Publications by authors named "Mejias A"

186 Publications

Measuring the Burden of RSV in Children to Precisely Assess the Impact of Preventive Strategies.

Pediatrics 2020 07 16;146(1). Epub 2020 Jun 16.

Division of Pediatric Infectious Diseases and Center for Vaccines and Immunity, Nationwide Children's Hospital, Columbus, Ohio.

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http://dx.doi.org/10.1542/peds.2020-1727DOI Listing
July 2020

Hepatitis in children with tuberculosis: a case report and review of the literature.

BMC Pulm Med 2020 Jun 16;20(1):173. Epub 2020 Jun 16.

Division of Pediatric Infectious Diseases, Nationwide Children's Hospital, Columbus, OH, USA.

Background: Hepatitis in young children with tuberculosis (TB) outside miliary TB is not well described and represents a challenge because of the hepatotoxicity associated with first-line anti-TB treatment.

Case Presentation: We report an antibiotic naïve 13-month-old male from Nepal with pulmonary TB and hepatitis, who improved after TB treatment. We also performed a literature review for TB-associated hepatitis in children.

Conclusions: Liver function tests should be considered, when feasible, in infants and young children with pulmonary TB. Testing could help to identify and manage patients with TB-associated hepatic abnormalities, and also to establish a baseline for detection and management of liver injury associated with anti-TB therapy.
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http://dx.doi.org/10.1186/s12890-020-01215-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7298953PMC
June 2020

Baseline and Disease-Induced Transcriptional Profiles in Children with Sickle Cell Disease.

Sci Rep 2020 06 2;10(1):9013. Epub 2020 Jun 2.

Center for Microbial Pathogenesis, The Abigail Wexner Research Institute, Columbus, OH, USA.

Acute chest syndrome (ACS) is a significant cause of morbidity and mortality in sickle cell disease (SCD), but preventive, diagnostic, and therapeutic options are limited. Further, ACS and acute vasoccclusive pain crises (VOC) have overlapping features, which causes diagnostic dilemmas. We explored changes in gene expression profiles among patients with SCD hospitalized for VOC and ACS episodes to better understand ACS disease pathogenesis. Whole blood RNA-Seq was performed for 20 samples from children with SCD at baseline and during a hospitalization for either an ACS (n = 10) or a VOC episode (n = 10). Respiratory viruses were identified from nasopharyngeal swabs. Functional gene analyses were performed using modular repertoires, IPA, Gene Ontology, and NetworkAnalyst 3.0. The VOC group had a numerically higher percentage of female, older, and hemoglobin SS participants compared to the ACS group. Viruses were detected in 50% of ACS cases and 20% of VOC cases. We identified 3004 transcripts that were differentially expressed during ACS episodes, and 1802 transcripts during VOC episodes. Top canonical pathways during ACS episodes were related to interferon signaling, neuro-inflammation, pattern recognition receptors, and macrophages. Top canonical pathways in patients with VOC included IL-10 signaling, iNOS signaling, IL-6 signaling, and B cell signaling. Several genes related to antimicrobial function were down-regulated during ACS compared to VOC. Gene enrichment nodal interactions demonstrated significantly altered pathways during ACS and VOC. A complex network of changes in innate and adaptive immune gene expression were identified during both ACS and VOC episodes. These results provide unique insights into changes during acute events in children with SCD.
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http://dx.doi.org/10.1038/s41598-020-65822-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7265336PMC
June 2020

Metabolomics profiling of tobacco exposure in children with cystic fibrosis.

J Cyst Fibros 2020 09 30;19(5):791-800. Epub 2020 May 30.

Division of Pulmonary Medicine, Nationwide Children's Hospital, Columbus, OH, USA; Center for Microbial Pathogenesis, The Abigail Wexner Research Institute at Nationwide Children's Hospital, W510, 700 Children's Drive, Columbus, OH 43205, USA. Electronic address:

Background: Inflammation is integral to early disease progression in children with CF. The effect of modifiable environmental factors on infection and inflammation in persons with CF is poorly understood. Our prior studies determined that secondhand smoke exposure (SHSe) is highly prevalent in young children with CF. SHSe is associated with increased inflammation, heightened bacterial burden, and worsened clinical outcomes. However, the specific metabolite and signaling pathways that regulate responses to SHSe in CF are relatively unknown.

Methods: High-resolution metabolomics was performed on plasma samples from infants (n = 25) and children (n = 40) with CF compared to non-CF controls (n = 15). CF groups were stratified according to infant or child age and SHSe status.

Results: Global metabolomic profiles segregated by age and SHSe status. SHSe in CF was associated with changes in pathways related to steroid biosynthesis, fatty acid metabolism, cysteine metabolism, and oxidative stress. CF infants with SHSe demonstrated enrichment for altered metabolite localization to the small intestine, liver, and striatum. CF children with SHSe demonstrated metabolite enrichment for organs/tissues associated with oxidative stress including mitochondria, peroxisomes, and the endoplasmic reticulum. In a confirmatory analysis, SHSe was associated with changes in biomarkers of oxidative stress and cellular adhesion including MMP-9, MPO, and ICAM-1.

