Publications by authors named "Marsha S Anderson"

31 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

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

Climate Change and the Practice of Medicine: Essentials for Resident Education.

Acad Med 2021 03;96(3):355-367

A. Bernstein is assistant professor of pediatrics, Harvard Medical School and Boston Children's Hospital, Boston, Massachusetts; ORCID: http://orcid.org/0000-0003-1703-1041.

Despite calls for including content on climate change and its effect on health in curricula across the spectrum of medical education, no widely used resource exists to guide residency training programs in this effort. This lack of resources poses challenges for training program leaders seeking to incorporate evidence-based climate and health content into their curricula. Climate change increases risks of heat-related illness, infections, asthma, mental health disorders, poor perinatal outcomes, adverse experiences from trauma and displacement, and other harms. More numerous and increasingly dangerous natural disasters caused by climate change impair delivery of care by disrupting supply chains and compromising power supplies. Graduating trainees face a knowledge gap in understanding, managing, and mitigating these many-faceted consequences of climate change, which-expected to intensify in coming decades-will influence both the health of their patients and the health care they deliver. In this article, the authors propose a framework of climate change and health educational content for residents, including how climate change (1) harms health, (2) necessitates adaptation in clinical practice, and (3) undermines health care delivery. The authors propose not only learning objectives linked to the Accreditation Council for Graduate Medical Education core competencies for resident education but also learning formats and assessment strategies in each content area. They also present opportunities for implementation of climate and health education in residency training programs. Including this content in residency education will better prepare doctors to deliver anticipatory guidance to at-risk patients, manage those experiencing climate-related health effects, and reduce care disruptions during climate-driven extreme weather events.
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http://dx.doi.org/10.1097/ACM.0000000000003719DOI Listing
March 2021

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

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

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

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

Infliximab Plus Intravenous Immunoglobulin (IVIG) Versus IVIG Alone as Initial Therapy in Children With Kawasaki Disease Presenting With Coronary Artery Lesions: Is Dual Therapy More Effective?

Pediatr Infect Dis J 2018 10;37(10):976-980

Pediatric Infectious Disease, Department of Pediatrics, Children's Hospital Colorado, University of Colorado School of Medicine, Aurora, Colorado.

Background: We previously demonstrated that 80% of Kawasaki disease (KD) patients who develop coronary artery lesions (CALs) have them at diagnosis. We postulated that KD patients presenting with CALs represent a group that may benefit from more aggressive initial therapy. Infliximab has been shown to decrease inflammation in KD patients when added to standard therapy. We compared outcomes of KD patients with CALs initially treated with intravenous immunoglobulin (IVIG) alone versus IVIG plus infliximab.

Methods: Medical records of KD patients from January 2009 to July 2016 were retrospectively reviewed. CALs were defined as a left anterior descending or right coronary artery Z score ≥2.5. KD patients with CALs on initial echocardiogram treated with IVIG alone were compared with those treated with IVIG plus infliximab. Clinical characteristics were compared between groups using Wilcoxon rank-sum test, χ test and Fischer's exact tests; length of stay was analyzed using log-normal regression and need for additional therapy using logistic regression. Effect of treatment on CALs between groups was assessed using linear mixed models.

Results: Sixty-nine KD patients with CALs at presentation were included. Fifteen of 34 (44%) patients treated with IVIG alone required additional therapy compared with 4 of 35 (11%) patients treated with IVIG plus infliximab (P = 0.003). There were no significant differences between treatment groups for length of stay, CALs or C-reactive protein fall.

Conclusions: IVIG plus infliximab as initial therapy reduces the need for additional therapy in KD patients presenting with CALs. Intensified initial therapy, consisting of infliximab plus IVIG, could be considered for this group of KD patients.
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http://dx.doi.org/10.1097/INF.0000000000001951DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6093799PMC
October 2018

Optimizing Your Mentoring Relationship: A Toolkit for Mentors and Mentees.

MedEdPORTAL 2016 Sep 23;12:10459. Epub 2016 Sep 23.

Professor, Department of Pediatrics, Drexel University College of Medicine.

Introduction: Mentorship is a vital component of academic and professional development. Mentees report positive impacts from mentorship programs, yet institutions and societies may struggle to meet their mentees' needs due to factors such as mentor fatigue and lack of mentor training. To address this in our own professional society, the Association of Pediatric Program Directors, we developed a mentor toolkit in order to utilize a variety of mentoring models, provide faculty development for midlevel mentors, and offer guidance to mentees.

