niveles de carga viral (CV) de SARS-CoV-2 similares a los de los adultos, pero el impacto de la CV en los niños continua siendo incierto cuando se compara entre aquellos que son asintomáticos y sintomáticos. El objetivo de este estudio fue evaluar la CV al momento del diagnóstico en ninos asintomáticos y sintomáticos infectados por SARS-CoV-2. El análisis de CV se realizó retrospectivamente a partir de muestras de hisopados nasofaríngeos de 82 niños infectados por SARS-CoV-2 entre marzo y octubre de 2020. De ellos, 31 eran asintomáticos. Encontramos que el grupo sintomático tenía valores de CV significativamente más altos en comparación con el grupo asintomático (mediana = 7,41 vs. 4,35 log10 copias/ml, respectivamente). No obstante, 8 de los 31 ninos asintomáticos presentaron valores de CV elevados, equivalentes a los observados por encima del primer cuartil del grupo sintomático. El análisis por grupos de edad reveló que la mediana de CV fue más alta en los niños sintomáticos, aunque esta diferencia fue significativa solamente en los menores de 5 anos. A su vez, los valores de CV obtenidos a partir de los 82 niños infectados por SARS-CoV-2 no mostraron diferencias significativas según el grupo etario, el sexo, la enfermedad de base, los síntomas y la gravedad de la COVID-19. Este estudio enfatiza la necesidad del análisis de la CV en ninos infectados por SARS-CoV-2, quienes podrían contribuir a la propagación del virus en la comunidad. Esta preocupación podría extenderse a los trabajadores de la salud que están en contacto con los ninños.

COVID-19 in immunocompromised children: comparison of SARS-CoV-2 viral load dynamics between the first and third waves.

SARS-CoV-2 dynamics across different COVID-19 waves has been unclear in immunocompromised children. We aimed to compare the dynamics of SARS-CoV-2 RNA viral load (VL) during the first and third waves of COVID-19 in immunocompromised children. A retrospective and longitudinal cohort study was conducted in a pediatric referral hospital of Argentina. The study included 28 admitted immunocompromised children with laboratory confirmed SARS-CoV-2 infection. Thirteen acquired the infection during COVID-19 first wave (May to August 2020, group 1 (G1)) and fifteen in the third wave (January to March 2022, group 2 (G2)). RNA viral load measure and its dynamic reconstruction were performed in nasopharyngeal swabs by validated quantitative, real time RT-PCR, and linear mixed-effects model, respectively. Of the 28 children included, 54% were girls, most of them had hemato-oncological pathology (57%), and the median age was 8 years (interquartile range (IQR): 3-13). The dynamic of VL was similar in both groups (P = 0.148), starting from a level of 5.34 log10 copies/mL (95% confidence interval (CI): 4.47-6.21) in G1 and 5.79 log10 copies/mL (95% CI: 4.93-6.65) in G2. Then, VL decayed with a rate of 0.059 (95% CI: 0.038-0.080) and 0.088 (95% CI: 0.058-0.118) log10 copies/mL per day since diagnosis and fell below the limit of quantification at days 51 and 39 after diagnosis in G1 and G2, respectively. Our results evidenced a longer viral RNA persistence in immunocompromised pediatric patients and no difference in VL dynamic between COVID-19 first wave-attributed to ancestral infections-and third wave-attributed to Omicron infections.

Comparison of SARS-CoV-2 viral load in asymptomatic and symptomatic children attended in a referral public pediatric hospital in Argentina.

At present, different reports have shown that children reach similar SARS-CoV-2 viral load (VL) levels compared to adults; however, the impact of VL on children remains ambiguous when asymptomatic versus symptomatic cases are compared. Thus, the aim of this study was to assess VL at the time of diagnosis in asymptomatic and symptomatic SARS-CoV-2 infected children. VL analysis was retrospectively carried out from nasopharyngeal swabs on 82 SARS-CoV-2 infected children, from March to October 2020. Of the 82 children, 31 were asymptomatic. Symptomatic patients had significantly higher VL values compared to asymptomatic ones (median=7.41 vs 4.35log10 copies/ml, respectively). Notwithstanding, 8 out of 31 asymptomatic children had high VL levels, overlapping levels observed above the first quartile in the symptomatic group. Analysis of different age groups revealed that median VL values were higher in the symptomatic groups, although there was only a significant difference in children younger than 5 years of age. On the other hand, there was no significant difference between the VL values from the 82 SARS-CoV-2 infected children according to age, sex, underlying disease, symptoms or severity of COVID-19 related disease. This study emphasizes the importance of VL analysis in SARS-CoV-2 infected children, who could contribute to viral spread in the community. This concern could be extended to healthcare workers, who are in contact with children.

