Publications by authors named "Samuel R Dominguez"

125 Publications

IVIG Compared to IVIG Plus Infliximab in Multisystem Inflammatory Syndrome in Children.

Pediatrics 2021 Sep 22. Epub 2021 Sep 22.

Department of Pediatrics, Section of Infectious Diseases, University of Colorado School of Medicine and Children's Hospital Colorado, Aurora, CO.

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http://dx.doi.org/10.1542/peds.2021-052702DOI Listing
September 2021

Temporal clustering of Kawasaki disease cases around the world.

Sci Rep 2021 Nov 19;11(1):22584. Epub 2021 Nov 19.

Department of Pediatrics, UCSD School of Medicine, University of California San Diego and Rady Children's Hospital San Diego, 9500 Gilman Dr., La Jolla, CA, 92037, USA.

In a single-site study (San Diego, CA, USA), we previously showed that Kawasaki Disease (KD) cases cluster temporally in bursts of approximately 7 days. These clusters occurred more often than would be expected at random even after accounting for long-term trends and seasonality. This finding raised the question of whether other locations around the world experience similar temporal clusters of KD that might offer clues to disease etiology. Here we combine data from San Diego and nine additional sites around the world with hospitals that care for large numbers of KD patients, as well as two multi-hospital catchment regions. We found that across these sites, KD cases clustered at short time scales and there were anomalously long quiet periods with no cases. Both of these phenomena occurred more often than would be expected given local trends and seasonality. Additionally, we found unusually frequent temporal overlaps of KD clusters and quiet periods between pairs of sites. These findings suggest that regional and planetary range environmental influences create periods of higher or lower exposure to KD triggers that may offer clues to the etiology of KD.
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http://dx.doi.org/10.1038/s41598-021-01961-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8605018PMC
November 2021

IVIG Compared to IVIG Plus Infliximab in Multisystem Inflammatory Syndrome in Children.

Pediatrics 2021 Sep 21. Epub 2021 Sep 21.

Department of Pediatrics, Section of Infectious Diseases, University of Colorado School of Medicine and Children's Hospital Colorado, Aurora, CO;

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http://dx.doi.org/10.1542/peds.2021-052702DOI Listing
September 2021

SARS-CoV-2 persistence in immunocompromised children.

Pediatr Blood Cancer 2021 12 28;68(12):e29277. Epub 2021 Aug 28.

Department of Pediatrics (Infectious Diseases and Hospital Medicine and Epidemiology), University of Colorado School of Medicine and Children's Hospital Colorado, Aurora, Colorado, USA.

Objectives: We evaluated the length of time immunocompromised children (ICC) remain positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), identified factors associated with viral persistence, and determined cycle threshold (C ) values of children with viral persistence as a surrogate of viral load.

Methods: We conducted a retrospective cohort study of ICC at a pediatric hospital from March 2020 to March 2021. Immunocompromised status was defined as primary, secondary, or acquired due to medical comorbidities/immunosuppressive treatment. The primary outcome was time to first of two consecutive negative SARS-CoV-2 polymerase chain reaction (PCR) tests at least 24 hours apart. Testing of sequential clinical specimens from the same subject was conducted using the Centers for Disease Control (CDC) 2019-nCoV real-time reverse transcriptase (RT)-PCR Diagnostic Panel assay. Descriptive statistics, Kaplan-Meier curve median event times and log-rank tests were used to compare outcomes between groups.

Results: Ninety-one children met inclusion criteria. Median age was 15.5 years (interquartile range [IQR] 8-18), 64% were male, 58% were White, and 43% were Hispanic/Latinx. Most (67%) were tested in outpatient settings and 58% were asymptomatic. The median time to two negative tests was 42 days (IQR 25.0-55.0), with no differences in median time by illness presentation or level of immunosuppression. Seven children had more than one sample available for repeat testing, and five of seven (71%) children had initial C values of <30 (moderate to high viral load); four children had C values of <30, 3-4 weeks later, suggesting persistent moderate to high viral loads.

Conclusions: Most ICC with SARS-CoV-2 infection had mild disease, with prolonged viral persistence >6 weeks and moderate to high viral load.
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http://dx.doi.org/10.1002/pbc.29277DOI Listing
December 2021

Antimicrobial Resistance Trends at a Pediatric Hospital in Guatemala City, 2005-2019.

J Pediatric Infect Dis Soc 2021 Aug 26. Epub 2021 Aug 26.

Microbiology Laboratory, Hospital Roosevelt, Guatemala City, Guatemala.

Antimicrobial resistance (AMR) is increasing worldwide. We analyzed AMR rates for bacterial species identified from pediatric blood cultures between 2005 and 2019 at a single institution in Guatemala. We found significantly increased rates in Gram-negative resistance, with a high prevalence of carbapenem-resistant Acinetobacter and Klebsiella harboring the New Delhi metallo-beta-lactamase gene.
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http://dx.doi.org/10.1093/jpids/piab048DOI Listing
August 2021

Clinical Impact of the Expanded BioFire Blood Culture Identification 2 Panel in a U.S. Children's Hospital.

Microbiol Spectr 2021 09 25;9(1):e0042921. Epub 2021 Aug 25.

University of Colorado School of Medicine, Department of Pediatrics, Aurora, Colorado, USA.

