Norovirus in children under 2 years of age: an epidemiological study in Panama during the COVID-19 pandemic.

Introduction: Norovirus infection is a common cause of acute gastroenteritis (AGE). Surveillance activities are important to aid investigation into effective norovirus control strategies, including vaccination. Here, we report ancillary findings related to the incidence, prevalence, and etiology of AGE caused by norovirus in Panama after adjustment of study methodology to comply with national coronavirus disease 2019 (COVID-19) mandates. Methods: In January 2020, children aged <2 years began enrolling into an epidemiological study in Panama to estimate the burden of norovirus in preparation for evaluating upcoming prevention strategies. This included an observational, longitudinal, community-based AGE surveillance study and a hospital-based AGE surveillance study. For the longitudinal study, healthy children aged 5-18 months were enrolled from January 6 through March 23, 2020, with a follow-up of approximately 6 months. The last participant was contacted on September 23, 2020. For the hospital-based study, starting on January 21, 2020, children aged <2 years who were admitted to the Hospital del Niño Dr. José Renán Esquivel in Panama City due to AGE were evaluated. The last sample was collected on September 29, 2020. Collected stool samples were tested for norovirus as well as astrovirus, sapovirus, and various enteropathogens. Unfortunately, this study was disrupted by the subsequent implementation of disease transmission control procedures for the COVID-19 pandemic, and the study methodology was revised to comply with COVID-19 mandates. Results: In the longitudinal surveillance cohort [N = 400 (Chiriquí, n = 239; Panama, n = 161)], a total of 185 AGE episodes were documented (Chiriquí, n = 85; Panama, n = 100) resulting in an overall AGE incidence of 11.6 (95% CI: 9.99-13.4) episodes per 100 child-months. The norovirus-related AGE incidence was 0.3 (95% CI: 0.10-0.73) episodes per 100 child-months (5/185 AGE episodes) and the prevalence of norovirus was 4.6% (13/282 stool samples collected). In the hospital-based surveillance cohort, at least one pathogen was detected in 50% of samples (44/88 stool samples collected) and norovirus prevalence was 6.8% (6/88 stool samples collected). Discussion: This report demonstrates how the occurrence of the COVID-19 pandemic hindered the conduct of clinical trials. However, this also created unique research opportunities to investigate the potential impact of pandemic control measures on the etiology of infectious diarrheal disease.

Genetic and phenotypic stability of poliovirus shed from infants who received novel type 2 or Sabin type 2 oral poliovirus vaccines in Panama: an analysis of two clinical trials.

BACKGROUND: Sabin strains used in oral poliovirus vaccines (OPV) can revert to virulence and, in rare instances, cause disease or generate vaccine-derived strains leading to outbreaks in areas of low immunisation coverage. A novel OPV2 (nOPV2) was designed to stabilise the viral genome against reversion and reduce recombination events that might lead to virulent strains. In this study, we evaluated the genetic and phenotypic stability of shed poliovirus following administration of one dose of monovalent OPV2 (mOPV2) or nOPV2 to infants aged 18-22 weeks. METHODS: In two similarly designed clinical trials (NCT02521974 and NCT03554798) conducted in Panama, infants aged 18-22-weeks, after immunisation with three doses of bivalent OPV (types 1 and 3) and one dose of inactivated poliovirus vaccine, were administered one or two doses of mOPV2 or nOPV2. In this analysis of two clinical trials, faecally shed polioviruses following one dose of mOPV2 or nOPV2 were isolated from stools meeting predetermined criteria related to sample timing and viral presence and quantity and assessed for nucleotide polymorphisms using next-generation sequencing. A transgenic mouse neurovirulence test was adapted to assess the effect of the possible phenotypic reversion of shed mOPV2 and nOPV2 with a logistic regression model. FINDINGS: Of the 91 eligible samples, 86 were able to be sequenced, with 72 evaluated in the transgenic mouse assay. Sabin-2 poliovirus reverts rapidly at nucleotide 481, the primary attenuation site in domain V of the 5' untranslated region of the genome. There was no evidence of neurovirulence-increasing polymorphisms in domain V of shed nOPV2. Reversion of shed Sabin-2 virus corresponded with unadjusted paralysis rates of 47·6% at the 4 log10 50% cell culture infectious dose (CCID50) and 76·7% at the 5 log10 CCID50 inoculum levels, with rates of 2·8% for 4 log10 CCID50 and 11·8% for 5 log10 CCID50 observed for shed nOPV2 samples. The estimated adjusted odds ratio at 4·5 log10 of 0·007 (95% CI 0·002-0·023; p<0·0001) indicates significantly reduced odds of mouse paralysis from virus obtained from nOPV2 recipients compared with mOPV2 recipients. INTERPRETATION: The data indicate increased genetic stability of domain V of nOPV2 relative to mOPV2, with significantly lower neurovirulence of shed nOPV2 virus compared with shed mOPV2. While this vaccine is currently being deployed under an emergency use listing, the data on the genetic stability of nOPV2 will support further regulatory and policy decision-making regarding use of nOPV2 in outbreak responses. FUNDING: Bill & Melinda Gates Foundation.

