Search

Background Antibiotics are prescribed to most pediatric intensive care unit (PICU) patients, but data describing indications and appropriateness of antibiotic orders in this population are lacking. Methods We performed a multicenter point prevalence study that included children admitted to 10 geographically diverse PICUs over 4 study days in 2019. Antibiotic orders were reviewed for indication, and appropriateness was assessed using a standardized rubric. Results Of 1462 patients admitted to participating PICUs, 843 (58%) had at least 1 antibiotic order. A total of 1277 antibiotic orders were reviewed. Common indications were empiric therapy for suspected bacterial infections without sepsis or septic shock (260 orders, 21%), nonoperative prophylaxis (164 orders, 13%), empiric therapy for sepsis or septic shock (155 orders, 12%), community-acquired pneumonia (CAP; 118 orders, 9%), and post-operative prophylaxis (94 orders, 8%). Appropriateness was assessed for 985 orders for which an evidence-based rubric for appropriateness could be created. Of these, 331 (34%) were classified as inappropriate. Indications with the most orders classified as inappropriate were empiric therapy for suspected bacterial infection without sepsis or septic shock (78 orders, 24%), sepsis or septic shock (55 orders, 17%), CAP (51 orders, 15%), ventilator-associated infections (47 orders, 14%), and post-operative prophylaxis (44 orders, 14%). The proportion of antibiotics classified as inappropriate varied across institutions (range, 19%–43%). Conclusions Most PICU patients receive antibiotics. Based on our study, we estimate that one-third of antibiotic orders are inappropriate. Improved antibiotic stewardship and research focused on strategies to optimize antibiotic use in critically ill children are needed.

BackgroundMultisystem inflammatory syndrome in children (MIS-C) commonly involves cardiac injury with both systolic and diastolic dysfunction. Left atrial strain (LAS) detects subclinical diastolic dysfunction in adults but is infrequently used in children. We evaluated LAS in MIS-C and the associations with systemic inflammation and cardiac injury.MethodsIn this retrospective cohort study, conventional parameters and LAS (reservoir [LAS-r], conduit [LAS-cd], and contractile [LAS-ct]) obtained from admission echocardiograms of MIS-C patients were compared to healthy controls and between MIS-C patients with and without cardiac injury (BNP >500 pg/ml or troponin-I >0.04 ng/ml). Correlation and logistic regression analyses were performed to assess LAS associations with admission inflammatory and cardiac biomarkers. Reliability testing was performed.ResultsMedian LAS components were reduced in MIS-C patients (n=118) compared to controls (n=20) (LAS-r: 31.8 vs. 43.1%, pConclusionsLAS analysis, particularly the absence of a LAS-ct peak, was reproducible and may be superior to conventional echocardiographic parameters for detecting diastolic dysfunction in MIS-C. No strain parameters on admission were independently associated with cardiac injury.

Infants younger than 6 months of age are at high risk for complications of coronavirus disease 2019 (Covid-19) and are not eligible for vaccination. Transplacental transfer of antibodies against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) after maternal Covid-19 vaccination may confer protection against Covid-19 in infants.We used a case-control test-negative design to assess the effectiveness of maternal vaccination during pregnancy against hospitalization for Covid-19 among infants younger than 6 months of age. Between July 1, 2021, and March 8, 2022, we enrolled infants hospitalized for Covid-19 (case infants) and infants hospitalized without Covid-19 (control infants) at 30 hospitals in 22 states. We estimated vaccine effectiveness by comparing the odds of full maternal vaccination (two doses of mRNA vaccine) among case infants and control infants during circulation of the B.1.617.2 (delta) variant (July 1, 2021, to December 18, 2021) and the B.1.1.259 (omicron) variant (December 19, 2021, to March 8, 2022).A total of 537 case infants (181 of whom had been admitted to a hospital during the delta period and 356 during the omicron period; median age, 2 months) and 512 control infants were enrolled and included in the analyses; 16% of the case infants and 29% of the control infants had been born to mothers who had been fully vaccinated against Covid-19 during pregnancy. Among the case infants, 113 (21%) received intensive care (64 [12%] received mechanical ventilation or vasoactive infusions). Two case infants died from Covid-19; neither infant's mother had been vaccinated during pregnancy. The effectiveness of maternal vaccination against hospitalization for Covid-19 among infants was 52% (95% confidence interval [CI], 33 to 65) overall, 80% (95% CI, 60 to 90) during the delta period, and 38% (95% CI, 8 to 58) during the omicron period. Effectiveness was 69% (95% CI, 50 to 80) when maternal vaccination occurred after 20 weeks of pregnancy and 38% (95% CI, 3 to 60) during the first 20 weeks of pregnancy.Maternal vaccination with two doses of mRNA vaccine was associated with a reduced risk of hospitalization for Covid-19, including for critical illness, among infants younger than 6 months of age. (Funded by the Centers for Disease Control and Prevention.).

