Delivered by Publishing Technology to: Swets IP: 192.87.50.3 On: Wed, 14 Mar 2012 12:36:08 Copyright (c) Oceanside Publications, Inc. All rights reserved. For permission to copy go to https://www.oceansidepubl.com/permission.htm Crenotherapy modulates the expression of proinflammatory cytokines and immunoregulatory peptides in nasal secretions of children with chronic rhinosinusitis Annalisa Passariello, M.D., Ph.D., 1,2 Margherita Di Costanzo, M.D., 1 Gianluca Terrin, M.D., Ph.D., 3 Antonio Iannotti, M.D., 4 Pietro Buono, M.D., Ph.D., 1,5 Umberto Balestrieri, M.D., 4 Gianni Balestrieri, M.D., 4 Enrico Ascione, M.D., 4 Monica Pedata, M.D., 1 Francesco Berni Canani, M.D., 6 and Roberto Berni Canani, M.D., Ph.D. 1 ABSTRACT Background: The effect of crenotherapy on major mucosal markers of inflammation, TNF alpha, human beta-defensins 2 (hBD-2), and calprotectin, are largely unexplored in pediatric chronic rhinosinusitis (CRS). The aim of this study was to investigate the effects of crenotherapy with sulfate-sodium-chloride water on mucosal markers of inflammation in children with CRS. Methods: Children with CRS received 15-day crenotherapy consisting of sulfate-sodium-chloride thermal water inhalations by nasal aerosol (15 minutes/day). Concentrations of nasal mucosal markers of inflammation (TNF alpha, hBD-2, and calprotectin) were measured before and after crenotherapy. Presence of specific symptoms (nasal obstruction, nasal discharge, facial pain, sense of smell, and cough), value of symptoms score sino-nasal 5 (SN5), quality of life (QoL) score (1 [worse] to 10 [optimal]) were also assessed. Results: After crenotherapy a significant reduction was observed in TNF alpha (from 0.14  0.02 to 0.08  0.01; p  0.001), calprotectin (from 2.9  1.0 to 1.9  0.5; p  9.001), and hBD-2 (from 2.0  0.1 to 0.9  0.6; p  0.001) concentrations. A significant (p  0.05) reduction in number of subjects presenting symptoms of nasal obstruction (100% versus 40%), nasal discharge (33% versus 13%), facial pain (30% versus 10%), and sense of smell (60% versus 20%) was observed. A significant improvement of SN5 (from 3.07  0.76 to 2.08  0.42; p  0.001) was observed after the crenotherapy. QoL also improved after crenotherapy (from 4.2  1.1 to 6.6  1.0; p  0.001). Conclusion: Crenotherapy induced a down-regulation of nasal mucosal inflammatory mediators in children with CRS. (Am J Rhinol Allergy 26, e15–e19, 2012; doi: 10.2500/ajra.2012.26.3733) C hronic rhinosinusitis (CRS) is one of the most common diseases in western countries. Although the exact pathogenesis of CRS remains unclear, the underlying mechanisms involve different in- flammatory mediators, such as proinflammatory cytokines (TNF-) and several antimicrobial and immunoregulatory peptides, including calprotectin and human -defensins 2 (hBD-2). 1,2 Although the eosin- ophilic inflammation is typical of adult patients with CRS, the inflam- matory response in children is characterized by a mixed lymphocyte population, macrophages and neutrophils, suggesting differences in the pathogenic mechanism. 3 Neutrophils play a fundamental role in the inflammatory process; they release inflammatory cytokines, such as TNF-, and antimicrobial peptide, including defensins and calpro- tectin. 4–6 Calprotectin is among the most abundant cytoplasmic pro- teins in neutrophils and macrophages, and it is found in all body fluids in proportion to the degree of inflammation. 7 Elevated serum levels of calprotectin have been reported in several inflammatory conditions, including cystic fibrosis, rheumatoid arthritis, and sys- temic infections. 8–11 Human -defensin 2 is an inducible antimicrobial peptide widely expressed by epithelial cells and involved most obvi- ously in mucosal response in inflammatory and/or infectious condi- tions. 12,13 Human -defensin 2 exerts chemotactic properties on den- dritic cells and human neutrophils. 14,15 Elevated levels of hBD-2 have been founded in many human diseases characterized by chronic inflammation. 16–19 Crenotherapy (from the Greek , spring fountain), is a com- plex of practices using water, with different mineral components and different physical properties, to cure many pathologies, mainly dis- eases of the respiratory, digestive and urinary tract, of the skin, and rheumatic diseases. 20 Crenotherapy has been approved as a drug in many countries, with specific therapeutic indications, targeted doses, and contraindications, but the exact mechanisms of action are still under active research. Clinical findings suggest an anti-inflammatory effect of crenotherapy in adult respiratory system diseases, 21–26 but data in the pediatric population are still very limited. The aim of this study was to investigate the effects of crenotherapy with sulfate- sodium-chloride water on mucosal markers of inflammation in chil- dren with CRS. METHODS Study Design The present investigation was a prospective study on pediatric patients with CRS. The study protocol was approved by the Ethics Committee of the University of Naples “Federico II.” Written in- formed consent was obtained from all care givers of subjects before the procedures were performed. Population The trial was performed in collaboration with family pediatricians, who were in the Italian public health care system, for children up to 16 years of age. The family pediatricians were invited to contact the study coordinator at the Department of Pediatrics if a case of CRS was From the 1 Department of Pediatrics, University of Naples “Federico II,” Naples, Italy, 2 Neonatology Unit, AORN Monaldi, Naples, 3 Department of Women’s Health and Territorial Medicine, University of Rome “La Sapienza,” Rome, Italy, 4 Otolaryngology and Thermal Medicine, Thermal Study Center G. Jasolino, Ischia, Naples, Italy, 5 ASL North of Naples, Rizzoli Hospital, Ischia, Naples, Italy, and 6 Department of Otolar- yngology, Maggiore Hospital, Bologne, Italy Funded by the research grants provided by the Thermal Research Foundation, Rome, Italy, and by Associazione Termalisti dell’Isola di Ischia, Italy; The staff of these two institutions did not participate in the protocol development, study oversight, regulatory reporting, or monitoring the progress of the study; in addition, they did not have access to outcome data until the trial was closed The authors have no conflicts of interest to declare pertaining to this article Address correspondence and reprint requests to Roberto Berni Canani, M.D., Ph.D., Department of Pediatrics, University of Naples “Federico II,” Via S Pansini 5, Naples 80131, Italy E-mail address: berni@unina.it Copyright © 2012, OceanSide Publications, Inc., U.S.A. American Journal of Rhinology & Allergy e15 DO NOT COPY