Hepatitis A antibody persistence 8 and 10 years after 1-dose and 2-dose vaccination in children from Panama.

BACKGROUND: Hepatitis A virus (HAV) remains a global public health concern, which is potentially growing in Latin America, due to an expected shift from high to intermediate endemicity levels. The use of HAV vaccines in pediatric national immunization programs (NIPs), either as a 2-dose or a 1-dose schedule, has been explored in Latin American countries; however, evidence demonstrating long-term protection in this population is limited in the region. We evaluated long-term antibody persistence following a 1-dose partial series and the recommended 2-dose schedule used in Panama's pediatric NIP. METHODS: Two independent cross-sectional serological surveys were conducted at year 8 (Y8) and Y10 following vaccination under the NIP with 1 or 2 doses of an inactivated HAV vaccine (Havrix, GSK). Seropositivity (anti-HAV antibody concentration ≥ 15 mIU/mL) rates and antibody geometric mean concentrations (GMCs) were assessed at each serosurvey. Non-inferiority of 1 dose versus 2 doses was also explored. RESULTS: This study (NCT02712359) included 600 and 599 children at Y8 and Y10 post-vaccination, respectively. Seropositivity rates were 74.3% (95% confidence interval [CI]: 69.0; 79.2) and 97.7% (95% CI: 95.3; 99.1) at Y8 and 71.9% (95% CI: 66.4; 76.9) and 96.3% (95% CI: 93.5; 98.2) at Y10, in the 1-dose and 2-dose groups, respectively. Antibody GMCs were lower in the 1-dose versus the 2-dose group in both surveys. Non-inferiority was not demonstrated since the lower limit of the 2-sided 95% CI for the between-group difference in seropositivity rates (1-dose minus 2-dose) was < -10%. CONCLUSION: Anti-HAV antibody persistence was observed in lower percentages of children receiving 1 dose versus 2 doses of Havrix, at 8 and 10 years post-vaccination in Panama. Further investigations are needed to confirm antibody persistence and conclude on the protection afforded beyond 10 years in the pediatric population in Latin America.

Enterovirus D68 infection among hospitalized children with severe acute respiratory illness in El Salvador and Panama, 2012-2013.

We assessed EV-D68 epidemiology and phylogenetics among children aged ≤9 years hospitalized with severe acute respiratory illnesses at five sites in Panama and El Salvador during 2012-2013. Respiratory specimens positive for enterovirus or rhinovirus were tested by real-time RT-PCR for EV-D68, and partial VP1 gene sequences were determined. Of 715 enrolled children, 17 from sites in both countries were EV-D68-positive and commonly had a history of asthma or wheezing. Phylogenetically, 15 of 16 sequences fell into Clade B1, and one into Clade A2. The Central American EV-D68s were closely related genetically to contemporaneous strains from North America, South America, and the Caribbean.

Costs associated with acute respiratory illness and select virus infections in hospitalized children, El Salvador and Panama, 2012-2013.

