Multicenter Prospective Study of Biomarkers for Diagnosis of Invasive Candidiasis in Children and Adolescents.

BACKGROUND: Diagnosis of invasive candidiasis (IC) relies on insensitive cultures; the relative utility of fungal biomarkers in children is unclear. METHODS: This multinational observational cohort study enrolled patients aged >120 days and <18 years with concern for IC from 1 January 2015 to 26 September 2019 at 25 centers. Blood collected at onset of symptoms was tested using T2Candida, Fungitell (1→3)-ß-D-glucan, Platelia Candida Antigen (Ag) Plus, and Platelia Candida Antibody (Ab) Plus assays. Operating characteristics were determined for each biomarker, and assays meeting a defined threshold considered in combination. Sterile site cultures were the reference standard. RESULTS: Five hundred participants were enrolled at 22 centers in 3 countries, and IC was diagnosed in 13 (2.6%). Thirteen additional blood specimens were collected and successfully spiked with Candida species, to achieve a 5.0% event rate. Valid T2Candida, Fungitell, Platelia Candida Ag Plus, and Platelia Candida Ab Plus assay results were available for 438, 467, 473, and 473 specimens, respectively. Operating characteristics for T2Candida were most optimal for detecting IC due to any Candida species, with results as follows: sensitivity, 80.0% (95% confidence interval, 59.3%-93.2%), specificity 97.1% (95.0%-98.5%), positive predictive value, 62.5% (43.7%-78.9%), and negative predictive value, 98.8% (97.2%-99.6%). Only T2Candida and Platelia Candida Ag Plus assays met the threshold for combination testing. Positive result for either yielded the following results: sensitivity, 86.4% (95% confidence interval, 65.1%- 97.1%); specificity, 94.7% (92.0%-96.7%); positive predictive value, 47.5% (31.5%-63.9%); and negative predictive value, 99.2% (97.7%-99.8%). CONCLUSIONS: T2Candida alone or in combination with Platelia Candida Ag Plus may be beneficial for rapid detection of Candida species in children with concern for IC. CLINICAL TRIALS REGISTRATION: NCT02220790.

Comparison of RT-PCR Cycle Threshold Values from Respiratory Specimens in Symptomatic and Asymptomatic Children with SARS-CoV-2 Infection.

BACKGROUND: Understanding viral kinetics of SARS-CoV-2 is important to assess risk of transmission, manage treatment, and determine the need for isolation and protective equipment. The impact of viral load in asymptomatic infected children is important to understand transmission potential. We sought to determine whether children deemed to be asymptomatic had a difference in the PCR cycle threshold (Ct) value of respiratory samples from symptomatic children with SARS-CoV-2 infection. METHODS: This was a retrospective cross-sectional study to compare PCR Ct values of children who tested positive for SARS-CoV-2 by respiratory samples collected over a 4-month period at a large tertiary care children's hospital. RESULTS: We analyzed 728 children who tested positive for SARS-CoV-2 by RT-PCR from a respiratory sample over a 4-month period and for whom data was available in the electronic medical record. Overall, 71.2% of infected children were symptomatic. The mean Ct value for symptomatic patients (Ct mean 19.9, SD 6.3) was significantly lower than asymptomatic patients (Ct mean 23.5, SD 6.5) (P value < 0.001, CI 95th 2.6 - 4.6). The mean PCR Ct value was lowest in children less than 5 years of age. CONCLUSIONS: In this retrospective review of children who tested positive by RT-PCR for SARS CoV-2, the mean Ct was significantly lower in symptomatic children and was lowest in children under 5 years of age, indicating that symptomatic children and younger children infected with SARS-CoV-2 may have a higher viral load in the nasopharynx compared to asymptomatic children. Further studies are needed to assess the transmission potential from asymptomatic children.

Comparison of Reverse-Transcription Polymerase Chain Reaction Cycle Threshold Values From Respiratory Specimens in Symptomatic and Asymptomatic Children With Severe Acute Respiratory Syndrome Coronavirus 2 Infection.