Effectiveness of a program for the reduction of central venous catheter-related bacteremias in a Pediatric Cardiovascular Unit / Efectividad de un programa de reducción de bacteriemias relacionadas con catéter venoso central en una unidad cardiovascular pediátrica

INTRODUCTION: Central venous catheter (CVC)- related bacteremias are common in pediatric patients following surgery for complex congenital heart disease admitted to a pediatric cardiac intensive care unit (PCICU) and have a high morbidity and mortality. OBJECTIVE: To analyze the effectiveness of an interdisciplinary program for the prevention of CVC-related bacteremias in the PCICU. MATERIAL AND METHODS: Quasi-experimental, before and after implementation study without a control group. Study period: 01-01-2008 to 12- 31-2018. Population: PCICU staff who care for patients following surgery for complex heart disease at a hospital. Pre-intervention period: 01- 01-2008 to 12-31-2008; intervention period: 01-01- 2009 to 01-01-2018. Intervention: implementation of an ongoing improvement program. The rate of CVC-related bacteremias/1000 days and CVC use/100 days, RACHS score, standardized infection ratio (SIR), relative risk (RR), and 95% confidence interval (CI) were analyzed and a p value < 0.05 was considered statistically significant. The reference rate was estimated as the average for the 2008-2009 period and the annual and reference rates were compared. RESULTS: The bacteremia reference rate for 2008- 2009 was 10.6/1000 days of CVC to analyze the SIR. A RACHS score over 3 was similar across all studied periods. The annual comparison showed a statistically significant reduction (p < 0.05) in the SIR. The comparison between the baseline bacteremia rate/1000 days of CVC (11.9) and the final rate (3.8) showed a significant reduction (RR: 0.16; 95 % CI: 0.07-0.35; p < 0.001). CONCLUSIONS: The program was effective; the rate of CVC-related bacteremias in the PCICU showed a progressive, significant reduction.

Introducción. Las bacteriemias relacionadas con catéteres venosos centrales (CVC) son frecuentes en pacientes pediátricos posquirúrgicos de cardiopatías congénitas complejas internados en la unidad de cuidados intensivos pediátricos cardiovascular (UCIP-CV) y tienen alta morbimortalidad. OBJETIVO: Analizar la efectividad de un programa interdisciplinario para prevención de bacteriemias relacionadas con CVC en la UCIP-CV. Material y métodos. Estudio de implementación, cuasiexperimental, antes-después, sin grupo control. Período de estudio del 1 de enero de 2008 al 31 de diciembre de 2018. Población: equipo de salud de la UCIP-CV que atiende pacientes posquirúrgicos de cardiopatías complejas de un hospital. Período preintervención del 1 de enero de 2008 al 31 de diciembre de 2008; período de intervención del 1 de enero de 2009 al 1 de enero de 2018. Intervención: implementación de un programa de mejora continua. Se analizaron tasas de bacteriemias CVC/1000 días y de uso de CVC/100 días, puntaje de RACHS, razón estandarizada de infecciones (REI), riesgo relativo (RR), intervalo de confianza del 95 % (IC95%), estimando una p < 0,05 como estadísticamente significativa. La tasa de referencia se estimó como el promedio del período 2008/2009 y se comparó la tasa anual con la tasa de referencia. RESULTADOS: La tasa de referencia de bacteriemia 2008/2009 fue 10,6/1000 días CVC para analizar la REI. El puntaje de RACHS mayor a 3 fue similar en todos los períodos analizados. Se observó una reducción de la REI estadísticamente significativa (p < 0,05) en la comparación anual. Al comparar la tasa de bacteriemia/1000 días de CVC inicial de 11,9 vs. final de 3,8, se observó una reducción significativa (RR: 0,16; IC95%: 0,07-0,35; p < 0,001). CONCLUSIONES: El programa fue efectivo; se observó reducción progresiva y significativa de la tasa de bacteriemias relacionadas con CVC en la UCIP-CV.

