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.

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.

Clinical and molecular characterization of Costello syndrome in unrelated Mexican patients.

This study intends to describe for the first time a cohort of Mexican patients with Costello syndrome. The five exons of the HRAS gene were amplified in DNA samples from 13 patients with a clinical suspicion of Costello syndrome. PCR products were sequenced using the Ready Reaction Big Dye Terminator v.3.0 Kit and an ABI PRISM 310 sequencer. Only five patients (38%) showed causal variant in codon 12 of the HRAS gene (four with the p.Gly12Ser and one with the p.Gly12Ala variant). Three patients showed silent polymorphic variants (p.His27His and p.Leu159Leu). Clinical features in patients carrying the causal variant were variable. The alternative diagnosis of cardio-facio-cutaneous syndrome was considered in patients who did not have a causative variant in HRAS.

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.

Physician-to-Physician Electronic Consultation: A Tool for the Pediatric Infectious Diseases Specialist to Document Encounters and Quantify Effort.

E-consults replace "curbside" interactions, facilitate provider-specialist communication, document within the medical record, and track relative value units (RVUs). Pediatric infectious diseases (PID) E-consults commonly relate to vaccines, exposures, diagnoses, and treatments. The documented RVU effort of 197 consecutive PID E-consults was equivalent to 70 level 4 new outpatient consults.

Congenital syphilis: Missed opportunities and the case for rescreening during pregnancy and at delivery.

Two infants treated for syphilis born to at risk mothers who screened negative at their first prenatal visit but were not rescreened at delivery are described. The first presented with classic, but unrecognized, features of congenital syphilis. In the second case, possible early maternal syphilis was diagnosed soon after delivery using the treponemal first reverse-screening algorithm. Although the child's physical exam was normal and the maternal rapid plasma reagin (RPR) negative, the child was treated for syphilis because maternal confirmatory treponemal tests suggested recent seroconversion. Given the re-emergence of congenital syphilis, our report aims to demonstrate the importance of rescreening women at increased risk and improve awareness of common manifestations of the syphilis disease in the newborn. For women at increased risk, repeat syphilis testing early in the third trimester and again at delivery in communities and populations with a high prevalence of syphilis is recommended.

A multicenter study to define the epidemiology and outcomes of Clostridioides difficile infection in pediatric hematopoietic cell and solid organ transplant recipients.

Hematopoietic cell transplant (HCT) and solid organ transplant (SOT) recipients are at increased risk for Clostridioides difficile infection (CDI). We conducted a multicenter retrospective study to describe the incidence of CDI in children transplanted between January 2010 and June 2013. Nested case-control substudies, matched 1:1 by transplant type, institution, patient age, and time of year (quartile) of transplant, identified CDI risk factors. Cohorts included 1496 HCT and 1090 SOT recipients. Among HCT recipients, 355 CDI episodes were diagnosed in 265 recipients (18.2%). Nested case-control study identified prior history of CDI (odds ratio [OR] 2.6, 95% confidence interval [CI] 1.5-4.7), proton pump inhibitors (PPIs; OR 2.1, 95% CI 1.3-3.4), and exposure to third- (OR 2.4, 95% CI 1.4-4.2) or fourth-generation (OR 2.1, 95% CI 1.2-3.7) cephalosporins as risk factors. Notably, fluoroquinolone exposure appeared protective (OR 0.6, 95% CI 0.3-0.9). Ninety-two episodes of CDI were diagnosed among 79 SOT recipients (7.3%), and exposure to PPIs (OR 2.4, 95% CI 1.1-5.4) and third-generation cephalosporin therapy (OR 3.9, 95% CI 1.4-10.5) were identified as risk factors. Strategies to decrease PPI use and changes in the class of prophylactic antibiotics may impact CDI incidence and warrant further study.

A comparison of hospitalized children with enterovirus D68 to those with rhinovirus.

BACKGROUND: During the Fall of 2014, numerous children were hospitalized with asthma or respiratory distress related to Enterovirus D68 (EV-D68). A large proportion initially tested positive for rhinovirus. During this period our laboratory noted a cross-reactivity between EV-D68 and the rhinovirus component of the GenMark multiplex respiratory viral panel. Many other laboratories used assays not designed to distinguish these Picornoviridae. METHODS: To compare the presentation and outcomes of patients with rhinovirus and EV-D68, 103 GenMark rhinovirus positive nasopharyngeal swabs from hospitalized children were retested for EV-D68. RESULTS: EV-D68 positive patients versus EV-D68 negative patients were more likely to have a history of asthma (33.3% vs. 11.0%, P = 0.02) and to present with acute respiratory illness (66.7% vs. 40.2%, P = 0.048), especially status asthmaticus (47.6% vs. 2.4%, P < 0.001). On admission they had more wheezing, respiratory distress, and lower respiratory tract involvement, and were more likely to be treated with steroids and discharged home on asthma medications. Respiratory viral coinfection was less common in EV-D68 positive vs EV-D68 negative patients. In patients without a respiratory viral coinfection the overall findings were similar. CONCLUSION: Patients with EV-D68 versus rhinovirus were more likely to have a history of asthma, to present with status asthmaticus, to wheeze on admission, and to receive treatment with asthma medications in hospital and at discharge. The inability of common assays to distinguish EV-D68 from rhinoviruses raises the possibility that the role of EV-D68 as a viral trigger of asthma has been under appreciated. Pediatr Pulmonol. 2017;52:827-832. © 2017 Wiley Periodicals, Inc.