Haemophilus influenzae causes serious invasive disease in children and is described as an infrequent cause of neonatal early-onset sepsis (EOS). Here we present the clinical and microbiologic features of 10 cases of EOS due to H. influenzae in Utah.

Background Streptococcus pneumoniae is the leading cause of meningitis in children and is associated with significant morbidity and mortality. Despite conjugate pneumococcal vaccines that have otherwise been successful in reducing invasive disease caused by vaccine serotypes, the incidence of pneumococcal meningitis remains relatively unchanged. Using genome-wide association, we identified sequence elements associated with pneumococcal central nervous system (CNS) infection. Methods From 1996 to 2018, 366 clinical pneumococcal isolates were collected from pediatric patients and paired with clinical metadata. All isolates underwent whole-genome sequencing and in silico serotyping. Fifty-four clinical isolates were from children with CNS infection. Sequence element enrichment analysis was performed using elastic net and linear mixed modeling statistical methods to find genetic variants associated with CNS infection. We identified associated genes by mapping statistically associated variants to a serotype 19F reference S. pneumoniae genome. Results CNS isolates spanned 22 unique serotypes; the most common were 22F (n = 6), 7F (n = 5), 18C (n = 4), and 35B (n = 4). We identified two intergenic sequence variants and one intragenic sequence variant significantly associated with CNS infection (p < 1.48 × 10-7). The top intragenic candidate in our analysis was located within cpsC, a gene involved in regulation of capsule synthesis. The CNS infection-associated cpsC variant was found in serotypes 22F (n = 1), 18C (n = 4), and 14 (n = 2). Conclusion The diversity of pneumococcal isolates associated with CNS infection suggests the importance of genetic determinants beyond capsular serotype. We identified a number of novel microbial genetic variants significantly associated with pneumococcal CNS infection across serotypes, including a coding mutation in cpsC. Functional characterization of cpsC variants is needed to inform mechanisms contributing to pneumococcal CNS virulence. Disclosures Anne J. Blaschke, MD, PhD, BioFire Diagnostics/Biomerieux: Advisor/Consultant|BioFire Diagnostics/Biomerieux: Grant/Research Support|BioFire Diagnostics/Biomerieux: IP licensed to BioFire Diagnostics through the University of Utah and royalties received through the University of Utah related to the FilmArray|Merck: Advisor/Consultant.

Autoantibodies against type I interferons (IFNs) occur in approximately 10% of adults with life-threatening COVID-19. The frequency of anti-IFN autoantibodies in children with severe sequelae of SARS-CoV-2 infection is unknown.To quantify anti-Type I IFN autoantibodies in a multi-center cohort of children with severe COVID-19, Multisystem Inflammatory Syndrome in Children (MIS-C), and mild SARS-CoV-2 infections.Circulating anti-IFNa2 antibodies were measured by a radioligand binding assay. Whole exome sequencing (WES), RNA-sequencing, and functional studies of peripheral blood mononuclear cells were used to study any patients with levels of anti-IFNα2 autoantibodies exceeding the assay's positive control.Among 168 patients with severe COVID-19, 199 with MIS-C, and 45 with mild SARS-CoV-2 infections, only one had high levels of anti-IFNα2 antibodies. Anti-IFNα2 autoantibodies were not detected in patients treated with intravenous immunoglobulin prior to sample collection. WES identified a missense variant in the ankyrin domain of NFKB2, encoding the p100 subunit of NF-kB essential for non-canonical NF-kB signaling. Her peripheral blood mononuclear cells exhibited impaired cleavage of p100 characteristic of NFKB2 haploinsufficiency, an inborn error of immunity with a high prevalence of autoimmunity.High levels of anti-IFNα2 autoantibodies in children and adolescents with MIS-C, severe COVID-19, and mild SARS-CoV-2 infections are rare, but can occur in patients with inborn errors of immunity.Anti-IFNα2 autoantibodies should prompt diagnostic evaluation for inborn errors of immunity if identified in children or adolescents.