Efectividad de un programa de reducción de bacteriemias relacionadas con catéter venoso central en una unidad cardiovascular pediátrica / Effectiveness of a program for the reduction of central venous catheter-related bacteremias in a Pediatric Cardiovascular Unit

Introducción. Las bacteriemias relacionadas con catéteres venosos centrales (CVC) son frecuentes en pacientes pediátricos posquirúrgicos de cardiopatías congénitas complejas internados en la unidad de cuidados intensivos pediátricos cardiovascular (UCIP-CV) y tienen alta morbimortalidad. Objetivo. Analizar la efectividad de un programa interdisciplinario para prevención de bacteriemias relacionadas con CVC en la UCIP-CV. Material y métodos. Estudio de implementación, cuasiexperimental, antes-después, sin grupo control. Período de estudio del 1 de enero de 2008 al 31 de diciembre de 2018. Población: equipo de salud de la UCIP-CV que atiende pacientes posquirúrgicos de cardiopatías complejas de un hospital. Período preintervención del 1 de enero de 2008 al 31 de diciembre de 2008; período de intervención del 1 de enero de 2009 al 1 de enero de 2018. Intervención: implementación de un programa de mejora continua. Se analizaron tasas de bacteriemias CVC/1000 días y de uso de CVC/100 días, puntaje de RACHS, razón estandarizada de infecciones (REI), riesgo relativo (RR), intervalo de confianza del 95 % (IC95%), estimando una p < 0,05 como estadísticamente significativa. La tasa de referencia se estimó como el promedio del período 2008/2009 y se comparó la tasa anual con la tasa de referencia. Resultados. La tasa de referencia de bacteriemia 2008/2009 fue 10,6/1000 días CVC para analizar la REI. El puntaje de RACHS mayor a 3 fue similar en todos los períodos analizados. Se observó una reducción de la REI estadísticamente significativa (p < 0,05) en la comparación anual. Al comparar la tasa de bacteriemia/1000 días de CVC inicial de 11,9 vs. final de 3,8, se observó una reducción significativa (RR: 0,16; IC95%: 0,07-0,35; p < 0,001). Conclusiones. El programa fue efectivo; se observó reducción progresiva y significativa de la tasa de bacteriemias relacionadas con CVC en la UCIP-CV.

Introduction. Central venous catheter (CVC)related bacteremias are common in pediatric patients following surgery for complex congenital heart disease admitted to a pediatric cardiac intensive care unit (PCICU) and have a high morbidity and mortality. Objective.To analyze the effectiveness of an interdisciplinary program for the prevention of CVC-related bacteremias in the PCICU. Material and methods. Quasi-experimental,before and after implementation study without a control group. Study period: 01-01-2008 to 1231-2018. Population: PCICU staff who care for patients following surgery for complex heart disease at a hospital. Pre-intervention period: 0101-2008 to 12-31-2008; intervention period: 01-012009 to 01-01-2018. Intervention: implementation of an ongoing improvement program. The rate of CVC-related bacteremias/1000 days and CVC use/100 days, RACHS score, standardized infection ratio (SIR), relative risk (RR), and 95% confidence interval (CI) were analyzed and a p value < 0.05 was considered statistically significant. The reference rate was estimated as the average for the 2008-2009 period and the annual and reference rates were compared. Results. The bacteremia reference rate for 20082009 was 10.6/1000 days of CVC to analyze the SIR. A RACHS score over 3 was similar across all studied periods. The annual comparison showed a statistically significant reduction (p < 0.05) in the SIR. The comparison between the baseline bacteremia rate/1000 days of CVC (11.9) and the final rate (3.8) showed a significant reduction (RR: 0.16; 95 % CI: 0.07­0.35; p < 0.001). Conclusions. The program was effective; the rate of CVC-related bacteremias in the PCICU showed a progressive, significant reduction.

Carbapenem-resistant Enterobacteriaceae bloodstream infections: A case-control study from a pediatric referral hospital in Argentina.