Conclusions: SHSe in young children and infants with CF is associated with altered global metabolomics profiles and specific biochemical pathways, including enhanced oxidative stress. SHSe remains an important but understudied modifiable variable in early CF disease.
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http://dx.doi.org/10.1016/j.jcf.2020.05.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7492400PMC
September 2020

Immune profiles provide insights into respiratory syncytial virus disease severity in young children.

Sci Transl Med 2020 04;12(540)

Center for Vaccines and Immunity, The Research Institute at Nationwide Children's Hospital, Columbus, OH 43205, USA.

Respiratory syncytial virus (RSV) is associated with major morbidity in infants, although most cases result in mild disease. The pathogenesis of the disease is incompletely understood, especially the determining factors of disease severity. A better characterization of these factors may help with development of RSV vaccines and antivirals. Hence, identification of a "safe and protective" immunoprofile induced by natural RSV infection could be used as a as a surrogate of ideal vaccine-elicited responses in future clinical trials. In this study, we integrated blood transcriptional and cell immune profiling, RSV loads, and clinical data to identify factors associated with a mild disease phenotype in a cohort of 190 children <2 years of age. Children with mild disease (outpatients) showed higher RSV loads, greater induction of interferon (IFN) and plasma cell genes, and decreased expression of inflammation and neutrophil genes versus children with severe disease (inpatients). Additionally, only infants with severe disease had increased numbers of HLA-DR monocytes, not present in outpatients. Multivariable analyses confirmed that IFN overexpression was associated with decreased odds of hospitalization, whereas increased numbers of HLA-DR monocytes were associated with increased risk of hospitalization. These findings suggest that robust innate immune responses are associated with mild RSV infection in infants.
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http://dx.doi.org/10.1126/scitranslmed.aaw0268DOI Listing
April 2020

Age and environmental exposures influence the fecal bacteriome of young children with cystic fibrosis.

Pediatr Pulmonol 2020 07 10;55(7):1661-1670. Epub 2020 Apr 10.

The Abigail Wexner Research Institute at Nationwide Children's Hospital, Center for Microbial Pathogenesis, Columbus, Ohio.

Background: Mechanisms that facilitate early infection and inflammation in cystic fibrosis (CF) are unclear. We previously showed that young CF children with secondhand smoke exposure (SHSe) have increased susceptibility to respiratory infections. We aimed to define the impact of SHSe and other external factors upon the fecal bacteriome in early CF.

Methods: Twenty CF infants and children were enrolled, clinical data recorded, and hair nicotine measured as an objective surrogate of SHSe. Fecal samples were collected at clinic visits and bacteriome 16S rRNA gene sequencing performed.

Results: SHSe was associated with increased alpha diversity and increased relative abundance of Acinetobacter and Akkermansia, along with decreased Bifidobacterium and Lactobacillus. Recent antibiotic exposure predicted bacterial population structure in children less than 2 years of age and was associated with decreased Bacteroides relative abundance. Age was the strongest predictor of overall fecal bacterial composition and positively associated with Blautia and Parabacteroides. Weight for length was negatively associated with Staphylococcus relative abundance.

Conclusions: SHSe and other external factors such as antibiotics appear to alter fecal bacterial composition in young CF children, but the strongest predictor of overall composition was age. These findings have implications for understanding the intestinal microbiome in young CF children.
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http://dx.doi.org/10.1002/ppul.24766DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7593804PMC
July 2020

The journey to a respiratory syncytial virus vaccine.

Ann Allergy Asthma Immunol 2020 07 23;125(1):36-46. Epub 2020 Mar 23.

Center for Vaccines and Immunity, Abigail Wexner Research Institute at Nationwide Children's Hospital, Columbus, Ohio; Division of Pediatric Infectious Diseases, Nationwide Children's Hospital, The Ohio State University, Columbus, Ohio.

Objective: The high burden associated with respiratory syncytial virus (RSV) has made the development of RSV vaccine(s) a global health high priority. This review summarizes the journey to an RSV vaccine, the different strategies and challenges associated with the development of preventive strategies for RSV, and the diverse products that are undergoing clinical testing.

Data Sources: Studies on RSV biology, immunology, epidemiology, and monoclonal antibodies (mAbs) and vaccines were searched using MEDLINE. We also searched PATH.org and ClinicalTrials.gov for updated information regarding the status of RSV vaccines and mAbs undergoing clinical trials.

Study Selections: We selected relevant studies conducted in infants and young children, pregnant women, and elderly population for the prevention of RSV infection.

Results: Identification of a safe and immunogenic vaccine has been an important but elusive initiative for more than 60 years for different reasons, including the legacy of formalin-inactivated vaccine, our limited understanding of the immune response to RSV and how it relates to clinical disease severity, or the need for different end points according to the different vaccine platforms. Nevertheless, there are currently 39 vaccines and mAbs under development and 19 undergoing clinical trials.