BACKGROUND: Understanding viral kinetics of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is important to assess risk of transmission, manage treatment, and determine the need for isolation and protective equipment. The impact of viral load in asymptomatic infected children is important to understand transmission potential. We sought to determine whether children deemed to be asymptomatic had a difference in the polymerase chain reaction (PCR) cycle threshold (Ct) value of respiratory samples from symptomatic children with SARS-CoV-2 infection. METHODS: This was a retrospective cross-sectional study to compare PCR Ct values of children who tested positive for SARS-CoV-2 by respiratory samples collected over a 4-month period at a large tertiary care children's hospital. RESULTS: We analyzed 728 children who tested positive for SARS-CoV-2 by reverse-transcription PCR (RT-PCR) from a respiratory sample over a 4-month period and for whom data were available in the electronic medical record. Overall, 71.2% of infected children were symptomatic. The mean Ct value for symptomatic patients (Ct mean, 19.9 [standard deviation, 6.3]) was significantly lower than for asymptomatic patients (Ct mean, 23.5 [standard deviation, 6.9]) (P < .001; 95% confidence interval, 2.6-4.6). The mean PCR Ct value was lowest in children <5 years of age. CONCLUSIONS: In this retrospective review of children who tested positive by RT-PCR for SARS-CoV-2, the mean Ct was significantly lower in symptomatic children and was lowest in children <5 years of age, indicating that symptomatic children and younger children infected with SARS-CoV-2 may have a higher viral load in the nasopharynx compared to asymptomatic children. Further studies are needed to assess the transmission potential from asymptomatic children.

Clinical application of cell-free next-generation sequencing for infectious diseases at a tertiary children's hospital.

BACKGROUND: Children affected by infectious diseases may not always have a detectable infectious etiology. Diagnostic uncertainty can lead to prolonged hospitalizations, inappropriately broad or extended courses of antibiotics, invasive diagnostic procedures, and difficulty predicting the clinical course and outcome. Cell-free plasma next-generation sequencing (cfNGS) can identify viral, bacterial, and fungal infections by detecting pathogen DNA in peripheral blood. This testing modality offers the ability to test for many organisms at once in a shotgun metagenomic approach with a rapid turnaround time. We sought to compare the results of cfNGS to conventional diagnostic test results and describe the impact of cfNGS on clinical care in a diverse pediatric population at a large academic children's hospital. METHODS: We performed a retrospective chart review of hospitalized subjects at a tertiary pediatric hospital to determine the diagnostic yield of cfNGS and its impact on clinical care. RESULTS: We describe the clinical application of results from 142 cfNGS tests in the management of 110 subjects over an 8-month study period. In comparison to conventional testing as a reference standard, cfNGS was found to have a positive percent agreement of 89.6% and negative percent agreement of 52.3%. Furthermore, 32.4% of cfNGS results were directly applied to make a clinical change in management. CONCLUSIONS: We demonstrate the clinically utility of cfNGS in the management of acutely ill children. Future studies, both retrospective and prospective, are needed to clarify the optimal indications for testing.

Management and outcomes of pediatric septic thrombophlebitis: a case series.

Septic thrombophlebitis is a potentially life-threatening condition. Pediatric hematologists are often consulted to provide recommendations regarding anticoagulation management. We conducted a ten-year retrospective, single-center study of hospitalized pediatric patients who were treated for septic thrombophlebitis. Our primary outcome was resolution of thrombophlebitis. Twenty-eight patients were included in the study. Eighty-nine percent of patients received both antibiotic and anticoagulation therapy. The median durations of intravenous and total antibiotic therapy were 47.5 days (range 14-120) and 65 days (range 14-281), respectively, and median duration of anticoagulation therapy was 92 days (range 41-268). Resolution of thrombosis defined by magnetic resonance imaging, computed tomography, or ultrasound imaging was documented in 16 of 28 (57%) patients. Despite the high rate of persistent thrombosis, there was a low risk of relapse of infection in cases where antibiotic and/or anticoagulation was discontinued prior to complete resolution of the thrombus. Further research is needed to determine if duration of antibiotic and/or anticoagulation treatment can be shortened.

Notes from the field: fatal rat-bite fever in a child - San Diego County, California, 2013.

In August 2013, the County of San Diego Health and Human Services Agency was notified of a fatal case of rat-bite fever (RBF) in a previously healthy male, aged 10 years, who owned pet rats. Two days before his death, the patient experienced rigors, fevers, vomiting, headaches, and leg pains. His physician noted a fever of 102.6°F (39.2ºC), documented a normal examination, diagnosed viral gastroenteritis, and prescribed anti-nausea medication. During the next 24 hours, the patient experienced vomiting and persistent fever. He was confused and weak before collapsing at home. Paramedics reported the patient was unresponsive and had dilated pupils; resuscitation was initiated in the field and was continued for >1 hour after arrival at the emergency department but was unsuccessful. A complete blood count performed during resuscitation revealed anemia (hemoglobin 10.0 g/dL [normal = 13.5-18.0 g/dL], thrombocytopenia (platelets 40,000/µL [normal = 140,000-440,000/µL]), leukocytosis (white blood cells 17,900 cells/µL [normal = 4,000-10,500/µL]) with 16% band neutrophils; the patient also had evidence of disseminated intravascular coagulation. No rash or skin breakdown was noted. Lung, liver, and epiglottis tissue collected postmortem was positive for Streptobacillus moniliformis DNA by polymerase chain reaction.