OBJECTIVES To evaluate risk factors for postdischarge sequelae in children and adolescents hospitalized for acute coronavirus disease 2019 (COVID-19) or multisystem inflammatory syndrome in children (MIS-C). METHODS Multicenter prospective cohort study conducted in 25 United States pediatric hospitals. Patients RESULTS Of 358 eligible patients, 2 to 4 month survey data were available for 119 of 155 (76.8%) with acute COVID-19 and 160 of 203 (78.8%) with MIS-C. Thirteen (11%) patients with acute COVID-19 and 12 (8%) with MIS-C had a readmission. Thirty-two (26.9%) patients with acute COVID-19 had persistent symptoms (22.7%) or activity impairment (14.3%) and 48 (30.0%) with MIS-C had persistent symptoms (20.0%) or activity impairment (21.3%). For patients with acute COVID-19, persistent symptoms (aRR, 1.29 [95% CI, 1.04–1.59]) and activity impairment (aRR, 1.37 [95% CI, 1.06–1.78]) were associated with more organ systems involved. Patients with MIS-C and pre-existing respiratory conditions more frequently had persistent symptoms (aRR, 3.09 [95% CI, 1.55–6.14]) and those with obesity more frequently had activity impairment (aRR, 2.52 [95% CI, 1.35–4.69]). New morbidities were infrequent (9% COVID-19, 1% MIS-C). CONCLUSIONS Over 1 in 4 children hospitalized with acute COVID-19 or MIS-C experienced persistent symptoms or activity impairment for at least 2 months. Patients with MIS-C and respiratory conditions or obesity are at higher risk of prolonged recovery.

Despite significant improvements in recent years, maternal and neonatal health outcomes remain poor in many regions of the world. One such area is in the remote mountainous regions of Nepal. The purpose of this study is to describe the current antenatal care practices and delivery support in a mountainous district of Nepal.This study took place in Solukhumbu District between December 2015 and February 2018. A household survey was created using evidence-based maternal and neonatal care indicators. Women who had delivered within the previous two years were surveyed regarding antenatal and delivery care they received. A standardized health facility survey was used to evaluate the operational status of health facilities. The study was approved by the Nepal Ministry of Health and the University of Utah IRB.A total of 487 households and 19 facilities were surveyed. 35.7% (174/487) of deliveries occurred in a health facility (hospital, primary health care center or birthing center). 35.2% (171/486) of deliveries were attended by a skilled birth attendant. 52.8% (47/89) of women who did not deliver in a facility noted that transportation issues and not having sufficient time to travel during labor prevented them from delivering in a facility. No health posts had staff trained in obstetric and neonatal emergencies.The majority of women in Solukhumbu District do not receive high quality antenatal and delivery care. An intervention that would make antenatal care and delivery support more accessible could improve maternal and infant outcomes in this district and other similar regions.

Multisystem inflammatory syndrome in children (MIS-C), linked to antecedent severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, is associated with considerable morbidity. Prevention of SARS-CoV-2 infection or coronavirus disease 2019 (COVID-19) by vaccination might also decrease MIS-C likelihood.In a multicenter case-control public health investigation of children ages 5-18 years hospitalized from July 1, 2021 to April 7, 2022, we compared the odds of being fully vaccinated (two doses of BNT162b2 vaccine ≥28 days before hospital admission) between MIS-C case-patients and hospital-based controls who tested negative for SARS-CoV-2. These associations were examined by age group, timing of vaccination, and periods of Delta and Omicron variant predominance using multivariable logistic regression.We compared 304 MIS-C case-patients (280 [92%] unvaccinated) with 502 controls (346 [69%] unvaccinated). MIS-C was associated with decreased likelihood of vaccination (aOR, 0.16 95% CI, 0.10-0.26), including among children ages 5-11 years (aOR, 0.22 95% CI, 0.10-0.52), ages 12-18 years (aOR, 0.10 95% CI, 0.05-0.19), and during the Delta (aOR, 0.06 95% CI, 0.02-0.15) and Omicron (aOR, 0.22 95% CI, 0.11-0.42) variant-predominant periods. This association persisted beyond 120 days after the second dose (aOR, 0.08, 95% CI, 0.03-0.22) in 12-18 year-olds. Among all MIS-C case-patients, 187 (62%) required intensive care unit admission and 280 (92%) vaccine-eligible patients were unvaccinated.Vaccination with two doses of BNT162b2 is associated with reduced likelihood of MIS-C in children ages 5-18 years. Most vaccine eligible hospitalized patients with MIS-C were unvaccinated.

