INTRODUCTION: Procalcitonin (PCT) is a useful biomarker in the initial evaluation of febrile infants for serious bacterial infections (SBIs). However, PCT is not always available locally and must at times be frozen and shipped to a reference laboratory for research studies. We sought to compare PCT measured locally versus centrally at a reference laboratory during a research study. MATERIALS AND METHODS: This was a secondary analysis of a multicenter study of febrile infants ≤60 days evaluated for SBIs from June 2016 to April 2019. A PCT cutoff value of 0.5 ng/mL was used to stratify infants at low-versus high-risk of SBIs. Statistical analyses consisted of Spearmans correlation, Bland-Altman difference plotting, Passing-Bablok regression, Deming regression, and Fishers exact testing at the 0.5 ng/mL threshold. RESULTS: 241 febrile infants had PCT levels measured both locally and at the reference laboratory. PCT levels measured locally on 5 different platforms and from the frozen research samples demonstrated strong Spearmans correlation (ρ = 0.83) and had similar mean PCT values with an average relative difference of 0.02%. Eleven infants with SBIs had PCT values < 0.5 ng/mL in both the clinical and research samples. Six other infants had differences in SBI prediction based on PCT values at the 0.5 ng/mL threshold between the clinical and research platforms. CONCLUSIONS: We found no significant differences in detection of febrile infants at high risk for SBI based on locally (on multiple platforms) versus centrally processed PCT. Testing at a central reference laboratory after freezing and shipping is an accurate and reliable alternative for research studies or when rapid turnaround is not required.

Objectives

To develop the infrastructure and demonstrate the feasibility of conducting microarray-based RNA transcriptional profile analyses for the diagnosis of serious bacterial infections in febrile infants 60 days and younger in a multicenter pediatric emergency research network.

Methods

We designed a prospective multicenter cohort study with the aim of enrolling more than 4000 febrile infants 60 days and younger. To ensure success of conducting complex genomic studies in emergency department (ED) settings, we established an infrastructure within the Pediatric Emergency Care Applied Research Network, including 21 sites, to evaluate RNA transcriptional profiles in young febrile infants. We developed a comprehensive manual of operations and trained site investigators to obtain and process blood samples for RNA extraction and genomic analyses. We created standard operating procedures for blood sample collection, processing, storage, shipping, and analyses. We planned to prospectively identify, enroll, and collect 1 mL blood samples for genomic analyses from eligible patients to identify logistical issues with study procedures. Finally, we planned to batch blood samples and determined RNA quantity and quality at the central microarray laboratory and organized data analysis with the Pediatric Emergency Care Applied Research Network data coordinating center. Below we report on establishment of the infrastructure and the feasibility success in the first year based on the enrollment of a limited number of patients.

Results

We successfully established the infrastructure at 21 EDs. Over the first 5 months we enrolled 79% (74 of 94) of eligible febrile infants. We were able to obtain and ship 1 mL of blood from 74% (55 of 74) of enrolled participants, with at least 1 sample per participating ED. The 55 samples were shipped and evaluated at the microarray laboratory, and 95% (52 of 55) of blood samples were of adequate quality and contained sufficient RNA for expression analysis.

Conclusions

It is possible to create a robust infrastructure to conduct genomic studies in young febrile infants in the context of a multicenter pediatric ED research setting. The sufficient quantity and high quality of RNA obtained suggests that whole blood transcriptional profile analysis for the diagnostic evaluation of young febrile infants can be successfully performed in this setting.

Background

We sought to determine if fever in the early postintravenous immunoglobulin (IVIG) time period (first 36 hours after IVIG completion) for Kawasaki disease, with or without additional infliximab, can predict IVIG resistance and coronary artery abnormalities (CAA).

Methods

Acute Kawasaki disease subjects enrolled in a clinical trial of infliximab plus IVIG (n = 96) versus placebo/IVIG (n = 94) had temperatures recorded every 6 hours after completion of IVIG infusion. Fever was defined as temperature >38.0°C; patients with persistent or recrudescent fever >36 hours after completion of IVIG were classified as IVIG resistant. Multivariable logistic regression by fever pattern was performed to predict outcomes (IVIG resistance and CAA).

Results

There was no difference in the time to defervescence between the infliximab/IVIG group (n = 96) versus placebo/IVIG group (n = 94). There was no fever after completion of IVIG in the majority of subjects [66% of those with no CAA (n = 139) and 76.5% of those with CAA, (n = 51)]. Although subjects with at least 1 fever 24-36 hours post-IVIG had a higher probability of IVIG resistance [odds ratio = 30.6 (95% confidence interval: 6.7-139.8); P < 0.0001], fever at 24-36 hours was not associated with higher likelihood of CAA. There were also 11% (n = 19) of IVIG responders who had fever at 24-36 hours post-IVIG. The majority of subjects with CAA (43 of 51, 84.3%) were identified by the initial echocardiogram, so the effect of fever on development of CAA could not be assessed.