The BioFire blood culture identification (BCID) panel decreases time to pathogen identification and time to optimal antimicrobial therapy. The BioFire blood culture identification 2 (BCID2) panel is an expanded panel with 17 additional targets and resistance genes; however, there are limited data on its impact in pediatric patients. We compared the BioFire BCID2 panel and the BCID panel by assaying BCID2 simultaneously with the current standard of care on 191 consecutive blood culture specimens at Children's Hospital Colorado. The primary outcome was equivalence, measured as percent agreement between the two panels and standard culture. The theoretical reduction in time to optimal therapy was calculated overall, with subanalyses performed on species and Gram-negative resistance genes. The percent agreement was equivalent between the two panels, with BCID at 98% (95% confidence interval [CI], 95 to 100%) and BCID2 at 97% (95% CI, 93 to 99%); the difference was 1.2% (95% CI, -0.8, 3.1%;  < 0.0001). There was not a significant reduction in time to theoretical optimal therapy with BCID2 compared to BCID for all cultures (reduction of 9 h,  = 0.3). Notably, 13 Enterococcus faecalis isolates were detected on BCID2, which would have resulted in a theoretical reduction in time to optimal antimicrobial therapy of 34 h ( = 0.0046). Five CTX-M genes were detected for enteric bacteria. The BioFire BCID2 panel had equal rates of detection compared to the BioFire BCID panel in pediatric patients. It had the advantage of detecting more organisms at the species level, and significantly reducing time to theoretical optimal antimicrobial therapy for Enterococcus faecalis. With the additional resistance genes, it also has the potential to impact care with earlier identification of resistant enteric pathogens. The BioFire BCID2 panel is an accurate panel that is equivalent to the BioFire BCID panel compared to standard culture. The BioFire BCID2 panel offers several advantages over the BioFire BCID panel, including enterococcal species identification, Gram-negative resistance gene detection, Salmonella identification, and the added A/C and SCCmec right extremity junction (MREJ) target for better Staphylococcus aureus and coagulase-negative Staphylococcus (CoNS) differentiation. Most importantly, it provides additional clinical impact with the potential to decrease the time to optimal antimicrobial therapy compared to the BioFire BCID panel, with likely further impact at institutions with a higher prevalence of Gram-negative resistance.
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http://dx.doi.org/10.1128/Spectrum.00429-21DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8552780PMC
September 2021

Effect of Rapid Respiratory Virus Testing on Antibiotic Prescribing Among Children Presenting to the Emergency Department With Acute Respiratory Illness: A Randomized Clinical Trial.

JAMA Netw Open 2021 Jun 1;4(6):e2111836. Epub 2021 Jun 1.

Department of Pediatrics (Infectious Diseases and Epidemiology), University of Colorado School of Medicine and Children's Hospital Colorado, Aurora.

Importance: There is high usage of antibiotics in the emergency department (ED) for children with acute respiratory illnesses. Studies have reported decreased antibiotic use among inpatients with rapid respiratory pathogen (RRP) testing.

Objective: To determine whether RRP testing leads to decreased antibiotic use and health care use among children with influenzalike illness (ILI) in an ED.

Design, Setting, And Participants: A randomized clinical trial among children aged 1 month to 18 years presenting to an ED with ILI from December 1, 2018, to November 30, 2019, was conducted. Data were analyzed March 23, 2020, to April 2, 2021. All children received a nasopharyngeal swab for RRP testing and were randomized 1:1 to the intervention group or control group (results not given, routine clinical care). Results were available in 45 minutes. Intention-to-treat analyses and modified intention-to-treat (clinician knows results) analyses were conducted using multivariable Poisson regression.

Interventions: Rapid respiratory pathogen test results given to clinicians.

Main Outcomes And Measures: Antibiotic prescribing was the primary outcome; influenza antiviral prescribing, ED length of stay, hospital admission, and recurrent health care visits were the secondary outcomes.

Results: Among 931 ED visits (intervention group, 452 children group and control group, 456 children after exclusion of those not meeting criteria or protocol violations), a total of 795 RRP test results (85%) were positive. The median age of the children was 2.1 years (interquartile range, 0.9-5.6 years); 509 (56%) were boys. Most children (478 [53%]) were Hispanic, 688 children (76%) received government insurance, and 314 (35%) had a high-risk medical condition. In the intention-to-treat intervention group, children were more likely to receive antibiotics (relative risk [RR], 1.3; 95% CI, 1.0-1.7), with no significant differences in antiviral prescribing, medical visits, and hospitalization. In inverse propensity-weighted modified intention-to-treat analyses, children with test results known were more likely to receive antivirals (RR, 2.6; 95% CI, 1.6-4.5) and be hospitalized (RR, 1.8; 95% CI, 1.4-2.5); there was no significant difference in antibiotic prescribing (RR, 1.1; 95% CI, 0.9-1.4).

Conclusions And Relevance: The use of RRP testing in the ED for ILI did not decrease antibiotic prescribing in this randomized clinical trial. There is a limited role for RRP pathogen testing in children in this setting.

Trial Registration: ClinicalTrials.gov Identifier: NCT03756753.
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http://dx.doi.org/10.1001/jamanetworkopen.2021.11836DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8178728PMC
June 2021

Clinical Impact of a Diagnostic Gastrointestinal Panel in Children.

Pediatrics 2021 05 9;147(5). Epub 2021 Apr 9.

Infectious Diseases, and.