Methods: Most of these tools were designed to be administered in an interactive format such as a workshop or seminar with think-pair-share opportunities. The toolkit begins by providing a definition of and reinforcing the benefits and the characteristics of effective mentoring relationships. Next, we discuss the important role that mentees have in creating and maintaining effective mentoring relationships (i.e., mentee-driven mentoring). We then introduce a mentoring mosaic activity designed to help mentees examine their professional network and think about how they might expand it to fulfill the spectrum of their mentoring needs. Next, we present guidelines for the implementation of four mentoring models that can be used within one's institution: traditional dyadic mentoring, peer group mentoring, meet the professor mentoring, and speed mentoring. We then provide tools that can be used to help facilitate effective mentoring development.

Results: This toolkit has successfully served as a self-guided resource at national meetings for many years, garnering positive feedback from mentors and mentees alike.

Discussion: The principles and methods are easily generalizable and may be used to guide mentorship programs within institutional and professional societies, as well as to assist mentors and mentees in optimizing their individual mentoring relationships.
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http://dx.doi.org/10.15766/mep_2374-8265.10459DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6464436PMC
September 2016

Kawasaki Disease and Exposure to Fine Particulate Air Pollution.

J Pediatr 2016 10 2;177:179-183.e1. Epub 2016 Aug 2.

Department of Economics, Brigham Young University, Provo, UT.

Objective: To analyze associations of short-term exposure to fine particulate matter (diameter ≤ 2.5 µm [PM2.5]), a measurable component of urban pollution, with the event date of fever onset for patients with Kawasaki disease (KD) residing in 7 metropolitan regions.

Study Design: A case-crossover study design was used. Time trends, seasonality, month, and weekday were controlled for by matching. We assembled PM2.5 exposure measurements from urban monitors and imputed PM2.5 to provide day-to-day temporal variability and resolution for time series indexes of exposures. Selected exposure windows (to 14 days) of PM2.5 were examined.

Results: A total of 3009 KD events were included for which the subject resided within a study metropolitan area and the event date occurred during years with available PM2.5. The estimated ORs (with 95% CIs) of an event of KD associated with a 10 µg/m(3) PM2.5 lagged moving average concentration of lagged exposure period (ie, concurrent, preceding day[s]) revealed no evidence of a consistent, statistically significant, positive association between elevated PM2.5 exposure and increased risk of KD. Extended analysis with stratification by city, sex, age, ethnic origin, incomplete or complete clinical manifestations, the presence of coronary aneurysm, and intravenous immunoglobulin resistance did not provide evidence of a consistent, statistically significant, positive association between elevated exposure to PM2.5 and increased risk of KD for any of the strata studied.

Conclusions: This multicity study failed to establish a risk of the event of KD with short-term fine particulate exposure. Our negative findings add to the growing field of environmental epidemiology research of KD.
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http://dx.doi.org/10.1016/j.jpeds.2016.06.061DOI Listing
October 2016

Myocardial Strain and Strain Rate in Kawasaki Disease: Range, Recovery, and Relationship to Systemic Inflammation/Coronary Artery Dilation.

J Clin Exp Cardiolog 2016 Apr 21;7(4). Epub 2016 Apr 21.

Department of Pediatrics and Section of Cardiology, Children's Hospital Colorado/University of Colorado, Denver, USA.

Background: Kawasaki Disease (KD), a systemic vasculitis of medium sized vessels, is the most common cause of acquired heart disease among children in the developed world. Some KD patients demonstrate echocardiographic evidence of depressed myocardial mechanics. However, the incidence, etiology, and reversibility of abnormal mechanics in KD patients remain undefined.

Methods And Results: We retrospectively studied 41 KD patients and measured myocardial strain and strain rate by velocity vector imaging from pre-treatment and convalescent echocardiograms. Pre-treatment procalcitonin, C-reactive protein (CRP), and coronary artery z-scores were obtained in all patients and compared between the groups with preserved versus depressed acute phase mechanics. The change in mechanics between the acute and convalescent phases was also assessed. Patients with initially low longitudinal strain improved by the convalescent period (mean difference - 4.0%; p<0.005) with the greatest improvement occurring in patients with the lowest initial strain (-7.3%; p<0.05). Patients with higher initial strain did not change significantly by the convalescent period. Patients with lower longitudinal and circumferential strain demonstrated higher median procalcitonin levels (1.2 vs. 0.3 ng/mL; p<0.05 and 1.8 vs. 0.4 ng/mL; p<0.05 respectively) and a trend towards higher CRP, but no difference in coronary artery z-scores. Strain rate was not associated with inflammatory markers or coronary artery z-scores.

