Sequential Intravenous-Oral Therapy for Pediatric Streptococcus anginosus Intracranial Infections.

BACKGROUND: Streptococcus anginosus group is a common cause of pediatric intracranial infections but treatment recommendations, including use of oral therapy, are poorly defined. METHODS: We performed a retrospective review from 2004 to 2019 of all patients with S anginosus group pyogenic intracranial infections at Children's Hospital Colorado, highlighting patients transitioned to oral therapy. The primary endpoint was worsening infection necessitating intravenous antibiotics or a source control procedure after transition to oral therapy. RESULTS: Of 107 patients with S anginosus intracranial infections, 61 were transitioned to exclusive oral therapy after a median intravenous duration of 37 days, overwhelmingly with a levofloxacin-based regimen. Only 1 treatment failure was noted in a patient who did not fill their prescription. Patients with epidural infections were more likely to be transitioned to oral therapy within the first 28 days of treatment (defined as "early"). Patients with parenchymal infections, bacteremia, co-pathogens, higher inflammatory markers, and requiring >1 source control procedure were less likely to be transitioned early to oral therapy. Complications of a central catheter and/or intravenous medications contributed to 56% of oral transitions. CONCLUSIONS: Levofloxacin-based oral regimens were effective and well tolerated. Patients with less severe infections were more likely to be transitioned early to oral therapy. Criteria for transitioning patients to oral antibiotics for intracranial infections should be established to minimize risks inherent with central catheters.

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

OBJECTIVES: To compare initial treatment with intravenous immunoglobulin (IVIG) versus IVIG plus infliximab in multisystem inflammatory syndrome in children (MIS-C). METHODS: Single-center retrospective cohort study of patients with MIS-C who met Centers for Disease Control and Prevention criteria and received treatment from April 2020 to February 2021. Patients were included and compared on the basis of initial therapy of either IVIG alone or IVIG plus infliximab. The primary outcome was need for additional therapy 24 hours or more after treatment initiation. RESULTS: Seventy-two children with MIS-C met inclusion criteria. Additional therapy was needed in 13 of 20 (65%) who received IVIG alone and 16 of 52 (31%) who received IVIG plus infliximab (P = .01). The median (interquartile range) ICU lengths of stay were 3.3 (2.2 to 3.8) and 1.8 (1.1 to 2.1) days, respectively (P = .001). New or worsened left ventricular dysfunction developed in 4 of 20 (20%) and 2 of 52 (4%) (P = .05), and new vasoactive medication requirement developed in 3 of 20 (15%) and 2 of 52 (4%), respectively (P = .13). The median percentage changes in the C-reactive protein level at 24 hours posttreatment compared with pretreatment were 0% (-29% to 66%) and -46% (-62% to -15%) (P < .001); and at 48 hours posttreatment, -5% (-41% to 57%) and -70% (-79% to -49%) respectively (P < .001). There was no significant difference in hospital length of stay, time to fever resolution, vasoactive medication duration, or need for diuretics. CONCLUSIONS: Patients with MIS-C initially treated with IVIG plus infliximab compared with those treated with IVIG alone were less likely to require additional therapy and had decreased ICU length of stay, decreased development of left ventricular dysfunction, and more rapid decline in C-reactive protein levels.

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

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.

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

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.

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

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.

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

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.

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?

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.

Clinical Care Guideline for Improving Pediatric Acute Musculoskeletal Infection Outcomes.