Objectives: Many hospitals have transitioned from conventional stool diagnostics to rapid multiplex polymerase chain reaction gastrointestinal panels (GIP). The clinical impact of this testing has not been evaluated in children. In this study, we compare use, results, and patient outcomes between conventional diagnostics and GIP testing.

Methods: This is a multicenter cross-sectional study of children who underwent stool testing from 2013 to 2017. We used bivariate analyses to compare test use, results, and patient outcomes, including length of stay (LOS), ancillary testing, and hospital charges, between the GIP era (24 months after GIP introduction) and conventional diagnostic era (historic control, 24 months before).

Results: There were 12 222 tests performed in 8720 encounters. In the GIP era, there was a 21% increase in the proportion of children who underwent stool testing, with a statistically higher percentage of positive results (40% vs 11%), decreased time to result (4 vs 31 hours), and decreased time to treatment (11 vs 35 hours). Although there was a decrease in LOS by 2 days among those who received treatment of a bacterial and/or parasitic pathogen (5.1 vs 3.1; < .001), this represented only 3% of tested children. In the overall population, there was no statistical difference in LOS, ancillary testing, or charges.

Conclusions: The GIP led to increased pathogen detection and faster results. This translated into improved outcomes for only a small subset of patients, suggesting that unrestricted GIP use leads to low-value care. Similar to other novel rapid diagnostic panels, there is a critical need for diagnostic stewardship to optimize GIP testing.
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http://dx.doi.org/10.1542/peds.2020-036954DOI Listing
May 2021

Risk Factors for Severe COVID-19 in Children.

Pediatr Infect Dis J 2021 04;40(4):e137-e145

Department of Pediatrics, School of Medicine, University of Colorado, Aurora, CO.

Background: There are limited pediatric data regarding severe COVID-19 disease. Our study aims to describe the epidemiology and identify risk factors for severe COVID-19 disease in children.

Methods: This is a retrospective cohort study among children with positive SARS-CoV-2 PCR from March to July 2020 at Children's Hospital Colorado. Risk factors for severe disease were analyzed as defined by hospital admission, respiratory support, or critical care. Univariable and multivariable analyses were conducted.

Results: Among 454 patients identified with SARS-CoV-2, 191 (42.1%) were females, median age 11 years. Fifty-five percent of all patients identified as Hispanic compared with 29% among all hospital visits in 2019 (P < 0.0001). In multivariable analyses, age 0-3 months or >20 years [adjusted odds ratio (aOR), 7.85; P < 0.0001 and aOR, 5.1; P = 0.03, respectively], preterm birth history (aOR, 3.7; P = 0.03), comorbidities [including immunocompromise (aOR, 3.5; P = 0.004), gastrointestinal condition (aOR, 2.7; P = 0.009), diabetes (aOR, 6.6; P = 0.04), asthma (aOR, 2.2; P = 0.04)], and specific symptoms at presentation were predictors for admission. Age 0-3 months or >20 years, asthma, gastrointestinal condition, and similar symptoms at presentation were also predictors for respiratory support. Elevated C-reactive protein was associated with the need for critical care with median of 17.7 mg/dL (IQR, 5.3-22.9) versus 1.95 mg/dL (IQR, 0.7-5.5) among patients requiring critical versus no critical care (OR, 1.2; P = 0.02).

Conclusions: Extremes of age, comorbid conditions, and elevated CRP are predictors of severe disease in children. Findings from this study can inform pediatric providers and public health officials to tailor clinical management, pandemic planning, and resource allocation.
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http://dx.doi.org/10.1097/INF.0000000000003043DOI Listing
April 2021

Reliability of in Predicting Phenotypic Susceptibilities of Coagulase-Negative Staphylococci and .

Open Forum Infect Dis 2020 Dec 24;7(12):ofaa553. Epub 2020 Dec 24.

Section of Pediatric Infectious Diseases, Children's Hospital Colorado and the University of Colorado School of Medicine, Aurora, Colorado, USA.

The gene is commonly used to identify resistance in , but historically is not used for coagulase-negative staphylococci (CoNS). Analysis of 412 staphylococcal blood cultures (2014-2018) revealed that the absence of had high concordance (100%) with oxacillin susceptibility for and CoNS alike.
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http://dx.doi.org/10.1093/ofid/ofaa553DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7759207PMC
December 2020

A Pediatric Infectious Diseases Perspective of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) and Novel Coronavirus Disease 2019 (COVID-19) in Children.

J Pediatric Infect Dis Soc 2020 Nov;9(5):596-608

Division of Pediatric Infectious Diseases and Tropical Medicine, Department of Pediatrics, University of Maryland School of Medicine, Baltimore, Maryland, USA.

Understanding the role that children play in the clinical burden and propagation of severe acute respiratory syndrome coronavirus 2, responsible for coronavirus disease 2019 (COVID-19) infections, is emerging. While the severe manifestations and acute clinical burden of COVID-19 have largely spared children compared with adults, understanding the epidemiology, clinical presentation, diagnostics, management, and prevention opportunities and the social and behavioral impacts on child health is vital. Foremost is clarifying the contribution of asymptomatic and mild infections to transmission within the household and community and the clinical and epidemiologic significance of uncommon severe post-infectious complications. Here, we summarize the current knowledge, identify resources, and outline research opportunities. Pediatric infectious diseases clinicians have a unique opportunity to advocate for the inclusion of children in epidemiological, clinical, treatment, and prevention studies to optimize their care as well as to represent children in the development of guidance and policy during pandemic response.
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http://dx.doi.org/10.1093/jpids/piaa099DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7499621PMC
November 2020

Analysis of COVID-19 convalescent plasma for SARS-CoV-2 IgG using two commercial immunoassays.