Conclusions: The range of strain found in our cohort was large. Improvement in mean strain was driven primarily by patients with lower initial strain. Lower strain was associated with increased markers of systemic inflammation, but not proximal coronary artery changes.
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http://dx.doi.org/10.4172/2155-9880.1000432DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4866607PMC
April 2016

Procalcitonin (PCT) and Kawasaki Disease: Does PCT Correlate With IVIG-Resistant Disease, Admission to the Intensive Care Unit, or Development of Coronary Artery Lesions?

J Pediatric Infect Dis Soc 2016 Sep 20;5(3):297-302. Epub 2015 Apr 20.

Department of Pediatrics, Section of Infectious Diseases.

Background: Kawasaki disease (KD) remains a clinical diagnosis due to the absence of a sensitive and specific diagnostic test. There are limited published data on the usefulness of procalcitonin (PCT) as a biomarker for the diagnosis or prognosis of children with KD. We hypothesized that PCT might be useful in predicting coronary artery lesions (CALs) and intravenous immunoglobulin (IVIG) resistance.

Methods: Eighty-five children with KD who were hospitalized within the first 10 days of illness were retrospectively reviewed. PCT was measured on stored serum or plasma samples obtained at the time of admission (pre-IVIG). Data were analyzed to determine whether there were statistically significant associations with PCT, erythrocyte sedimentation rate, and C-reactive protein levels and the incidence of CALs, pediatric intensive care unit admission, or IVIG-resistant disease in KD patients.

Results: PCT values in children hospitalized with acute KD ranged from 0.1 ng/mL to 143.9 ng/mL, with a median of 0.49 ng/mL (IQR 0.23-1.29 ng/mL). There was no correlation of PCT with patient age, race, or sex, but it was correlated with day of illness. KD patients with a PCT ≥ 0.5 ng/mL had a significantly higher incidence of IVIG-resistant disease (29% versus 7%, P = .02). There was no association between PCT and development of CALs in our sample.

Conclusions: Additional research is needed to establish the sensitivity and specificity of PCT for the diagnosis of KD. PCT may be of value in predicting which children are at increased risk for IVIG-resistant disease.
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http://dx.doi.org/10.1093/jpids/piv019DOI Listing
September 2016

Concurrent Respiratory Viruses and Kawasaki Disease.

Pediatrics 2015 Sep 24;136(3):e609-14. Epub 2015 Aug 24.

Sections of Infectious Diseases, and

Background: The diagnosis of Kawasaki disease (KD) remains challenging without a definitive diagnostic test and currently is guided by using clinical patient characteristics and supported by laboratory data. The role of respiratory viruses in the pathogenesis of KD is not fully understood.

Methods: Charts of patients with KD admitted to Children's Hospital Colorado from January 2009 to May 2013 were retrospectively reviewed. Patients with KD who had a nasopharyngeal wash submitted for multiplex polymerase chain reaction (PCR) viral testing were included. Clinical characteristics, laboratory data, and outcomes of patients with and without positive respiratory viral PCR results were compared.

Results: Of 222 patients with KD admitted to the hospital, 192 (86%) had a respiratory viral PCR test performed on or shortly after admission. Ninety-three (41.9%) of the 192 patients with KD had a positive respiratory viral PCR, and the majority were positive for rhinovirus/enterovirus. No statistically significant differences were found in the clinical characteristics and laboratory values between the groups with and without positive respiratory viral PCR findings. Both groups had the same frequency of upper respiratory and gastrointestinal symptoms and had the same incidence of admission to the PICU, intravenous immunoglobulin-resistant disease, and coronary artery lesions.

Conclusions: No differences in clinical presentations or outcomes in children with KD stratified according to positive or negative respiratory viral PCR testing were observed. A positive respiratory viral PCR or presence of respiratory symptoms at the time of presentation should not be used to exclude a diagnosis of KD.
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http://dx.doi.org/10.1542/peds.2015-0950DOI Listing
September 2015

Tissue Doppler Imaging as a Predictor of Immunoglobulin Resistance in Kawasaki Disease.

Pediatr Cardiol 2015 Dec 21;36(8):1618-23. Epub 2015 May 21.

Pediatric Cardiology, Children's Hospital Colorado, University of Colorado School of Medicine, 13123 East 16th Avenue, B100, Aurora, CO, 80045, USA.