BACKGROUND AND OBJECTIVES: Although acute respiratory illness (ARI) is a leading cause of hospitalization among young children, few data are available about cost of hospitalization in middle-income countries. We estimated direct and indirect costs associated with severe ARI resulting in hospitalization among children aged <10 years in El Salvador and Panama through the societal perspective. METHODS: During 2012 and 2013, we surveyed caregivers of children hospitalized with ARI about their direct medical (i.e., outpatient consultation, medications, hospital fees), non-medical (transportation, childcare), and indirect costs (lost wages) at discharge and 7 days after discharge. We multiplied subsidized hospital bed costs derived from administrative data by hospitalization days to estimate provider costs. RESULTS: Overall, 638 children were enrolled with a median age of 12 months (IQR 6-23). Their median length of hospitalization was 4 days (IQR 3-6). In El Salvador, caregivers incurred a median of US$38 (IQR 22-72) in direct and indirect costs per illness episode, while the median government-paid hospitalization cost was US$118 (IQR 59-384) generating an overall societal cost of US$219 (IQR 101-416) per severe ARI episode. In Panama, caregivers incurred a median of US$75 (IQR 39-135) in direct and indirect costs, and the health-care system paid US$280 (IQR 150-420) per hospitalization producing an overall societal cost of US$393 (IQR 258-552). CONCLUSIONS: The cost of severe ARI to caregivers and the health care system was substantive. Our estimates will inform models to estimate national costs of severe ARI and cost-benefit of prevention and treatment strategies.

A randomized, double-blind, placebo-controlled trial evaluating the safety of early oseltamivir treatment among children 0-9 years of age hospitalized with influenza in El Salvador and Panama.

BACKGROUND: Oseltamivir reduces symptom duration among children with uncomplicated influenza, but few data exist on treatment efficacy and tolerability among hospitalized children, particularly among infants aged <1 year. We evaluated tolerability and efficacy of oseltamivir treatment of children aged 0-9 years hospitalized with influenza. METHODS: We conducted a double-blind, randomized, placebo-controlled trial at tertiary care hospitals in El Salvador and Panama. Primary outcomes were length of hospitalization and increased work of breathing. Children were eligible if hospitalized <7 days after symptom onset with cough or sore throat plus tachypnea. Children were randomized 1:1 to receive oseltamivir or placebo; had swabs collected at enrollment for influenza RT-PCR testing; were assessed at enrollment and every 12 h for work of breathing; and were followed for adverse events through 7 days after discharge. Analyses were intention-to-treat. RESULTS: Overall, 683 children were randomized (oseltamivir, n = 341, placebo n = 342). Fifty-three percent were aged <1 year and 30 had influenza (oseltamivir, n = 19; placebo, n = 11). The study was terminated early after enrollment of 21% of the sample size due to lower than anticipated participant accrual. Using Kaplan-Meier analysis, there was no significant difference in median length of hospitalization (3 days, IQR 2-4 vs. 5 days, IQR 3-7, p = 0.22) and increased work of breathing (36 h, IQR 24-72 vs. 96 h, IQR 13-108, p = 0.14) between oseltamivir versus placebo recipients. There was no difference in adverse events between groups. CONCLUSION: Oseltamivir treatment was well tolerated among hospitalized children, including among infants aged <1 year.

Tuberculosis diseminada: Presentaciones inusuales en pediatría

Un 15 a 25% de los casos de tuberculosis presentan infecciones extrapulmonares. El diagnóstico temprano y tratamiento adecuado ayuda a reducir el riesgo de complicaciones y secuelas. La implementación del tratamiento estrictamente vigilado ha mejorado el control global de la tuberculosis, sin embargo es menos efectivo en las áreas donde prevalece la infección por VIH, la tuberculosis multidrogoresistente, la pobreza y donde la baciloscopia es la herramienta diagnóstica, la cual es excluyente en niños. La falta de un método sensible retarda el diagnóstico en la infancia, se realizan esfuerzos para el desarrollo de métodos simpli cados pero aún se carece de ellos. Se reportan 2 casos de tuberculosis diseminada en pacientes pediátricos, indígenas, Vih negativos, en dos grupos etarios extremos. Un lactante de 11 meses con tuberculosis miliar, cavitaciones pulmonares, efusión pleural y neumonía bacteriana complicada agregada y un adolescente de 13 años con meningitis tuberculosa e infartos isquémicos, neumonía con efusión y engrosamiento pleural. Ambos casos de interés por la relevancia epidemiológica de esta patología en la región y la variabilidad en la presentación clínica lo que impone mantener un alto índice de sospecha clínica en presencia de cualquiera de los criterios diagnósticos de tuberculosis.

