Silvia González Ayala

Adjuvant Glycerol and/or Dexamethasone to Improve the Outcomes of Childhood Bacterial Meningitis: A Prospective, Randomized, Double- Blind, Placebo-Controlled Trial

BACKGROUND Despite favorable meta-analyses, no study involving third-generation cephalosporins for the treatment of childhood bacterial meningitis has documented a benefit of adjuvant dexamethasone therapy if the outcomes are examined individually. METHODS We conducted a prospective, randomized, double-blind trial comparing adjuvant dexamethasone or glycerol with placebo in children aged from 2 months through 16 years in Latin America. Ceftriaxone was administered to all children; children were randomized to also receive dexamethasone intravenously, glycerol orally, both agents, or neither agent. Primary end points were death, severe neurological sequelae, or deafness, with the first 2 end points forming a composite end point. A subgroup analysis for Haemophilus influenzae type b meningitis was undertaken. Intention-to-treat analysis was performed using binary logistic regression models. RESULTS H. influenzae type b, pneumococci, and meningococci were the main agents found among 654 patients; dexamethasone was given to 166, dexamethasone and glycerol were given to 159, glycerol was given to 166, and placebo was given to 163. No adjuvant therapy significantly affected death or deafness. In contrast, glycerol and dexamethasone plus glycerol reduced severe neurological sequelae, compared with placebo; the odds ratios were 0.31 (95% confidence interval [95% CI], 0.13-0.76; P=.010) and 0.39 (95% CI, 0.17-0.93; P=.033), respectively. For neurological sequelae and death, the odds ratios were 0.44 (95% CI, 0.25-0.76; P=.003) and 0.55 (95% CI, 0.32-0.93; P=.027), respectively. Dexamethasone therapy prevented deafness in patients with H. influenzae type b meningitis only if patients were divided grossly into dexamethasone recipients and nonrecipients and if timing between dexamethasone and ceftriaxone administration was not taken into account (odds ratio, 0.27; 95% CI, 0.09-0.77; P=.014). CONCLUSION Oral glycerol therapy prevents severe neurological sequelae in patients with childhood meningitis. Safety, availability, low cost, and oral administration also add to its usefulness, especially in resource-limited settings.

Safety and pharmacokinetics of urtoxazumab, a humanized monoclonal antibody, against shiga-like toxin 2 in healthy adults and in pediatric patients infected with shiga-like toxin-producing Escherichia coli.

ABSTRACT Shiga-like toxin-producing Escherichia coli (STEC) infection causes diarrhea, which is often bloody and which can result in potentially life-threatening hemolytic-uremic syndrome (HUS). Urtoxazumab, a humanized monoclonal antibody directed against the Shiga-like toxin 2 (Stx2) produced by STEC, has been developed as a promising agent for the prevention of HUS. Single randomized, intravenous, double-blind, placebo-controlled doses of urtoxazumab were administered to assess its safety and pharmacokinetics in healthy adults (0.1 to 3.0 mg/kg of body weight) and STEC-infected pediatric patients (1.0 and 3.0 mg/kg). No dose-related safety trends were noted, nor were antiurtoxazumab antibodies detected. The disposition of urtoxazumab showed a biexponential decline, regardless of the dose. In healthy adults, the mean terminal elimination half-life was consistent across the dose groups and ranged from 24.6 days (3.0-mg/kg dose group) to 28.9 days (0.3-mg/kg dose group). The mean maximum serum drug concentration (Cmax) ranged from 2.6 μg/ml at 0.1 mg/kg to 71.7 μg/ml at 3.0 mg/kg. The disposition of urtoxazumab following the administration of doses of 1.0 and 3.0 mg/kg in pediatric patients showed mean Cmaxs of 19.6 and 56.1 μg/ml, respectively. Urtoxazumab was well tolerated, appears to be safe at doses of up to 3.0 mg/kg, and is a potential candidate for the prevention of HUS in pediatric patients.

Influence of Admission Findings on Death and Neurological Outcome from Childhood Bacterial Meningitis

A post hoc analysis of 654 children with bacterial meningitis showed that the level of consciousness is the most important predictor of death and/or neurological sequelae, more than is etiology per se. This finding emphasizes the need of including a measurement of the presenting status in all studies examining treatment efficacy.

Hearing Impairment in Childhood Bacterial Meningitis Is Little Relieved by Dexamethasone or Glycerol