Kawasaki disease (KD) is characterized by myocarditis and left ventricular dysfunction during the acute phase of the illness. Despite treatment with intravenous immunoglobulin (IVIG), a significant number of patients are IVIG resistant. We evaluated KD patients in the acute phase of illness using tissue Doppler imaging (TDI) to assess whether myocardial dysfunction may predict IVIG resistance. All patients with acute KD presenting to Children's Hospital Colorado from February 2007 through March 2014 were included in this study and underwent echocardiograms with TDI evaluation at diagnosis. Patients were divided into two groups: IVIG resistant and IVIG responder. Group differences were assessed using Wilcoxon-Mann-Whitney and Chi-square testing. Receiver operating characteristic (ROC) curve analysis was utilized to determine threshold values of TDI measurements associated with IVIG resistance. Fifty-one age-matched IVIG resistant patients were compared to 51 IVIG responder patients [median age, IQR 44.57 (20.13-77.07) vs. 33.49 (17.30-62.89) months, p < 0.44]. There were significant differences in the septal and mitral early diastolic velocities (E') (p < 0.001 and p < 0.01), respectively. ROC analysis demonstrated that tricuspid E' <0.15 cm/s, septal E' <0.12 cm/s, and mitral E' <0.16 cm/s were good predictors of IVIG unresponsiveness (AUC = 0.66, 0.66, and 0.70, respectively). There were no differences between the systolic velocities and late diastolic velocities (A'). IVIG resistant KD patients present with significantly greater diastolic dysfunction compared to responders in patients with KD. TDI may be a useful tool to differentiate KD patients at higher risk of IVIG resistance.
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http://dx.doi.org/10.1007/s00246-015-1206-5DOI Listing
December 2015

Severe Neuroinvasive West Nile Virus Infection in a Child with Undiagnosed Addison's Disease.

IDCases 2014 ;1(3):29-31

Department of Pediatrics, Section of Infectious Diseases, Children's Hospital Colorado, University of Colorado School of Medicine, Aurora, Colorado 80045, USA.

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http://dx.doi.org/10.1016/j.idcr.2014.04.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4131694PMC
January 2014

Strengthening the associate program director workforce: needs assessment and recommendations.

Acad Pediatr 2014 Jul-Aug;14(4):332-4

Department of Pediatrics Drexel University College of Medicine, Section of General Pediatrics St. Christopher's Hospital for Children, Philadelphia, Pa.

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http://dx.doi.org/10.1016/j.acap.2014.05.003DOI Listing
December 2015

Advances in the treatment of Kawasaki disease.

Curr Opin Pediatr 2013 Feb;25(1):103-9

Department of Pediatrics, Section of Infectious Diseases, Children's Hospital Colorado, University of Colorado School of Medicine, Aurora, Colorado 80045, USA.

Purpose Of Review: Intravenous immunoglobulin (IVIG) and aspirin is the standard initial therapy in the treatment of Kawasaki disease. Some patients have persistent or recrudescent fever despite this therapy. Although there is no conclusive body of evidence defining the best second and third-line therapies for Kawasaki patients, there have been several recent studies published describing the results of these therapies.

Recent Findings: This review summarizes the current recommendations for the initial therapy and describes the second and third-line therapies studied in Japan and the United States. A recent study in a Japanese population of Kawasaki disease patients at high risk for IVIG resistance found that the group receiving steroids, in addition to IVIG and aspirin, had fewer coronary artery abnormalities than the group receiving IVIG and aspirin alone. Small studies of etanercept and infliximab have showed these TNF-alpha blockers to be well tolerated and effective in the resolution of fever.

Summary: Although most practitioners in the USA use IVIG as a second-line therapy for those Kawasaki disease patients who have persistent or recrudescent fever, promising new therapies are under study. Infliximab and steroids are currently the two agents that have been most studied. However, larger studies and studies in genetically diverse populations are needed.
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http://dx.doi.org/10.1097/MOP.0b013e32835c1122DOI Listing
February 2013

Kawasaki disease and the pediatric gastroenterologist: a diagnostic challenge.

J Pediatr Gastroenterol Nutr 2013 Mar;56(3):297-9

Ain Shams University. Department of Pediatrics, University of Colorado School of Medicine and Children's Hospital, Aurora, CO 80045, USA.

Background And Objectives: Gastrointestinal symptoms and signs are rarely the main clinical presentation of Kawasaki disease (KD). In the present study, we report a series of patients with KD in whom a gastroenterology consult was obtained before consideration of the diagnosis of KD.