A 15-25% of cases of tuberculosis have extrapulmonary infections. The early diagnosis and appropriate treatment helps to reduce the risk of complications and sequelae. The implementation of the strictly secure treatment has improved the global tuberculosis control, however it is less e ective in areas where the infection by HIV, TB multidrugoresistant, poverty prevails and where the sputum smear is the diagnostic tool, which is exclusive in children. The lack of a sensible approach delays the diagnosis in childhood, e orts for the development of simpli ed methods, but still are lacking them. Reported 2 cases of disseminated tuberculosis in patients paediatric, indigenous peoples, HIV-negative, in two extreme age groups. An infant of 11 months with miliary tuberculosis, pulmonary cavitations, pleural e usion and added complicated bacterial pneumonia and a teenager of 13 years with tuberculous meningitis and ischemic stroke, pneumonia with e usion and pleural thickening. Both cases of interest in the epidemiological relevance of this pathology in the region and the variability in clinical presentation which imposes maintain a high index of clinical suspicion in the presence of any of the diagnostic criteria of tuberculosis.

Impacto del serotipo 5 en la enfermedad invasora por Streptococcus pneumoniae en la población pediátrica ingresada en el Hospital Materno Infantil José Domingo de Obaldía

La vigilancia de la enfermedad invasora por Streptococcus pneumoniae permite detectar los cambios geográficos y cronológicos en los serotipos circulantes y en la sensibilidad antimicrobiana, monitorizando además el impacto de las vacunas sobre la enfermedad. Objetivos: Describir los serotipos aislados y la sensibilidad antimicrobiana en los pacientes pediatrics hospitalizados con enfermedad invasora por Streptococcus pneumoniae. Describir la enfermedad invasora por Streptococcus pneumoniae y sus complicaciones clínicas asociadas. Metodología: Estudio retrospectivo, longitudinal, incluye pacientes pediátricos hospitalizados en el Hospital Materno Infantil José Domingo de Obaldía en el periodo de enero de 2010 a junio de 2011; los cuales se cursaron con enfermedad invasora por Streptococcus pneumoniae como etiología en este periodo. El diagnóstico microbiológico se realizó por coaglutinación en líquidos corporales y cultivo del microorganismo. La cepa se aisló en el laboratorio de microbiología y se tipificó en el Laboratorio Central. La enfermedad invasora fue definida por el cuadro clínico y el aislamiento de Streptococcus pneumoniae de un sitio previamente estéril. Variables analizadas: edad, sexo, procedencia, sitio de infección, complicaciones, tiempo hospitalario, mortalidad, ingreso a UCI, anemia, VIH , letalidad. Resultados: Se revisaron 25 expedientes de pacientes con enfermedad invasora y aislamiento de Streptococcus pneumoniae. Dos fueron excluidos. 20 pacientes fueron menores de 5 años y 3 mayores de 5 años. 11 varones y 12 niñas. El 91% fueron indigenas. El 60.8% procedía de la Comarca Ngöbe Buglé. Promedio hospitalario 25.3 días, rango 1-93 días. 60.8% ingresó con enfermedad grave a la UCIP; 92.8% ameritó ventilación mecánica y 78.5% presentó choque. 34%(8) cursó con compromiso de SNC y el 30% (7) bacteriemia. Se tipificaron 14 cepas , el (78.5%) fue serotipo 5. Todos los aislados fueron sensibles a penicilina. 31% (5) resistentes a TMP/SMX. El 74% de los casos tenia hemoglobina menor de 10 g y solamente 3 habían completado su vacunación con PCV-7. Todo fueron VIH negativo. 30% de los pacientes fallecieron. Conclusiones: En los caso evaluados encontramos un predominio del Streptococcus pneumoniae tipo 5 en el 78.5% de los casos. Los serotipos 24F, 18C y 4 fueron aislados en 1 caso cada uno; el 100% fue sensible a penicilina. La población más afectada fue la raza indígena y los menores de 5 años. El SNC y respiratorio fueron los sitios primarios de infección. El 61% ingreso con enfermedad grave y el 30% falleció.

