Impact of the bacterial nasopharyngeal microbiota on the severity of genus enterovirus lower respiratory tract infection in children: A case-control study

Introduction: Rhinoviruses (RV) and enteroviruses (EV) are among the main causative etiologies of lower respiratory tract infection (LRTI) in children. The clinical spectrum of RV/EV infection is wide, which could be explained by diverse environmental, pathogen-, and host-related factors. Little is known about the nasopharyngeal microbiota as a risk factor or disease modifier for RV/EV infection in pediatric patients. This study describes distinct nasopharyngeal microbiota profiles according to RV/EV LRTI status in children. Methods: Cross-sectional case-control study, conducted at Hospital Sant de Déu (Barcelona, Spain) from 2017 to 2020. Three groups of children <5 years were included: healthy controls without viral detection (Group A), mild or asymptomatic controls with RV/EV infection (Group B), and cases with severe RV/EV infection admitted to the pediatric intensive care unit (PICU) (Group C). Nasopharyngeal samples were collected from participants for viral DNA/RNA detection by multiplex-polymerase chain reaction and bacterial microbiota characterization by 16S rRNA gene sequencing. Results: A total of 104 subjects were recruited (A = 17, B = 34, C = 53). Children's nasopharyngeal microbiota composition varied according to their RV/EV infection status. Richness and diversity were decreased among children with severe infection. Nasopharyngeal microbiota profiles enriched in genus Dolosigranulum were related to respiratory health, while genus Haemophilus was specifically predominant in children with severe RV/EV LRTI. Children with mild or asymptomatic RV/EV infection showed an intermediate profile. Conclusions: These results suggest a close relationship between the nasopharyngeal microbiota and different clinical presentations of RV/EV infection.This project is supported by the Spanish National Health Institute Carlos III (Grant id. PI17/349). Cofunded by European Regional Development Fund/European Social Fund “A way to make Europe”/“Investing in your future.”S

Concentrations of nitrogen compounds are related to severe rhinovirus infection in infants. A time-series analysis from the reference area of a pediatric university hospital in Barcelona

Background: There is scarce information focused on the effect of weather conditions and air pollution on specific acute viral respiratory infections, such as rhinovirus (RV), with a wide clinical spectrum of severity. Objective: The aim of this study was to analyze the association between episodes of severe respiratory tract infection by RV and air pollutant concentrations (NOx and SO2 ) in the reference area of a pediatric university hospital. Methods: An analysis of temporal series of daily values of NOx and SO2 , weather variables, circulating pollen and mold spores, and daily number of admissions in the pediatric intensive care unit (PICU) with severe respiratory RV infection (RVi) in children between 6 months and 18 years was performed. Lagged variables for 0-5 days were considered. The study spanned from 2010 to 2018. Patients with comorbidities were excluded. Results: One hundred and fifty patients were admitted to the PICU. Median age was 19 months old (interquartile range [IQR]: 11-47). No relationship between RV-PICU admissions and temperature, relative humidity, cumulative rainfall, or wind speed was found. Several logistic regression models with one pollutant and two pollutants were constructed but the best model was that which included average daily NOx concentrations. Average daily NOx concentrations were related with the presence of PICU admissions 3 days later (odds ratio per IQR-unit increase: 1.64, 95% confidence interval: 1.20-2.25)). Conclusions: This study has shown a positive correlation between NOx concentrations at Lag 3 and children's PICU admissions with severe RV respiratory infection. Air pollutant data should be taken into consideration when we try to understand the severity of RVis.This project was partially supported by the Spanish National Health Institute Carlos III (Grant id. PI17/349). Desiree Henares received a grant for predoctoral training in research into Health by the Spanish National Health Institute Carlos III (project number: FI17/00248). The funders have not influenced the design or analysis, nor have they had any role inpreparing the manuscript.S

Lower Respiratory Tract Infection and Genus Enterovirus in Children Requiring Intensive Care: Clinical Manifestations and Impact of Viral Co-Infections

