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.

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).

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.

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.

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.

Impact of genotypic diversity on selection of subtype-specific drug resistance profiles during raltegravir-based therapy in individuals infected with B and BF recombinant HIV-1 strains.

BACKGROUND: Current knowledge on HIV-1 resistance to integrase inhibitors (INIs) is based mostly on subtype B strains. This contrasts with the increasing use of INIs in low- and middle-income countries, where non-B subtypes predominate. MATERIALS AND METHODS: HIV-1 drug resistance genotyping was performed in 30 HIV-1-infected individuals undergoing virological failure to raltegravir. Drug resistance mutations (DRMs) and HIV-1 subtype were characterized using Stanford HIVdb and phylogenetic analyses. RESULTS: Of the 30 integrase (IN) sequences, 14 were characterized as subtype F (47%), 8 as subtype B (27%), 7 as BF recombinants (23%) and 1 as a putative CRF05_DF (3%). In 25 cases (83%), protease and reverse transcriptase (PR-RT) sequences from the same individuals confirmed the presence of different BF recombinants. Stanford HIVdb genotyping was concordant with phylogenetic inference in 70% of IN and 60% of PR-RT sequences. INI DRMs differed between B and F IN subtypes, with Q148K/R/H, G140S and E138K/A being more prevalent in subtype B (63% versus 0%, P = 0.0021; 50% versus 0%, P = 0.0096; and 50% versus 0%, P = 0.0096, respectively). These differences were independent of the time on raltegravir therapy or viral load at the time of genotyping. INI DRMs in subtype F IN genomes predicted a lower level of resistance to raltegravir and no cross-resistance to second-generation INIs. CONCLUSIONS: Alternative resistance pathways to raltegravir develop in subtypes B and F IN genomes, with implications for clinical practice. Evaluating the role of HIV-1 subtype in development and persistence of mutations that confer resistance to INIs will be important to improve algorithms for resistance testing and optimize the use of INIs.

Pre-treatment drug resistance and HIV-1 subtypes in infants from Argentina with and without exposure to antiretroviral drugs for prevention of mother-to-child transmission.

OBJECTIVES: To assess the prevalence and patterns of pre-treatment HIV drug resistance (PDR) and HIV-1 subtype in infants from Argentina with exposure to different antiretroviral drugs (ARVs) for the prevention of mother-to-child transmission (PMTCT). PATIENTS AND METHODS: HIV-1 genotyping was performed in 115 infants (median age = 2.3 months) born between 2007 and 2014 to screen for drug resistance mutations (DRMs) before starting first-line ART. HIV-1 subtype was characterized by phylogenetic and recombination analysis. RESULTS: Overall, DRMs were found in 34 of 115 infants (PDR level 30% to any ARV, 3.5% to PIs, 12% to NRTIs and 22% to NNRTIs). Of the 115 infants, 22 (19.1%) were ARV-unexposed. Another 93 were ARV-exposed: 28 (24.3%) to short-course zidovudine monotherapy ARV prophylaxis; 25 (21.7%) to nevirapine-based ARV prophylaxis; 12 (10.4%) to perinatal infant zidovudine prophylaxis + maternal combination ART with NNRTIs; and 28 (24.3%) to perinatal infant zidovudine prophylaxis+maternal combination ART with PIs. Transmitted drug resistance among ARV-unexposed infants was 32% (5% to PIs, 9% to NRTIs and 18% to NNRTIs). ART-exposed infants showed multi-class ARV resistance. Importantly, vertical transmission of a triple-class-resistant virus was confirmed in one case. Patterns of DRMs predicted high-level resistance to NNRTIs in a similar and high proportion (>50%) of infants with at least one DRM independently of ARV exposure. BF recombinants were found in 74%, subtype B in 20%, subtype C in 3% and novel AG and AB recombinants in 3%. CONCLUSIONS: PDR in HIV-1-infected children from Argentina is among the highest reported, jeopardizing successful lifelong suppressive ART as well as the efficacy of current PMTCT regimens.

CCL3L1 and CCR5 influence cell-mediated immunity and affect HIV-AIDS pathogenesis via viral entry-independent mechanisms.