The monitoring of the invading disease by S. pneumoniae allows detecting geographic and temporary changes in antimicrobial sensitivity, besides monitoring the impact of the vaccines on the disease. Objectives: To describe to the isolate serotypes and antimicrobial sensitivy of Streptococcus pneumoniae to associate invasive disease in the pediatric patients hospitalized. Besides clinical manifestations and complications. Methods: Retrospective, longitudinal study. Pediatrics patients hospitalized in the Maternal Hospital in January 2010 to June 2011; in which Streptococcus pneumoniae was isolated as etiology of invasive disease. The microbiological diagnosis for Streptococcus pneumoniae was realized with coaglutination and culture of body fluids. The strain was isolated in the microbiology laboratory and it was typified in the Central Laboratory in Panama City. An invasive disease was defined by clinical manifestations and the isolation of Streptococcus pneumoniae of a previously sterile site. Analyzes variables: age, sex, origins, site of infection, complications, hospital time, death, admission to UCI, anemia , HIV, lethality. Results: 25 files with Streptococcus pneumoniae isolation and invasive disease were reviewed. Two were excluded. 20 patients were younger than 5 years and 3 oldest of 5 years. 11 were boys and 12 girls. 91% were indigenous. 60.8% came from Comarca Ngöbe Bugle. Hospital average 25, 3 days with range 1-93 days. 60.8% had serious disease and went to the UCIP; 92.8% need mechanical ventilation and 78.5% suffering shock. 34% (8) presented with commitment respiratory and SNC simultaneously. 70% (20) patients with pneumonia presented pleural effusion. 21,7% pericardial effusion and 30% (7) bacteremia. 14 isolate were typified, serotype 5 (78.5%). All were sensible to penicillin; TMP/SMX resistant 31% (5). 74% had hemoglobin less than 10 g and only 3 had completed their vaccination with PCV-7. All were HIV negative. 30% lethality. Conclusions: Streptococcus pneumoniae serotype 5 were strains predominance in the 78.5%. Others as 24 F, 18C and 4, 1 case of each serotypes; 100% were sensible to penicillin. The people more affected was indigenous race and the younger than 5 years. The respiratory and SNC were the primary infections sites. 61% come with serious illness and 30% died.

Human rotavirus vaccine is highly efficacious when coadministered with routine expanded program of immunization vaccines including oral poliovirus vaccine in Latin America.

BACKGROUND: The efficacy of a rotavirus vaccine against severe rotavirus gastroenteritis when coadministered with routine Expanded Program on Immunization (EPI) vaccines including oral polio vaccine (OPV) was evaluated in this study. METHODS: Double-blind, randomized (2:1), placebo-controlled study conducted across 6 Latin American countries. Healthy infants (N = 6568) 6 to 12 weeks of age received 2 doses of RIX4414 vaccine or placebo following a 0, 1- to 2-month schedule. Routine vaccines including OPV were coadministered according to local EPI schedule. Vaccine efficacy (VE) against severe rotavirus gastroenteritis caused by circulating wild-type rotavirus from 2 weeks post-Dose 2 until 1 year of age was calculated with 95% confidence interval [CI]. Safety was assessed during the entire study period. Immunogenicity of RIX4414 and OPV was also assessed. RESULTS: During the efficacy follow-up period (mean duration = 7.4 months), 7 and 19 cases of severe rotavirus gastroenteritis were reported in the vaccine and placebo groups, respectively, with a VE of 81.6% (95% CI: 54.4-93.5). VE against severe rotavirus gastroenteritis caused by G1 type was 100% (95% CI: <0-100) and 80.6% (95% CI: 51.4-93.2) against the pooled non-G1 rotavirus types, respectively. There was no difference (P = 0.514) in the incidence of serious adverse events reported in the 2 groups. Antirotavirus IgA seropositivity rate at 1 to 2 months post-Dose 2 was 61.4% (95% CI: 53.7-68.6) in the RIX4414 group; similar seroprotection rates (≥96.0%) against the 3 antipoliovirus types was observed 1 month post-Dose 3 of OPV in both groups. CONCLUSION: RIX4414 was highly efficacious against severe rotavirus gastroenteritis caused by the circulating wild-type rotavirus (G1 and non-G1) when coadministered with routine EPI vaccines including OPV.