BackgroundDetection of SARS-CoV-2 antigens in blood has high sensitivity in adults with acute COVID-19, but sensitivity in pediatric patients is unclear. Recent data suggest that persistent SARS-CoV-2 spike antigenemia may contribute to multisystem inflammatory syndrome in children (MIS-C). We quantified SARS-CoV-2 nucleocapsid (N) and spike (S) antigens in blood of pediatric patients with either acute COVID-19 or MIS-C using ultrasensitive immunoassays (Meso Scale Discovery).MethodsPlasma was collected from inpatients (ResultsSpecificities of N and S assays were 95-97% and 100%, respectively. In acute COVID-19 patients, N/S plasma assays had 89%/64% sensitivity, respectively; sensitivity in patients with concurrent nasopharyngeal swab cycle threshold (Ct) ≤ 35 were 93%/63%. Antigen concentrations ranged from 1.28-3,844 pg/mL (N) and 1.65-1,071 pg/mL (S) and correlated with disease severity. In MIS-C, antigens were detected in 3/53 (5.7%) samples (3 N-positive: 1.7, 1.9, 121.1 pg/mL; 1 S-positive: 2.3 pg/mL); the patient with highest N had positive nasopharyngeal RT-PCR (Ct 22.3) concurrent with blood draw.ConclusionsUltrasensitive blood SARS-CoV-2 antigen measurement has high diagnostic yield in children with acute COVID-19. Antigens were undetectable in most MIS-C patients, suggesting that persistent antigenemia is not a common contributor to MIS-C pathogenesis.Key pointsIn a U.S. pediatric cohort tested with ultrasensitive immunoassays, SARS-CoV-2 nucleocapsid antigens were detectable in most patients with acute COVID-19, and spike antigens were commonly detectable. Both antigens were undetectable in almost all MIS-C patients.

Background Detection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antigens in blood has high sensitivity in adults with acute coronavirus disease 2019 (COVID-19), but sensitivity in pediatric patients is unclear. Recent data suggest that persistent SARS-CoV-2 spike antigenemia may contribute to multisystem inflammatory syndrome in children (MIS-C). We quantified SARS-CoV-2 nucleocapsid (N) and spike (S) antigens in blood of pediatric patients with either acute COVID-19 or MIS-C using ultrasensitive immunoassays (Meso Scale Discovery). Methods Plasma was collected from inpatients ( Results Specificities of N and S assays were 95–97% and 100%, respectively. In acute COVID-19 patients, N/S plasma assays had 89%/64% sensitivity; sensitivities in patients with concurrent nasopharyngeal swab cycle threshold (Ct) ≤35 were 93%/63%. Antigen concentrations ranged from 1.28–3844 pg/mL (N) and 1.65–1071 pg/mL (S) and correlated with disease severity. In MIS-C, antigens were detected in 3/53 (5.7%) samples (3 N-positive: 1.7, 1.9, 121.1 pg/mL; 1 S-positive: 2.3 pg/mL); the patient with highest N had positive nasopharyngeal RT-PCR (Ct 22.3) concurrent with blood draw. Conclusions Ultrasensitive blood SARS-CoV-2 antigen measurement has high diagnostic yield in children with acute COVID-19. Antigens were undetectable in most MIS-C patients, suggesting that persistent antigenemia is not a common contributor to MIS-C pathogenesis.