Although host defense against human immunodeficiency virus 1 (HIV-1) relies mainly on cell-mediated immunity (CMI), the determinants of CMI in humans are poorly understood. Here we demonstrate that variations in the genes encoding the chemokine CCL3L1 and HIV coreceptor CCR5 influence CMI in both healthy and HIV-infected individuals. CCL3L1-CCR5 genotypes associated with altered CMI in healthy subjects were similar to those that influence the risk of HIV transmission, viral burden and disease progression. However, CCL3L1-CCR5 genotypes also modify HIV clinical course independently of their effects on viral load and CMI. These results identify CCL3L1 and CCR5 as major determinants of CMI and demonstrate that these host factors influence HIV pathogenesis through their effects on both CMI and other viral entry-independent mechanisms.

[Descriptive study of bone and joint infections in children in times of community-acquired methicillin- resistant Staphylococcus aureus (CA-MRSA)]. / Estudio descriptivo de infecciones osteo-articulares en niños en tiempos de Staphylococcus aureus resistente a meticilina de la comunidad (SARM-Co).

BACKGROUND: Bone and joint infections (BJI) are relatively common in children, and community -acquired methicillin resistant Staphylococcus aureus (CA-MRSA) is the leading cause in some countries. AIM: To evaluate epidemiological data, clinical and microbiological features and outcome of BJI. METHODS: A prospective descriptive study was conducted. RESULTS: 40 patients (p) completed the study. Bacterial cultures were positives in 30 p (75%): CA-MRSA was found in 19 p, methicillin-sensitive S. aureus in 6 p, and others in 5 p. Cultures were negatives in 10 p (25%). Median treatment duration was 28 days (r: 21-40 d); Analyzing patients with CA-MRSA positive cultures separately, initial CRP was higher (Md 76 vs 50 mg/L, p < 0.02), normalization occurred later (Md 14 days vs 7days, p < 0.03), and duration of treatment (Md 32 days vs 23, p < 0.004) as well as hospital stay (Md 9 days vs 7, p = 0.12) were longer. Sequelae were present in 3 p and 1 relapsed: All of them with CA-SAMR. CONCLUSION: CA-MRSA was the leading cause of BJI and was associated with higher CRP on admission, later normalization and longer treatment duration. Complications as drainage requirement, and sequelae were common in those p.

[Paradoxical reaction during tuberculosis treatment in immunocompetent children: case report]. / Reacción paradojal al tratamiento antituberculoso en un paciente inmunocompetente: a propósito de un caso.

Tuberculosis is an important public health problem. It is estimated that around 5-10% of patients with tuberculosis present with central nervous system involvement; meningitis and tuberculoma being two of the most frequent manifestations. The paradoxical reaction in patients undergoing antituberculosis treatment is infrequent, nevertheless it is an important consideration in patients, who after an appropriate initial response to specific treatment, present with worsening clinical and radiological signs or the appearance of new lesions.

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.

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.

Unusual substitutions in HIV-1 vif from children infected perinatally without progression to AIDS for more than 8 years without therapy.

The HIV-1 vif gene encodes for an accessory protein that is central for virus replication due mainly to its capacity to counteract the antiviral action of host APOBEC3 restriction factors. In order to evaluate whether HIV-1 vif alterations account for a delayed progression to AIDS in children infected perinatally, the vif genes from a group of 11 patients who exhibited an extremely slow disease progression (slow progressors) were studied by direct sequencing. In addition, the vif genes from a group of 93 children with typical disease progression (typical progressors) were analyzed for comparison. Phylogenetic analysis indicated that sequences from slow progressors did not have a common origin, discarding a shared ancestor of reduced virulence. There were no differences in the diversity between the vif genes from slow and typical progressors. No gross defects showing a clear distinction among sequences from both groups of children were found. However, in the deduced Vif proteins, changes V13I, V55T, and L81M were observed only in sequences from slow progressors. By analyzing sequences stored in databases, these mutations were determined as unusual substitutions occurring at highly conserved Vif sites across different HIV-1 clades, but were observed with an increased frequency in sequences from elite controllers. These mutations were in the Vif regions reported as relevant for protein activity. These findings suggest that the Vif sequences from slow progressors carry unusual substitutions, which may alter the protein function and may contribute to viral attenuation.

Concordance of CCR5 genotypes that influence cell-mediated immunity and HIV-1 disease progression rates.