Background: Antibiotic-resistant gram-negative bloodstream infections (BSI) remain a leading cause morbidity and mortality in pediatric patients with a high impact on the public health system. Data in resource-limited countries, including those in Latin America and the Caribbean region, are scarce. The aim of the study was to identify risk factors for acquiring carbapenem-resistant Enterobacteriaceae (CRE) bacteremia in children and to assess the use of resources. Methods: A retrospective case-control study was conducted to analyze demographic, epidemiological, clinical, microbiological, and outcome data as well as the use of resources between 2014 and 2019. Univariate and logistic regression analysis was performed in order to identify risk factors associated with CRE-BSI. The R software version 4.1.2 was used. Results: A total of 46 cases with CRE-BSI and 92 controls with gram-negative non-CRE-BSI were included. No statistical difference was observed regarding: median age (36 months; IQR, 11.2-117 vs. 48 months, IQR 13-119), male sex (50 vs. 60%), and underlying disease (98 vs. 91%) in cases vs. controls, respectively. The most frequent mechanism of CRE bacteremia were: KPC in 74%, OXA in 15%, and NDM in 6.5%. A total of 54.3% of cases vs. 32.6 % (p = 0.016) of controls were admitted to the pediatric intensive care unit (PICU), and 48 vs. 21% (p = 0.001) required mechanical ventilation. Bacteremia secondary to intra-abdominal infection was observed in 56.5% of cases vs. 35% of controls (p = 0.032). Previous colonization with CRE was detected in 76% of cases vs. 8% of controls. Combination antimicrobial treatment was most frequent in cases vs. control (100 vs. 56.5%). No difference was observed in median length of hospital stay (22 days; IQR, 19-31 in cases vs. 17.5 days; IQR, 10-31 in controls; p = 0.8). Overall case fatality ratio was 13 vs. 5.5%, respectively. The most statistically significant risk factors included previous PICU stay (OR, 4; 95%CI, 2-8), invasive procedures/surgery (OR, 3; 95%CI, 1-7), central venous catheter placement (OR, 6.5; 95%CI, 2-19), urinary catheter placement (OR, 9; 95%CI 4-20), mechanical ventilation (OR, 4; 95%CI, 2-10), liver transplantation (OR, 8; 95%CI, 2-26), meropenem treatment (OR, 8.4; 3.5-22.6) in univariate analysis. The logistic regression model used for multivariate analysis yielded significant differences for previous meropenem treatment (OR, 13; 95%CI, 3-77; p = 0.001), liver transplantation (OR, 13; 95%CI, 2.5-100; p = 0.006), and urinary catheter placement (OR, 9; 95%CI, 1.4-94; p = 0.03). Conclusion: CRE-BSI affects hospitalized children with underlying disease, mainly after liver transplantation, with previous urinary catheter use and receiving broad-spectrum antibiotics, leading to high PICU requirement and mortality. These risk factors will have to be taken into account in our region in order to establish adequate health policies and programs to improve antimicrobial stewardship.

HIV-1 subtype F integrase polymorphisms external to the catalytic core domain contribute to severe loss of replication capacity in context of the integrase inhibitor resistance mutation Q148H.

BACKGROUND: In prior studies, HIV-1 BF recombinants with subtype F integrases failed to develop resistance to raltegravir through the Q148H mutational pathway. We aimed to determine the role of subtype-specific polymorphisms in integrase on drug susceptibility, viral replication and integration. METHODS: Integrase sequences were retrieved from the Los Alamos Database or obtained from the Garrahan HIV cohort. HIV-1 infectious molecular clones with or without Q148H (+ G140S) resistance mutations were constructed using integrases of subtype B (NL4-3) or F1(BF) ARMA159 and URTR23. Integrase chimeras were generated by reciprocal exchanges of a 200 bp fragment spanning amino acids 85-150 of the catalytic core domain (CCD) of NL4-3-Q148H and either ARMA159-Q148H or URTR23-Q148H. Viral infections were quantified by p24 ELISA and Alu-gag integration PCR assay. RESULTS: At least 18 different polymorphisms distinguish subtype B from F1(BF) recombinant integrases. In phenotypic experiments, p24 at Day 15 post-infection was high (105-106 pg/mL) for WT and NL4-3-Q148H; by contrast, it was low (102-104 pg/mL) for both F1(BF)-Q148H + G140S viruses, and undetectable for the Q148H mutants. Compared with WT viruses, integrated DNA was reduced by 5-fold for NL4-3-Q148H (P = 0.05), 9-fold for URTR23-Q148H (P = 0.01) and 16000-fold for ARMA159-Q148H (P = 0.01). Reciprocal exchange between B and F1(BF) of an integrase CCD region failed to rescue the replicative defect of F1(BF) integrase mutants. CONCLUSIONS: The functional impairment of Q148H in the context of subtype F integrases from BF recombinants explains the lack of selection of this pathway in vivo. Non-B polymorphisms external to the integrase CCD may influence the pathway to integrase strand transfer inhibitor resistance.