ImportanceMinimal data are available regarding the postdischarge treatment of multisystem inflammatory syndrome in children (MIS-C).ObjectivesTo evaluate clinical characteristics associated with duration of postdischarge glucocorticoid use and assess postdischarge clinical course, laboratory test result trajectories, and adverse events in a multicenter cohort with MIS-C.Design, Setting, and ParticipantsThis retrospective cohort study included patients with MIS-C hospitalized with severe illness and followed up for 3 months in an ambulatory setting. Patients younger than 21 years who were admitted between May 15, 2020, and May 31, 2021, at 13 US hospitals were included. Inclusion criteria were inpatient treatment comprising intravenous immunoglobulin, diagnosis of cardiovascular dysfunction (vasopressor requirement or left ventricular ejection fraction ≤55%), and availability of complete outpatient data for 3 months.ExposuresGlucocorticoid treatment.Main Outcomes and MeasuresMain outcomes were patient characteristics associated with postdischarge glucocorticoid treatment, laboratory test result trajectories, and adverse events. Multivariable regression was used to evaluate factors associated with postdischarge weight gain (≥2 kg in 3 months) and hyperglycemia during illness.ResultsAmong 186 patients, the median age was 10.4 years (IQR, 6.7-14.2 years); most were male (107 [57.5%]), Black non-Hispanic (60 [32.3%]), and Hispanic or Latino (59 [31.7%]). Most children were critically ill (intensive care unit admission, 163 [87.6%]; vasopressor receipt, 134 [72.0%]) and received inpatient glucocorticoid treatment (178 [95.7%]). Most were discharged with continued glucocorticoid treatment (173 [93.0%]); median discharge dose was 42 mg/d (IQR, 30-60 mg/d) or 1.1 mg/kg/d (IQR, 0.7-1.7 mg/kg/d). Inpatient severity of illness was not associated with duration of postdischarge glucocorticoid treatment. Outpatient treatment duration varied (median, 23 days; IQR, 15-32 days). Time to normalization of C-reactive protein and ferritin levels was similar for glucocorticoid duration of less than 3 weeks vs 3 or more weeks. Readmission occurred in 7 patients (3.8%); none was for cardiovascular dysfunction. Hyperglycemia developed in 14 patients (8.1%). Seventy-five patients (43%) gained 2 kg or more after discharge (median 4.1 kg; IQR, 3.0-6.0 kg). Inpatient high-dose intravenous and oral glucocorticoid therapy was associated with postdischarge weight gain (adjusted odds ratio, 6.91; 95% CI, 1.92-24.91).Conclusions and RelevanceIn this multicenter cohort of patients with MIS-C and cardiovascular dysfunction, postdischarge glucocorticoid treatment was often prolonged, but clinical outcomes were similar in patients prescribed shorter courses. Outpatient weight gain was common. Readmission was infrequent, with none for cardiovascular dysfunction. These findings suggest that strategies are needed to optimize postdischarge glucocorticoid courses for patients with MIS-C.

BackgroundInvasive Staphylococcus aureus infections are a common cause of morbidity and mortality in children. In the early 2000's the proportion of infections due the methicillin-resistant S. aureus (MRSA) increased rapidly. We described the clinical and molecular epidemiology of invasive S. aureus disease in a pediatric population.MethodsWe prospectively identified children in Utah with invasive S. aureus infections. Medical records were reviewed to determine diagnosis and clinical characteristics. Isolates were genotyped using multi-locus sequence typing. The presence of genes encoding the Panton-Valentine leukocidin (PVL) was determined using polymerase chain reaction.ResultsOver a 4-year period between January 2009 and December 2012, we identified 357 children, hospitalized at Primary Children's Hospital, with invasive S. aureus infections and isolates available for the study. Methicillin-susceptible S. aureus (MSSA) caused 79% of disease, while MRSA caused only 21% of disease. Mortality associated with invasive S. aureus infection was 3.6%. The most common diagnoses were osteoarticular infections (38%) followed by central line associated blood stream infections (19%) and pneumonia (12%). We identified 41 multi-locus sequence types. The majority of isolates belonged to 6 predominant clonal complexes (CC5, CC8, CC15, CC30, CC45, CC59). PVL was present in a minority (16%) of isolates, of which most were ST8 MRSA.ConclusionsMSSA was the primary cause of invasive S. aureus infections at our institution throughout the study period. A limited number of predominant strains accounted for the majority of invasive disease. The classic virulence factor PVL was uncommon in MSSA isolates. Further study is needed to improve our understanding of S. aureus virulence and disease pathogenesis.

Background Following widespread use of the Haemophilus influenzae serotype b (Hib) vaccine, H. influenzae serotype a (Hia) has emerged as an important pathogen in children in some regions. We describe the clinical features and molecular epidemiology of invasive Hia disease in children in Utah over an 11-year period. Methods We identified cases of invasive Hia disease, defined as detection of Hia from a normally sterile site, in children aged Results We identified 51 children with invasive Hia. The average annual incidence was 1.7 cases per 100 000 children aged Conclusions Hia is a significant cause of severe invasive bacterial infection in Utah. The majority of infections were caused by ST62 isolates, a phylogenetic division II Hia type that lacks the IS1016-bexA duplication-deletion. Hia ST62 has not been commonly reported elsewhere, suggesting a unique molecular epidemiology in our population.

