Candida species are the most common cause of invasive fungal infections in children and the third most common etiology of healthcare-associated bloodstream infections in the United States, Europe and Latin America.1,2 Children with critical illness, intra-abdominal pathology and underlying immunocompromising conditions remain at high risk for infection.3 Moreover, children with invasive candidiasis present a significant burden to the US health care system, with a mean increased hospital length of stay of 21 days, approximately $92,000 in excess hospital costs and an attributable mortality between 10 and 30%.4,5
Despite the burden of pediatric invasive candidiasis, the current consensus guidelines for invasive candidiasis lack pediatric-specific recommendations.6 In addition, children are different compared with adults according to their baseline comorbidities, lack of available indicated drugs and use of more myelosuppressive chemotherapy for underlying cancers. There have been a number of prospective multi-center studies regarding pediatric invasive candidiasis in specific regions of the world,7,8 but additional research is needed to fill important knowledge gaps in pediatric candidiasis. The International Pediatric Fungal Network (PFN; www.ipfn.org) was established with the goal of improving the quality of pediatric data to better inform pediatric fungal epidemiology as well as diagnostic and treatment strategies.
The aims of this study were to (1) compare the distribution of Candida species associated with pediatric invasive candidiasis in US versus non-US centers, (2) compare the difference in antifungal agents used between US versus non-US centers and (3) compare the frequency of clinician-determined antifungal therapy adverse events (AE) associated with treatment of Candida infections.
Study Design and Case Definitions
The PFN has been previously described in detail.7 For this study, investigators enrolled patients ≥ 3 months to ≤ 18 years of age who were diagnosed with invasive candidiasis between August 1, 2007, and September 31, 2012. Our previous report included 196 pediatric patients.7 The coordinating center was Duke University (Durham, NC), and institutional review board approval was obtained locally for each study site.
Patients with proven candidiasis were identified according to the European Organization for Research and Treatment of Cancer and Mycoses Study Group consensus revised definitions.9 Proven disease was defined as recovery of a Candida species from the blood or from a normally sterile site that was associated with clinical or radiographic evidence of an abnormality consistent with an infectious disease process.9 Date of infection was defined as the first date of clinical disease as determined by the site investigator. Episodes of invasive candidiasis in the same patient separated by clinical and microbiological resolution ≥14 days apart were treated as separate episodes.
Clinical data were prospectively collected from 20 US centers and 10 non-US centers (see Acknowledgments for listing of sites) and entered into the PFN database using Research Electronic Data Capture (REDCap)10 as previously described.7 Data collected included: (1) clinical signs at time of presentation; (2) center location and infecting Candida species; (3) antifungal therapy administered and associated AE as determined by the study site investigator and (4) outcome of infection, including death. Site location was dichotomized between US and non-US sites because of the lack of power to further delineate individual study site location. Data were captured regarding each antifungal agent administered for ≥ 2 consecutive days. AE and cause of death were determined by the study site physician according to defined terminology, as previously described.7
Descriptive analyses were performed to report the frequency of Candida species and antifungal therapy AE at US and non-US study sites. Proportion of each Candida species and antifungal AE was compared between US and non-US sites using the χ2 test. P< 0.05 indicated statistical significance. Statistical analyses were performed with SAS version 9.3 (SAS Institute, Cary, NC).
A total of 441 episodes of invasive candidiasis were identified in 423 patients from 30 participating (20 US and 10 international) PFN sites; 98% (431/441) completed the 12-week follow-up case report form. There was a mean of 14.7 (range: 1–42; median: 11; interquartile range: 3.75, 24) episodes of invasive candidiasis recorded from each site. Patients were more commonly male, 62% (272/441) with a mean age of 4.2 years (1.2–12.2).
Infecting Candida Isolates
Of the 449 Candida isolates recovered from 441 episodes of invasive candidiasis, Candida albicans (40%) was the most common species (Table 1), but collectively the non-albicans Candida species predominated (60%). Thirteen invasive candidiasis episodes were associated with recovery of 2 or more distinct Candida species.
