Acta Pdiatrica ISSN 08035253

REGULAR ARTICLE

Effectiveness of erdosteine, a second generation mucolytic agent, in children with acute rhinosinusitis: a randomized, placebo controlled, double-blinded clinical study
E Unuvar (eminu@istanbul.edu.tr)1, Z Tamay1, I Yldz1, S Toprak2, A Klc3, S Aydn1, G Klc1, N Guler1, F Oguz3, M Sdal3
1.Department of Pediatrics, Istanbul School of Medicine, Istanbul University, Capa, Istanbul, Turkey 2.Department of Forensic Medicine, University of Gazi Osman Pas a, Tokat, Turkey 3.Department of Pediatrics, Institution of Child Health, Istanbul University, Capa, Istanbul, Turkey

Keywords Children, Erdosteine, Infection, Mucolytic, Rhinosinusitis Correspondence Emin Unuvar, Tunusbagi Caddesi, Melek Isik Ap. No 6 D 3 Dogancilar, Uskudar, TR-34605, Istanbul, Turkey. Tel: +90 536 359 9526 | Fax: +90 212 531 0529 | Email: eminu@istanbul.edu.tr Received 30 June 2009; revised 14 November 2009; accepted 23 November 2009. DOI:10.1111/j.1651-2227.2009.01646.x

Abstract Aim: To evaluate whether mucolytic agents have an adjuvant role with antibiotics in the treatment of children with rhinosinusitis. Methods: Ninety-two children with rhinosinusitis were recruited for this randomized, placebo controlled, double-blinded clinical trial. Mean age was 8.5 3.2 years. Erdosteine (58 mg kg day) was administered to 49 children, and 43 children received placebo. Changes in symptoms were recorded with the standard S5 scoring for 14 days. Complete resolution of symptoms on day 14 was considered to be clinical improvement. Results: Eighty-one participants completed the study. Forty-one were in the treatment group and 40 in the placebo group. The average S5 scoring value at the onset of study was 11.0 in treatment group and 12.1 in placebo group. On day 14, mean scores were 3.1 in the treatment group and 2.8 in the placebo group. Complete improvement was 78% in the treatment group and 74.4% in the placebo group. There was no signicant difference between the groups. There were no clinically detected serious side effects or complications in both groups. Conclusion: Use of erdosteine as a mucolytic agent in children with acute rhinosinusitis does not directly affect the success of treatment.

INTRODUCTION Acute rhinosinusitis is a common infection that occurs after a viral upper respiratory tract infection in 1015% of patients (1,2). Although rhinosinusitis commonly causes morbidity, it rarely results in mortality. The diagnosis of sinusitis in children mainly depends on clinical symptoms (3,4). Antibiotics are effective in the treatment of sinusitis, and they signicantly improve the clinical outcomes compared with placebo groups (5,6). However, other studies demonstrated minimal efcacy of antibiotics in the treatment of acute rhinosinusitis (79). The differences in the outcomes of these clinical trials are likely because of the heterogeneity of the patients clinical presentations. It is now clear that patients with severe symptoms benet from antibiotherapy. Antibiotics improve the symptoms, radiological ndings and prognosis of the acute rhinosinusitis (10). The effectiveness of adjuvant therapies in addition to antibiotics is not clear in paediatric age group (11). Nasal saline irrigation may provide relief for a short period of time, but this effect is not different compared with placebo (12). Nasal corticosteroids, decongestant drugs, mucolytic agents, inhibitors of leukotrienes are commonly prescribed, but none of them offers additional benet in the treatment

of rhinosinusitis (1,13). Topical steroids are only effective in chronic allergic rhinitis (14). In the medical literature, the adjuvant effect of mucolytic agents in childhood rhinosinusitis is not well documented (14). The aim of our study is to evaluate whether mucolytic agents have an adjuvant role with antibiotics in the treatment of children with rhinosinusitis. This randomized, placebo controlled, double blinded clinical trial was planned to determine the effect of erdosteine, a mucolytic agent, in children with clinically diagnosed rhinosinusitis.

METHODS Patient population and institution This clinical trial was carried out among children who were between 3 and 12 years of age and were clinically diagnosed to have acute rhinosinusitis from October 1, 2007 to May 31, 2008 in the outpatient clinic of Department of Pediatrics at Istanbul Faculty of Medicine. The research clinic is a university paediatrics clinic where paediatric patients are cared. Our trial was planned and carried out in full compliance with CONSORT regulations harbouring the basic principles of randomized drug trials (15).