J Immunol Methods 2020 11 20;486:112837. Epub 2020 Aug 20.

Department of Pediatrics, University of Colorado School of Medicine, 13123 East 16th Avenue, Box 065, Aurora, CO 80045, United States of America; Children's Hospital Colorado, 13123 East 16(th) Avenue, Aurora, CO 80045, United States of America.

Coronavirus Disease 2019 (COVID-19) convalescent plasma (CCP) was approved by the FDA for use in severe cases of COVID-19 under an emergency Investigational New Drug (IND) protocol. Eligibility criteria for CCP donors includes documentation of evidence of COVID-19 either by viral RNA detection at the time of illness or positive SARS-CoV-2 IgG after recovery if diagnostic testing for COVID-19 was not performed at the time of illness. In addition to analysis of CCP, analysis of SARS-CoV-2 IgG provides information for possible past exposure and may support diagnosis when SARS-CoV-2 PCR is negative and clinical suspicion for COVID-19 is high. Furthermore, assays with high sensitivity and specificity for SARS-CoV-2 IgG are critical for understanding community exposure rates to SARS-CoV-2. Currently, there are several assays that test for antibodies to SARS-CoV-2 using a variety of methods, including point-of-care lateral flow-based devices, high throughput immunoassay analyzers, and manual methods such as ELISA. These assays target a number of SARS-CoV-2 antigens, including the nucleocapsid protein (N), full length spike protein (S), S1 subunit, or receptor binding domain (RBD) of the S protein. Given the heterogeneity among methods for, and antigenic targets used in SARS-CoV-2 antibody assays, it is necessary for careful evaluation of these assays prior to implementation for clinical use. We compared two assays that had received the CE mark of regulatory approval and that used either the N antigen or S1-RBD antigen as the target for analysis of a large set of CCP samples. Our data indicates that sensitivity and specificity vary between these assays and that more than one antigenic target may be required to improve the sensitivity and specificity of IgG detection to SARS-CoV-2.
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http://dx.doi.org/10.1016/j.jim.2020.112837DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7438987PMC
November 2020

Evaluation for Arboviral Infection Among Children Hospitalized in Colorado With Aseptic Meningitis and Encephalitis.

Pediatr Infect Dis J 2020 11;39(11):e382-e384

From the Arboviral Diseases Branch, Centers for Disease Control and Prevention, Fort Collins, Colorado and.

Among 39 children hospitalized in Colorado with aseptic meningitis or encephalitis, 16 (41%) had an etiology identified, including 2 (5%) with West Nile virus infection. Despite extensive testing, no other arboviral infections were identified. Arboviral infection should be considered in children with neuroinvasive disease during arboviral season with testing directed toward viruses endemic to the region and type of exposure.
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http://dx.doi.org/10.1097/INF.0000000000002856DOI Listing
November 2020

Circulating microRNAs differentiate Kawasaki Disease from infectious febrile illnesses in childhood.

J Mol Cell Cardiol 2020 09 4;146:12-18. Epub 2020 Jul 4.

Pediatric Cardiology, Children's Hospital Colorado, University of Colorado School of Medicine, Aurora, CO, USA.

Background: Kawasaki Disease (KD) is an acute vasculitis of unknown etiology in children that can lead to coronary artery lesions (CAL) in 25% of untreated patients. There is currently no diagnostic test for KD, and the clinical presentation is often difficult to differentiate from other febrile childhood illnesses. Circulating microRNAs (miRNAs) are small noncoding RNA molecules that control gene expression by inducing transcript degradation or by blocking translation. We hypothesize that the expression of circulating miRNAs will differentiate KD from non-KD febrile illnesses in children.

Methods: Circulating miRNA profiles from 84 KD patients and 29 non-KD febrile controls (7 viral and 22 bacterial infections) were evaluated. 3 ul of serum from each subject was submitted to 3 freeze/heat cycles to ensure miRNA release from microvesicles or interaction with serum proteins. miRNAs were reverse transcribed using a pool of primers specific for each miRNA. Real-time PCR reactions were performed in a 384 well plate containing sequence-specific primers and TaqMan probes in the ABI7900. '.

Results: KD patients (3.6 ± 2.2 yrs., 58% male) were found to have a unique circulating miRNA profile, including upregulation of miRNA-210-3p, -184, and -19a-3p (p < .0001), compared to non-KD febrile controls (8.5 ± 6.1 yrs., 72% male).

Conclusions: Circulating miRNAs can differentiate KD from infectious febrile childhood diseases, supporting their potential as a diagnostic biomarker for KD.
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http://dx.doi.org/10.1016/j.yjmcc.2020.06.011DOI Listing
September 2020

Impact of FilmArray meningitis encephalitis panel on HSV testing and empiric acyclovir use in children beyond the neonatal period.

Diagn Microbiol Infect Dis 2020 Aug 17;97(4):115085. Epub 2020 May 17.

University of Colorado School of Medicine Aurora, CO USA; Children's Hospital Colorado Aurora, CO USA.