Risk factors for the development of Clostridium difficile infection in hospitalized children.

PURPOSE OF REVIEW: This article defines the risk factors for Clostridium difficile infection (CDI) in hospitalized children in light of recent studies demonstrating a change in the epidemiology of these infections in both adults and children. RECENT FINDINGS: Antibiotic exposure within the past 4-12 weeks was noted in a majority of published cases of pediatric CDI, and that remains a key risk factor for infection. Past and/or prolonged hospitalization increase a child's risk for CDI as they increase potential contact with C. difficile spores. Of all CDI, hospital-acquired infection remains more common. Many comorbid conditions have been linked with CDI, with the strongest association existing in children with cancer and inflammatory bowel disease. Severe infections occur infrequently in pediatric patients. Markers established in adults for severe CDI resulting in colectomy or transfer to ICU have not been shown to correlate in pediatric patients. SUMMARY: Recent antibiotic exposure and hospitalization remain key risk factors for CDI in the hospitalized pediatric patient. Patients with comorbid conditions such as malignancy and inflammatory bowel disease are at higher risk for CDI. Resistant infections and severe outcomes are not common in the pediatric population.

Reducing pediatric ambulatory central line-associated bloodstream infections in patients at a single institution home health agency.

We conducted a quality improvement project from 2019 to 2021 at a single home health agency to reduce rates of central line-associated bloodstream infection in our ambulatory pediatric population. Annualized central line-associated bloodstream infection rates per 1,000 catheter line days decreased by 20 % during the study period, from a rate of 1.023 to 0.810. This decrease was sustained in the 10-month post-study period with a center line shift of 1.090 to 0.658.

Adjunctive Diagnostic Studies Completed Following Detection of Candidemia in Children: Secondary Analysis of Observed Practice From a Multicenter Cohort Study Conducted by the Pediatric Fungal Network.

BACKGROUND: Adjunctive diagnostic studies (aDS) are recommended to identify occult dissemination in patients with candidemia. Patterns of evaluation with aDS across pediatric settings are unknown. METHODS: Candidemia episodes were included in a secondary analysis of a multicenter comparative effectiveness study that prospectively enrolled participants age 120 days to 17 years with invasive candidiasis (predominantly candidemia) from 2014 to 2017. Ophthalmologic examination (OE), abdominal imaging (AbdImg), echocardiogram, neuroimaging, and lumbar puncture (LP) were performed per clinician discretion. Adjunctive diagnostic studies performance and positive results were determined per episode, within 30 days from candidemia onset. Associations of aDS performance with episode characteristics were evaluated via mixed-effects logistic regression. RESULTS: In 662 pediatric candidemia episodes, 490 (74%) underwent AbdImg, 450 (68%) OE, 426 (64%) echocardiogram, 160 (24%) neuroimaging, and 76 (11%) LP; performance of each aDS per episode varied across sites up to 16-fold. Longer durations of candidemia were associated with undergoing OE, AbdImg, and echocardiogram. Immunocompromised status (58% of episodes) was associated with undergoing AbdImg (adjusted odds ratio [aOR] 2.38; 95% confidence intervals [95% CI] 1.51-3.74). Intensive care at candidemia onset (30% of episodes) was associated with undergoing echocardiogram (aOR 2.42; 95% CI 1.51-3.88). Among evaluated episodes, positive OE was reported in 15 (3%), AbdImg in 30 (6%), echocardiogram in 14 (3%), neuroimaging in 9 (6%), and LP in 3 (4%). CONCLUSIONS: Our findings show heterogeneity in practice, with some clinicians performing aDS selectively, potentially influenced by clinical factors. The low frequency of positive results suggests that targeted application of aDS is warranted.

Pediatric Osteoarticular Infections Caused by Mycobacteria Tuberculosis Complex: A 26-Year Review of Cases in San Diego, CA.