Conclusion: Over the past decade, there have been significant advances in our knowledge of RSV molecular and structural biology and in understanding the human immune response to RSV. Despite the barriers, there are several promising mAbs and RSV vaccines undergoing clinical trials that hope to offer protection to the most vulnerable populations.
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http://dx.doi.org/10.1016/j.anai.2020.03.017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7311299PMC
July 2020

Respiratory syncytial virus treatment and the respiratory microbiome.

Lancet Respir Med 2020 10 20;8(10):941-943. Epub 2020 Mar 20.

Center for Vaccines and Immunity, Abigail Wexner Research Institute, and Division of Pediatric Infectious Diseases, Nationwide Children's Hospital, The Ohio State University College of Medicine, Columbus, OH, USA.

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http://dx.doi.org/10.1016/S2213-2600(20)30106-5DOI Listing
October 2020

Live Attenuated Vaccine With a Stabilized Mutation and Gene Deletion for Prevention of Respiratory Syncytial Virus Disease in Young Children.

J Infect Dis 2020 02;221(4):501-503

Center for Vaccines and Immunity, Abigail Wexner Research Institute at Nationwide Children's Hospital, Columbus, Ohio, USA.

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http://dx.doi.org/10.1093/infdis/jiz604DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6996857PMC
February 2020

Recurrent wheezing during the first 3 years of life in a birth cohort of moderate-to-late preterm infants.

Pediatr Allergy Immunol 2020 02 13;31(2):124-132. Epub 2019 Nov 13.

Division of Infectious Diseases, Department of Pediatrics, Nationwide Children's Hospital, The Ohio State University, Columbus, OH, USA.

Background: Data addressing short- and long-term respiratory morbidity in moderate-late preterm infants are limited. We aim to determine the incidence of recurrent wheezing and associated risk and protective factors in these infants during the first 3 years of life.

Methods: Prospective, multicenter birth cohort study of infants born at 32 to 35  weeks' gestation and followed for 3 years to assess the incidence of physician-diagnosed recurrent wheezing. Allergen sensitization and pulmonary function were also studied. We used multivariate mixed-effects models to identify risk factors associated with recurrent wheezing.

Results: A total of 977 preterm infants were enrolled. Rates of recurrent wheezing during year (Y)1 and Y2 were similar (19%) but decreased to 13.3% in Y3. Related hospitalizations significantly declined from 6.3% in Y1 to 0.75% in Y3. Independent risk factors for recurrent wheezing during Y2 and Y3 included the following: day care attendance, acetaminophen use during pregnancy, and need for mechanical ventilation. Atopic dermatitis on Y2 and male sex on Y3 were also independently associated with recurrent wheezing. Palivizumab prophylaxis for RSV during the first year of life decreased the risk or recurrent wheezing on Y3. While there were no differences in rates of allergen sensitization, pulmonary function tests (FEV ) were significantly lower in children who developed recurrent wheezing.

Conclusions: In moderate-to-late premature infants, respiratory symptoms were associated with lung morbidity persisted during the first 3 years of life and were associated with abnormal pulmonary function tests. Only anti-RSV prophylaxis exerted a protective effect in the development of recurrent wheezing.
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http://dx.doi.org/10.1111/pai.13134DOI Listing
February 2020

Risk of childhood wheeze and asthma after respiratory syncytial virus infection in full-term infants.

Pediatr Allergy Immunol 2020 01 23;31(1):47-56. Epub 2019 Oct 23.

Center for Vaccines and Immunity, Abigail Wexner Research Institute at Nationwide Children's Hospital & The Ohio State University, Columbus, OH, USA.

Background: Most studies addressing the association between RSV and recurrent wheezing (RW) and asthma have been conducted in patients at risk for lung morbidity. Data in full-term infants are limited.

Methods: The risk of RW/asthma during the first 5 years of life in full-term infants hospitalized with RSV during the first year (Y) of life was estimated using 2010-16 data from three claims databases in USA (Truven MarketScan Commercial Claims and Encounters Database [CCAE], Truven Health MarketScan Multi-State Medicaid [MDCD], and Optum Clinformatics Extended Data Mart-Socio-Economic Status [SES]). Full-term infants with and without RSV infection and ≥ 2 years of continuous health plan enrollment from birth were included. Incidence rates of RW/asthma, cumulative incidence, adjusted incidence rate ratios (aIRR), and odds ratios (aOR) were calculated.

Results: During the 16-year study, 38,494 (CCAE), 62 846 (MDCD), and 23 099 (SES) matched infant pairs were included in each cohort. In the CCAE database, RW/asthma incidence/1000 patient-years (69.7 vs 28.7, aIRR: 2.4 [2.3-2.5]); cumulative incidence (17.6%-25.2% vs 5.0%-11.4%); and aOR (Y2: 4.1 [3.9-4.4]; Y3: 3.2 [3.0-3.3]; Y4: 2.9 [2.7-3.1]; Y5: 2.6 [2.5-2.9]) were higher in the RSV vs. non-RSV cohort. Results in the SES insured population were comparable, while cumulative incidence and aIRR were higher in the Medicaid population (MDCD).

