INTERNATIONAL PEDIATRIC FUNGAL NETWORK

Current Studies

The International Pediatric Fungal Network has multiple ongoing research projects dedicated to improving the diagnosis, treatment, and outcomes of pediatric patients with invasive fungal infections.

IPFN Study 007: DOMINIC: Non-Invasive Diagnosis of Pediatric Pulmonary Invasive Mold Infections (NCT03827694)

Currently enrolling
Invasive mold infections (IMI) are opportunistic illnesses in immunocompromised patients with the most common site of injection being the pulmonary parenchyma. The morbidity and mortality associated with pulmonary IMI (PIMI) is significant, but early diagnosis has the potential to improve outcomes. Advancements in diagnostic approaches and therapeutic interventions are necessary to improve diagnostic efficiency and to establish evidence-based therapeutic approaches. Our primary objective is to assess a comprehensive non-invasive diagnostic approach utilizing a fungal biomarker assay, fungal PCRs, cell-free next-generation DNA/RNA sequencing and a molecular RNAseq platform.

Aim 1: Establish a comprehensive non-invasive diagnostic blood testing approach to confirm the presence or absence of IMI in high-risk children with newly identified possible PIMI.

Aim 2: Compare outcomes for children with possible PIMI treated with empiric antifungal therapy versus an invasive diagnostic procedure followed by management based on results.

Aim 3: Explore the utility of detecting breath metabolites for identifying mold pathogens in the pulmonary parenchyma. We will enroll 400 patients to obtain 300 evaluable participants through the International Pediatric Fungal Network (IPFN) and the Children’s Oncology Group (COG) sites over a period of four years. This study will assemble a prospective cohort of pediatric patients with underlying conditions placing them at risk for PIMI.

Inclusion criteria:

• Males or females age > 120 days and < 22 years old
• Have at least one of the following conditions:
  • ​Hematopoietic stem cell transplant (HSCT)
  • Aplastic anemia
  • Any hematologic malignancy
• ​New (96 hr) imaging
  • ​Nodule > 5 mm
  • Cavitary lesion
  • Halo sign
  • Reverse halo sign
  • Air crescent sign
  • Wedge-shaped and segmental or lobar consolidation
• ​Prolonged neutropenia (> 5 days in the prior 30 days OR systemic Graft vs Host Disease (GVHD)
• Informed consent > 18 years old; parental/guardian permission /informed consent < 18, and if appropriate, child assent

Exclusion criteria:

• Weight < 3 kg
• Prior inclusion in study
  
• Patient received 3+ days of anti-mold, antifungal agent for directed therapy for previously diagnosed presumed or definitive invasive mold disease at any site.
  

​NB: Does not include anti-mold, antifungal agents for prophylaxis, empiric therapy for prolonged fever, neutropenia.

Past Studies

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: PEACE: Comparative Effectiveness of Treatments of Pediatric Candidemia (NCT01869829)
​Enrollment completed, analysis ongoing

PEACE was a multi-center (US and International sites), prospective observational comparative-effectiveness study. The primary aim of the study was to compare the effectiveness of echinocandin versus amphotericin B or triazole antifungal therapy for pediatric invasive candidiasis and invasive candidemia. The study collected data on 750 events of proven/probably invasive candidiasis in children and adolescents.

IPFN Study 006: BIOPIC (BIOmarkers for Pediatric Invasive Candidiasis): Evaluation of Fungal Biomarkers for Diagnosis of Pediatric Candidemia (NCT02220790)
Enrollment completed, analysis ongoing

This study will determine if fungal biomarkers can improve the time to diagnosis of invasive candidiasis in high risk pediatric patients as compared to traditional blood cultures. Additionally, these same fungal biomarkers will be evaluated to measure response to antifungal tratment in those high risk patients that develop invasive candidiasis.

We will prospectively enroll 500 patients throughout all International Pediatric Fungal Network (IPFN) sites over 4 years. In order to increase the tuility of these biomarkers, we will only enroll pediatric patients who are at "high-risk" forr developing candidiasis (defined in inclusion criteria below, and based on previous epidemiologic studies.) When an eligible patient has a blood culture drawn for clinical care, he or she will be enrolled and have research blood for biomarker testing drawn as soon as possible. The day that the clinical blood culture is drawn is "Day 0."

Most patients will not go on to develop invasive candidiasis, as defined by the international Mycoses Study Group / European Organization for the Treatment of Cancer (MSG/EORTC) definitions, and will not have any more blood drawn in this study. For those patients that do develop invasive candidiasis, we will also potentially draw study blood for the same biomarker tests on days +5, +7, and +14. This equates to 5, 7, and 14 days after “Day 0”. Blood for biomarkers will be drawn from patients using the kits and tubes provided by the IPFN.

Inclusion criteria for initial study enrollment:

• Males or females age >120 days and <18 years
• Have at least one of the following conditions:
  • ​admitted to a non-neonatal ICU with any underlying disease
  • being imminently transferred to a non-neonatal ICU with any underlying disease
  • gastro-intestinal insufficiency (e.g., chronic short-gut syndrome) and admitted to anywhere in the hospital
  • hematologic malignancy (limited to AML, ALL, Non-Hodgkin's lymphoma, and myelodysplastic syndrome) and admitted to anywhere in the hospital
  • solid tumor malignancy and admitted to anywhere in the hospital
  • hematopoietic stem cell or bone marrow transplant and admitted to anywhere in the hospital
  • aplastic anemia and admitted to anywhere in the hospital
• Have > 1 blood culture drawn for clinical concern of infection at time of enrollment
• Have > 1 central catheter (arterial or venous)
• Clinician initiates and/or changes any systemic antimicrobial therapy at the time of enrollment
• Parent/guardian permission (informed consent) and, if appropriate, child assent

​Inclusion criteria for subsequent research blood samples:

• Patient meets all criteria for initial enrollment, has the initial study blood sample collected, AND is diagnosed with invasive candidiasis according to the international definitions between day 0 and day +14

Exclusion criteria:

• Diagnosis of possible, probable or proven invasive fungal infection within the 30 days prior to study enrollment
• Previous inclusion in this study.
• Weight < 4 kg (Due to contraints of no more than 3 ml/kg of blood to be drawn over an 8 week period). Subjects that fall below 4 kg during the study period will not have more than 0.75 ml/kg of blood drawn each time.
• Patient receiving empiric antifungal therapy for prolonged neutropenia or fever that was started prior to the time that the clinically indicated blood culture was drawn.
• If blood cultures are obtained and anti-infectives are added/changed ONLY as part of a local protocol and not driven by clinical concern for infection.

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