Brian T Fisher1,2, Craig L K Boge1, Rui Xiao2, Sydney Shuster1, Dawn Chin-Quee3, John Allen3, Shareef Shaheen3, Randall Hayden4, Sri Suganda4, Theoklis E Zaoutis1,2, Yeh Chung Chang3, Dwight E Yin5, Anna R Huppler6, Lara Danziger-Isakov7, William J Muller8, Emmanuel Roilides9, José Romero10, Paul K Sue11, David Berman12, Rachel L Wattier13, Natasha Halasa14, Alice Pong15, Gabriela Maron16, Pere Soler-Palacin17, Susan C Hutto18, Blanca E Gonzalez19, Christine M Salvatore20, Sujatha Rajan21, Michael Green22, Elizabeth Doby Knackstedt23, Sarmistha B Hauger24, William J Steinbach3. 1. Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA. 2. Department of Biostatistics, Epidemiology and Informatics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA. 3. Duke University, Durham, North Carolina, USA. 4. Department of Pathology, St Jude Children's Research Hospital, Memphis, Tennessee, USA. 5. Children's Mercy and University of Missouri-Kansas City School of Medicine, Kansas City, Missouri, USA. 6. Medical College of Wisconsin and Children's Wisconsin, Milwaukee, Wisconsin, USA. 7. Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA. 8. Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA. 9. Infectious Disease Unit, 3rd Department of Pediatrics, School of Medicine, Aristotle University and Hippokration Hospital, Thessaloniki, Greece. 10. Arkansas Children's Hospital Research Institute, Little Rock, Arkansas, USA. 11. University of Texas Southwestern Medical Center, Dallas, Texas, USA. 12. John Hopkins All Children's Hospital, St Petersburg, Florida, USA. 13. University of California-San Francisco, San Francisco, California, USA. 14. Vanderbilt University Medical Center, Nashville, Tennessee, USA. 15. University of California San Diego, San Diego, California, USA. 16. St Jude Children's Research Hospital, Memphis, Tennessee, USA. 17. Hospital Universitari Vall d'Hebron, Barcelona, Catalonia, Spain. 18. University of Alabama, Birmingham, Birmingham, Alabama, USA. 19. Cleveland Clinic Foundation, Cleveland, Ohio, USA. 20. Weill Cornell Medicine, New York, New York, USA. 21. Cohen Children's Medical Center of New York, New Hyde Park, New York, USA. 22. UPMC Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania, USA. 23. University of Utah, Salt Lake City, Utah, USAand. 24. Dell Children's Medical Center, Austin, Texas, USA.
Abstract
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)-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. 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.
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)-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. 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.