Conclusion: Although there are limitations in this study, including possible coding errors and missing covariates, we showed that full-term infants with severe RSV infection during the first year of life, spanning several respiratory seasons and a geographically diverse population, are at significant risk of RW/asthma during childhood.
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http://dx.doi.org/10.1111/pai.13131DOI Listing
January 2020

Whole-blood transcriptomic responses to lumacaftor/ivacaftor therapy in cystic fibrosis.

J Cyst Fibros 2020 03 29;19(2):245-254. Epub 2019 Aug 29.

Center for Vaccines and Immunity, Nationwide Children's Hospital, Columbus, OH, USA.

Background: Cystic fibrosis (CF) remains without a definitive cure. Novel therapeutics targeting the causative defect in the cystic fibrosis transmembrane conductance regulator (CFTR) gene are in clinical use. Lumacaftor/ivacaftor is a CFTR modulator approved for patients homozygous for the CFTR variant p.Phe508del, but there are wide variations in treatment responses preventing prediction of patient responses. We aimed to determine changes in gene expression related to treatment initiation and response.

Methods: Whole-blood transcriptomics was performed using RNA-Seq in 20 patients with CF pre- and 6 months post-lumacaftor/ivacaftor (drug) initiation and 20 non-CF healthy controls. Correlation of gene expression with clinical variables was performed by stratification via clinical responses.

Results: We identified 491 genes that were differentially expressed in CF patients (pre-drug) compared with non-CF controls and 36 genes when comparing pre-drug to post-drug profiles. Both pre- and post-drug CF profiles were associated with marked overexpression of inflammation-related genes and apoptosis genes, and significant under-expression of T cell and NK cell-related genes compared to non-CF. CF patients post-drug demonstrated normalized protein synthesis expression, and decreased expression of cell-death genes compared to pre-drug profiles, irrespective of clinical response. However, CF clinical responders demonstrated changes in eIF2 signaling, oxidative phosphorylation, IL-17 signaling, and mitochondrial function compared to non-responders. Top overexpressed genes (MMP9 and SOCS3) that decreased post-drug were validated by qRT-PCR. Functional assays demonstrated that CF monocytes normalized calcium (increases MMP9 expression) concentrations post-drug.

Conclusions: Transcriptomics revealed differentially regulated pathways in CF patients at baseline compared to non-CF, and in clinical responders to lumacaftor/ivacaftor.
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http://dx.doi.org/10.1016/j.jcf.2019.08.021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7048645PMC
March 2020

Molecular and Clinical Comparison of Enterovirus D68 Outbreaks among Hospitalized Children, Ohio, USA, 2014 and 2018.

Emerg Infect Dis 2019 11 17;25(11):2055-2063. Epub 2019 Nov 17.

Enterovirus D68 (EV-D68) causes respiratory tract infections and neurologic manifestations. We compared the clinical manifestations from 2 EV-D68 outbreaks in 2014 and 2018 and a low-activity period in 2016 among hospitalized children in central Ohio, USA, and used PCR and sequencing to enable phylogenetic comparisons. During both outbreak periods, infected children had respiratory manifestations that led to an increase in hospital admissions for asthma. The 2018 EV-D68 outbreak appeared to be milder in terms of respiratory illness, as shown by lower rates of pediatric intensive care unit admission. However, the frequency of severe neurologic manifestations was higher in 2018 than in 2014. During the same period in 2016, we noted neither an increase in EV-D68 nor a significant increase in asthma-related admissions. Phylogenetic analyses showed that EV-D68 isolates from 2018 clustered differently within clade B than did isolates from 2014 and are perhaps associated with a different EV-D68 subclade.
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http://dx.doi.org/10.3201/eid2511.190973DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6810223PMC
November 2019

Respiratory Syncytial Virus Vaccines: Are We Making Progress?

Pediatr Infect Dis J 2019 10;38(10):e266-e269

From the Center for Vaccines and Immunity, Abigail Wexner Research Institute at Nationwide Children's Hospital, Columbus, OH.

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http://dx.doi.org/10.1097/INF.0000000000002404DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8404780PMC
October 2019

Infant Immune Response to Respiratory Viral Infections.

Immunol Allergy Clin North Am 2019 08 15;39(3):361-376. Epub 2019 May 15.