HIV-1 pretreatment drug resistance in vertically infected children is associated with poor virological response to protease inhibitor (PI)-based first-line antiretroviral therapy (ART): results from a cohort study in Argentina.

BACKGROUND: Increasing evidence from adult cohorts suggests an important role of HIV-1 pretreatment drug resistance (PDR) in ART failure, in spite of treatment being fully active according to baseline genotyping tests. Whether this is also true for children is unknown. METHODS: Virological and immunological parameters were longitudinally assessed in a group of 39 HIV-1 vertically infected children starting first-line lopinavir/ritonavir-based ART at a median of 5.0 months (IQR = 3.0-9.0). Evolution of viral load (VL) over time was compared between children with and without baseline PDR, as defined by the WHO mutation list. RESULTS: Resistance-associated mutations (RAMs) in the HIV-1 pol gene were present in nine HIV-1-infected children (23%) before initiation of first-line ART (PDR group). Of them, six carried RAMs associated with NNRTIs (NNRTI-PDR subgroup). At 4-8 weeks after ART initiation, the proportion of children achieving ≥1 log VL reduction was 87% for the no-PDR group versus 33% and 16.7% for the PDR group and the NNRTI-PDR subgroup, respectively. During follow-up, children with no PDR reached virological suppression almost four times faster than children with PDR or NNRTI-PDR [no-PDR = 631 days and PDR = 2134 days (P = 0.1249) and NNRTI-PDR = 2134 days (P = 0.0447)]. CD4 T cells remained similar between the study groups over time. CONCLUSIONS: HIV-1 baseline genotyping at diagnosis in vertically infected children is important for improved personalized medicine. While the mechanism is unclear, cases with PDR (particularly to NNRTIs) require closer monitoring of their first-line ART regimens in order to avoid early virological failures and prevent further accumulation of resistance.

[Epidemiological characteristics according to the progress of SARS-CoV-2 pandemic in a highly complex pediatric hospital in Argentina: a descriptive study]. / Características epidemiológicas según el avance de la pandemia SARS-CoV-2 en un hospital pediátrico de alta complejidad en Argentina: estudio descriptivo.

BACKGROUND: The knowledge of the clinical and evolutionary characteristics of children with SARS-CoV-2 is continuously updated. The true impact of the disease in the pediatric population is still unknown. AIM: To describe the clinical characteristics, the use of resources and the evolution of children with COVID-19 in the Garrahan Pediatric Hospital, Buenos Aires, Argentina, in the first 20 weeks from the identification of the first case. METHODS: Descriptive, analytical, retrospective study. The epidemiological, clinical, evolutionary characteristics and the use of hospital resources of patients < 18 years with confirmed COVID-19 are described. In addition, these characteristics were compared according to whether they occurred in the first 10 epidemiological weeks from the first case of COVID-19 in the hospital or in the following ten weeks. RESULTS: n: 280. The median age was 83 months (IQR 33-144). 209 patients (74.6%) were hospitalized. The median days of hospitalization was 8 days (IQR 3-13). According to the WHO severity classification, there were 184 mild cases (65.7%), 3 moderate (1.1%), 16 severe (5.7%) and 20 critical patients (7.1%). The main reasons for admission to the ICU were not related to SARS-CoV-2 infection. When comparing the characteristics of the patients in the two periods, in the first period there was a higher frequency of underlying comorbidities, immunosuppressive treatment, the consultation was later and the patients had more requirements for ICU admission. Two children (0.7%) died in relation to the infection, both with severe comorbidities and severe bacterial coinfections. CONCLUSION: In this study, patients with underlying disease predominated. The mild form of the disease was the most frequent presentation. At the beginning of the pandemic, there were more patients under immunosuppressive treatment, the consultation was later and the hospitalization was more frequent, prolonged and with more serious clinical pictures.

Case Report: Hyperinflammatory Status in an Immunocompromised Child With a Highly Sustained Viral Load of SARS-CoV-2.