Diagnóstico y tratamiento de la neutropenia febril en niños con cáncer: Consenso de la Sociedad Latinoamericana de Infectología Pediátrica / Diagnosis and treatment of febrile neutropenia in pediatric cancer patients: Consensus of the Sociedad Latinoamericana de Infectología Pediátrica

La Sociedad Latinoamericana de Infectología Pediátrica, a través de su Comité de Infecciones en Niños Inmunocomprometidos, propone un documento de consenso sobre "Diagnóstico y tratamiento de la neutropenia febril en niños con cáncer". Este documento-guía aborda el manejo de la neutrope-nia febril orientado a la atención de niños con cáncer en América Latina. Se realizó una búsqueda exhaustiva de la literatura, y se consideró particularmente la experiencia publicada proveniente de centros de nuestro continente, que aporta una mirada regional y adecuada a la realidad de nuestros países. El manuscrito contiene un panorama epidemiológico de la Región y recomendaciones para la evaluación clínica y de laboratorio necesarios para el manejo de estos pacientes, establece criterios de categorización de riesgo de infecciones bacterianas invasoras, analiza las medidas de cuidado general de los pacientes en el ambiente hospitalario y extra-hospitalario, propone diferentes enfoques terapéuticos de acuerdo a las realidades epidemiológicas institucionales, parámetros clínicos y de categorización de riesgo, establece diferentes algoritmos de seguimiento según la evolución de cada paciente, especifica las situaciones en que está indicada algún tipo de profilaxis y da los lineamientos generales sobre el tipo y oportunidad de terapia antifúngica a utilizar en ellos. Se ha puesto especial énfasis en entregar, de forma práctica, y con la mayor evidencia posible, las recomendaciones para el mejor manejo de los niños con cáncer, fiebre y neutropenia, buscando la equidad y la excelencia en todos los centros oncológicos latinoamericanos.

This document is a consensus guideline on the "Diagnosis and treatment of febrile neutropenia in children with cancer" developed by the Committee for Infectious Diseases in Immunocompromised Children of the Sociedad Latinoamericana de Infectología Pediátrica. This guideline discusses the management of febrile neutropenia focused on Latin American children with cancer. It is based on a thorough review of the literature, with particular attention to experiences reported by centers within the continent in order to provide recommendations applicable to the region. The manuscript includes a description of the regional epidemiology of cancer and infections in children, recommendations for clinical and laboratory studies required for patient management, description of a classification method to identify patients at different risk for invasive bacterial infections, outpatient and inpatient general care strategies and differential treatment strategies adjusted to local epidemiological realities, different algorithms for patient follow-up according to clinical course, a discussion of the rationale for prophylaxis strategies in specific situations including general guidelines for antifungal treatment. The Guidelines intend to provide practical, evidence-based recommendations in order to promote the best possible management for children with cancer, fever and neutropenia, throughout oncology centers of Latin America.

DTPw-HB and Hib primary and booster vaccination: combined versus separate administration to Latin American children.

This multicentre study was designed to establish the reactogenicity and immunogenicity profiles of primary and booster vaccination with diphtheria, tetanus, and pertussis whole-cell-hepatitis B/Haemophilus influenzae type-b (DTPw-HB/Hib) administered as either a syringe mix or as separate injections in 400 Latin American children. Both vaccine regimens were equally well tolerated and elicited post-primary excellent seropositivity rates at or close to 100% for all five component antigens. With regard to HB, 100% of subjects in the combined vaccination group, and 98.8% subjects in the separate injection vaccination group reached seroprotective antibody concentrations (>or=10 mIU/ml) 1 month after the primary vaccination course. Equally high anti-PRP antibody concentrations were reached 1 month after vaccination, with 100% of seroprotected subjects in the combined vaccination group (antibody concentrations >or=0.15 microg/ml), against 99.4% in the separate injection vaccination group. Seroprotective anti-HBs and anti-PRP antibody concentration levels persisted approximately 1 year after the primary vaccination course, just prior to booster vaccination. Finally, a significant increase of all antibody concentrations could be observed after the booster vaccination, since all but one subject in the separate injection vaccination group had protective levels of anti-HBs and anti-PRP antibodies 1 month after the booster dose. These results suggest that the combination of DTPw-HB and Hib vaccines provides an effective means for increasing vaccine coverage in childhood vaccination programmes.