Center for Vaccines and Immunity, The Research Institute at Nationwide Children's Hospital, The Ohio State Collage of Medicine, 700 Children's Drive, Columbus, OH 43205, USA; Division of Infectious Diseases, Department of Pediatrics, Nationwide Children's Hospital, The Ohio State Collage of Medicine, 700 Children's Drive, Columbus, OH 43205, USA; Department of Pharmacology and Pediatrics, Malaga Medical Shool, Malaga University (UMA), Malaga, Spain. Electronic address:

Of all respiratory viruses that affect infants, respiratory syncytial virus (RSV) and rhinovirus (RV) represent the leading pathogens causing acute disease (bronchiolitis) and are associated with the development of recurrent wheezing and asthma. The immune system in infants is still developing, and several factors contribute to their increased susceptibility to viral infections. These factors include differences in pathogen detection, weaker interferon responses, lack of immunologic memory toward the invading pathogen, and T-cell responses that are balanced to promote tolerance and restrain inflammation. These aspects are reviewed here with a focus on RSV and RV infections.
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http://dx.doi.org/10.1016/j.iac.2019.03.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6625527PMC
August 2019

Recent Trends in RSV Immunoprophylaxis: Clinical Implications for the Infant.

Am J Perinatol 2019 07 25;36(S 02):S63-S67. Epub 2019 Jun 25.

Center for Vaccines and Immunity, The Research Institute at Nationwide Children's Hospital, The Ohio State University College of Medicine, Columbus, Ohio.

Respiratory syncytial virus (RSV) remains the leading cause for hospitalizations in infants worldwide, resulting in significant health and financial burden. Since 1998, the humanized monoclonal antibody palivizumab remains the only available option licensed for the prevention of severe RSV disease in high-risk children, namely premature infants and those with chronic lung disease and congenital heart disease. In 2014, the American Academy of Pediatrics modified the recommendations on the use of RSV prophylaxis in these high-risk children, and limited its use to premature infants born at < 28 weeks' gestational age (wGA). Following this last guidance update, studies have confirmed that premature infants of 29 to 34 wGA remain at high risk for severe RSV disease, especially those of younger chronologic age. New and more cost-effective strategies are being developed that would help alleviate both the health and financial burden associated with severe RSV disease.
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http://dx.doi.org/10.1055/s-0039-1691803DOI Listing
July 2019

Community-Acquired Pneumonia in Children: Myths and Facts.

Am J Perinatol 2019 07 25;36(S 02):S54-S57. Epub 2019 Jun 25.

Center for Vaccines and Immunity, The Research Institute at Nationwide Children's Hospital, Columbus, Ohio.

Community-acquired pneumonia (CAP) is the leading cause of death in children < 5 years of age worldwide. It is also one of the most frequent infectious diseases in children, leading to large antibiotic use and hospitalization even in the industrialized countries. However, the optimal management of CAP in children is still not well defined. Currently, respiratory viruses are considered the most frequent etiologic agents, but detection of viruses in the upper respiratory tract does not guarantee causation of pneumonia, nor precludes the presence of a bacterial pathogen. In both the upper and lower respiratory tract, respiratory viruses and pathogenic bacteria interact. Emerging evidence indicates that dual viral-bacterial infections function synergistically in many cases and together likely enhance the severity of CAP. Therefore, new and advanced technologies capable of sensitively and specifically discriminating viral, bacterial, and viral-bacterial coinfections are needed. Instead of focusing on the pathogen, analysis of host immune transcriptome profiles from children with CAP can potentially offer diagnostic signatures, help to assess disease severity, and eventually, prognostic indicators. An optimized management strategy by using molecular pathogen testing and transcriptome profiling will facilitate prompt, more appropriate, and targeted therapies, which in turn will lead to improved clinical outcomes in children with CAP.
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http://dx.doi.org/10.1055/s-0039-1691801DOI Listing
July 2019

Viral Bacterial Interactions in Children: Impact on Clinical Outcomes.

Pediatr Infect Dis J 2019 06;38(6S Suppl 1):S14-S19

From the Department of Pediatrics, Division of Pediatric Infectious Diseases, Nationwide Children's Hospital-The Ohio State University College of Medicine, Columbus, OH.

Respiratory viral infections are associated with significant morbidity and mortality in children < 5 years of age worldwide. Among all respiratory viruses, respiratory syncytial virus (RSV) is the world's leading cause of bronchiolitis and pneumonia in young children. There are known populations at risk for severe disease but the majority of children who require hospitalization for RSV infection are previously healthy. Viral and host factors have been associated with the pathogenesis of RSV disease; however, the mechanisms that explain the wide variability in the clinical presentation are not completely understood. Recent studies suggest that the complex interaction between the respiratory microbiome, the host's immune response and the virus may have an impact on the pathogenesis and severity of RSV infection. In this review, we summarize the current evidence regarding the epidemiologic link, the mechanisms of viral-bacterial interactions, and the associations between the upper respiratory tract microbiome and RSV disease severity.
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http://dx.doi.org/10.1097/INF.0000000000002319DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6581203PMC
June 2019

[Disseminated cat scratch disease: The wide variety of clinical presentations].

An Pediatr (Engl Ed) 2019 Jun 7;90(6):393-395. Epub 2018 Jul 7.