OBJECTIVE. Several studies have evaluated dexamethasone for prevention of hearing loss in childhood bacterial meningitis, but results have varied. We compared dexamethasone and/or glycerol recipients with placebo recipients, and measured hearing at 3 threshold levels. METHODS. Children aged 2 months to 16 years with meningitis were treated with ceftriaxone but were double-blindly randomly assigned to receive adjuvant dexamethasone intravenously, glycerol orally, both agents, or neither agent. We used the Glasgow coma scale to grade the presenting status. The end points were the better ears ability to detect sounds of >40 dB, ≥60 dB, and ≥80 dB, with these thresholds indicating any, moderate-to-severe, or severe impairment, respectively. All tests were interpreted by an external audiologist. Influence of covariates in the treatment groups was examined by binary logistic regression. RESULTS: Of the 383 children, mostly with meningitis caused by Haemophilus influenzae type b or Streptococcus pneumoniae, 101 received dexamethasone, 95 received dexamethasone and glycerol, 92 received glycerol, and 95 received placebo. Only the presenting condition and young age predicted impairment independently through all threshold levels. Each lowering point in the Glasgow scale increased the risk by 15% to 21% (odds ratio: 1.20, 1.21, and 1.15 [95% confidence interval: 1.06–1.35, 1.07–1.37, and 1.01–1.31]; P = .005, .003, and .039) for any, moderate-to-severe, or severe impairment, respectively. Each increasing month of age decreased the risk by 2% to 6% (P = .0001, .0007, and .041, respectively). Neither dexamethasone nor glycerol prevented hearing loss at these levels regardless of the causative agent or timing of antimicrobial agent. CONCLUSIONS: With bacterial meningitis, the childs presenting status and young age are the most important predictors of hearing impairment. Little relief is obtained from current adjuvant medications.

The current situation of meningococcal disease in Latin America and recommendations for a new case definition from the Global Meningococcal Initiative

The Global Meningococcal Initiative (GMI) is an international group of scientists and clinicians with expertise in meningococcal disease (MD). It promotes MD prevention through education and research. Given geographic differences in disease epidemiology, prevention strategies (e.g., vaccination) should be country-specific to ensure local needs are met. However, regional policies/recommendations and standardized disease diagnostic criteria should be implemented to improve surveillance and control strategies, and allow for more robust data comparisons. Consequently, the GMI convened a meeting with Latin American representatives to discuss the burden of MD and vaccination practices/policies, and consider if the global GMI recommendations could be tailored. The group determined that as robust, uniform epidemiologic data are required to make informed health-policy decisions, it would be useful to first summarize the regional situation herein (including disease surveillance, case definitions, epidemiology, vaccination and outbreak control strategies) and then determine a consensus-based meningococcal case definition for use throughout the region.

National Immunization Commission: strengthening evidence-based decision making in Argentina.

In Argentina, the National Technical Advisory Group on Immunizations is represented by the National Immunization Commission (CoNaIn), an organization created by the Ministry of Health in 2000. Recently, the Argentine government has decided to prioritize vaccination as a state policy, emphasizing this strategy as a sign of social equity so CoNaIn was restructured to increase its capacity to formulate sound and evidence-based recommendations. The commission shall consist of a group of immunization experts, representatives of scientific societies, the immunization program and the Ministry of Health. Its functions include the formulation of recommendations on the introduction of vaccines into the immunization program. The recommendations are based on technical, programmatic and social criteria. This decision-making process transparent with the support and advice of experts and scientific societies and guided by available evidence decisions help strengthen the Ministry of Health immunization policy generating greater confidence and support from the population and health professionals.

Epidemiological and Molecular Evidence of Two Events of Father-to-Child HIV Type 1 Horizontal Transmission

HIV-1 infection in children less than 15 years of age is mainly due to mother-to-child transmission. The aim of this work was to investigate molecular evidence to prove father-to-be horizontal transmission in two possible events of transmission. In the first event a boy was identified as HIV infected at 2-3 years of age. At the same time infection was confirmed in the father, while mother and siblings were negative. In the second event a girl was negative for HIV at age 1 and identified as HIV-1 infected at age 6. The fathers HIV infection was diagnosed in the same period while the mother was repeatedly negative. No evidence of sexual assault or transfusion was recorded in any case. Peripheral blood mononuclear cells were obtained from both fathers and children. After PCR amplification, the C2V3 region of the envelope gene and the region coding for amino acid 132 of p24 up to amino acid 40 of p7 of the gag gene were sequenced. Genetic distance measurements and phylogenetic tree analysis showed that in both cases the fathers and childs viral sequences were closely related. They were distinct when compared to Argentina sequences including sequences from the same geographic region. Epidemiological and molecular data strongly suggest that horizontal transmission had occurred, probably related to the close father-to-child contact.

Evaluation of minority populations of HIV type-1 with K103N and M184V drug resistance mutations among children in Argentina.

BACKGROUND The aim of this study was to describe the frequency of minority populations of viruses carrying mutations K103N and M184V in drug-naive HIV type-1 (HIV-1)-infected children, and to further evaluate their effect on the selection of drug-resistant viruses within highly active antiretroviral therapy (HAART). METHODS Newly diagnosed vertically HIV-1-infected children were evaluated. The HIV-1 pol gene was sequenced for subtyping and antiretroviral drug resistance analysis. Standard genotypic sequencing and sequence-selective real-time PCR (SPCR) to quantify minority viral populations were used. RESULTS From December 2004 to July 2006, we included 35 children who were studied at baseline and during their first HAART regimen (follow-up median time 29.4 months). Of them, 82.9% were infected with intersubtype B/F recombinant variants. At baseline, all children had a drug-susceptible viral population that was studied by bulk sequencing. SPCR showed that 4 children had between 2-10% of M184V, 11 had <0.7%, 18 had no detectable mutation and 2 could not be amplified. No K103N minority populations were found. Once under HAART, children who had 2-10% of M184V at baseline further selected it in percentages >20% in less time than those with -0.1-0.6% or without minority populations (P=0.01). CONCLUSIONS It was shown that having 2-10% of M184V at baseline enhanced its selection in high percentages in a short time after HAART initiation. Further research regarding the presence of minority quasispecies before initiation of HAART in large paediatric populations should be undertaken to evaluate their clinical effect during HAART.