Methods: We retrospectively reviewed all patients with KD admitted to Children's Hospital Colorado from January 2009 through February 2011 with prominent gastrointestinal symptoms, resulting in gastrointestinal service consultation before their diagnosis of KD.

Results: We identified 7 of 118 (6%) patients with KD who met our criteria. All 7 patients were males, and the median age at admission was 9.7 years. All patients had abdominal pain and fever at presentation. Vomiting, diarrhea, and clinical jaundice were present in 70%, 50%, and 43% of patients, respectively. Aminotransferases and/or γ-glutamyl transpeptidase abnormalities were observed in 6 (89%) patients. All of the patients had fever and rash on admission, and 86% had nonexudative conjunctivitis and 71% had mucosal changes. Median duration of illness at gastroenterology consultation was 5 days, whereas median duration of illness at infectious disease consultation was 6 days. One patient developed coronary artery dilation and 2 patients had intravenous immunoglobulin-resistant KD.

Conclusions: Gastroenterologists should be aware of gastrointestinal presentations of KD. Unexplained gastrointestinal symptoms in the presence of fever, and 1 or 2 of the major clinical signs of KD, should prompt consideration of KD in the differential diagnosis.
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http://dx.doi.org/10.1097/MPG.0b013e3182794432DOI Listing
March 2013

Preventing coronary artery abnormalities: a need for earlier diagnosis and treatment of Kawasaki disease.

Pediatr Infect Dis J 2012 Dec;31(12):1217-20

Department of Pediatrics, University of Colorado School of Medicine and Children's Hospital Colorado, Aurora,CO 80045 ,

Objectives: The aim of this study was to explore the timing of coronary artery (CA) abnormalities in light of the expanding clinical spectrum of Kawasaki disease (KD).

Methods: We reviewed all cases of KD admitted to Children's Hospital Colorado from January 2007 through February 2011 who had CA abnormalities. A retrospective chart review was conducted to collect demographic, clinical, laboratory and echocardiogram (ECHO) data. CA abnormalities were defined as Z score ≥2.5 or presence of ectasia or aneurysms.

Results: A total of 210 patients with KD were identified. Fifty-seven (27.1%) of the 210 children with KD had CA abnormalities. Forty-six of the 57 (81%) children with CA abnormalities had CA abnormalities noted on their initial ECHO. Of the 46 children who had CA abnormalities detected on their initial ECHO, 37 (80%) had their ECHO on or before illness day 10. The median day of illness when abnormalities were detected on initial ECHO was day 7 (interquartile range: 5-8; range: 2-24 days). Only 25 of the 46 children (54%) were classified as complete KD, but 40 (87%) had the triad of conjunctivitis, rash and mucous membrane involvement. Thirteen (28%) had intravenous immunoglobulin-resistant disease.

Conclusion: The majority of CA abnormalities in children with KD were identified in the initial ECHO, during the first week of illness. Earlier diagnosis and treatment is needed to impact the incidence of CA abnormalities in children with KD. Increased clinical suspicion and earlier use of ECHO in the initial workup of children with suspected KD may lead to more rapid diagnosis and treatment.
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http://dx.doi.org/10.1097/INF.0b013e318266bcf9DOI Listing
December 2012

Abnormal liver panel in acute kawasaki disease.

Pediatr Infect Dis J 2011 Feb;30(2):141-4

Department of Pediatrics, Ain-Shams University School of Medicine, Cairo, Egypt.

Background And Aims: abnormalities of liver panel (liver function test [LFT]) are frequently documented in patients with Kawasaki disease (KD). We sought to define the spectrum of abnormalities in liver panel tests in children with KD. We studied the characteristics of KD patients who presented with an abnormal liver panel and their response to treatment.

Methods: we retrospectively reviewed the medical records of all KD patients admitted between 2004 and 2009 with one or more LFTs done at presentation and compared patients with and without at least 1 abnormal liver panel test including alanine aminotransferase, aspartate aminotransferase, gamma glutamyl transferase, and bilirubin. These patients were divided into 2 groups: those with normal LFTs (normal LFT group) and those with at least one abnormal LFT at presentation (abnormal LFT group).

Results: Of 259 patients, 240 (92.7%) patients with KD reviewed had one or more LFTs performed. One hundred nine (45.4%) had at least 1 abnormal liver panel test. Patients in the abnormal LFT group presented earlier (P = 0.01) and were more likely to have intravenous immunoglobulin (IVIG) resistant disease (P = 0.01). There was no significant difference between groups in development of coronary artery abnormalities or aneurysms. Multivariate analysis identified C-reactive protein and total bilirubin at admission as significant predictors for IVIG resistant disease.