Infectious Diseases, Nationwide Children's Hospital (NCH), Columbus, Ohio, EE.UU.. Electronic address:

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http://dx.doi.org/10.1016/j.anpedi.2018.06.002DOI Listing
June 2019

Respiratory Syncytial Virus, Rhinoviruses, and Recurrent Wheezing: Unraveling the Riddle Opens New Opportunities for Targeted Interventions.

JAMA Pediatr 2019 06;173(6):520-521

Center for Vaccines and Immunity, The Research Institute at Nationwide Children's Hospital, Columbus, Ohio.

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http://dx.doi.org/10.1001/jamapediatrics.2019.0370DOI Listing
June 2019

Characterization of mammalian Lipocalin UTRs in silico: Predictions for their role in post-transcriptional regulation.

PLoS One 2019 6;14(3):e0213206. Epub 2019 Mar 6.

Instituto de Biologia y Genetica Molecular-Departamento de Bioquimica y Biologia Molecular y Fisiologia, Universidad de Valladolid-CSIC, Valladolid, Spain.

The Lipocalin family is a group of homologous proteins characterized by its big array of functional capabilities. As extracellular proteins, they can bind small hydrophobic ligands through a well-conserved β-barrel folding. Lipocalins evolutionary history sprawls across many different taxa and shows great divergence even within chordates. This variability is also found in their heterogeneous tissue expression pattern. Although a handful of promoter regions have been previously described, studies on UTR regulatory roles in Lipocalin gene expression are scarce. Here we report a comprehensive bioinformatic analysis showing that complex post-transcriptional regulation exists in Lipocalin genes, as suggested by the presence of alternative UTRs with substantial sequence conservation in mammals, alongside a high diversity of transcription start sites and alternative promoters. Strong selective pressure could have operated upon Lipocalins UTRs, leading to an enrichment in particular sequence motifs that limit the choice of secondary structures. Mapping these regulatory features to the expression pattern of early and late diverging Lipocalins suggests that UTRs represent an additional phylogenetic signal, which may help to uncover how functional pleiotropy originated within the Lipocalin family.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0213206PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6402760PMC
December 2019

Multiple sites PCR testing for enteroviruses in young febrile infants.

Lancet Infect Dis 2019 03;19(3):239-240

Division of Infectious Diseases, Nationwide Children's Hospital, Columbus, OH, USA; The Ohio State University, College of Medicine, Columbus, OH, USA.

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http://dx.doi.org/10.1016/S1473-3099(19)30042-8DOI Listing
March 2019

A decade of antimicrobial resistance in Staphylococcus aureus: A single center experience.

PLoS One 2019 12;14(2):e0212029. Epub 2019 Feb 12.

Department of Pediatrics, Division of Neonatology, Center for Perinatal Research, The Research Institute at Nationwide Children's Hospital, Nationwide Children's Hospital - The Ohio State University College of Medicine, Columbus, Ohio, United States of America.

Background: The emergence of community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) resulted in the recommended use of clindamycin and trimethoprim-sulfamethoxazole (TMP-SMX) for suspected S. aureus infections. The objective of this study was to determine the resistance to methicillin, clindamycin, and TMP-SMX in S. aureus isolates during a 10-year period.

Methods: Retrospective review of the antimicrobial susceptibilities of all S. aureus isolates in the outpatient and inpatient settings at Nationwide Children's Hospital from 1/1/2005 to 12/31/2014. Duplicate isolates from the same site and year and those obtained for MRSA surveillance or from patients with cystic fibrosis were excluded.

Results: Of the 57,788 S. aureus isolates from 2005-2014, 40,795 (71%) were included. In the outpatient setting, methicillin resistance decreased from 54% to 44% (p<0.001) while among inpatient isolates, no significant change was observed. From 2009-2014, resistance to clindamycin among outpatient isolates increased from 16% to 17% (p = 0.002) but no significant trend was observed among inpatient isolates (18% to 22%). Similarly, TMP-SMX resistance increased in outpatient S. aureus isolates from 2005-2014 (0.9% to 4%, p<0.001) but not among inpatient isolates. Among both inpatient and outpatient isolates, methicillin-susceptible S. aureus (MSSA) exhibited higher resistance to both clindamycin and TMP-SMX than MRSA. In addition, resistance to methicillin, clindamycin and TMP-SMX varied widely according to the site of specimen collection.

Conclusion: In a decade where >40,000 S. aureus isolates were identified at a large pediatric hospital, substantial changes in methicillin, clindamycin, and TMP-SMX resistance occurred. These findings highlight the importance of ongoing surveillance of the local antimicrobial resistance in S. aureus in order to guide empiric antimicrobial therapy.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0212029PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6372177PMC
November 2019

Secondhand smoke alters arachidonic acid metabolism and inflammation in infants and children with cystic fibrosis.

Thorax 2019 03 19;74(3):237-246. Epub 2019 Jan 19.

Center for Vaccines and Immunity, The Research Institute at Nationwide Children's Hospital, Columbus, Ohio, USA.