Following implementation of the FilmArray meningitis and encephalitis panel, which enables rapid syndromic cerebrospinal fluid testing, HSV testing doubled in children >60 days with suspected central nervous system infection at Children's Hospital Colorado. Acyclovir initiation was unchanged, but duration decreased. Diagnostic and antimicrobial stewardship is needed for MEP optimization.
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http://dx.doi.org/10.1016/j.diagmicrobio.2020.115085DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7384938PMC
August 2020

Vancomycin-Nonsusceptible Enterococci Mediated by at a Large Children's Hospital: Prevalence, Susceptibility, and Impact on Care of Enterococcal Bacteremia.

Open Forum Infect Dis 2020 May 6;7(5):ofaa160. Epub 2020 May 6.

Section of Infectious Diseases, Children's Hospital Colorado, Aurora, Colorado, USA.

and have inherent vancomycin resistance and, though known as pathogens, have not been well characterized in pediatric patients. We identified a significant prevalence of these enterococcal species among immunocompromised patients at a large pediatric institution and describe the impact on patient care, antibiotic stewardship, and infection control.
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http://dx.doi.org/10.1093/ofid/ofaa160DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7246344PMC
May 2020

Multicentre validation of a computer-based tool for differentiation of acute Kawasaki disease from clinically similar febrile illnesses.

Arch Dis Child 2020 08 5;105(8):772-777. Epub 2020 Mar 5.

Department of Pediatrics, University of California San Diego, La Jolla, California, USA

Background: The clinical features of Kawasaki disease (KD) overlap with those of other paediatric febrile illnesses. A missed or delayed diagnosis increases the risk of coronary artery damage. Our computer algorithm for KD and febrile illness differentiation had a sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of 94.8%, 70.8%, 93.7% and 98.3%, respectively, in a single-centre validation study. We sought to determine the performance of this algorithm with febrile children from multiple institutions across the USA.

Methods: We used our previously published 18-variable panel that includes illness day, the five KD clinical criteria and readily available laboratory values. We applied this two-step algorithm using a linear discriminant analysis-based clinical model followed by a random forest-based algorithm to a cohort of 1059 acute KD and 282 febrile control patients from five children's hospitals across the USA.

Results: The algorithm correctly classified 970 of 1059 patients with KD and 163 of 282 febrile controls resulting in a sensitivity of 91.6%, specificity of 57.8% and PPV and NPV of 95.4% and 93.1%, respectively. The algorithm also correctly identified 218 of the 232 KD patients (94.0%) with abnormal echocardiograms.

Interpretation: The expectation is that the predictive accuracy of the algorithm will be reduced in a real-world setting in which patients with KD are rare and febrile controls are common. However, the results of the current analysis suggest that this algorithm warrants a prospective, multicentre study to evaluate its potential utility as a physician support tool.
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http://dx.doi.org/10.1136/archdischild-2019-317980DOI Listing
August 2020

Impact of Multiplex Testing on the Identification of Pediatric Clostridiodes Difficile.

J Pediatr 2020 03;218:157-165.e3

Section of Infectious Diseases, Department of Pediatrics, University of Colorado School of Medicine and Children's Hospital Colorado, Aurora, CO.

Objectives: To evaluate whether the implementation of a multiplex gastrointestinal pathogen panel (GIP) was associated with changes in Clostridioides difficile (C difficile) testing and detection rates.

Study Design: We conducted an observational study using interrupted time series analysis and included pediatric patients with testing capable of detecting C difficile. From 2013 to 2015 ("conventional diagnostic era"), stool testing included C difficile-selective polymerase chain reaction and other pathogen-specific tests. From 2015 to 2017 ("GIP era"), C difficile polymerase chain reaction was available along with the GIP, which detected 22 pathogens including C difficile, and replaced the need for additional tests. Outcomes included C difficile testing and detection rates in ambulatory, emergency department, and inpatient settings.

Results: There were 6841 tests performed and 1214 C difficile positive results. Across the 3 settings, GIP era had significantly higher C difficile testing (1.7-2.3 times higher) and C difficile detection rates (1.9-3.4 times higher) compared with conventional diagnostic era. After adjusting for the number of tests performed, detection rates were no longer significantly different. Of C difficile positive GIPs, 31% were coinfected with another organism. With GIP testing, patients 1 year of age had a significantly higher C difficile percent positivity than 2-year-old (P = .02) and 3- to 18-year-old children (P < .01). Younger children with C difficile were more likely to be coinfected (P < .01).

Conclusions: Introducing a multiplex panel led to increased C difficile testing, which resulted in increased C difficile detection rates and potential identification and treatment of colonized patients. This highlights an important target for diagnostic stewardship and the challenges associated with multiplex testing.
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http://dx.doi.org/10.1016/j.jpeds.2019.11.036DOI Listing
March 2020

A multicenter study to define the epidemiology and outcomes of Clostridioides difficile infection in pediatric hematopoietic cell and solid organ transplant recipients.

Am J Transplant 2020 08 10;20(8):2133-2142. Epub 2020 Mar 10.

Department of Pediatrics, Albert Einstein College of Medicine and Children's Hospital at Montefiore, Bronx, New York, USA.