Background Streptococcus pneumoniae is among the most common causes of invasive bacterial infections in children, including pneumonia, bacteremia, and meningitis. Over 90 different serotypes (ST) of pneumococcus exist, with enrichment of some ST within specific invasive phenotypes. Other than capsular genes, molecular determinants of particular invasive phenotypes remain largely unknown. Although vaccination targeting especially invasive ST capsular antigens has successfully decreased the incidence of invasive pneumococcal disease (IPD), new ST have emerged, suggesting methods to target other aspects of pneumococcal invasiveness are needed. Methods Pneumococcal isolates from IPD were collected from children presenting to Primary Children’s Hospital from 1996–2018. All viable isolates underwent next-generation sequencing (Illumina), quality control filtering for contamination and low coverage, de novo genome assembly with SPADES, and annotation with PROKKA. Clinical phenotypes were manually validated with physician chart review. Isolates were serotyped via Quelling and in silico using SeroBA. ROARY was used for pan-genome assembly, and SCOARY for microbial genome-wide association studies. RAxML was used for phylogenetic analysis. Results A total of 354 viable pneumococcal isolates were available for genomic analysis including a spectrum of invasive phenotypes: pneumonia (n = 138, of which 54 were complicated by empyema), CNS infection (n = 50), SSTI/bone infections (n = 42), and isolated bacteremia (n = 68). Thirteen samples were censored for poor coverage or genetic contamination. Invasive isolates spanned 37 capsular ST. The pneumococcal pan-genome comprised 6462 genes, of which only 23% were shared by at least 99% of samples. Phylogenetic relatedness resulted in clustering of some ST (e.g., ST1, ST3), whereas others (eg ST19A) were more broadly distributed. Empyema and meningitis phenotypes were distributed across the phylogenetic tree, but enriched in distinct clusters that crossed ST clusters. Genes involved in empyemagenic pneumococcal capsule production, and those implicated in sensing of preferred sugars or non-preferred sugar metabolism were statistically correlated with the empyema phenotype. Conclusion There is marked genetic diversity among invasive pneumococcal isolates, potentially contributing to the variability of disease phenotypes observed. Clustering of invasive phenotypes across ST suggests a genetic signature for invasive phenotypes other than capsule genes alone, further supported by enrichment of specific genes associated with alternative sugar metabolism in empyema isolates. Critical determinants of invasive phenotypes will inform future efforts at disease prevention and treatment.

Background Streptococcus pneumoniae is the most common cause of pneumonia in children, including empyema, a severe complication with increasing incidence in the post-pneumococcal vaccine era. Only a subset of > 90 serotypes cause empyema. Virulence determinants of empyema remain largely unknown. Methods We performed Illumina sequencing of invasive Pneumococcal isolates from pediatric patients at Primary Children’s Hospital (Salt Lake City, UT) isolated between 1996–2018, de novo genome assembly (SPADES), annotation (PROKKA), serotyping (Quelling and SeroBA), and pan-genome assembly (ROARY). SCOARY and pyseer were used for microbial GWAS. Maximum likelihood phylogeny was calculated using RAxML/Gubbins. Results 366 pneumococcal isolates were analyzed from 39 serotypes and multiple phenotypes including pneumonia (n=76), empyema (n=63), CNS infection (n=54), and isolated bacteremia (n=79). Serotypes and empyema phenotype clustered roughly by phylogeny. Most analyzed empyema isolates after 2010 were serotype 3 (19/25); prior to PCV-13 introduction serotypes 1 (8/38), 7F (7/38), and 19A (11/38) were more highly represented. Genes implicated in capsule synthesis, transposases, and metabolism were statistically correlated with the empyema phenotype. Conclusion Specific capsular or metabolic genes may confer optimal fitness for pleural disease. Further characterization of these genetic associations is needed and will inform future treatment and prevention. Disclosures Carrie L. Byington, MD, BioFire (Other Financial or Material Support, Royalties for Intellectual Property)IDbyDNA (Advisor or Review Panel member) Krow Ampofo, MBChB, Merck (Grant/Research Support)