Infection by rhinovirus (RV) and enterovirus (EV) in children ranges from asymptomatic infection to severe lower respiratory tract infection (LRTI). This cohort study evaluates the clinical impact of RV/EV species, alone or in codetection with other viruses, in young children with severe LRTI. Seventy-one patients aged less than 5 years and admitted to the Paediatric Intensive Care Unit (PICU) of a reference children's hospital with RV or EV (RV/EV) LRTI were prospectively included from 1/2018 to 3/2020. A commercial PCR assay for multiple respiratory pathogens was performed in respiratory specimens. In 22/71, RV/EV + respiratory syncytial virus (RSV) was found, and 18/71 had RV/EV + multiple viral detections. Patients with single RV/EV detection required invasive mechanical ventilation (IMV) as frequently as those with RSV codetection, whereas none of those with multiple viral codetections required IMV. Species were determined in 60 samples, 58 being RV. No EV-A, EV-C, or EV-D68 were detected. RV-B and EV-B were only found in patients with other respiratory virus codetections. There were not any associations between RV/EV species and severity outcomes. To conclude, RV/EV detection alone was observed in young children with severe disease, while multiple viral codetections may result in reduced clinical severity. Differences in pathogenicity between RV and EV species could not be drawn.This project is supported by the Spanish National Health Institute Carlos III (Grant id. PI17/349). DH received a grant for predoctoral training in research into Health by the Spanish National Health Institute Carlos III (project number: FI17/00248). DH also received a grant from Sociedad Española de Enfermedades Infecciosas y Microbiología Clínica (SEIMC) for a research stay. The funders have not influenced the design or analysis, nor have they had any role in preparing the manuscript.S

Low transmission of SARS-CoV-2 derived from children in family clusters: An observational study of family households in the Barcelona Metropolitan Area, Spain

Background: Family clusters offer a good opportunity to study viral transmission in a stable setting. We aimed to analyze the specific role of children in transmission of SARS-CoV-2 within households. Methods: A prospective, longitudinal, observational study, including children with documented acute SARS-CoV-2 infection attending 22 summer-schools in Barcelona, Spain, was performed. Moreover, other patients and families coming from other school-like environments that voluntarily accessed the study were also studied. A longitudinal follow-up (5 weeks) of the family clusters was conducted to determine whether the children considered to be primary cases were able to transmit the virus to other family members. The household reproduction number (Re*) and the secondary attack rate (SAR) were calculated. Results: 1905 children from the summer schools were screened for SARS-CoV-2 infection and 22 (1.15%) tested positive. Moreover, 32 additional children accessed the study voluntarily. Of these, 37 children and their 26 households were studied completely. In half of the cases (13/26), the primary case was considered to be a child and secondary transmission to other members of the household was observed in 3/13, with a SAR of 14.2% and a Re* of 0.46. Conversely, the SAR of adult primary cases was 72.2% including the kids that gave rise to the contact tracing study, and 61.5% without them, and the estimated Re* was 2.6. In 4/13 of the paediatric primary cases (30.0%), nasopharyngeal PCR was persistently positive > 1 week after diagnosis, and 3/4 of these children infected another family member (p<0.01). Conclusions: Children may not be the main drivers of the infection in household transmission clusters in the study population. A prolonged positive PCR could be associated with higher transmissibility

Estudio del papel de la microbiota nasofaríngea en la gravedad de la infección por Rino/Enterovirus humano en niños menores de 5 años