BACKGROUND: Osteoarticular infections (OAIs) account for 10%-20% of extrapulmonary Mycobacteria tuberculosis (MTB) complex infections in children and 1%-2% of all pediatric tuberculosis infections. Treatment regimens and durations typically mirror recommendations for other types of extrapulmonary MTB, but there are significant variations in practice, with some experts suggesting a treatment course of 12 months or longer. METHODS: We conducted a retrospective review of children diagnosed with MTB complex OAI and cared for between December 31, 1992, and December 31, 2018, at a tertiary care pediatric hospital near the United States-Mexico border. RESULTS: We identified 21 children with MTB complex OAI during the study period. Concurrent pulmonary disease (9.5%), meningitis (9.5%), and intra-abdominal involvement (14.3%) were all observed. MTB complex was identified by culture from operative samples in 15/21 children (71.4%); 8/15 (53.3%) cultures were positive for Mycobacterium bovis. Open bone biopsy was the most common procedure for procurement of a tissue sample and had the highest culture yield. The median duration of antimicrobial therapy was 52 weeks (interquartile range, 46-58). Successful completion of therapy was documented in 15 children (71.4%). Nine children (42.9%) experienced long-term sequelae related to their infection. CONCLUSION: Among the 21 children with MTB complex OAI assessed, 8 of 15 (53.3%) children with a positive tissue culture had M. bovis, representing a higher percentage than in previous reports and potentially reflecting its presence in unpasteurized dairy products in the California-Baja region. Bone biopsy produced the highest culture yield in this study. Given the rarity of this disease, multicenter collaborative studies are needed to improve our understanding of the presentation and management of pediatric MTB complex OAI.

AN 8-YEAR-OLD CALIFORNIA GIRL WITH ASYMPTOMATIC HEPATIC CYSTS.

Echinococcus infections are rare in the United States but may present a growing public health threat. We present the case of an 8-year-old female patient from Southern California who was diagnosed with hepatic echinococcosis after the incidental discovery of large hepatic cysts.

Children with atopic dermatitis appear less likely to be infected with community acquired methicillin-resistant Staphylococcus aureus: the San Diego experience.

Given the increasing rate of community-acquired methicillin resistant Staphylococcus aureus skin infections in the population, such infections might be concurrently increasing in patients with atopic dermatitis. This study assessed current and prior rates of community-acquired methicillin resistant Staphylococcus aureus and methicillin-susceptible Staphylococcus aureus skin and soft tissue infections in children with atopic dermatitis compared to the general pediatric population. Other antibiotic sensitivity and resistance patterns, including clindamycin-inducible resistance, were also identified. Retrospective study of all skin and soft tissue isolates were positive for Staphylococcus aureus during two distinct 1-year periods, obtained by the outpatient services and the emergency department at Rady Children's Hospital, the major regional pediatric health center in San Diego, California. Of the Staphylococcus aureus isolates obtained from January to December 2000, none from atopic dermatitis patients were methicillin resistant Staphylococcus aureus, while 4.2% of those obtained from the general outpatient pediatric population showed methicillin resistance. In the period from June 2007 to May 2008, 11 of 78 isolates (14.1%) from children with atopic dermatitis were methicillin resistant Staphylococcus aureus. This was significantly lower than the rate of increase noted in the general pediatric population (658 of 1482, or 44.4%, in 2007/2008, p < 0.05). Clindamycin-inducible resistance was noted in 1.9% of the isolates in the general population; all six tested isolates from atopic patients lacked clindamycin-inducible resistance. In this study, children with atopic dermatitis had a much lower rate of community-acquired methicillin resistant Staphylococcus aureus infection compared to the general outpatient pediatric population. Clindamycin-inducible resistance was very low in both groups.

Use of Plasma Metagenomic Next-generation Sequencing for Pathogen Identification in Pediatric Endocarditis.

Pediatric infective endocarditis incurs significant morbidity and generally occurs among children with underlying heart disease. Identification of a pathogen is critical in determining appropriate therapy. However, standard diagnostic testing has limited sensitivity. We describe a case series of children with infective endocarditis in whom plasma next-generation sequencing (Karius, Redwood, CA) identified an organism in 8 of 10 cases.

Comparative Effectiveness of Echinocandins vs Triazoles or Amphotericin B Formulations as Initial Directed Therapy for Invasive Candidiasis in Children and Adolescents.