Coronavirus disease 2019 (COVID-19) is spreading throughout the world. Limited data are available for the dynamics of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viral load (VL) in immunocompromised pediatric patients. Here, we report the clinical characteristics and the dynamics of SARS-CoV-2 VL of a pediatric patient with acute myeloid leukemia who developed a hyperinflammatory status mimicked MIS-C. The clinical course was characterized by the late onset of fever, GI symptoms, rash, and respiratory distress, including oxygen requirement with sustained VL of SARS-CoV-2 around 7 log10 RNA copies/mL for 6 weeks. It is important to note that the hyperinflammatory status developed early at the third week of hospitalization-in a context of high VL and immunocompromised status. All these characteristics make this clinical case unique. On the other hand, while many reports have characterized the dynamics of SARS-CoV-2 VL in adults and immunocompetent hosts, it remains unreported in pediatrics-even less in immunosuppressed children.

Causes of Microcephaly in the Zika Era in Argentina: A Retrospective Study.

There are gaps in understanding the causes and consequences of microcephaly. This paper describes the epidemiological characteristics, clinical presentations, and etiologies of children presenting microcephaly during the Zika outbreak in Argentina. This observational retrospective study conducted in the pediatric hospital of Juan P. Garrahan reviewed the medical records of 40 children presenting microcephaly between March 2017 and November 2019. The majority (60%) were males and born full-term. At first evaluation, microcephaly was defined as congenital (31/40, 77%) and associated with other features (68%) such as seizures, developmental delay, non-progressive chronic encephalopathy, and West Syndrome. It was found manifestations restricted to central nervous system (55%), ocular (8/40, 20%), and acoustic (9/40, 23%) defects, and abnormal neuroimaging findings (31/39, 79%). Non-infectious diseases were the primary cause of isolated microcephaly (21/37, 57%), largely related to genetic diseases (13/21, 62%). Only 3 were children were diagnosed with Congenital Zika infection (3/16, 7.5%).

Características epidemiológicas según el avance de la pandemia SARS-CoV-2 en un hospital pediátrico de alta complejidad en Argentina: estudio descriptivo / Epidemiological characteristics according to the progress of SARS-CoV-2 pandemic in a highly complex pediatric hospital in Argentina: a descriptive study

INTRODUCCIÓN: El conocimiento de las características clínicas y evolutivas de los niños con SARS-CoV-2 está siendo continuamente actualizado. El verdadero impacto de la enfermedad en la población pediátrica es todavía desconocido. OBJETIVO: Describir las características clínicas, el uso de recursos y la evolución de niños con COVID-19 en el Hospital de Pediatría Garrahan, Buenos Aires, Argentina, en las primeras 20 semanas desde la identificación del primer caso. PACIENTES Y MÉTODOS: Estudio descriptivo analítico, retrospectivo. Se describen las características epidemiológicas, clínicas, evolutivas y el uso de recursos hospitalarios de pacientes < 18 años con COVID-19 confirmado. Además, se compararon dichas características según se presentaran en las primeras 10 semanas epidemiológicas desde el primer caso de COVID-19 en el hospital o en las 10 siguientes. RESULTADOS: n: 280. La mediana de edad fue 83 meses (RIC 33-144). Fueron hospitalizados 209 pacientes (74,6 %). La mediana de días de internación fue de 8 días (RIC 3-13). Según la clasificación de gravedad de la OMS, fueron casos leves 184 (65,7%), moderados 3 (1,1%), graves 16 (5,7%) y 20 pacientes críticos (7,1%). Los principales motivos de ingreso a UCI no se relacionaron con la infección por SARS-CoV-2. Al comparar las características de los pacientes en los dos períodos, en el primer período hubo más frecuencia de comorbilidades subyacentes, tratamiento inmunosupresor, la consulta fue más tardía y los pacientes tuvieron más requerimientos de internación en UCI. Fallecieron en relación con la infección dos niños (0,7%), ambos con comorbilidades graves y coinfecciones bacterianas graves. CONCLUSIÓN: En este estudio predominaron los pacientes con enfermedad de base. La forma leve de la enfermedad fue la presentación más frecuente. Al inicio de la pandemia, hubo más pacientes bajo tratamiento inmunosupresor, la consulta fue más tardía y la internación fue más frecuente, prolongada y con cuadros clínicos más graves.