[spa] INTRODUCCIÓN: Los Rinovirus (RV) y Enterovirus (EV) son una de las principales causas de infección del tracto respiratorio superior (ITRS) e inferior (ITRI). Las manifestaciones clínicas producidas por los RV/EV son múltiples y heterogéneas, pudiendo causar desde infecciones asintomáticas hasta infecciones graves con compromiso vital. Esta variabilidad se ha relacionado con múltiples factores, dependientes del propio virus, del huésped o del ambiente. En los últimos años la microbiota nasofaríngea viral y bacteriana está cobrando protagonismo como un posible factor modulador de la gravedad de las infecciones respiratorias, pero existe poca evidencia acerca de su relación con la infección por RV/EV. HIPÓTESIS: La co-infección viral podría ser un factor modificador de la gravedad de la ITRI por RV/EV en niños menores de 5 años. Por otra parte, los niños menores de 5 años con ITRI grave por RV/EV podrían presentar una microbiota nasofaríngea bacteriana distinta a la de niños con infección respiratoria banal y niños sanos, en tanto que determinadas composiciones de microbiota nasofaríngea bacteriana se asociarían con salud respiratoria. En este sentido, la composición de la microbiota nasofaríngea bacteriana en el escenario de la infección por RV/EV variaría de acuerdo con la gravedad de los síntomas. OBJETIVOS: Describir el impacto clínico de la co-infección viral en pacientes con ITRI grave por RV/EV que precisan ingreso en una unidad de cuidados intensivos pediátricos (UCIP). Describir y comparar la microbiota nasofaríngea bacteriana de niños con ITRI grave por RV/EV, niños con infección respiratoria banal por estos microorganismos y niños sanos, identificando perfiles de microbiota bacteriana nasofaríngea relaciona- dos con salud respiratoria, y evaluando la relación de ésta con la gravedad de la infección por estos microorganismos. MÉTODOS: Se realizaron dos estudios observacionales, en los que se reclutaron niños menores de 5 años atendidos en el hospital Sant Joan de Déu entre 2017-2020. En el primer estudio se incluyeron pacientes que precisaron ingreso en la UCIP de dicho centro, diagnosticados de ITRI por RV/EV mediante realización de un panel de PCR múltiple en aspirado nasofaríngeo, que era además capaz de detectar 6 virus respiratorios más. Se analizaron 3 grupos de pacientes en función de si presentaron mono-infección por RV/EV, co-infección con virus respiratorio sincitial (VRS), o co-infección con múltiples virus, considerando como variables resultado la necesidad de ventilación mecánica invasiva (VMI), y la estancia en UCIP superior a la media de la muestra (5 días). El segundo estudio con diseño caso-control se definieron 3 grupos: el grupo caso en el que se incluyeron niños con ITRI grave por RV/EV que precisaron ingreso en la UCIP, y que se pareó por rango de edad y sexo con dos grupos controles: niños sanos y niños con infección respiratoria banal por RV/EV. Se caracterizó la microbiota nasofaríngea bacteriana de estos 3 grupos mediante técnicas de secuenciación masiva basadas en la tecnología del gen 16S rRNA. PRINCIPALES RESULTADOS: En la presente tesis se ha identificado que la co-infección de RV/EV con múltiples virus respiratorios no representa un factor que incremente la gravedad de dicha infección. Los pacientes que presentaron una ITRI grave por RV/EV en mono-infección precisaron VMI y tuvieron una estancia media en UCIP significativamente mayor que los pacientes con múltiples co-infecciones. Por otra parte, se han descrito diferentes perfiles de microbiota nasofaríngea bacteriana en función de la presentación clínica de la infección por RV/EV. Los niños sanos presentaron una microbiota nasofaríngea rica y diversa, con mayor abundancia de especies comensales como Dolosigranulum pigrum y Corynebacterium spp. En cambio, los niños con ITRI grave por RV/EV presentaron una microbiota nasofaríngea significativamente menos rica y diversa que los controles sanos, con una menor abundancia de Dolosigranulum y una mayor abundancia de Haemophilus. Los niños con infección respiratoria banal RV/EV mostraron niveles intermedios de riqueza y diversidad entre ambos grupos. CONCLUSIONES: Los RV/EV en mono-infección pueden constituir el agente etiológico de ITRI grave en el paciente pediátrico. La co-infección con otros virus respiratorios no resulta un factor determinante que incremente la gravedad de las ITRI por RV/EV. Se han caracterizado diferentes perfiles de microbiota nasofaríngea bacteriana en función de la gravedad de las manifestaciones clínicas de la infección por RV/EV, con una disbiosis progresiva de dicha microbiota desde la que presentan los pacientes asintomáticos hasta la descrita en aquellos que precisaron ingreso en la UCIP, caracterizada por una pérdida de riqueza y diversidad, reducción de bacterias comensales como Dolosigranulum y aumento de bacterias del género Haemophilus

Estudio del papel de la microbiota nasofaríngea en la gravedad de la infección por Rino/Enterovirus humano en niños menores de 5 años