BACKGROUND: Acute pediatric musculoskeletal infections are common, leading to significant use of resources and antimicrobial exposure. In order to decrease variability and improve the quality of care, Children's Hospital Colorado implemented a clinical care guideline (CCG) for these infections. The purpose of this study is to evaluate clinical and resource outcomes PRE and POST this CCG. METHODS: Retrospective chart review evaluated patients admitted to a large pediatric quaternary referral center (CHCO) diagnosed with acute osteomyelitis, septic arthritis, pyomyositis, and/or musculoskeletal abscess prior to and after guideline implementation. Primary outcomes included length of stay and overall antibiotic use, with additional secondary clinical, process, and therapeutic outcomes examined. RESULTS: 82 patients were identified in both the pre-CCG and post-CCG cohorts. There was a reduction in the median of all primary outcomes, including length of stay (0.6 median days decrease, P = .04), length of IV antibiotic therapy (4.9 median days decrease, P < .0001), and days of IV antibiotic therapy (6.4 median days decrease, P = .0004). Our median length of stay post-CCG was 4.9 days, the shortest reported length of stay for pediatric acute musculoskeletal infections to date. Additionally, there was a 24.5 hour reduction in median length of fever (P = .02), faster CRP normalization (P < .0001), 50% decrease in the number of related readmissions (P = .02), 34% decrease in central venous catheters placed (P < .0001), decreased time to first culture (P = .02), and 79% pathogen identification post-CCG (P = .056). CONCLUSIONS: Implementation of a CCG for acute musculoskeletal infections improves patient, process and resource outcomes.

Adverse Events in Pediatric Patients Receiving Long-term Oral and Intravenous Antibiotics.

BACKGROUND AND OBJECTIVE: Children receiving long-term antibiotic therapy (LTAT) at Children's Hospital Colorado (CHCO) are treated with both oral and intravenous (i.v.) agents and often experience complications not comprehensively described by the literature. We sought to describe adverse drug events (ADEs) and venous access complications (VACs) in pediatric patients managed with oral and i.v. antibiotics so as to inform clinical decision-making, drug monitoring, and patient counseling at CHCO. METHODS: We conducted a retrospective review of children receiving LTAT through the CHCO infectious disease service from 2006 to 2012. Demographic, microbiologic, diagnostic data, ADEs, and VACs were recorded for each patient. RESULTS: From 2006 to 2012, 521 patients received 1876 courses, accounting for 71,306 days of antimicrobial therapy. A total of 219 patients (42%) developed an ADE with discontinuation of the offending agent in 65% of courses associated with an ADE. The most common ADEs were neutropenia, rash, and diarrhea. Central lines were placed in 376 patients with 106 (28%) experiencing ≥1 VACs. I.v. agents were associated with a fourfold increase in the rate of ADEs compared with oral agents, and a fivefold increase when VACs were included. CONCLUSIONS: Practitioners may make more informed decisions and risk assessments by using descriptive ADE information for specific agents and mode of drug delivery to mitigate risk, thereby improving the quality of care. Patients should be counseled regarding risks of LTAT, including increased risk with i.v. therapy, and actively monitored for side effects.

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

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.

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

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.

Concurrent Respiratory Viruses and Kawasaki Disease.

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.

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

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.

Influence of Culture Results on Management and Outcome of Pediatric Osteomyelitis and/or Septic Arthritis.

Children with uncomplicated osteomyelitis and/or septic arthritis were more likely (P < .01) to have positive focus than blood cultures. Those who grew a pathogen and/or started on a single antibiotic were more likely to be discharged on a single antibiotic, and those sent home on oral therapy had fewer adverse events.

The constitutive capacity of human keratinocytes to kill Staphylococcus aureus is dependent on beta-defensin 3.

Normal skin is often exposed to bacteria, including potent pathogens such as E. coli, Staphylococcus aureus, and Streptococcus sp., but these microbes usually do not cause skin inflammation or infection in healthy individuals. Therefore, we hypothesized that there must be a constitutive mechanism for rapid destruction and elimination of small numbers of bacteria which penetrate the stratum corneum from everyday activities. This study found that exposure of keratinocytes cultured from a number of individuals to S. aureus resulted in approximately 2-3 log better killing than by HaCaT cells within 1 hour. Killing required contact between the keratinocytes and the bacteria, but was not dependent on internalization. Contact between the bacteria and the keratinocytes resulted in rapid deposition of several antimicrobial peptides onto the bacteria, but only human beta-defensin (HBD) 3 accumulated at levels sufficient to account for killing when S. aureus were exposed to human skin explants. Blocking peptide binding of HBD3 inhibited killing of the bacteria, indicating an essential role for beta-defensin 3 in the constitutive killing of bacteria by normal keratinocytes.