Conclusion: we report the largest US single center study of the spectrum of liver panel abnormalities in children with acute KD. Abnormalities of LFTs are frequently found in patients with acute KD and children with abnormal LFTs were at higher risk for IVIG resistance.
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http://dx.doi.org/10.1097/INF.0b013e3181f6fe2aDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3096016PMC
February 2011

Facilitated peer group mentoring: a case study of creating leadership skills among the associate program directors of the APPD.

Acad Pediatr 2010 May-Jun;10(3):161-4

Department of Pediatrics, Drexel University College of Medicine, Philadelphia, Pa, USA.

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http://dx.doi.org/10.1016/j.acap.2010.03.002DOI Listing
September 2010

Kawasaki disease in a pediatric intensive care unit: a case-control study.

Pediatrics 2008 Oct 22;122(4):e786-90. Epub 2008 Sep 22.

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

Objectives: We conducted a case-control study to ascertain the clinical presentations, risk factors, and clinical outcomes of children who had Kawasaki disease and were admitted to the ICU of our children's hospital.

Methods: We reviewed charts of all children who had a discharge diagnosis of Kawasaki disease and were admitted to the ICU from 1995 through 2007. For each patient, we identified 3 season-matched control subjects who had Kawasaki disease and were not admitted to the ICU.

Results: We identified 423 patients with Kawasaki disease. Of those, 14 (3.3%) were admitted to the ICU and met our inclusion criteria. ICU admission diagnoses were most commonly toxic shock or septic shock. Thirteen (92.8%) of 14 patients who were admitted to the ICU met criteria for complete Kawasaki disease before treatment. There was no significant difference in age in ICU patients compared with season-matched control subjects with Kawasaki disease. ICU patients were significantly more likely to be female and to have higher band counts, lower platelet counts, lower albumin levels, and higher C-reactive protein values. Time from admission to treatment with intravenous immunoglobulin was delayed in ICU patients. ICU patients were more likely to have intravenous immunoglobulin-refractory disease and require therapy with a second dose of intravenous immunoglobulin, infliximab, or steroids.

Conclusions: We present a case-control study of patients who had Kawasaki disease and presented severely ill, in shock, and requiring admission to the ICU. These patients frequently were misdiagnosed because of failure to appreciate the full spectrum of disease severity seen in patients with Kawasaki disease. These patients' illnesses was often mistaken for toxic or septic shock, leading to a delay in treatment with intravenous immunoglobulin. Patients who have Kawasaki disease and are admitted to the ICU are at increased risk for intravenous immunoglobulin-refractory disease and may be at risk for development of more severe coronary artery disease.
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http://dx.doi.org/10.1542/peds.2008-1275DOI Listing
October 2008

Multiplex MassTag-PCR for respiratory pathogens in pediatric nasopharyngeal washes negative by conventional diagnostic testing shows a high prevalence of viruses belonging to a newly recognized rhinovirus clade.

J Clin Virol 2008 Oct;43(2):219-22

Department of Pediatrics, The Children's Hospital, University of Colorado Denver School of Medicine, Aurora, CO, USA.

Background: Respiratory infections are the most common infectious diseases in humans worldwide and are a leading cause of death in children less than 5 years of age.

Objectives: Identify candidate pathogens in pediatric patients with unexplained respiratory disease.

Study Design: Forty-four nasopharyngeal washes collected during the 2004-2005 winter season from pediatric patients with respiratory illnesses that tested negative for 7 common respiratory pathogens by culture and direct immunofluorescence assays were analyzed by MassTag-PCR. To distinguish human enteroviruses (HEV) and rhinoviruses (HRV), samples positive for picornaviruses were further characterized by sequence analysis.

Results: Candidate pathogens were detected by MassTag PCR in 27 of the 44 (61%) specimens that previously were rated negative. Sixteen of these 27 specimens (59%) contained picornaviruses; of these 9 (57%) contained RNA of a recently discovered clade of rhinoviruses. Bocaviruses were detected in three patients by RT-PCR.

Conclusions: Our study confirms that multiplex MassTag-PCR enhances the detection of pathogens in clinical specimens, and shows that previously unrecognized rhinoviruses, that potentially form a species HRV-C, may cause a significant amount of pediatric respiratory disease.
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http://dx.doi.org/10.1016/j.jcv.2008.06.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2603178PMC
October 2008

The new University of Colorado medical school curriculum: a pediatric perspective.