Conclusions

Fever in the first 36 hours after IVIG completion is not predictive of CAA. Our data support refraining from retreatment until 36 hours after completion of IVIG.

Background

Important therapeutic decisions are made based on the presence or absence of fever in patients with Kawasaki disease (KD), yet no standard method or threshold exists for temperature measurement during the diagnosis and treatment of these patients. We sought to compare surface and internal (rectal or oral) routes of temperature measurement for the detection of fever as a marker of treatment resistance.

Methods

From a randomized, placebo-controlled trial of infliximab as an adjunct to primary intravenous immunoglobulin treatment for acute KD, we collected concurrent (within 5 minutes) axillary and internal temperature measurements and performed receiver-operating characteristic and Bland-Altman analyses. We also determined the ability of surface temperatures to detect treatment resistance defined by internal temperature measurements.

Results

Among 452 oral-axillary and 439 rectal-axillary pairs from 159 patients, mean axillary temperatures were 0.25 and 0.43 °C lower than oral and rectal temperatures and had high receiver-operating characteristic areas under curves. However, axillary temperatures ≥ 38.0 °C had limited sensitivity to detect fever defined by internal temperatures. Axillary thresholds of 37.5 and 37.2 °C provided maximal sensitivity and specificity to detect oral and rectal temperatures ≥ 38.0 °C, respectively.

Conclusions

Axillary temperatures are an insensitive metric for fevers defining treatment resistance. Clinical trials should adopt temperature measurement by the oral or rectal routes for adjudication of treatment resistance in KD.

Reports of the test accuracy of the urinalysis for diagnosing urinary tract infections (UTIs) in young febrile infants have been variable. We evaluated the test characteristics of the urinalysis for diagnosing UTIs, with and without associated bacteremia, in young febrile infants. We performed a planned secondary analysis of data from a prospective study of febrile infants ≤60 days old at 26 emergency departments in the Pediatric Emergency Care Applied Research Network. We evaluated the test characteristics of the urinalysis for diagnosing UTIs, with and without associated bacteremia, by using 2 definitions of UTI: growth of ≥50 000 or ≥10 000 colony-forming units (CFUs) per mL of a uropathogen. We defined a positive urinalysis by the presence of any leukocyte esterase, nitrite, or pyuria (>5 white blood cells per high-power field). Of 4147 infants analyzed, 289 (7.0%) had UTIs with colony counts ≥50 000 CFUs/mL, including 27 (9.3%) with bacteremia. For these UTIs, a positive urinalysis exhibited sensitivities of 0.94 (95% confidence interval [CI]: 0.91-0.97), regardless of bacteremia; 1.00 (95% CI: 0.87-1.00) with bacteremia; and 0.94 (95% CI: 0.90-0.96) without bacteremia. Specificity was 0.91 (95% CI: 0.90-0.91) in all groups. For UTIs with colony counts ≥10 000 CFUs/mL, the sensitivity of the urinalysis was 0.87 (95% CI: 0.83-0.90), and specificity was 0.91 (95% CI: 0.90-0.92). The urinalysis is highly sensitive and specific for diagnosing UTIs, especially with ≥50 000 CFUs/mL, in febrile infants ≤60 days old, and particularly for UTIs with associated bacteremia.

Objective

Few prospective studies have assessed the occurrence of radiographic pneumonia in young febrile infants. We analyzed factors associated with radiographic pneumonias in febrile infants 60 days or younger evaluated in pediatric emergency departments.

Study design

We conducted a planned secondary analysis of a prospective cohort study within 26 emergency departments in a pediatric research network from 2008 to 2013. Febrile (≥38°C) infants 60 days or younger who received chest radiographs were included. Chest radiograph reports were categorized as "no," "possible," or "definite" pneumonia. We compared demographics, Yale Observation Scale scores (>10 implying ill appearance), laboratory markers, blood cultures, and viral testing among groups.