Background Antibiotics are prescribed in up to 80% of pediatric intensive care unit (PICU) patients, but multicenter studies systematically evaluating antibiotic indications and appropriateness in this high-utilizing population are lacking. Methods A multicenter point prevalence study was conducted at 10 geographically diverse tertiary care US children’s hospitals. All PICU patients < 21 years of age who were receiving systemic antibiotics at 8:00 AM on each study day were included. Study days occurred in February and March 2019. Data were abstracted by critical care and/or infectious diseases trained clinicians using standardized data collection forms and definitions of antibiotic appropriateness. Results 408 of 732 PICU patients (56%) received 618 antibiotics on the two study days. Empiric therapy for suspected bacterial infections without sepsis was the most common indication for antibiotics (22%), followed by treatment of community-acquired pneumonia and empiric therapy for septic shock (12% each, Figure 1). Overall, 194 antibiotic orders (32%) were classified as inappropriate and 158 patients (39%) received at least one inappropriate antibiotic. Vancomycin, cefepime, and ceftriaxone were the antibiotics most often inappropriately prescribed (Figure 2). Antibiotics prescribed inappropriately for the top 5 indications shown in Figure 1 accounted for 77% of all inappropriate antibiotic use. Prolonged ( >4 days) empiric therapy and prolonged ( >24 hours) post-operative prophylaxis were the most common reasons antibiotics prescribed for these indications were classified as inappropriate. Pneumonia and ventilator-associated infections were the most common infections for which antibiotics were prescribed inappropriately (46%). Reasons for inappropriate antibiotic use included lack of evidence supporting a bacterial infection (no radiographic infiltrate or significant increase in respiratory support) and use of unnecessarily broad antibiotics (Table 1). Conclusion Inappropriate antibiotic use is common in the PICU, particularly for pneumonia. Studies focused on defining optimal treatment strategies, as well as improved diagnostic approaches to curtail prolonged courses of empiric therapy, should be prioritized. Disclosures All authors: No reported disclosures.

Background Haemophilus influenzae causes serious invasive disease across all ages, but has not been widely described in neonatal early-onset sepsis (EOS). EOS, likely caused by organisms acquired from the mother, can lead to significant morbidity and mortality, particularly for preterm infants. There are reports of increasing ampicillin resistance in H. influenzae. We describe a case series of EOS due to H. influenzae at our institution. Methods Neonatal H. influenzae EOS was identified based on positive sterile site cultures at Results Twelve neonates with H. influenzae EOS were identified over 11 years. Nine were preterm (24 hours). All infants had signs and symptoms of sepsis within 24 hours of birth. The majority (10/12) had a blood culture positive for H. influenzae from the time of delivery. Two infants had negative delivery blood cultures but a H. influenzae-positive placental culture. No infant had > 1 day of bacteremia. One H. influenzae isolate was serotype b, one serotype c and one non-typeable, but most isolates (9/12) were not serotyped. Only one isolate produced a β-lactamase. All infants were empirically started on ampicillin and gentamicin at delivery. Nine infants underwent lumbar puncture, two were suggestive of meningitis but cultures were negative. Five infants developed interventricular hemorrhage and six required vasoactive medications. No infant died. Conclusion H. influenzae is an infrequent but important cause of neonatal EOS. H. influenzae EOS occurred in infants with known risk factors, including prolonged rupture of membranes, prematurity, and low birth weight. Recognition of H. influenzae as a potential pathogen in EOS has implications for the use of empiric antibiotic therapy particularly ampicillin, in septic neonates. Disclosures All authors: No reported disclosures.

Background Following widespread use of the Haemophilus influenzaeserotype b (Hib) vaccine,H. influenzae serotype a (Hia) has emerged as an important pathogen in children. Rates of Hia disease are particularly high in Utah. We describe the clinical features and molecular epidemiology of invasive Hia disease in children in Utah over 11 years. Methods Cases of invasive Hia disease in children less than 18 years were identified through electronic clinical and microbiology records. Demographic data and clinical outcomes were abstracted from the medical record for all cases. Available Hia isolates were collected for molecular analysis. Isolates were genotyped by multi-locus sequence typing (MLST) and clonal division was determined using sodC PCR. Presence or absence of the putative virulence-associated IS1016-bexA duplication-deletion was evaluated. Results We identified 51 children with invasive Hia between 2007 and 2017. Median age was 11.3 months. The average annual incidence was 1.7 cases per 100,000 children aged Conclusion Hia is an important cause of severe invasive bacterial infection in Utah. Molecular analyses revealed that a majority of infections were caused by ST62 isolates, a clonal division II Hia type lacking the IS1016-bexA duplication-deletion. Hia ST62 has not been commonly reported in other settings, suggesting a unique molecular epidemiology in our population. Disclosures All authors: No reported disclosures.