Programa de Doctorat en Medicina i Recerca Translacional / Tesi realitzada a l'Hospital Sant Joan de Déu[spa] INTRODUCCIÓN: Los Rinovirus (RV) y Enterovirus (EV) son una de las principales causas de infección del tracto respiratorio superior (ITRS) e inferior (ITRI). Las manifestaciones clínicas producidas por los RV/EV son múltiples y heterogéneas, pudiendo causar desde infecciones asintomáticas hasta infecciones graves con compromiso vital. Esta variabilidad se ha relacionado con múltiples factores, dependientes del propio virus, del huésped o del ambiente. En los últimos años la microbiota nasofaríngea viral y bacteriana está cobrando protagonismo como un posible factor modulador de la gravedad de las infecciones respiratorias, pero existe poca evidencia acerca de su relación con la infección por RV/EV. HIPÓTESIS: La co-infección viral podría ser un factor modificador de la gravedad de la ITRI por RV/EV en niños menores de 5 años. Por otra parte, los niños menores de 5 años con ITRI grave por RV/EV podrían presentar una microbiota nasofaríngea bacteriana distinta a la de niños con infección respiratoria banal y niños sanos, en tanto que determinadas composiciones de microbiota nasofaríngea bacteriana se asociarían con salud respiratoria. En este sentido, la composición de la microbiota nasofaríngea bacteriana en el escenario de la infección por RV/EV variaría de acuerdo con la gravedad de los síntomas. OBJETIVOS: Describir el impacto clínico de la co-infección viral en pacientes con ITRI grave por RV/EV que precisan ingreso en una unidad de cuidados intensivos pediátricos (UCIP). Describir y comparar la microbiota nasofaríngea bacteriana de niños con ITRI grave por RV/EV, niños con infección respiratoria banal por estos microorganismos y niños sanos, identificando perfiles de microbiota bacteriana nasofaríngea relaciona- dos con salud respiratoria, y evaluando la relación de ésta con la gravedad de la infección por estos microorganismos. MÉTODOS: Se realizaron dos estudios observacionales, en los que se reclutaron niños menores de 5 años atendidos en el hospital Sant Joan de Déu entre 2017-2020. En el primer estudio se incluyeron pacientes que precisaron ingreso en la UCIP de dicho centro, diagnosticados de ITRI por RV/EV mediante realización de un panel de PCR múltiple en aspirado nasofaríngeo, que era además capaz de detectar 6 virus respiratorios más. Se analizaron 3 grupos de pacientes en función de si presentaron mono-infección por RV/EV, co-infección con virus respiratorio sincitial (VRS), o co-infección con múltiples virus, considerando como variables resultado la necesidad de ventilación mecánica invasiva (VMI), y la estancia en UCIP superior a la media de la muestra (5 días). El segundo estudio con diseño caso-control se definieron 3 grupos: el grupo caso en el que se incluyeron niños con ITRI grave por RV/EV que precisaron ingreso en la UCIP, y que se pareó por rango de edad y sexo con dos grupos controles: niños sanos y niños con infección respiratoria banal por RV/EV. Se caracterizó la microbiota nasofaríngea bacteriana de estos 3 grupos mediante técnicas de secuenciación masiva basadas en la tecnología del gen 16S rRNA. PRINCIPALES RESULTADOS: En la presente tesis se ha identificado que la co-infección de RV/EV con múltiples virus respiratorios no representa un factor que incremente la gravedad de dicha infección. Los pacientes que presentaron una ITRI grave por RV/EV en mono-infección precisaron VMI y tuvieron una estancia media en UCIP significativamente mayor que los pacientes con múltiples co-infecciones. Por otra parte, se han descrito diferentes perfiles de microbiota nasofaríngea bacteriana en función de la presentación clínica de la infección por RV/EV. Los niños sanos presentaron una microbiota nasofaríngea rica y diversa, con mayor abundancia de especies comensales como Dolosigranulum pigrum y Corynebacterium spp. En cambio, los niños con ITRI grave por RV/EV presentaron una microbiota nasofaríngea significativamente menos rica y diversa que los controles sanos, con una menor abundancia de Dolosigranulum y una mayor abundancia de Haemophilus. Los niños con infección respiratoria banal RV/EV mostraron niveles intermedios de riqueza y diversidad entre ambos grupos. CONCLUSIONES: Los RV/EV en mono-infección pueden constituir el agente etiológico de ITRI grave en el paciente pediátrico. La co-infección con otros virus respiratorios no resulta un factor determinante que incremente la gravedad de las ITRI por RV/EV. Se han caracterizado diferentes perfiles de microbiota nasofaríngea bacteriana en función de la gravedad de las manifestaciones clínicas de la infección por RV/EV, con una disbiosis progresiva de dicha microbiota desde la que presentan los pacientes asintomáticos hasta la descrita en aquellos que precisaron ingreso en la UCIP, caracterizada por una pérdida de riqueza y diversidad, reducción de bacterias comensales como Dolosigranulum y aumento de bacterias del género Haemophilus

Concentrations of nitrogen compounds are related to severe rhinovirus infection in infants. A time-series analysis from the reference area of a pediatric university hospital in Barcelona

