Alev Yilmaz1,2, Alberto Caldas Afonso3, Ipek Akil4, Bagdagul Aksu5,6, Harika Alpay7, Bahriye Atmis8,9, Ozlem Aydog10, Aysun Karabay Bayazıt9, Meral Torun Bayram11, Ilmay Bilge12, Ipek Kaplan Bulut13, Bahar Buyukkaragoz14, Elif Comak15, Belde Kasap Demir16,17, Nida Dincel18, Osman Donmez19, Mehmet Akif Durmus20, Hasan Dursun21, Ruhan Dusunsel22, Ali Duzova23, Pelin Ertan4, Asuman Gedikbasi24, Nilufer Goknar25, Sercin Guven7, Duygu Hacihamdioglu26, Augustina Jankauskiene27, Mukaddes Kalyoncu28, Salih Kavukcu11, Bahriye Uzun Kenan14, Nuran Kucuk29, Bahar Kural30, Mieczysław Litwin31, Giovanni Montini32,33, William Morello32, Ahmet Nayir5,6, Lukasz Obrycki31, Beyhan Omer34, Ebru Misirli Ozdemir35, Nese Ozkayin36, Dusan Paripovic37, Cemile Pehlivanoglu38, Seha Saygili39, Susanne Schaefer40, Ferah Sonmez41, Yilmaz Tabel42, Nesrin Tas23, Mehmet Tasdemir12, Ana Teixeira3, Demet Tekcan10, Sebahat Tulpar43, Ozde Nisa Turkkan5, Berfin Uysal44,45, Metin Uysalol46, Daiva Vaiciuniene27, Sevgi Yavuz47, Sibel Yel22, Tarik Yildirim48, Zeynep Yuruk Yildirim5,6, Nurdan Yildiz7, Selcuk Yuksel49, Eray Yurtseven50, Franz Schaefer40, Rezan Topaloglu23. 1. Division of Pediatric Nephrology, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Türkiye. alev.yilmaz@istanbul.edu.tr. 2. Department of Pediatrics Basic Sciences, Institute of Child Health, Istanbul University, Istanbul, Türkiye. alev.yilmaz@istanbul.edu.tr. 3. Division of Pediatric Nephrology, Centro Materno Infantil Do Norte, Centro Hospitalar Universitário Do Porto, Porto, Portugal. 4. Division of Pediatric Nephrology, Faculty of Medicine, Celal Bayar University, Manisa, Türkiye. 5. Division of Pediatric Nephrology, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Türkiye. 6. Department of Pediatrics Basic Sciences, Institute of Child Health, Istanbul University, Istanbul, Türkiye. 7. Division of Pediatric Nephrology, Faculty of Medicine, Marmara University, Istanbul, Türkiye. 8. Pediatric Nephrology, Erzurum Training and Research Hospital, Erzurum, Türkiye. 9. Division of Pediatric Nephrology, Faculty of Medicine, Cukurova University, Adana, Türkiye. 10. Division of Pediatric Nephrology, Faculty of Medicine, Ondokuz Mayis University, Samsun, Türkiye. 11. Division of Pediatric Nephrology, Faculty of Medicine, Dokuz Eylul University, Izmir, Türkiye. 12. Division of Pediatric Nephrology, Department of Pediatrics, School of Medicine, Koc University, Istanbul, Türkiye. 13. Division of Pediatric Nephrology, Faculty of Medicine, Ege University, Izmir, Türkiye. 14. Division of Pediatric Nephrology, Faculty of Medicine, Gazi University, Ankara, Türkiye. 15. Division of Pediatric Nephrology, Faculty of Medicine, Akdeniz University, Antalya, Türkiye. 16. Division of Pediatric Nephrology, Tepecik Training and Research Hospital, University of Health Sciences, Izmir, Türkiye. 17. Division of Pediatric Nephrology, Izmir Katip Celebi University Faculty of Medicine, Izmir, Türkiye. 18. Division of Pediatric Nephrology, Dr Behcet Uz Children Diseases Training and Research Hospital, University of Health Sciences, Izmir, Türkiye. 19. Division of Pediatric Nephrology, Faculty of Medicine, Uludag University, Bursa, Türkiye. 20. Department of Medical Microbiology, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Türkiye. 21. Division of Pediatric Nephrology, Okmeydani Training and Research Hospital, University of Health Sciences, Istanbul, Türkiye. 22. Division of Pediatric Nephrology, Faculty of Medicine, Erciyes University, Kayseri, Türkiye. 23. Division of Pediatric Nephrology, Faculty of Medicine, Hacettepe University, Ankara, Türkiye. 24. Department of Rare Diseases, Institute of Child Health, Istanbul University, Istanbul, Türkiye. 25. Division of Pediatric Nephrology, Bagcilar Training and Research Hospital, University of Health Sciences, Istanbul, Türkiye. 26. Division of Pediatric Nephrology, Faculty of Medicine, Bahcesehir University, Istanbul, Türkiye. 27. Clinic of Pediatrics, Institute of Experimental and Clinical Medicine, Vilnius University, Vilnius, Lithuania. 28. Division of Pediatric Nephrology, Faculty of Medicine, Karadeniz Technic University, Trabzon, Türkiye. 29. Division of Pediatric Nephrology, Kartal Training and Research Hospital, Istanbul, Türkiye. 30. Department of Pediatrics, Health Science University Bakırköy Sadi Konuk Training and Research Hospital, Istanbul, Türkiye. 31. Division of Nephrology, Kidney Transplantation and Hypertension, The Children's Memorial Health Institute, Warsaw, Poland. 32. Pediatric Nephrology, Dialysis and Transplant Unit, Fondazione IRCCS Ca' Granda - Ospedale Maggiore Policlinico, Milan, Italy. 33. Department of Clinical Sciences and Community Health, University of Milano, Milan, Italy. 34. Department of Biochemistry, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Türkiye. 35. Department of Pediatrics, Okmeydani Training and Research Hospital, Istanbul, Türkiye. 36. Division of Pediatric Nephrology, Faculty of Medicine, Trakya University, Edirne, Türkiye. 37. Division of Pediatric Nephrology, University Children's Hospital, Belgrade, Serbia. 