Mycobacterium genavense-induced spindle cell pseudotumor in a pediatric hematopoietic stem cell transplant recipient: Case report and review of the literature.

We describe the first reported pediatric patient to our knowledge with a spindle cell pseudotumor caused by Mycobacterium genavense in a hematopoietic stem cell transplant recipient, and review the literature of such an entity in the transplant population.

Piperacillin-Tazobactam-induced Adverse Drug Events in Pediatric Patients on Outpatient Parenteral Antimicrobial Therapy.

We report a significantly higher occurrence of adverse events associated with prolonged courses of piperacillin-tazobactam compared with other antibacterial agents used for pediatric outpatient parenteral antimicrobial therapy. These adverse events were characterized by a constellation of clinical findings including fever, hematologic abnormalities and transaminitis. Adverse events related to piperacillin-tazobactam should be considered in patients who develop a febrile illness associated with a prolonged course of therapy.

Invasive Aspergillus infection requiring lobectomy in a CYP2C19 rapid metabolizer with subtherapeutic voriconazole concentrations.

Individuals who carry the CYP2C19*17 gain-of-function allele have lower voriconazole exposure and are therefore at risk of failing therapy. Utilizing CYP2C19 genotype to optimize voriconazole dosage may be a cost-effective method of improving treatment outcomes. However, there are limited data describing what initial voriconazole dosage should be used in those with increased CYP2C19 metabolic capacity. Herein, we present a case report of a pediatric CYP2C19 rapid metabolizer (i.e., CYP2C19*1/*17) requiring a voriconazole dosage of 14 mg/kg twice daily (usual pediatric dosage ranges from 7 to 9 mg/kg twice daily). This case report supports the clinical utility of using CYP2C19 genotype to guide voriconazole dosing, and provides data for establishing an initial voriconazole dose in pediatric CYP2C19 rapid metabolizers.

Selecting suitable solid organ transplant donors: Reducing the risk of donor-transmitted infections.

Selection of the appropriate donor is essential to a successful allograft recipient outcome for solid organ transplantation. Multiple infectious diseases have been transmitted from the donor to the recipient via transplantation. Donor-transmitted infections cause increased morbidity and mortality to the recipient. In recent years, a series of high-profile transmissions of infections have occurred in organ recipients prompting increased attention on the process of improving the selection of an appropriate donor that balances the shortage of needed allografts with an approach that mitigates the risk of donor-transmitted infection to the recipient. Important advances focused on improving donor screening diagnostics, using previously excluded high-risk donors, and individualizing the selection of allografts to recipients based on their prior infection history are serving to increase the donor pool and improve outcomes after transplant. This article serves to review the relevant literature surrounding this topic and to provide a suggested approach to the selection of an appropriate solid organ transplant donor.

Pulmonary nodules in an immunocompetent child with cat scratch disease.

We describe an immunocompetent child with cat scratch disease and pulmonary nodules as part of her initial presentation. Although pulmonary manifestations have been reported with cat scratch disease, nodules are rare in the normal host.

Influenza A/H1N1/09-10 infections in a NICU during the 2009-2010 H1N1 pandemic.

Few cases of the pandemic influenza A H1N1 have been reported in very low birth weight infants. We report here a small outbreak in our NICU of 3 cases of influenza A/H1N1/09-10 in very low birth weight infants during the 2009-2010 H1N1 pandemic and describe their clinical presentations and favorable outcomes despite the lack of treatment.

Staphylococcus aureus infections in adolescents.

Staphylococcus aureus infections are important causes of morbidity and mortality in the pediatric population. Over the past decade, community-associated methicillin-resistant S. aureus has emerged as an adolescent pathogen with disease ranging from mild skin and soft tissue infections to severe sepsis syndrome. Various conditions and behaviors common to adolescents render them more susceptible to staphylococcal infections. This review focuses on the problem of S. aureus in the adolescent population, including an outline on the approach, treatment, and prevention of these infections.