Background: Mechanisms that facilitate early infection and inflammation in cystic fibrosis (CF) are unclear. We previously demonstrated that children with CF and parental-reported secondhand smoke exposure (SHSe) have increased susceptibility to bacterial infections. SHSe hinders arachidonic acid (AA) metabolites that mediate immune function in patients without CF, and may influence CF immune dysfunction. We aimed to define SHSe's impact on inflammation mediators and infection in children with CF.

Methods: Seventy-seven children with CF <10 years of age 35 infants <1 year; 42 children 1-10 years) were enrolled and hair nicotine concentrations measured as an objective surrogate of SHSe. AA signalling by serum and macrophage lipidomics, inflammation using blood transcriptional profiles and in vitro macrophage responses to bacterial infection after SHSe were assessed.

Results: Hair nicotine concentrations were elevated in 63% of patients. Of the AA metabolites measured by plasma lipidomics, prostaglandin D (PGD) concentrations were decreased in children with CF exposed to SHSe, and associated with more frequent hospitalisations (p=0.007) and worsened weight z scores (p=0.008). Children with CF exposed to SHSe demonstrated decreased expression of the prostaglandin genes PTGES3 and PTGR2 and overexpression of inflammatory pathways. These findings were confirmed using an in vitro model, where SHSe was associated with a dose-dependent decrease in PGD and increased methicillin-resistant survival in human CF macrophages.

Conclusions: Infants and young children with CF and SHSe have altered AA metabolism and dysregulated inflammatory gene expression resulting in impaired bacterial clearance. Our findings identified potential therapeutic targets to halt early disease progression associated with SHSe in the young population with CF.
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http://dx.doi.org/10.1136/thoraxjnl-2018-211845DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7642975PMC
March 2019

Molecular Distance to Health Transcriptional Score and Disease Severity in Children Hospitalized With Community-Acquired Pneumonia.

Front Cell Infect Microbiol 2018 30;8:382. Epub 2018 Oct 30.

Division of Infectious Diseases, Nationwide Children's Hospital, Columbus, OH, United States.

Community-acquired pneumonia (CAP) is a leading cause of hospitalization and mortality in children. Diagnosis remains challenging and there are no reliable tools to objectively risk stratify patients or predict clinical outcomes. Molecular distance to health (MDTH) is a genomic score that measures the global perturbation of the transcriptional profile and may help classify patients by disease severity. We evaluated the value of MDTH to assess disease severity in children hospitalized with CAP. Children hospitalized with CAP and matched healthy controls were enrolled in a prospective observational study. Blood samples were obtained for transcriptome analyses within 24 h of hospitalization. MDTH scores were calculated to assess disease severity and correlated with laboratory markers, such as white blood cell count, c-reactive protein (CRP), and procalcitonin (PCT), and clinical outcomes, including duration of fever and duration of hospitalization (LOS). Univariate and multivariable logistic regression were applied to assess factors associated with LOS and duration of fever after hospitalization. Among children hospitalized with CAP ( = 152), pyogenic bacteria (PB) were detected in 16 (11%), was detected in 41 (28%), respiratory viruses (RV) alone were detected in 78 (51%), and no pathogen was detected in 17 (11%) children. Statistical group comparisons identified 6,726 genes differentially expressed in patients with CAP vs. healthy controls ( = 39). Children with confirmed PB had higher MDTH scores than those with RV ( < 0.05) or ( < 0.01) detected alone. CRP ( = 0.39, < 0.0001), PCT ( = 0.39, < 0.0001), and MDTHs ( = 0.24, < 0.01) correlated with duration of fever, while only MDTHs correlated with LOS ( = 0.33, < 0.0001). Unadjusted analyses showed that both higher CRP and MDTHs were associated with longer LOS (OR 1.04 [1-1.07] and 1.12 [1.04-1.20], respectively), however, only MDTH remained significant when adjusting for other covariates (aOR 1.11 [1.01-1.22]). In children hospitalized with CAP MDTH score measured within 24 h of admission was independently associated with longer duration of hospitalization, regardless of the pathogen detected. This suggests that transcriptional biomarkers may represent a promising approach to assess disease severity in children with CAP.
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http://dx.doi.org/10.3389/fcimb.2018.00382DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6218690PMC
September 2019

Viral Load Dynamics and Clinical Disease Severity in Infants With Respiratory Syncytial Virus Infection.

J Infect Dis 2019 04;219(8):1207-1215

Center for Vaccines and Immunity, Nationwide Children's Hospital and The Ohio State University College of Medicine, Columbus.

Background: The association between respiratory syncytial virus (RSV) loads and clinical outcomes in children remains to be defined. In most studies, viral loads (VL) were evaluated in hospitalized children and at a single time-point. We investigated the relationship between VLs and disease severity in both outpatients and inpatients with RSV infection.

Methods: We enrolled previously healthy children with RSV infection. Disease severity was defined by level of care (outpatients vs ward vs pediatric intensive care unit [PICU]), and a clinical disease severity score (CDSS). Nasopharyngeal VLs by polymerase chain reaction and CDSS were measured at enrollment and daily in inpatients. VL decay according to disease severity was analyzed using linear mixed modeling.

