INTERNATIONAL PEDIATRIC FUNGAL NETWORK

The following are some of the previously completed research studies published by members of the IPFN.

IPFN Study 001: Results from a Prospective, International, Epidemiologic Study of Invasive Candidiasis in Children and Neonates.

Steinbach, WJ, et al. (2012). Pediatr Infect Dis J 31(12): 1252-1257.
A prospective, multi-center study of pediatric patients ≤18 years, and neonatal patients ≤28 days with invasive candidiasis between August 2007 and May 2011. The 42 sites enrolled 196 pediatric and 25 neonatal patients. Twenty-four percent of those patients enrolled who had an hematologic malignancy had neutropenia at the time of diagnosis of invasive candidiasis. Thirty-one children had an underlying gastrointestinal disorder, with short bowel syndrome being the most common. C. albicans was isolated in 44% of infections, followed by C. parapsilosis (22%), and C. glabrata (11%). The majority of the organisms were isolated from the blood (n=136 infections). Antifungal monotherapy was the most common treatment for pediatric patients (84%), and combination therapy was used in 7% of pediatric patients. The most commonly used therapies included flucaonzole (21%), liposomal amphotericin B (20%), and micafungin (18%). Treatment with amphotericin B deoxycholate led to 10 adverse events and treatment with liposomal amphotericin B lead to 5 adverse events. Among the pediatric patients that were followed for the entire 12-week period, 76% had a successful outcome. Death occurred in 19% of pediatric patients, and 55% died with active candidiasis. Among the neonatal patients that were enrolled, 92% (23/25) had an successful outcome. All of the neonates received antifungal monotherapy, and the most common was fluconazole (32%), followed by caspofungin (24%), liposomal amphotericin B (16%), and micafungin (8%).

IPFN Study 002: Candida Speciation, Antifungal Treatment, and Adverse Events in Pediatric Invasive Candidiasis: Results from 441 Infections in a Prospective, Multi-National Study
Palazzi, DL, et al. (2014). Pediatr Infect Dis J, 2014 Dec;33(12):1294-6.
​A multi-center prospective study of patients ≥3 months to 18 years diagnosed with invasive candidiasis between August 2007 and September 2012 was performed. A total of 441 infections, among 423 patients were enrolled. Of the isolates recovered, Candida albicans was the most common species (40%). However, non-albicans Candida species predominated (60%). When comparing the distribution of isolates recovered from US and non-US study sites, there was a difference in the proportions of Candida species recovered (p <0.001). C. albicans accounted for a lower proportion of all isolates in non-US sites compared to US sites (p=0.077, 43% vs 34%). C. guilliermondii was present in a higher proportion in non-US study sites compared to US study sites (p=0.028, 4% vs. 1%). In addition, there was a trend towards a larger proportion of C. krusei isolated in non-US sites compared to US study sites (p=0.104, 2.5% vs 6%). There was also a significant difference in adverse events related to antifungal therapy administered ≥2 consecutive days (p<0.001). Overall, only 51 (4.8%) of antifungal courses were associated with an adverse event, and 96% of these were mild or moderate severity. Moreover, significantly fewer adverse events occurred in non-US sites vs. US sites (2% vs 7%, p <0.001). This difference may be a result of reporting differences however. In addition, the use of a polyene as an antifungal caused 59% (30/51) of all adverse events. When compared to all other antifungal therapy courses, adverse events were more frequent during polyene therapy (14% vs 2%, p <0.001). More specifically, kidney-related AE were more commonly associated with polyenes compared to all other antifungal therapies (8% vs 0.2%, p <0.001). When examining outcomes, 84 patients died, but only 6 (7%) were attributable to active invasive candidiasis.

IPFN Study 003: A Prospective, International Cohort Study of Invasive Mold Infections in Children
Wattier, RL, et al. (2014). J Pediatr Infect Dis Soc, 2014 Jul; DOI:10.1093/jpids/piu074.
Children ≤18 years with proven or probably invasive mold infections were enrolled between August 2007 and September 2011. One hundred and thirty-one patients with invasive mold infections were enrolled. The most common mold infection was invasive aspergillosis (75%), followed by mucormycosis (13%). When examining risk factors, children infected with invasive aspergillosis and children with other types of invasive mold infections had similar underlying risk factors, except that children with invasive mold infections caused by non-Aspergillus species were more likely to have received mold-active antifungal agents prior to diagnosis. After multivariable adjustment for other predictors associated with treatment outcome, preceding corticosteroid therapy (adjusted OR=2.73, 95% CI: 1.17-6.37, p=0.023) and preceding neutropenia (adjusted OR=0.48, 95% CI: 0.25-0.93, p=0.031) remained significantly associated with treatment failure. In addition, after multivariable adjustment for confounding due to preceding neutropenia, preceding immunosuppression, preceding mold therapy, and disseminated infection, there was no statistically significant association between combination therapy and treatment outcome (adjusted OR: 0.93, 95% CI: 0.44-1/97, p=0.839). The most common antifungals used following diagnosis of an invasive mold infection were triazoles (82%) and polyenes (63%). Moreover, combination therapy was used in 53% of infections. However, the use of combination therapy was associated with an increased risk of adverse events (RR 1.98, 95% CI: 1.06-3.68, p=0.031). However, there was no detectable difference in outcome when comparing those who received combination therapy and those who did not receive combination therapy. Among the 131 infections, there were only 47 reported adverse events. Adverse events were more frequently reported following the use of voriconazole (n=22) and liposomal amphotericin B (n=17). When examining outcome, after 12 weeks of follow-up, 60% of patients had a successful outcome and the overall mortality was 30%.

IPFN Study 004: Failure to Validate a Multivariable Clinical Prediction Model to Identify Pediatric Intensive Care Unit Patients at High Risk for Candidemia
Fisher, BT, et al. (2015). J Pediatric Infect Dis Soc. 2015 Apr 29. [Epub ahead of print]
We attempted to validate a previously derived clinical prediction rule for candidemia in the pediatric intensive care unit. This multicenter case control study did not identify significant association of candidemia with most of the previously identified predictors. Additional study in larger cohorts with other predictor variables is needed.

IPFN Study 005: Comparative Effectiveness of Echinocandins vs Triazoles or Amphotericin B Formulations as Initial Directed Therapy for Invasive Candidiasis in Children and Adolescents
​Fisher, BT, et al. (2021). J Pediatric Infect Dis Soc. 2021; 10(11):994-1003.

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. 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. In children with invasive candidiasis, initial directed therapy with an echinocandin was associated with reduced failure rate at 14 days but not 30 days.

IPFN Study 006: Multicenter Prospective Study of Biomarkers for Diagnosis of Invasive Candidiasis in Children and Adolescents
Fisher, BT et al. (2022). Clin Infect Dis. 2022; Aug 25;75(2): 248-259.

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)-β-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. 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%).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.

IPFN Study 009: 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.

Wattier, RL et al. (2023). J Pediatric Infect Dis Soc. 2023 Aug 17.

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. 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%). 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.

Information about additional clinical trials for pediatric fungal infections can be found on ClinicalTrials.gov.