We used cutaneous delayed-type hypersensitivity responses, a powerful in vivo measure of cell-mediated immunity, to evaluate the relationships among cell-mediated immunity, AIDS, and polymorphisms in CCR5, the HIV-1 coreceptor. There was high concordance between CCR5 polymorphisms and haplotype pairs that influenced delayed-type hypersensitivity responses in healthy persons and HIV disease progression. In the cohorts examined, CCR5 genotypes containing -2459G/G (HHA/HHA, HHA/HHC, HHC/HHC) or -2459A/A (HHE/HHE) associated with salutary or detrimental delayed-type hypersensitivity and AIDS phenotypes, respectively. Accordingly, the CCR5-Δ32 allele, when paired with non-Δ32-bearing haplotypes that correlate with low (HHA, HHC) versus high (HHE) CCR5 transcriptional activity, associates with disease retardation or acceleration, respectively. Thus, the associations of CCR5-Δ32 heterozygosity partly reflect the effect of the non-▵32 haplotype in a background of CCR5 haploinsufficiency. The correlations of increased delayed-type hypersensitivity with -2459G/G-containing CCR5 genotypes, reduced CCR5 expression, decreased viral replication, and disease retardation suggest that CCR5 may influence HIV infection and AIDS, at least in part, through effects on cell-mediated immunity.

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.

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.

Clinical features and outcome of 2009 influenza A (H1N1) virus infections in children with malignant diseases: a case-control study.

BACKGROUND: The impact of the novel 2009 influenza A (H1N1) (2009 H1N1) virus in children with malignant diseases under therapy is not well known. OBJECTIVE: To analyze the clinical features and outcome in children with anticancer therapy infected with the 2009 H1N1 virus. PATIENTS AND METHODS: Descriptive, case-control study. Between May and July 2009, 24 cases of 2009 (H1N1) virus infections in children with malignant diseases were registered and 48 control cases of similar patients infected with common influenza A virus (IA) diagnosed between 2006 and 2008 were selected. RESULTS: Median age for cases was 72 months and for controls was 83 months (P ≥ 0.05). Children with IA showed neutropenia more frequently (52% vs. 17%), longer period of time with illness before diagnosis (3 d vs. 1.7 d), higher rate of earlier medical consultation (69% vs. 25%), and more antibiotic therapy courses (54% vs. 4%; P ≤ 0.05) than patients with 2009 H1N1 virus. Children infected with this virus presented hypoxemia more frequently (42% vs. 8%) and higher rates of intensive care unit hospitalizations (29% vs. 2%; P ≤ 0.05). Three children with 2009 H1N1 virus and 1 in the control group died. CONCLUSIONS: Children infected with 2009 H1N1 virus presented more morbidity and mortality than patients infected with seasonal IA virus.

[Reasons for inappropriate prescribing of antibiotics in a high-complexity pediatric hospital]. / Motivos de la prescripción inadecuada de antibióticos en un hospital pediátrico de alta complejidad.

OBJECTIVE: Determine the reasons for inappropriate prescription of antibiotics and identify opportunities to improve prescription of these drugs in pediatric patients hospitalized in intermediate and intensive care units. METHODS: A prospective, descriptive longitudinal study was conducted of pediatric patients in intermediate and intensive care units who received parenteral administration of antibiotics, with the exception of newborns, burn unit patients, and surgical prophylaxis patients. A univariate analysis and multiple logistic regression were performed. RESULTS: A total of 376 patients with a median of age of 50 months were studied (interquartile range [IQR] 14.5-127 months). Out of the total patients studied, 75% had one or more underlying conditions. A total of 40.6% of these patients had an oncologic pathology and 33.5% had neurological conditions. The remaining 25.9% had other underlying conditions. Antibiotic treatment was inappropriate in 35.6% of the patients studied (N = 134). In 73 (54.4%) of the 134 cases, inappropriate use was due to the type of antibiotic prescribed, the dose administered, or the treatment period. The 61 (45.5%) remaining cases did not require antibiotic treatment. In the multivariate analysis, the risk factors for inappropriate use of antibiotics were: administration of ceftriaxone OR 2 (95% CI, 1.3-3.7; P = 0.02); acute lower respiratory tract infection OR 1.8 (95% CI, 1.1-3.3; P < 0.04); onset of fever of unknown origin in hospital inpatients OR 5.55 (95% CI, 2.5-12; P < 0.0001); and febrile neutropenia OR 0.3 (95% CI, 0.1-0.7; P = 0.009). CONCLUSIONS: Inappropriate use of antibiotics was less common in the clinical conditions that were well-characterized. Prescribing practices that could be improved were identified through the preparation and circulation of guidelines for antibiotic use in hospital inpatients.

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%).

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.