Results: From February 2015 to March 2017, we enrolled 150 infants: 39 outpatients and 111 inpatients. VLs were higher in outpatients than in age-matched inpatients. Among inpatients, initial VLs were comparable in ward and PICU patients, and preceded the peak CDSS. However, after excluding infants treated with steroids, those hospitalized in the ward had higher VLs than infants requiring PICU care (P < .001). Dynamic analyses showed that VL decay was delayed in PICU patients, especially in those treated with steroids.

Conclusions: Higher VLs at presentation and a faster and consistent VL decline were both associated with less severe RSV disease in children.

Summary: Infants with less severe respiratory syncytial virus (RSV) disease had higher viral loads (VL) at presentation, and faster and consistent VL decline. Conversely, VL decay and overall viral exposure were prolonged and higher in infants severe RSV disease receiving steroids.
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http://dx.doi.org/10.1093/infdis/jiy655DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6452299PMC
April 2019

Re: "Discharge Criteria for Bronchiolitis: Does Age Matter?"

Pediatr Infect Dis J 2018 12;37(12):e350-e351

Center for Vaccines and Immunity, The Research Institute at Nationwide Children's Hospital, Columbus, OH Biostatistics Core, The Research Institute at Nationwide Children's Hospital, Columbus, OH Center for Vaccines and Immunity, The Research Institute at Nationwide Children's Hospital, Columbus, OH, Division of Pediatric Infectious Diseases, Nationwide Children's Hospital and The Ohio State University College of Medicine, Columbus, OH Center for Vaccines and Immunity, The Research Institute at Nationwide Children's Hospital, Columbus, OH, Division of Pediatric Infectious Diseases, Nationwide Children's Hospital and The Ohio State University College of Medicine, Columbus, OH.

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http://dx.doi.org/10.1097/INF.0000000000002065DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6446549PMC
December 2018

Post-viral atopic airway disease: pathogenesis and potential avenues for intervention.

Expert Rev Clin Immunol 2019 01 3;15(1):49-58. Epub 2018 Nov 3.

a Division of Allergy and Immunology , Nationwide Children's Hospital - The Ohio State University College of Medicine , Columbus , OH , USA.

: In early childhood, wheezing due to lower respiratory tract illness is often associated with infection by commonly known respiratory viruses such as respiratory syncytial virus (RSV) and human rhinovirus (RV). How respiratory viral infections lead to wheeze and/or asthma is an area of active research. : This review provides an updated summary of the published information on the development of post-viral induced atopy and asthma and the mechanisms involved. We focus on the contribution of animal models in identifying pathways that may contribute to atopy and asthma following respiratory virus infection, different polymorphisms that have been associated with asthma development, and current options for disease management and potential future interventions. : Currently there are no prophylactic therapies that prevent infants infected with respiratory viruses from developing asthma or atopy. Neither are there curative therapies for patients with asthma. Therefore, a better understanding of genetic factors and other associated biomarkers in respiratory viral induced pathogenesis is important for developing effective personalized therapies.
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http://dx.doi.org/10.1080/1744666X.2019.1541737DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6486879PMC
January 2019

[Paediatric research in Spain: Challenges and priorities. INVEST-AEP Platform].

An Pediatr (Engl Ed) 2018 Nov 9;89(5):314.e1-314.e6. Epub 2018 Oct 9.

Fundación La Paz (IdiPaz), Madrid, España; Departamento de Pediatría y Neonatología, Hospital Quironsalud, Madrid, España; Universidad Europea de Madrid, Madrid, España; RETIC SAMID Carlos III (RD16/0022/0004), Madrid, España; Red de Ensayos Clínicos en Pediatría (RECLIP), Santiago de Compostela, España.

Research is the cornerstone of medical progress. Paediatric research has its own nuances and represents an additional challenge due to the intrinsic characteristics of the paediatric population compared with adults. Despite the tremendous importance of childhood health and its impact during adulthood, society is still not convinced about the importance of conducting research in paediatrics. This also applies to paediatricians themselves, who think about research as a discipline that does not directly involve them. The Spanish Academy of Paediatrics has developed a specific research platform- INVEST-AEP- to try to help and answer the challenges associated with paediatric research in the society This article reflects the current status of paediatric research in Spain, and the goals achieved over the last few years due to the effort of paediatric researchers. In addition, a deeper analysis is provided as regards: a) the barriers that represent a hurdle for the development of broad and competitive paediatric research in our day to day work; b) the limited incentives and specific pre- and post-doctoral training; c) the high clinical burden for paediatricians or; d) the lack of specific infrastructure and dedicated funding for paediatrics. The mission, vision and values of INVEST-AEP are to develop an accessible roadmap for the development and implementation of paediatric research in Spain for the next few years.
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http://dx.doi.org/10.1016/j.anpedi.2018.09.001DOI Listing
November 2018
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