J Pediatr 2007 Nov;151(5 Suppl):S32-6

University of Colorado School of Medicine, Denver, Colorado, USA.

The University of Colorado School of Medicine has developed an innovative 4-year undergraduate curriculum. As a strong advocate for education and curriculum reform, Dr M. Douglas Jones Jr. created an environment for pediatrics to flourish in this new curriculum. Pediatric content has increased in all years of the curriculum, and pediatric faculty have had greater opportunities to teach and seek career development in medical education. In this report, we review the process that led to curriculum reform, provide an overview of the new curriculum design, and highlight examples of the positive impact this process has had on education in pediatrics. We hope that sharing our experience, may benefit others in medical education.
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http://dx.doi.org/10.1016/j.jpeds.2007.08.018DOI Listing
November 2007

Outbreak of neurologic enterovirus type 71 disease: a diagnostic challenge.

Clin Infect Dis 2007 Oct 13;45(8):950-7. Epub 2007 Sep 13.

Department of Pediatrics, Section of Infectious Diseases, University of Colorado School of Medicine, and The Children's Hospital, Denver, Colorado 80218, USA.

Background: Similar to poliovirus, enterovirus type 71 (EV71) causes severe disease, including aseptic meningitis, encephalitis, acute flaccid paralysis, and acute cardiopulmonary dysfunction. Large epidemics of EV71 infection have been reported worldwide.

Methods: After recognition of a cluster of cases of EV71 disease, we reviewed records of patients with EV71 disease who required hospitalization at The Children's Hospital in Denver, Colorado, from 2003 through 2005. The presence of enterovirus was detected by reverse-transcriptase polymerase chain reaction (PCR) and/or viral culture of specimens from multiple sources, and the virus was typed as EV71 using genetic sequencing.

Results: Eight cases of EV71 disease were identified in both 2003 and 2005. Fifty-six percent of patients with EV71 disease were < or = 6 months of age (range, 4 weeks to 9 years). All 16 patients had EV71 central nervous system infection. Enterovirus PCR (EV-PCR) of cerebrospinal fluid specimens yielded positive results for only 5 (31.2%) of the 16 patients; all of these patients were < 4 months of age and had less severe disease. However, EV-PCR of upper respiratory tract specimens yielded positive results for 8 (100%) of 8 patients, and EV-PCR of lower gastrointestinal tract specimens yielded positive results for 7 (87.5%) of 8 patients.

Conclusions: An outbreak of neurologic EV71 disease occurred in Denver, Colorado, during 2003 and 2005. Likely, EV71 disease remains unrecognized in other parts of the United States, because EV-PCR of cerebrospinal fluid frequently yields negative results. EV-PCR of specimens from the respiratory and gastrointestinal tracts had higher diagnostic yields than did EV-PCR of cerebrospinal fluid. EV71 infection should be considered in young children presenting with aseptic meningitis, encephalitis, acute flaccid paralysis, or acute cardiopulmonary collapse. EV71 infection may be an underrecognized emerging disease in the United States.
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http://dx.doi.org/10.1086/521895DOI Listing
October 2007

Blinded case-control study of the relationship between human coronavirus NL63 and Kawasaki syndrome.

J Infect Dis 2006 Dec 2;194(12):1697-701. Epub 2006 Nov 2.

Department of Pediatrics, The Children's Hospital, University of Colorado Health Science Center, Denver, CO, USA.

We conducted a blinded, case-control, retrospective study in pediatric patients hospitalized at The Children's Hospital, Denver, Colorado, to determine whether human coronavirus (HCoV)-NL63 infection is associated with Kawasaki syndrome (KS). Over the course of a 7-month period, nasopharyngeal-wash samples from 2 (7.7%) of 26 consecutive children with KS and 4 (7.7%) of 52 matched control subjects tested positive for HCoV-NL63 by reverse transcription-polymerase chain reaction. These data suggest that, although HCoV-NL63 was circulating in children in our community during the time of the study, the prevalence of infection with HCoV-NL63 was not greater in patients with KS than in control subjects.
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http://dx.doi.org/10.1086/509509DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7199878PMC
December 2006

Delayed diagnosis of Kawasaki syndrome: an analysis of the problem.

Pediatrics 2005 Apr;115(4):e428-33

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

Objective: Most pediatric providers in Colorado are familiar with Kawasaki syndrome (KS). However, in a recent outbreak, 30% of cases were diagnosed after illness day 10. We hypothesized that these children saw providers who were not familiar with KS, were given antibiotics for other diagnoses that delayed identification, had access-to-care issues, or presented atypically.