Hematopoietic cell transplant (HCT) and solid organ transplant (SOT) recipients are at increased risk for Clostridioides difficile infection (CDI). We conducted a multicenter retrospective study to describe the incidence of CDI in children transplanted between January 2010 and June 2013. Nested case-control substudies, matched 1:1 by transplant type, institution, patient age, and time of year (quartile) of transplant, identified CDI risk factors. Cohorts included 1496 HCT and 1090 SOT recipients. Among HCT recipients, 355 CDI episodes were diagnosed in 265 recipients (18.2%). Nested case-control study identified prior history of CDI (odds ratio [OR] 2.6, 95% confidence interval [CI] 1.5-4.7), proton pump inhibitors (PPIs; OR 2.1, 95% CI 1.3-3.4), and exposure to third- (OR 2.4, 95% CI 1.4-4.2) or fourth-generation (OR 2.1, 95% CI 1.2-3.7) cephalosporins as risk factors. Notably, fluoroquinolone exposure appeared protective (OR 0.6, 95% CI 0.3-0.9). Ninety-two episodes of CDI were diagnosed among 79 SOT recipients (7.3%), and exposure to PPIs (OR 2.4, 95% CI 1.1-5.4) and third-generation cephalosporin therapy (OR 3.9, 95% CI 1.4-10.5) were identified as risk factors. Strategies to decrease PPI use and changes in the class of prophylactic antibiotics may impact CDI incidence and warrant further study.
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http://dx.doi.org/10.1111/ajt.15826DOI Listing
August 2020

Two Blood Cultures With Age-Appropriate Volume Enhance Suspected Sepsis Decision-Making.

Open Forum Infect Dis 2020 Feb 27;7(2):ofaa028. Epub 2020 Jan 27.

Department of Pediatrics, University of Colorado School of Medicine, Aurora, Colorado, USA.

Background: Multiple blood cultures have been shown to improve pathogen yield and antimicrobial stewardship for adult patients with suspected serious bacterial infection (SBI). For children, the use of multiple blood cultures is less common and volume recommendations are more complicated, often resulting in single cultures with low volume.

Methods: In 2010, Children's Hospital Colorado instituted electronic medical record (EMR) decision support to recommend collection of 2 blood cultures before administration of antibiotics for suspected SBI. Recommended blood culture volumes were calculated by age rather than weight. We evaluated all children admitted to inpatient units between 2008 and 2009 (pre-intervention) and 2011 and 2013 (postintervention) who received antibiotics in the hospital after having blood cultures drawn in the emergency department, excluding those with a length of stay >8 days. We compared blood culture yield, isolate classification (pathogen vs contaminant), and antimicrobial modifications before and after the interventions.

Results: A total of 3948 children were included in the study. EMR guidelines were associated with a significantly higher number of children with multiple blood cultures drawn before antibiotic administration (88.0% vs 12.3%;  < .001) and an increased percentage of blood cultures with the recommended volume (74.3% vs 15.2%;  < .001), resulting in a significantly higher pathogen isolation rate and improved antimicrobial decisions. Multiple cultures helped define the role of common contaminants in the clinical decision process.

Conclusions: Multiple blood cultures with age-based volumes taken before starting antibiotics increase pathogen isolation rates and appropriate modification of antimicrobial treatment in children.
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http://dx.doi.org/10.1093/ofid/ofaa028DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7009551PMC
February 2020

Clinical characteristics of enterovirus A71 neurological disease during an outbreak in children in Colorado, USA, in 2018: an observational cohort study.

Lancet Infect Dis 2020 02 16;20(2):230-239. Epub 2019 Dec 16.

Section of Infectious Diseases, School of Medicine, University of Colorado, Aurora, CO, USA; Children's Hospital Colorado, Aurora, CO, USA.

Background: In May, 2018, Children's Hospital Colorado noted an outbreak of enterovirus A71 (EV-A71) neurological disease. We aimed to characterise the clinical features of EV-A71 neurological disease during this outbreak.

Methods: In this retrospective observational cohort study, children (younger than 18 years) who presented to Children's Hospital Colorado (Aurora, CO, USA) between March 1 and November 30, 2018, with neurological disease (defined by non-mutually exclusive criteria, including meningitis, encephalitis, acute flaccid myelitis, and seizures) and enterovirus detected from any biological specimen were eligible for study inclusion. The clinical characteristics of children with neurological disease associated with EV-A71 were compared with those of children with neurological disease associated with other enteroviruses during the same period. To explore the differences in clinical presentation of acute flaccid myelitis, we also used a subgroup analysis to compare clinical findings in children with EV-A71-associated acute flaccid myelitis during the study period with these findings in those with enterovirus D68 (EV-D68)-associated acute flaccid myelitis at the same hospital between 2013 and 2018.

Findings: Between March 10 and Nov 10, 2018, 74 children presenting to Children's Hospital Colorado were found to have enterovirus neurological disease; EV-A71 was identified in 43 (58%) of these children. The median age of the children with EV-A71 neurological disease was 22·7 months (IQR 4·0-31·9), and most of these children were male (34 [79%] children). 40 (93%) children with EV-A71 neurological disease had findings suggestive of meningitis, 31 (72%) children showed evidence of encephalitis, and ten (23%) children met our case definition of acute flaccid myelitis. All children with EV-A71 disease had fever and 18 (42%) children had hand, foot, or mouth lesions at or before neurological onset. Children with EV-A71 disease were best differentiated from those with other enteroviruses (n=31) by the neurological findings of myoclonus, ataxia, weakness, and autonomic instability. Of the specimens collected from children with EV-A71, this enterovirus was detected in 94% of rectal, 79% of oropharyngeal, 56% of nasopharyngeal, and 20% of cerebrospinal fluid specimens. 39 (93%) of 42 children with EV-A71 neurological disease who could be followed up showed complete recovery by 1-2 months. Compared with children with EV-D68-associated acute flaccid myelitis, children with EV-A71-associated acute flaccid myelitis were younger, showed neurological onset earlier after prodromal symptom onset, had milder weakness, showed more rapid improvement, and were more likely to completely recover.