Infecciones invasivas por Streptococcus pneumoniae: Estudio epidemiológico e importancia del desarrollo de un sistema de vigilancia

Las infecciones invasivas por streptococcus pnneumoniae(Spn)producen mortalidad elevada en paises en desarrollo,con tasa entre 4 y 100 veces mayores que las de Estados Unidos o Canada.Es el primer agente causal de neumonia en la infancia y de meningitis fuera de los brotes epidemicos po neisseria meningiditis.La OPS,a traves del grupo SIREVA,dedicado al desarrollo de vacunas en Latinoamerica,organizo un programa de vigilancia de infecciones invasivas por Spn en seis paises:argentina,Brasil,chile,colombia,Mexico y Uruguay iniciado en 1993 y que continua actualmente.En Argentina participan en la actualidad mas de 20 centros hospitalarios distribuidos en todas la areas geograficas del pais,actuando como Centro Nacional de referencia para la serotipificacion y determinacion de la resistencia a los antibioticos el Instituto ANLIS uDr.Carlos G Malbran.Objetivos.1)determinar los serotipos predominates,su resistencia a los antibioticos y los cambios temporales en infecciones invasivas por Spn de ninos menores de 5 anos de edad.2)Obtener informacion confiable para la formulacion de una vacuna conjugada adecuada para la region.Conclusiones.Un programa nacional de vigilancia de Spn invasivo fue desarrollado en Argentina y otros paises Latinoamericanos.Se identificaron por primera vez los serotipos predominantes en infecciones invasivas y se comprobo el incremento significativo de la resistencia a penicilina y otros antibioticos,similar a lo informado en casi todos los paises del mundo.Se obtuvo informacion epidemiologica valida para evaluar estrategias de prevencion en nuevas vacunas

Two cases of mother-to-child transmission of HIV and Trypanosoma cruzi in Argentina

Since numerous tropical pathogens lead to opportunistic infections in the context of the human immunodeficiency virus (HIV), coinfection could have significant effects on the course of HIV infection. 1 In this article we report two cases coinfected with HIV and Trypanosoma cruzi presenting unfavorable evolution despite correct treatment. Both patients were infected with both pathogens by mother-to-child transmission (MTCT) route, and both died due to a Klebsiella pneumoniae sepsis. Case 1: Child 1 was admitted to the Central Childrens Hospital in La Plata at age 1 month with respiratory difficulty and diarrhea. The patient was a preterm newborn with good weight for the gestational age, with no prenatal care. Both parents were illiterate, and were living with HIV for a year but without treatment, including during pregnancy. The father was an intravenous drug abuser, and had been incarcerated; a 2-year-old brother was HIV-negative but an elder sister had died of HIV/acquired immunodeficiency syndrome (AIDS). Chagas infection in the mother was probably congenital, since her mother emigrated from a high endemic zone. The child presented severe malnutrition and congenital heart disease (interventricular communication). The child started with shortness of breath and diarrhea with a 48-hour evolution, and also presented bilateral inguinal and cervical micropoliadenopaty, splenomegaly, thrush, hypoxemia, and opisthotonus position. Disturbances in the cerebrospinal fluid cell count became apparent and Streptococcus pneumoniae was cultivated. Therefore, the patient was received ceftriaxone at appropriate doses for meningitis treatment for ten days, and an erythrocyte transfusion was performed. Vaccination with DPT-HB-Hib and Salk was indicated. During hospitalization, he presented two episodes of seizures related with fever. Serologies for several pathogens were performed, and antibodies for T. cruzi, Toxoplasma gondii, Epstein-Barr virus (EBV), and HIV were detected. HIV infection was confirmed by polymerase chain reaction (PCR), and T. cruzi infection, by Microstrout (both infections were confirmed in at least two separate samples). Electroencephalography (EEG) and cerebral computed tomography (CT) were abnormal, with muscular hypertonia and opisthostonus, both bilateral clonus and positive Babinsky. The symptoms were interpreted as brain damage due to pneumococcocal meningoencephalitis. At the age of six months, he was released after 155 days in hospital. Then, at the age of 22 months, he presented with diarrhea and sepsis by K. pneumoniae with secondary dehydration. The patient died ten days later; he had been treated with zidovudine since delivery and for two months with combined HAART (lamivudine, stavudine, nelfinavir) and benzonidazol. Three resistance tests …