Comparing the overall distribution of isolates recovered from US versus non-US study sites, there was a difference in the proportions of Candida species isolated (P < 0.001). Although C. albicans was the most common species isolated overall, it accounted for a lower percentage of all isolates in non-US sites compared with US sites (Table 1). Additionally, Candida guilliermondii was recovered more frequently in non-US study sites, whereas a larger proportion of Candida krusei was isolated in US than in non-US study sites.
A total of 1072 courses of antifungal therapy administered for >2 consecutive days were captured from 20 US centers and 10 non-US centers. When comparing US versus non-US study sites, there was variation in the frequency at which certain antifungal agents were prescribed (P < 0.001). US study sites were more likely to prescribe amphotericin B lipid complex, micafungin, flucytosine, as well as echinocandins, and polyenes as a whole. Non-US study sites more commonly prescribed caspofungin and fluconazole.
Among the 84 patients that died (19% of the 441 episodes), only 6 (7%) deaths were attributable to active invasive candidiasis, 34 (40%) were considered to be because of the underlying disease with active invasive candidiasis, 17 (20%) to the underlying disease without active invasive candidiasis, 2 (2%) to another infection in addition to active invasive candidiasis, 5 (6%) to another infection without active invasive candidiasis, 14 (17%) to other causes of death with invasive candidiasis and 6 (7%) to other causes of death without active invasive candidiasis. Overall, among the patients that died with active invasive candidiasis, 6/56 (11%) deaths were directly attributable to the invasive fungal disease, whereas 50/56 (89%) were directly attributable to another cause.
Treatment-associated Adverse Events
Fifty-one (4.8%) antifungal courses were associated with an AE; 96% were mild or moderate and 2 were severe (4%). Mild or moderate AE affected the kidney (n = 20, 41%), liver (n = 7, 14%), central nervous system (n = 1, 2%) or other (n = 15, 31%) organs.
Polyene use (n = 216) was associated with 59% (30/51) of all reported AE. Amphotericin B deoxycholate treatment accounted for 15/30 (50%) of the polyene related AE, and 73% (11/15) of those involved the kidney. Together, liposomal amphotericin B and amphotericin B lipid complex were associated with 15 AE, and 47% (7/15) of those involved the kidney. There were 2 AE involving the kidney related to echinocandin use (n = 224). Of the 2 severe antifungal AE, 1 was related to liposomal amphotericin B treatment affecting the lungs, and the other was related to caspofungin treatment affecting the liver. In 614 courses of triazole use, there were 3, 4 and 1 mild to moderate AE affecting the skin, liver and central nervous system, respectively, as well as 2 AE affecting other organs.
AE were more frequent during polyene therapy (30/216, 14%) when compared with all other antifungal therapy courses (21/856, 2%; P < 0.001). Specifically, kidney-related AE were more commonly associated with polyenes (18/216, 8%) when compared with all other antifungal therapies (2/856, 0.2%; P < 0.001).
This study constitutes the largest, prospective multi-national report of invasive candidiasis in children. Similar to other studies, we found that, collectively, non-albicans Candida species account for many of the episodes of invasive candidiasis, although C. albicans is the most common single species.3,8 We found that non-US sites had a higher proportion of C. guillermandii and C. krusei, although both were relatively uncommon overall.
The mortality rate directly attributed to invasive candidiasis was low in our cohort (7%, 6/84), which is slightly less than previous pediatric reports.4 However, our method of defining attribution did not account for the indirect effect that invasive candidiasis may have on the underlying diseases or infections that were determined to be directly associated with death, and therefore we may be underreporting candidiasis as a cause of death. In addition, our cohort could have had better outcomes because of the availability of better treatment options.
In this cohort, antifungal therapy was well tolerated with relatively infrequent AE. As might be expected, polyenes were associated with AE significantly more than other antifungal agents, and 60% of these AE were renal toxicity. Nonetheless, renal AE were still only reported in 8% of polyene courses. The low number of AE associated with triazole use could be because of reporting errors among the sites, particularly seen by the low number of AE reported in non-US sites. Further research is needed to better define the comparative effectiveness of different antifungal options relative to the risk of AE. In a recently opened PFN study, outcome and AE event data will be prospectively collected, which will allow for a more in-depth analysis on the comparative benefits and risks of available antifungal therapies.