Results

Of 4778 infants, 1724 (36.1%) had chest radiographs performed; 2.7% (n = 46) had definite pneumonias, and 3.9% (n = 67) had possible pneumonias. Patients with definite (13/46 [28.3%]) or possible (15/67 [22.7%]) pneumonias more frequently had Yale Observation Scale score >10 compared with those without pneumonias (210/1611 [13.2%], P = 0.002) in univariable and multivariable analyses. Median white blood cell count (WBC), absolute neutrophil count (ANC), and procalcitonin (PCT) were higher in the definite (WBC, 11.5 [interquartile range, 9.8-15.5]; ANC, 5.0 [3.2-7.6]; PCT, 0.4 [0.2-2.1]) versus no pneumonia (WBC, 10.0 [7.6-13.3]; ANC, 3.4 [2.1-5.4]; PCT, 0.2 [0.2-0.3]; WBC, P = 0.006; ANC, P = 0.002; PCT, P = 0.046) groups, but of unclear clinical significance. There were no cases of bacteremia in the definite pneumonia group. Viral infections were more frequent in groups with definite (25/38 [65.8%]) and possible (28/55 [50.9%]) pneumonias than no pneumonias (534/1185 [45.1%], P = 0.02).

Conclusions

Radiographic pneumonias were uncommon, often had viruses detected, and were associated with ill appearance, but few other predictors, in febrile infants 60 days or younger.

Objectives

To determine the time to positivity for bacterial pathogens and contaminants in blood and cerebrospinal fluid (CSF) cultures in a cohort of febrile infants ≤60 days of age.

Methods

This was a secondary analysis of prospective observational multicenter study of noncritically ill infants ≤60 days of age with temperatures ≥38°C and blood cultures (December 2008 to May 2013). The main outcome was time to positivity for bacterial pathogens and contaminants.

Results

A total of 256 of 303 (84.49%) patients with positive blood cultures, and 73 of 88 (82.95%) with positive CSF cultures met inclusion criteria. Median time (interquartile range [IQR]) to positivity for blood cultures was 16.6 hours (IQR 12.6-21.9) for bacterial pathogens (n = 74) and 25.1 hours (IQR 19.8-33.0) for contaminants (n = 182); P < .001. Time to bacterial pathogen positivity was similar in infants 0 to 28 days of age (15.8 hours [IQR 12.6-21.0]) and 29 to 60 days of age (17.2 [IQR 12.9-24.3]; P = .328). Median time to positivity for CSF was 14.0 hours (IQR 1.5-21.0) for bacterial pathogens (n = 22) and 40.5 hours (IQR 21.2-62.6) for contaminants (n = 51); P < .001. A total of 82.4% (95% confidence interval, 71.8-90.3) and 81.8% (95% confidence interval, 59.7%-94.8%) of blood and CSF cultures showed bacterial pathogen positivity within 24 hours.

Conclusions

Among febrile infants ≤60 days of age, time to blood and CSF positivity was significantly shorter for bacterial pathogens than contaminants. Most blood and CSF cultures for bacterial pathogens were positive within 24 hours. With our findings, there is potential to reduce duration of hospitalization and avoid unnecessary antibiotics.

Background

Kawasaki disease, the most common cause of acquired heart disease in developed countries, is a self-limited vasculitis that is treated with high doses of intravenous immunoglobulin. Resistance to intravenous immunoglobulin in Kawasaki disease increases the risk of coronary artery aneurysms. We assessed whether the addition of infliximab to standard therapy (intravenous immunoglobulin and aspirin) in acute Kawasaki disease reduces the rate of treatment resistance.

Methods

We undertook a phase 3, randomised, double-blind, placebo-controlled trial in two children's hospitals in the USA to assess the addition of infliximab (5 mg per kg) to standard therapy. Eligible participants were children aged 4 weeks-17 years who had a fever (temperature ≥38·0°C) for 3-10 days and met American Heart Association criteria for Kawasaki disease. Participants were randomly allocated in 1:1 ratio to two treatment groups: infliximab 5 mg/kg at 1 mg/mL intravenously over 2 h or placebo (normal saline 5 mL/kg, administered intravenously). Randomisation was based on a randomly permuted block design (block sizes 2 and 4), stratified by age, sex, and centre. Patients, treating physicians and staff, study team members, and echocardiographers were all masked to treament assignment. The primary outcome was the difference between the groups in treatment resistance defined as a temperature of 38·0°C or higher at 36 h to 7 days after completion of the infusion of intravenous immunoglobulin. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, NCT00760435.