Interpretation: This outbreak of EV-A71 neurological disease, the largest reported in the Americas, was characterised by fever, myoclonus, ataxia, weakness, autonomic instability, and full recovery in most patients. Because EV-A71 epidemiology outside of Asia remains difficult to predict, identification of future outbreaks will be aided by prompt recognition of these distinct clinical findings, testing of non-sterile and sterile site specimens, and enhanced enterovirus surveillance.

Funding: None.
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http://dx.doi.org/10.1016/S1473-3099(19)30632-2DOI Listing
February 2020

Description of Enteropathic Escherichia coli Species in Pediatric Patients at a Quaternary Children's Hospital.

J Pediatric Infect Dis Soc 2020 Nov;9(5):573-579

Department of Pediatrics, Division of Infectious Diseases, Aurora, Colorado, USA.

Background: The epidemiology, demographics, clinical presentations, and outcomes associated with enteroaggregative Escherichia coli (EAEC), enteropathogenic E. coli (EPEC), and enterotoxigenic E. coli (ETEC) pathotypes in US children are not well understood.

Methods: This study was a retrospective chart review of all pediatric patients with a stool sample submitted to the Children's Hospital Colorado clinical microbiology laboratory for testing with the BioFire FilmArray Gastrointestinal Pathogen Panel from October 2015 through October 2017.

Results: During the study period, 5692 patient stool samples were submitted; 679 (13%) were positive for EAEC, EPEC, or ETEC. Of note, 163/232 (70%) patients with EAEC, 282/493 (57%) with EPEC, and 49/58 (85%) with ETEC had detection of at least 1 other pathogen. Of all E. coli-positive stool samples, only 158/679 (23%) were from low-risk patients who were singly infected with EAEC, EPEC, or ETEC. In this cohort, most cases were associated with acute diarrhea (50%), abdominal pain (61%), and/or cramping (49%) and presented without fever (14%), emesis (28%), or lethargy (7%). Thirteen (8%) of these 158 patients received antibiotics at the time of their initial presentation to care. Of the 145 patients who did not receive antibiotics at their initial visit, 23 (16%) returned to care due to persistence of symptoms.

Conclusions: Our results suggest that the majority of patients singly infected with EAEC, EPEC, or ETEC present with mild, self-limited, gastrointestinal (GI) complaints. Further research is needed to determine what role these pathogens might play in children who present with chronic or inflammatory GI symptoms.
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http://dx.doi.org/10.1093/jpids/piz081DOI Listing
November 2020

Pan-viral serology implicates enteroviruses in acute flaccid myelitis.

Nat Med 2019 11 21;25(11):1748-1752. Epub 2019 Oct 21.

Department of Pediatric Infectious Diseases, Kaiser Permanente Oakland Medical Center, Oakland, CA, USA.

Since 2012, the United States of America has experienced a biennial spike in pediatric acute flaccid myelitis (AFM). Epidemiologic evidence suggests non-polio enteroviruses (EVs) are a potential etiology, yet EV RNA is rarely detected in cerebrospinal fluid (CSF). CSF from children with AFM (n = 42) and other pediatric neurologic disease controls (n = 58) were investigated for intrathecal antiviral antibodies, using a phage display library expressing 481,966 overlapping peptides derived from all known vertebrate and arboviruses (VirScan). Metagenomic next-generation sequencing (mNGS) of AFM CSF RNA (n = 20 cases) was also performed, both unbiased sequencing and with targeted enrichment for EVs. Using VirScan, the viral family significantly enriched by the CSF of AFM cases relative to controls was Picornaviridae, with the most enriched Picornaviridae peptides belonging to the genus Enterovirus (n = 29/42 cases versus 4/58 controls). EV VP1 ELISA confirmed this finding (n = 22/26 cases versus 7/50 controls). mNGS did not detect additional EV RNA. Despite rare detection of EV RNA, pan-viral serology frequently identified high levels of CSF EV-specific antibodies in AFM compared with controls, providing further evidence for a causal role of non-polio EVs in AFM.
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http://dx.doi.org/10.1038/s41591-019-0613-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6858576PMC
November 2019

Acute Flaccid Myelitis Surveillance: A Signal Through the Noise.

Pediatrics 2019 11 7;144(5). Epub 2019 Oct 7.

Department of Pediatrics, School of Medicine, University of Colorado, Aurora, Colorado; and

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http://dx.doi.org/10.1542/peds.2019-2492DOI Listing
November 2019

Phase I/IIa Trial of Atorvastatin in Patients with Acute Kawasaki Disease with Coronary Artery Aneurysm.

J Pediatr 2019 12 24;215:107-117.e12. Epub 2019 Sep 24.

Kawasaki Disease Research Center, Department of Pediatrics, University of California San Diego, La Jolla, CA; Rady Children's Hospital-San Diego, San Diego, CA.

Objectives: To determine the safety, tolerability, pharmacokinetics, and immunomodulatory effects of a 6-week course of atorvastatin in patients with acute Kawasaki disease with coronary artery (CA) aneurysm (CAA).