BACKGROUND: The knowledge of the clinical and evolutionary characteristics of children with SARS-CoV-2 is continuously updated. The true impact of the disease in the pediatric population is still unknown. AIM: To describe the clinical characteristics, the use of resources and the evolution of children with COVID-19 in the Garrahan Pediatric Hospital, Buenos Aires, Argentina, in the first 20 weeks from the identification of the first case. METHODS: Descriptive, analytical, retrospective study. The epidemiological, clinical, evolutionary characteristics and the use of hospital resources of patients < 18 years with confirmed COVID-19 are described. In addition, these characteristics were compared according to whether they occurred in the first 10 epidemiological weeks from the first case of COVID-19 in the hospital or in the following ten weeks. RESULTS: n: 280. The median age was 83 months (IQR 33-144). 209 patients (74.6%) were hospitalized. The median days of hospitalization was 8 days (IQR 3-13). According to the WHO severity classification, there were 184 mild cases (65.7%), 3 moderate (1.1%), 16 severe (5.7%) and 20 critical patients (7.1%). The main reasons for admission to the ICU were not related to SARS-CoV-2 infection. When comparing the characteristics of the patients in the two periods, in the first period there was a higher frequency of underlying comorbidities, immunosuppressive treatment, the consultation was later and the patients had more requirements for ICU admission. Two children (0.7%) died in relation to the infection, both with severe comorbidities and severe bacterial coinfections. CONCLUSION: In this study, patients with underlying disease predominated. The mild form of the disease was the most frequent presentation. At the beginning of the pandemic, there were more patients under immunosuppressive treatment, the consultation was later and the hospitalization was more frequent, prolonged and with more serious clinical pictures.

Pediatric Inflammatory Multisystem Syndrome Associated With SARS-CoV-2: A Retrospective Cohort Study From Argentina.

OBJECTIVE: To evaluate the differential characteristics of SARS-COV-2 associated inflammatory multisystem syndrome (MIS-C) in children. METHODS: A retrospective cohort study was conducted.  The definition of MIS- C was based on WHO criteria. Temporally related COVID-19 patients were included as controls. RESULTS: 25 patients with MIS-C and 75 controls were included. Multivariate multiple logistic regression model of variables that showed to be significant in univariate analysis revealed that age ≥2 years (OR 24.7; 95% CI 1.03 -592.4; P=0.048), lymphopenia (OR 9.03, 95%CI 2.05-39.7; P=0.004), and platelet count <150x109/L (OR 11.7; 95% CI 1.88-75.22; P=0.009) were significantly associated with MIS-C. Presence of underlying disease seemed to reduce the risk of MIS-C (OR 0.06; 95% CI 0.01-0.3). CONCLUSIONS: MIS-C was more common in patients older than 2 years and in those with lymphopenia or thrombocytopenia. Underlying disease appears to reduce the risk of MIS-C.

Persistence of antibodies IgG to SARS-CoV2 in health care workers ­ Province of Buenos Aires / Persistencia de anticuerpos IgG contra SARS-CoV2 en personal de salud - provincia de Buenos Aires.

Aim: To evaluate the persistence of IgG antibodies to SARS-CoV2, in health workers of the public subsector of the Province of Buenos Aires, and correlate it with demographic variables (sex, age) and other health indicators (diagnosis of COVID-19, comorbidities and pregnancy). Methodology: Descriptive, observational, cross-sectional study. Health workers with a positive result in a first sample (N = 388) underwent a second test to evaluate the persistence of antibodies by ELISA. Results: Of the 386 people evaluated with a conclusive result, 296 had a first positive result between 30 and 90 days before the second test, of these, 90% had detectable antibodies. In those with a positive result more than 90 days ago (45), a significant decrease in persistence of 26.7% was observed. There were no significant associations between demographic and health variables and the second test result. Conclusion: Antibodies remain detectable for at least 90 days in 90% of the cases analyzed. It is main to continue this study over time to have a major period of time between tests. The information shown here throws interesting and promising data regarding the possible protection of new COVID-19 infections in personnel with high risk exposure. This evidence could contribute to decision-making, both at the local and regional level, for the adequate vaccination planning, as well as for the management in the event of a possible second wave scenario of COVID-19 pandemic in Latin America.