Findings

196 patients were enrolled and randomised: 98 to the infliximab group and 98 to placebo. One patient in the placebo group was withdrawn from the study because of hypotension before receiving treatment. Treatment resistance rate did not differ significantly (11 [11·2%] for infliximab and 11 [11·3%] for placebo; p=0·81). Compared with the placebo group, participants given infliximab had fewer days of fever (median 1 day for infliximab vs 2 days for placebo; p<0·0001). At week 2, infliximab-treated patients had greater mean reductions in erythrocyte sedimentation rate (p=0·009) and a two-fold greater decrease in Z score of the left anterior descending artery (p=0·045) than did those in the placebo group, but this difference was not significant at week 5. Participants in the infliximab group had a greater mean reduction in C-reactive protein concentration (p=0·0003) and in absolute neutrophil count (p=0·024) at 24 h after treatment than did those given placebo, but by week 2 this difference was not significant. At week 5, none of the laboratory values differed significantly compared with baseline. No significant differences were recorded between the two groups at any timepoint in proximal right coronary artery Z scores, age-adjusted haemoglobin values, duration of hospital stay, or any other laboratory markers of inflammation measured. No reactions to intravenous immunoglobulin infusion occurred in patients treated with infliximab compared with 13 (13·4%) patients given placebo (p<0·0001). No serious adverse events were directly attributable to infliximab infusion.

Interpretation

The addition of infliximab to primary treatment in acute Kawasaki disease did not reduce treatment resistance. However, it was safe and well tolerated and reduced fever duration, some markers of inflammation, left anterior descending coronary artery Z score, and intravenous immunoglobulin reaction rates.

Funding

US Food and Drug Administration, Robert Wood Johnson Foundation, and Janssen Biotech.

Background

Early identification of children with Kawasaki Disease (KD) is key for timely initiation of intravenous immunoglobulin (IVIG) therapy. However, the diagnosis of the disease remains challenging, especially in children with an incomplete presentation (inKD). Moreover, we currently lack objective tools for identification of non-response (NR) to IVIG.

Methods

Children with KD were enrolled and samples obtained before IVIG treatment and sequentially at 24 h and 4-6 weeks post-IVIG in a subset of patients. We also enrolled children with other febrile illnesses [adenovirus (AdV); group A streptococcus (GAS)] and healthy controls (HC) for comparative analyses. Blood transcriptional profiles were analyzed to define: a) the cKD and inKD biosignature, b) compare the KD signature with other febrile illnesses and, c) identify biomarkers predictive of clinical outcomes.

Results

We identified a cKD biosignature (n = 39; HC, n = 16) that was validated in two additional cohorts of children with cKD (n = 37; HC, n = 20) and inKD (n = 13; HC, n = 8) and was characterized by overexpression of inflammation, platelets, apoptosis and neutrophil genes, and underexpression of T and NK cell genes. Classifier genes discriminated KD from adenovirus with higher sensitivity and specificity (92% and 100%, respectively) than for GAS (75% and 87%, respectively). We identified a genomic score (MDTH) that was higher at baseline in IVIG-NR [median 12,290 vs. 5,572 in responders, p = 0.009] and independently predicted IVIG-NR.

Conclusion

A reproducible biosignature from KD patients was identified, and was similar in children with cKD and inKD. A genomic score allowed early identification of children at higher risk for non-response to IVIG.

To assess the performance of the Yale Observation Scale (YOS) score and unstructured clinician suspicion to identify febrile infants ≤60 days of age with and without serious bacterial infections (SBIs). We performed a planned secondary analysis of a prospective cohort of non-critically ill, febrile, full-term infants ≤60 days of age presenting to 1 of 26 participating emergency departments in the Pediatric Emergency Care Applied Research Network. We defined SBIs as urinary tract infections, bacteremia, or bacterial meningitis, with the latter 2 considered invasive bacterial infections. Emergency department clinicians applied the YOS (range: 6-30; normal score: ≤10) and estimated the risk of SBI using unstructured clinician suspicion (<1%, 1%-5%, 6%-10%, 11%-50%, or >50%). Of the 4591 eligible infants, 444 (9.7%) had SBIs and 97 (2.1%) had invasive bacterial infections. Of the 4058 infants with YOS scores of ≤10, 388 (9.6%) had SBIs (sensitivity: 51/439 [11.6%]; 95% confidence interval [CI]: 8.8%-15.0%; negative predictive value: 3670/4058 [90.4%]; 95% CI: 89.5%-91.3%) and 72 (1.8%) had invasive bacterial infections (sensitivity 23/95 [24.2%], 95% CI: 16.0%-34.1%; negative predictive value: 3983/4055 [98.2%], 95% CI: 97.8%-98.6%). Of the infants with clinician suspicion of <1%, 106 had SBIs (6.4%) and 16 (1.0%) had invasive bacterial infections. In this large prospective cohort of febrile infants ≤60 days of age, neither the YOS score nor unstructured clinician suspicion reliably identified those with invasive bacterial infections. More accurate clinical and laboratory predictors are needed to risk stratify febrile infants.