The murine model of Lyme disease provides a unique opportunity to study the localized host response to similar stimulus, Borrelia burgdorferi, in the joints of mice destined to develop severe arthritis (C3H) or mild disease (C57BL/6). Pathways associated with the response to infection and the development of Lyme arthritis were identified by global gene expression patterns using oligonucleotide microarrays. A robust induction of IFN-responsive genes was observed in severely arthritic C3H mice at 1 wk of infection, which was absent from mildly arthritic C57BL/6 mice. In contrast, infected C57BL/6 mice displayed a novel expression profile characterized by genes involved in epidermal differentiation and wound repair, which were decreased in the joints of C3H mice. These expression patterns were associated with disease state rather than inherent differences between C3H and C57BL/6 mice, because C57BL/6-IL-10−/− mice infected with B. burgdorferi develop more severe arthritis than C57BL/6 mice and displayed an early gene expression profile similar to C3H mice. Gene expression profiles at 2 and 4 wk postinfection revealed a common response of all strains that was likely to be important for the host defense to B. burgdorferi and mediated by NF-κB-dependent signaling. The gene expression profiles identified in this study add to the current understanding of the host response to B. burgdorferi and identify two novel pathways that may be involved in regulating the severity of Lyme arthritis.

The spirochete Borrelia burgdorferi, the etiologic agent of Lyme disease, causes severe subacute arthritis in susceptible inbred mouse strains, such as C3H/HeN, but only mild arthritis in resistant strains such as C57BL/6. The degree of Lyme arthritis severity is controlled in part by host genetics and several quantitative trait loci have been identified which contribute to this regulation. In addition, the anti-inflammatory cytokine IL-10 assumes an important role in the control of arthritis in C57BL/6 mice. However, the identification of genes and signaling pathways that dictate arthritis severity has remained elusive. In an attempt to elucidate such genes and pathways, the power of microarray analysis was combined with information gleaned from gene manipulation models. As a result of this approach, two novel gene profiles were identified: an IFN-inducible profile in arthritis-susceptible C3H and IL-10(-/-) mice, and an epidermal/differentiation profile in C57BL/6 mice. Application of this information to TLR2(-/-) mice, which also develop severe arthritis, indicated that they also upregulated IFN-responsive genes. These results provided new insight into the regulation of Lyme arthritis development and illustrated the utility of combining gene expression analyses with genetically manipulated mouse models in unraveling mechanisms underlying specific disease processes.

C57BL/6 mice deficient in TLR2 develop more severe arthritis following infection with Borrelia burgdorferi than do wild-type C57BL/6 mice, and this increase is suppressed by the simultaneous presence of the scid mutation. This suggested a requirement for lymphocytes in the development of subacute Lyme arthritis in TLR2(-/-) mice, a feature not commonly associated with this arthritis. The increased pathology of B. burgdorferi-infected TLR2(-/-) mice was also accompanied by an increase in mononuclear cell infiltration. In this study, T cells were found to be responsible for the increase in mononuclear cells in infected TLR2(-/-) C3H mice. Accordingly, transcripts for the IFN-inducible T cell chemokines, CXCL9 and CXCL10, were greatly enhanced in joint tissue from TLR2(-/-) mice, as were transcripts for a prototypical IFN-inducible gene IFN-gamma-induced GTPase (igtp). Treatment of murine synovial cells with sonicated B. burgdorferi resulted in induction of transcripts for chemokines and other IFN-inducible genes, irrespective of the presence of TLR2. The presence of T lymphocytes greatly enhanced the transcriptional response of synovial cells. These results suggest that the increased inflammatory cell infiltration in TLR2(-/-) C3H mice is the result of localized overproduction of T cell attracting chemokines.

Several quantitative trait loci regulating murine Lyme arthritis severity have been mapped, including a highly significant linkage found on chromosome 5, termed Bb2Bb3. Within this region, the Ncf1 gene of the phagocyte nicotinamide adenine dinucleotide phosphate (NADPH) oxidase has recently been identified as a major regulator of arthritis severity in rodent models of rheumatoid arthritis, an effect attributed to protective properties of reactive oxygen species. To assess the role of Ncf1 in Lyme arthritis, we introgressed Bb2Bb3 from severely arthritic C3H/He mice onto mildly arthritic C57BL/6 mice. This increased Lyme arthritis severity, whereas the reciprocal transfer conferred protection from disease. A single nucleotide polymorphism was identified in the Ncf1 gene that did not influence the protein sequence or expression of Ncf1. Although polymorphonuclear leukocytes from C57BL/6 mice generated a greater oxidative burst than polymorphonuclear leukocytes from C3H/He mice, studies with the Bb2Bb3 congenic mice demonstrated this difference was not linked to Ncf1 alleles. Furthermore, Lyme arthritis severity was not altered in mice lacking either the Ncf1 or Gp91phox subunits of the NADPH oxidase complex. Together, these results argue that Ncf1 is not a candidate gene for regulation of Lyme arthritis and reveal Lyme arthritis to be independent of NADPH oxidase activity, distinguishing it from other models of rheumatoid arthritis.