BACKGROUND: Invasive candidiasis is the most common invasive fungal disease in children and adolescents, but there are limited pediatric-specific antifungal effectiveness data. We compared the effectiveness of echinocandins to triazoles or amphotericin B formulations (triazole/amphotericin B) as initial directed therapy for invasive candidiasis. METHODS: This multinational observational cohort study enrolled patients aged >120 days and <18 years with proven invasive candidiasis from January 1, 2014, to November 28, 2017, at 43 International Pediatric Fungal Network sites. Primary exposure was initial directed therapy administered at the time qualifying culture became positive for yeast. Exposure groups were categorized by receipt of an echinocandin vs receipt of triazole/amphotericin B. Primary outcome was global response at 14 days following invasive candidiasis onset, adjudicated by a centralized data review committee. Stratified Mantel-Haenszel analyses estimated risk difference between exposure groups. RESULTS: Seven-hundred and fifty invasive candidiasis episodes were identified. After exclusions, 541 participants (235 in the echinocandin group and 306 in the triazole/amphotericin B group) remained. Crude failure rates at 14 days for echinocandin and triazole/amphotericin B groups were 9.8% (95% confidence intervals [CI]: 6.0% to 13.6%) and 13.1% (95% CI: 9.3% to 16.8%), respectively. The adjusted 14-day risk difference between echinocandin and triazole/amphotericin B groups was -7.1% points (95% CI: -13.1% to -2.4%), favoring echinocandins. The risk difference was -0.4% (95% CI: -7.5% to 6.7%) at 30 days. CONCLUSIONS: In children with invasive candidiasis, initial directed therapy with an echinocandin was associated with reduced failure rate at 14 days but not 30 days. These results may support echinocandins as initial directed therapy for invasive candidiasis in children and adolescents. CLINICAL TRIALS REGISTRATION: NCT01869829.

Use of whole-genome sequencing to detect an outbreak of Malassezia pachydermatis infection and colonization in a neonatal intensive care unit-California, 2015-2016.

Whole-genome sequencing confirmed the presence of a Malassezia pachydermatis outbreak among neonates in a neonatal intensive care unit. This technology supports the importance of adhering to infection prevention measures.

Synthesis and biological evaluation of flavan-3-ol derivatives as positive modulators of GABAA receptors.

We herein describe the synthesis and positive modulatory activities of a small library of flavan-3-ol derivatives on alpha(1)beta(2)gamma(2L) GABA(A) receptors. Structure-activity relationships of various substituents on the A, B and C rings were evaluated in a functional electrophysiological assay. A trans configuration and a 3-acetoxy moiety are essential for activity. Substitution of the B ring appears to be well tolerated, with substituents on the A ring playing a major role in determining activity.

Zygomycetes infections in pediatric hematology oncology patients: a case series and review of the literature.

Fungi from the Zygomycetes class are increasingly recognized causes of infection in immunosuppressed children, but no comprehensive literature review and few case series have been published on the topic. A case series of 6 pediatric oncology patients with Zygomycetes infections cared for at our institution was constructed, and a concurrent search of the English language literature for Zygomycetes infections in children with oncologic disorders was undertaken. Our case series described 6 patients (5 male) between the ages of 2.5 and 19.5 years. One patient was diagnosed with rhinocerebral disease, 2 with rhinosinusitis, 2 with pulmonary involvement, and 1 with a gastrointestinal presentation. Five patients survived. Our literature review identified 82 cases from 61 studies. The mean subject age was 10.8 years (1.4 to 21.0 y). About 92.7% of all patients suffered from some form of leukemia, with 70.7% suffering from acute lymphoblastic leukemia. Overall, 58.5% of reported patients survived, with individuals with disseminated disease showing the worst prognosis (68.2% mortality) and those with cutaneous disease the best (14.3% mortality). Survival is increasingly reported in the literature, perhaps as a result of improved diagnostic capabilities, increased physician awareness and increased reliance on adjunctive surgical therapy.

Community-acquired pneumonia in children: cell-free plasma sequencing for diagnosis and management.

Community-acquired pneumonia (CAP) is a common cause of pediatric hospital admission. Empiric antibiotic therapy for hospitalized children with serious CAP now targets the most likely pathogen(s), including those that may demonstrate significant antibiotic resistance. Cell-free plasma next-generation sequencing (CFPNGS) was first made available for Pediatric Infectious Diseases physicians in June 1, 2017, to supplement standard-of-care diagnostic techniques. A retrospective chart review was performed for children hospitalized with CAP between June 1, 2017, and January 22, 2018, to evaluate the impact of CFPNGS. We identified 15 hospitalized children with CAP without other underlying medical conditions for whom CFPNGS was performed. CFPNGS identified a pathogen in 13 of 15 (86%) children compared with 47% for those using standard culture and PCR-based methods alone. Changes in antibiotic management were made in 7 of 15 (47%) of children as a result of CFPNGS.