Methods: A retrospective chart review of 106 consecutive KS cases seen at the Children's Hospital in Denver during 1994-2000 was conducted.

Results: Twenty-five of 106 children (23.6%) were diagnosed after day 10 of illness (delayed-diagnosis group [DDG]), and these 25 cases were compared with 81 cases diagnosed on or before day 10 (early-diagnosis group [EDG]). There were no differences between patients in the DDG and EDG in age, gender, number of visits, specialty of the primary care physician, time to the first medical visit, number of antibiotics received, coronary artery abnormalities, white blood cell count, or erythrocyte sedimentation rate. Patients in the DDG had significantly more days of fever, rash, red eyes, and oral changes. A platelet count of >450000/mm3 occurred more often in the DDG (56%) than the EDG (30%). After additional analysis, patients in the EDG had close clustering of symptom onset in the first few days of illness, but patients in the DDG had onset of symptoms scattered over 9 days. Patients in the DDG were 2.8 times more likely to have coronary artery aneurysms than patients in the EDG (DDG: 24%; EDG: 8.6%).

Conclusions: Diagnosis after the 10th day of illness was not linked to type of medical provider, number of antibiotics received, or number of physician visits. Patients in the DDG exhibited the typical features of KS, but the onset of their symptoms was dispersed over time as opposed to the close clustering of symptoms in the EDG. Because coronary artery aneurysms occurred significantly more often in the patients in the DDG, more education is needed to teach health care providers to have a high index of suspicion for KS in young children presenting with fever/rash illnesses.
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http://dx.doi.org/10.1542/peds.2004-1824DOI Listing
April 2005

CP-64131, an aminobenzazepine with cytokine-like properties, stimulates human neutrophil functions through the p38-MAPK pathway.

J Leukoc Biol 2004 Aug 20;76(2):477-83. Epub 2004 May 20.

Bonfils Blood Center, 717 Yosemite Street, Denver, CO 80230, USA.

CP-64131 (CP), an aminobenzazepine with cytokine-like, physiologic effects similar to granulocyte-colony stimulating factor (G-CSF) and granulocyte macrophage (GM)-CSF, increases the number of neutrophils and stimulates marrow recovery after doxirubicin ablation. CP can also function as a neutrophil agonist, like formyl-Met-leu-Phe (fMLP). In these studies, we show that CP is unique in that it stimulates the p38-mitogen-activated protein kinase (MAPK) pathway but not extracellular signal-regulated kinase (ERK)1/2 or c-jun N-terminal kinase MAPKs in human neutrophils from peripheral blood. This is in contrast to other neutrophil agonists such as fMLP, interleukin (IL)-8, or GM-CSF, which stimulate multiple MAPK pathways. Like fMLP and IL-8, CP is capable of stimulating superoxide (O2-) production, CD11b expression, and cell polarization in human neutrophils. CP-stimulated O2- production is completely dependent on p38-MAPK activation, as determined by sensitivity to the p38-MAPK inhibitor SB203580. In contrast, SB203580 only partially inhibits expression of CD11b and has no effect on cell polarization stimulated by CP. Therefore, CP treatment of neutrophils activates p38-MAPK but has effects independent of p38-MAPK activation. In human embryonic kidney 293 cells, a human kidney epithelial cell line CP stimulates p38-MAPK and modestly activates ERK1/2. The findings define CP as a novel, small molecule, which has little cellular toxicity in vitro. CP has the ability to activate specific MAPK pathways in different cell types and should prove to be an effective agonist in combination with inhibitors to study biological responses regulated by MAPKs.
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http://dx.doi.org/10.1189/jlb.0903422DOI Listing
August 2004

Investigation of Kawasaki syndrome risk factors in Colorado.

Pediatr Infect Dis J 2002 Oct;21(10):976-8

Division of Viral and Rickettsial Diseases National Center for Infectious Diseases Centers for Disease Control and Prevention Atlanta, GA, USA.

Risk factors for Kawasaki syndrome (KS) were evaluated through a case-control study during an investigation of a KS cluster in Denver, CO. KS was associated with a humidifier in the child's room (odds ratio, 7.3; 95% confidence interval, 1.8 to 29.3) and possibly with an antecedent respiratory illness. The use of humidifiers should be further investigated as part of future studies of KS.
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http://dx.doi.org/10.1097/00006454-200210000-00018DOI Listing
October 2002
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