There are several limitations to this study. First, despite efforts to capture all patients with invasive candidiasis, selection bias is possible, as accrual was dependent on each study site’s resources and ability to obtain informed consent. Among the study sites that required consent, it is possible that missed subjects were sicker and thus our final cohort could underestimate the true mortality rate and frequency of AE. It is unlikely that this selection bias would be related to species type and thus would not differentially impact the reported epidemiology of Candida species at US and non-US sites. In addition, documentation of AE was dependent on local physician reporting and required that the antifungal agent be given for ≥2 consecutive days. It is possible that physician underreporting or missed AE occurring on the first day would result in an underestimation of AE rates. However, only 2 AE that occurred on day 1 of therapy were excluded from our analysis. Finally, in some international study sites, not all antifungals are registered for use in children, which could potentially cause bias.
This study highlights differences in the epidemiology and therapeutic management of invasive candidiasis between US versus non-US study sites. Despite this, the frequency of AE was relatively rare at both US and non-US sites, supporting the relative safety of antifungal therapeutic options and outcomes similar between US and non-US sites in pediatric patients.
This study was supported in part by an investigator-initiated study protocol funded by Astellas Pharma US. The PFN is indebted to the many study coordinators, research fellows and collaborators at all the PFN centers, as well as the parents and children who agreed to take part in this study. The following investigators and sites contributed to this study: US Sites: Mark Abzug, University of Colorado School of Medicine and Children’s Hospital Colorado (Aurora, CO); Antonio Arrieta, Children’s Hospital of Orange County (Orange, CA); David Berman, All Children’s Hospital (St. Petersburg, FL); Joseph Bliss, Brown University (Providence, Rhode Island); Lara Danziger-Isakov, Cleveland Clinic Children’s (Cleveland, OH); Christopher C. Dvorak, University of California-San Francisco (San Francisco, CA); Judith Guzman-Gottrill, Oregon Health Science University (Portland, OR); Natasha Halasa, Vanderbilt University (Nashville, TN); Sarmistha B. Hauger, Dell Children’s Medical Center (Austin, TX); Jill Hoffman, Children’s Hospital Los Angeles (Los Angeles, CA); Katherine M. Knapp, St. Jude Children’s Hospital (Memphis, TN); Debra L. Palazzi, Baylor College of Medicine and Texas Children’s Hospital (Houston, TX); Alice Pong, Rady Children’s Hospital San Diego (San Diego, CA); Sujatha Rajan, Schneider Children’s Hospital (New Hyde Park, NY); Jose Romero, Arkansas Children’s Hospital (Little Rock, AK); Tanvi S. Sharma, Children’s Hospital Boston (Boston, MA); William Steinbach, Duke University (Durham, NC); Melanie Wellington, University of Rochester (Rochester, NY); Theoklis E. Zaoutis, Children’s Hospital of Philadelphia (Philadelphia, PA); and Christine Ziebold, University of Iowa Children’s Hospital (Iowa City, IA). Non-US sites: Christoph Berger, University Children’s Hospital-Zurich (Zurich, Switzerland); Elio Castagnola, Istituto Giannina Gaslini (Genova, Italy); Arunaloke Charkabarti, Postgraduate Institute of Medical Education & Research (Chandigarh, India); Andreas H. Groll, University of Muenster (Muenster, Germany); Lena Klingspor, Karolinska University Hospital Huddinge (Stockholm, Sweden); Thomas Lehrnbecher, Johann Wolfgang Goethe University (Frankfurt, Germany); Irja Lutsar, University of Tartu (Tartu, Estonia); Emmanuel Roilides, Aristotle University School of Health Sciences and Hippokration Hospital (Thessaloniki, Greece); Lillian Sung, The Hospital for Sick Children (Toronto, Canada); and Ibrahim Zaid Bin Hussain, King Faisal Specialist Hospital (Riyadh, Saudia Arabia).
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