Objetivo: evaluar la persistencia de los anticuerpos IgG contra SARS-CoV2, en trabajadores de salud del subsector público de la Provincia de Buenos Aires, y correlacionarla con variables demográficas (sexo, edad) y otros indicadores de salud (diagnóstico de COVID-19, comorbilidades y embarazo). Metodología: Estudio descriptivo, observacional, de corte transversal. Al personal de salud con un resultado positivo en una primera muestra (N=388) se les realizó una segunda prueba para evaluar la persistencia de anticuerpos mediante ELISA. Resultados: De las 386 personas evaluadas con resultado concluyente, 296 contaban con un primer resultado positivo entre los 30 y los 90 días anteriores a la segunda prueba, el 90% presentó anticuerpos detectables. En aquellas personas con un resultado positivo hacía más de 90 días (45) se observó una caída significativa en la persistencia del 26,7%. No hubo asociaciones significativas entre las variables demográficas y de salud y el resultado de la segunda prueba. Conclusión: Los anticuerpos se mantienen detectables por al menos 90 días en el 90% de los casos analizados. Resulta fundamental continuar este estudio en el tiempo para contar con un período de tiempo mayor entre pruebas. La información aquí mostrada arroja datos interesantes y prometedores en cuanto a la posible protección de nuevos contagios de COVID-19 en personal con alta exposición de riesgo. Estas evidencias podrían contribuir a la toma de decisiones, tanto a nivel local como regional, para la adecuada planificación de la vacunación, así como también, para el manejo de la pandemia ante una posible segunda ola de casos en América Latina.

Unraveling HIV-1 diagnosis in special pediatric cases.

BACKGROUND: Early HIV-1 diagnosis and initiation of antiretroviral treatment is essential to prevent AIDS, and reduce mortality in children. HIV-1 molecular diagnosis in children before 18 months of age require, two independent samples to confirm a result. However, some patients have discordant virologic results in different samples, raising uncertainty for a conclusive diagnosis. We defined these patients as "special pediatric cases". OBJECTIVES: The aim of our study was to characterize the "special pediatric cases" among HIV-1 infected children diagnosed in a five-year period at our laboratory and evaluate the impact on the time to HIV-1 diagnosis. STUDY DESIGN: A total of 44 perinatally HIV-1 infected infants with molecular diagnostic performed at the Pediatric Garrahan Hospital were analyzed from 2013 to 2017. RESULTS: We identified eight "special pediatric cases". In the first samples, all of them had negative results by different DNA-PCR assays. Three infants had undetectable plasma viral load (pVL), four had low detectable pVL value, and one infant had no available pVL. All samples with detectable pVL, including those with low pVL (ie: 65copies/mL), had high pVL values at the end of the diagnosis. Considering the age of the HIV-1 infected children at the end of the diagnosis, five "special pediatric cases" (62 %) had a "late" positive diagnosis [mean (range) = 146 (89-268) days old]. CONCLUSIONS: These "special pediatric cases" are not as unusual as previously thought and are important diagnostic challenges. Also, this study add evidence to include the viral load assay in the molecular diagnostic algorithm for perinatal HIV-1 infection.

[Experience with daptomycin in a tertiary pediatric hospital]. / Experiencia con el uso de daptomicina en un hospital pediátrico de alta complejidad.

BACKGROUND: Vancomycin has been considered the treatment of choice especially for methicillin-resistant Staphylococcus aureus (MRSA) infections; but its poor tissue penetration, renal toxicity, and requiring of dosages monitoring, raises the need for new treatment alternatives such as daptomycin. AIMS: To analyze the safety and effectiveness of daptomycin in children. METHODS: Children with microbiologically documented infections treated with daptomycin were retrospectively included. RESULTS: The most frequent infections were endocarditis in 9 (32%), sepsis in 4 (14%), bacteremia in 7 (associated with catheter in 3) (25%), osteomyelitis in 3 (10%), peritonitis associated with dialysis in 3 (10%) and suppurative thrombophlebitis in 2 patients (p) (7%). Methicillin-resistant Staphylococcus aureus was the most common pathogen in 18 patients (64%). The indications for daptomycin were due to the failure of conventional treatment in 17 (61%), and the toxicity or intolerance to vancomycin in 11 patients (39%). The average duration of treatment was 19 days (95% ICR 7-42 days). Four patients (14%) completed outpatient treatment, 22 patients had a favorable response (79%). Adverse events were reported in 3 patients (2 creatinine-phosfo-kinase increase) and in one severe skin rash. CONCLUSIONS: Daptomycin demonstrated a favorable efficacy and safety in this pediatric population.