Background: There is scarce information focused on the effect of weather conditions and air pollution on specific acute viral respiratory infections, such as rhinovirus (RV), with a wide clinical spectrum of severity. Objective: The aim of this study was to analyze the association between episodes of severe respiratory tract infection by RV and air pollutant concentrations (NOx and SO2) in the reference area of a pediatric university hospital. Methods: An analysis of temporal series of daily values of NOx and SO2, weather variables, circulating pollen and mold spores, and daily number of admissions in the pediatric intensive care unit (PICU) with severe respiratory RV infection (RVi) in children between 6 months and 18 years was performed. Lagged variables for 0-5 days were considered. The study spanned from 2010 to 2018. Patients with comorbidities were excluded. Results: One hundred and fifty patients were admitted to the PICU. Median age was 19 months old (interquartile range [IQR]: 11-47). No relationship between RV-PICU admissions and temperature, relative humidity, cumulative rainfall, or wind speed was found. Several logistic regression models with one pollutant and two pollutants were constructed but the best model was that which included average daily NOx concentrations. Average daily NOx concentrations were related with the presence of PICU admissions 3 days later (odds ratio per IQR-unit increase: 1.64, 95% confidence interval: 1.20-2.25)). Conclusions: This study has shown a positive correlation between NOx concentrations at Lag 3 and children's PICU admissions with severe RV respiratory infection. Air pollutant data should be taken into consideration when we try to understand the severity of RVis

Lung Recruitment Maneuvers Assessment by Bedside Lung Ultrasound in Pediatric Acute Respiratory Distress Syndrome

The use of recruitment maneuvers (RMs) is suggested to improve severe oxygenation failure in patients with acute respiratory distress syndrome (ARDS). Lung ultrasound (LUS) is a non-invasive, safe, and easily repeatable tool. It could be used to monitor the lung recruitment process in real-time. This paper aims to evaluate bedside LUS for assessing PEEP-induced pulmonary reaeration during RMs in pediatric patients. A case of a child with severe ARDS due to Haemophilus influenzae infection is presented. Due to his poor clinical, laboratory, and radiological evolution, he was placed on venovenous extracorporeal membrane oxygenation (ECMO). Despite all measures, severe pulmonary collapse prevented proper improvement. Thus, RMs were indicated, and bedside LUS was successfully used for monitoring and assessing lung recruitment. The initial lung evaluation before the maneuver showed a tissue pattern characterized by a severe loss of lung aeration with dynamic air bronchograms and multiple coalescent B-lines. While raising a PEEP of 30 mmH2O, LUS showed the presence of A-lines, which was considered a predictor of reaeration in response to the recruitment maneuver. The LUS pattern could be used to assess modifications in the lung aeration, evaluate the effectiveness of RMs, and prevent lung overdistension

Personalized pulmonary vein antrum isolation guided by left atrial wall thickness for persistent atrial fibrillation

Aims: Pulmonary vein (PV) antrum isolation proved to be effective for treating persistent atrial fibrillation (PeAF). We sought to investigate the results of a personalized approach aimed at adapting the ablation index (AI) to the local left atrial wall thickness (LAWT) in a cohort of consecutive patients with PeAF. Methods and results: Consecutive patients referred for PeAF first ablation were prospectively enrolled. The LAWT three-dimensional maps were obtained from pre-procedure multidetector computed tomography and integrated into the navigation system. Ablation index was titrated according to the local LAWT, and the ablation line was personalized to avoid the thickest regions while encircling the PV antrum. A total of 121 patients (69.4% male, age 64.5 ± 9.5 years) were included. Procedure time was 57 min (IQR 50–67), fluoroscopy time was 43 s (IQR 20–71), and radiofrequency (RF) time was 16.5 min (IQR 14.3–18.4). The median AI tailored to the local LAWT was 387 (IQR 360–410) for the anterior wall and 335 (IQR 300–375) for the posterior wall. First-pass PV antrum isolation was obtained in 103 (85%) of the right PVs and 103 (85%) of the left PVs. Median LAWT values were higher for PVs without first-pass isolation as compared to the whole cohort (P = 0.02 for left PVs and P = 0.03 for right PVs). Recurrence-free survival was 79% at 12 month follow-up. Conclusion: In this prospective study, LAWT-guided PV antrum isolation for PeAF was effective and efficient, requiring low procedure, fluoroscopy, and RF time. A randomized trial comparing the LAWT-guided ablation with the standard of practice is in progress (ClinicalTrials.gov, NCT05396534)