Study Design: This was a Phase I/IIa 2-center dose-escalation study of atorvastatin (0.125-0.75 mg/kg/day) in 34 patients with Kawasaki disease (aged 2-17 years) with echocardiographic evidence of CAA. We measured levels of the brain metabolite 24(S)-hydroxycholesterol (24-OHC), serum lipids, acute-phase reactants, liver enzymes, and creatine phosphokinase; peripheral blood mononuclear cell populations; and CA internal diameter normalized for body surface area before atorvastatin treatment and at 2 and 6 weeks after initiation of atorvastatin treatment.

Results: A 6-week course of up to 0.75 mg/kg/day of atorvastatin was well tolerated by the 34 subjects (median age, 5.3 years; IQR, 2.6-6.4 years), with no serious adverse events attributable to the study drug. The areas under the curve for atorvastatin and its metabolite were larger in the study subjects compared with those reported in adults, suggesting a slower rate of metabolism in children. The 24-OHC levels were similar between the atorvastatin-treated subjects and matched controls.

Conclusions: Atorvastatin was safe and well tolerated in our cohort of children with acute Kawasaki disease and CAA. A Phase III efficacy trial is warranted in this patient population, which may benefit from the known anti-inflammatory and immunomodulatory effects of this drug.
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http://dx.doi.org/10.1016/j.jpeds.2019.07.064DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6878161PMC
December 2019

Identification of Enteropathogens by Multiplex PCR among Rural and Urban Guatemalan Children with Acute Diarrhea.

Am J Trop Med Hyg 2019 09;101(3):534-540

Hospital Roosevelt, Guatemala City, Guatemala.

Multiplex polymerase chain reaction (PCR) platforms have enhanced understanding of intestinal pathogens in low- and middle-income countries (LMICs). However, few such studies have been performed in Latin America, where poverty, poor sanitation, and undernutrition persist. Multiplex PCR (BioFire, Salt Lake City, UT) was used to identify viral, bacterial, and parasitic pathogens in stool collected on day 1 and 31 from children aged 6 to 35 months with acute, non-bloody diarrhea in two locations (rural and urban) in Guatemala. We analyzed correlation between pathogens and clinical, demographic, and socioeconomic variables; described patterns of pathogen acquisition, persistence, and clearance over the 30-day period; and calculated population attributable fractions (PAFs) for diarrheal causation for individual pathogens. We analyzed 316 subjects (144 urban; 172 rural) enrolled between March 2015 and January 2016. Rural subjects had significantly more malnutrition, animal exposure, and unimproved water/sanitation infrastructure. The majority of subjects had multiple pathogens/sample (4.8 rural and 2.7 urban). Few meaningful correlates were identified between individual pathogens and clinical, demographic, or environmental variables. pathotypes, , and had high rates of persistence between initial and 30-day follow-up. Statistically significant adjusted PAFs were identified for (14.9%, 95% CI: 3.2-23.1), norovirus (10.2%, 95% CI: 0.4-17.1), sapovirus (7.6%, 95% CI: 2.3-10.9), and adenovirus 40/41 (5.6%, 95% CI: 0.3-8.7). These observations further characterize the diversity and complexity of enteric pathogens in children in LMICs. Patterns of chronic symptomatic and asymptomatic infection among Latin American children are similar to those observed in other LMIC regions. Findings have direct implications for practitioners treating individuals with acute infectious diarrhea and should inform regional public health strategies.
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http://dx.doi.org/10.4269/ajtmh.18-0962DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6726947PMC
September 2019

Diagnostic and Treatment Trends in Children With Kawasaki Disease in the United States, 2006-2015.

Pediatr Infect Dis J 2019 10;38(10):1010-1014

From the Department of Pediatrics, University of Colorado School of Medicine.

Objective: To evaluate variations in treatment practice and compliance with national guidelines for the diagnostic evaluation of children with Kawasaki disease (KD).

Study Design: We used the Pediatric Hospital Information System database to analyze demographic, laboratory and treatment data from patients admitted with KD between January 1, 2006, and December 31, 2015.

Results: During the study period, 12,089 children with KD were diagnosed. Nearly all patients had a complete blood cell count, erythrocyte sedimentation rate, and C-reactive protein ordered. Fewer patients had alanine aminotransferase (48.6%) or a urinalysis (75.3%). A small percentage of children had abdominal imaging (11.5%), neck imaging (5.9%), and lumbar punctures (4.5%), and 36.0% of patients received antibiotic therapy. Obtaining echocardiograms pretreatment and the use of steroids and infliximab significantly increased over the study period (P < 0.001). For patients who failed initial intravenous immunoglobulin (IVIG) monotherapy, 82.0% received a second dose of IVIG, 7.7% received steroids, 6.5% received infliximab, and 3.9% received combination therapy. Patients receiving infliximab or steroids as second therapy had a higher response rate than those who received only a second IVIG dose (87.9% versus 83.0% versus 73.3%, P < 0.001).

Conclusions: KD remains a challenging diagnosis. Opportunities exist for earlier use of echocardiograms in the evaluation of children with potential KD. Significant variations in practice exist surrounding second-line therapy. Our data suggest superiority of second-line therapy use of infliximab or steroids over IVIG in terms of reducing need for additional therapies. Prospective, controlled studies are needed to confirm this finding.
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http://dx.doi.org/10.1097/INF.0000000000002422DOI Listing
October 2019
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