38. Division of Pediatric Nephrology, Umraniye Training and Research Hospital, Istanbul, Türkiye. 39. Division of Pediatric Nephrology, Cerrahpasa Faculty of Medicine, Istanbul University-Cerrahpasa, Istanbul, Türkiye. 40. Division of Pediatric Nephrology, Center for Pediatrics and Adolescent Medicine, Heidelberg University, Heidelberg, Germany. 41. Division of Pediatric Nephrology, Faculty of Medicine, Adnan Menderes University, Aydin, Türkiye. 42. Division of Pediatric Nephrology, Faculty of Medicine, Inonu University, Malatya, Türkiye. 43. Division of Pediatric Nephrology, Bakirkoy Dr Sadi Konuk Training and Research Hospital, Istanbul, Türkiye. 44. Division of Pediatric Nephrology, Dortcelik Children's Hospital, Bursa, Türkiye. 45. Division of Pediatric Nephrology, Bursa City Hospital, Bursa, Türkiye. 46. Division of Pediatric Emergency, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Türkiye. 47. Division of Pediatric Nephrology, Department of Pediatrics, Kanuni Sultan Suleyman Research and Training Hospital, University of Health Sciences, Istanbul, Türkiye. 48. Department of Pediatrics, Kanuni Sultan Suleyman Research and Training Hospital, University of Health Sciences, Istanbul, Türkiye. 49. Division of Pediatric Nephrology, Faculty of Medicine, Pamukkale University, Denizli, Türkiye. 50. Department of Biostatistics, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Türkiye.
Abstract
BACKGROUND: The accuracy of conventional urinalysis in diagnosing urinary tract infection (UTI) in children is limited, leading to unnecessary antibiotic exposure in a large fraction of patients. Urinary heat shock protein 70 (uHSP70) is a novel marker of acute urinary tract inflammation. We explored the added value of uHSP70 in discriminating UTI from other infections and conditions confused with UTI. METHODS: A total of 802 children from 37 pediatric centers in seven countries participated in the study. Patients diagnosed with UTI (n = 191), non-UTI infections (n = 178), contaminated urine samples (n = 50), asymptomatic bacteriuria (n = 26), and healthy controls (n = 75) were enrolled. Urine and serum levels of HSP70 were measured at presentation in all patients and after resolution of the infection in patients with confirmed UTI. RESULTS: Urinary (u)HSP70 was selectively elevated in children with UTI as compared to all other conditions (p < 0.0001). uHSP70 predicted UTI with 89% sensitivity and 82% specificity (AUC = 0.934). Among the 265 patients with suspected UTI, the uHSP70 > 48 ng/mL criterion identified the 172 children with subsequently confirmed UTI with 90% sensitivity and 82% specificity (AUC = 0.862), exceeding the individual diagnostic accuracy of leukocyturia, nitrite, and leukocyte esterase positivity. uHSP70 had completely normalized by the end of antibiotic therapy in the UTI patients. Serum HSP70 was not predictive. CONCLUSIONS: Urine HSP70 is a novel non-invasive marker of UTI that improves the diagnostic accuracy of conventional urinalysis. We estimate that rapid urine HSP70 screening could spare empiric antibiotic administration in up to 80% of children with suspected UTI. A higher resolution version of the Graphical abstract is available as Supplementary information.
BACKGROUND: The accuracy of conventional urinalysis in diagnosing urinary tract infection (UTI) in children is limited, leading to unnecessary antibiotic exposure in a large fraction of patients. Urinary heat shock protein 70 (uHSP70) is a novel marker of acute urinary tract inflammation. We explored the added value of uHSP70 in discriminating UTI from other infections and conditions confused with UTI. METHODS: A total of 802 children from 37 pediatric centers in seven countries participated in the study. Patients diagnosed with UTI (n = 191), non-UTI infections (n = 178), contaminated urine samples (n = 50), asymptomatic bacteriuria (n = 26), and healthy controls (n = 75) were enrolled. Urine and serum levels of HSP70 were measured at presentation in all patients and after resolution of the infection in patients with confirmed UTI. RESULTS: Urinary (u)HSP70 was selectively elevated in children with UTI as compared to all other conditions (p < 0.0001). uHSP70 predicted UTI with 89% sensitivity and 82% specificity (AUC = 0.934). Among the 265 patients with suspected UTI, the uHSP70 > 48 ng/mL criterion identified the 172 children with subsequently confirmed UTI with 90% sensitivity and 82% specificity (AUC = 0.862), exceeding the individual diagnostic accuracy of leukocyturia, nitrite, and leukocyte esterase positivity. uHSP70 had completely normalized by the end of antibiotic therapy in the UTI patients. Serum HSP70 was not predictive. CONCLUSIONS: Urine HSP70 is a novel non-invasive marker of UTI that improves the diagnostic accuracy of conventional urinalysis. We estimate that rapid urine HSP70 screening could spare empiric antibiotic administration in up to 80% of children with suspected UTI. A higher resolution version of the Graphical abstract is available as Supplementary information.