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Eligibility criteria for participants Patients older than 3 years of age presenting to the Pediatrics Outpatient Clinic during working hours (9 am4 pm) and diagnosed with acute rhinosinusitis were consecutively enrolled. Participants suitable for the trial were included in the study. Inclusion criteria were as follows: (1) Age older than 3 years and younger than 12 years; (2) symptoms of upper respiratory tract infection (running nose, cough, fever etc.) lasting longer than 10 days and not exceeding 30 days; (3) presence of severe symptoms of marked rhinosinusitis including fever of 39C, purulant anterior or retronasal rhinitis, halitosis, tender sinuses on palpation, facial asymmetry and orbital oedema; (4) not diagnosed and treated with antibiotics within the last 30 days; (5) absence of diagnosis of chronic rhinosinusitis; (6) absence of serious malformations in the nose and sinuses; (7) absence of chronic diseases such as cystic brosis, respiratory tract allergy, immune deciency and diabetes; (8) absence of an illness severe enough to require hospitalization; (9) no history of allergy to erdosteine; and (10) family signed consent form. Trial plan Qualied participants were randomized into two groups: group 1 took erdosteine, and group 2 received placebo. Erdosteine, which has mucolytic properties, is licensed for use in children in Turkey. Mucolytic agents are useful in decreasing the viscosity of mucus. In addition, erdosteine has antioxidant properties (1618). Erdosteine was chosen because of its availability in syrup form, twice daily dosage and its favourable taste. Erdosteine was orally administered in the suspension form (Erdostin suspension; Sandoz Drug GmBH, Istanbul, Turkey; 175 mg 5 mL) in two divided doses (daily dose is 58 mg kg for children). Placebo drug samples had similar taste and size but did not contain erdosteine. The aim of this clinical trial was primarily to determine the activity of mucolytic agents (1) in the relief of symptoms and (2) in clinical cure. Both drugs and placebo drug samples were prepared and provided by Sandoz Drug GmBH. Both doctors evaluating the patients and participant families were blinded to the group assignment. Clinical scoring At the onset of the study, the clinical examination of the patients was carried out by the senior physician. The S5 scoring system, which has been used previously, was used for clinical scoring. The ve symptoms of rhinosinusitis (nasal obstruction, day cough, night cough, headache or facial ache and coloured nasal discharge) were taken as the S5 criteria previously used (7). On the scale, symptoms were graded as 0 no symptoms, 1 moderate problem, 2 a severe condition and 3 extremely severe condition. The patients were asked to score their symptoms every day during the treatment. The patient responses were always the same, a little better, getting better, good, very good, bad or very bad. Good or better was evaluated as improvement, no problems left as complete cure, not good always the same as failure of treatment. The patients were examined for a total of three times (at the onset, 3rd

and 14th day of study) by a physician (Dr. I.Y.) during their follow-up, and signs of sinusitis were recorded. Improvement of symptoms, which were present at the initial examination, was also evaluated objectively. S5 scoring, a subjective criterion, was also tested objectively with clinical ndings. On day 14, decrease in S5 score, complete improvement of clinical ndings and complete disappearance of all the complaints were accepted as cure, and doing better as improvement. Randomization method Subjects fullling the inclusion criteria and providing voluntary consent were randomized according to list prepared in a computerized medium regarding the sample size. The entire randomization list was kept secret until the completion of trial numbers. Placebo drug Placebo drugs were prepared by the same drug company (Sandoz Drug GmBH). Placebo samples were undistinguishable from their bottles. The enrolling patients, their families, doctors and statistician were all blind to the drug groups. Carrying out the trial Randomized patients had their physical examinations on enrolment day (Dr. I.Y.) and re-examined on the day 3rd and 14th days of the treatment period. The evaluation was made according to clinical scoring with the likert scale previously used in rhinosinusitis trials in the literature. After the clinical evaluation, the families lled in scoring table given to them every day throughout the trial period (14 days). Evaluation results for each symptom were taken into consideration in the follow-up. Study was monitored for methodology regularly. Outcome measures As primary success criteria, complete disappearance of initial symptoms on day 14 of follow-up was regarded as cure, presence of some symptoms accepted as improvement and persistence of all symptoms was failure of treatment. Observation of an unexpected or unpredictable condition was dened as a complication. Patient compliance to treatment and drug adverse effects were taken as secondary success criteria. While drug adverse effects were dened as unexpected effects that can be related to the drug during the treatment, compliance to treatment was accepted as missing the drug dose <3 times during the entire treatment course. Exclusion criteria Exclusion criteria of the patients included and randomized in the study were dened as (1) voluntary request of the family to leave the trial, (2) absence of regular attendance to follow-up, (3) discovering that the patient did not use the drug, (4) occurrence of any kind of complications and or hospitalization and (5) presence of a chronic disease.

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2009 The Author(s)/Journal Compilation 2009 Foundation Acta Pdiatrica/Acta Pdiatrica 2010 99, pp. 585589

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Sample size Efcacy of the placebo drug was predicted to be 30%, and the contribution of the mucolytic agent to the treatment was 30%. By taking a beta error margin as 0.20 and alpha value as 0.05 and estimating a 30% patient loss, sample size was calculated as 130 with 80% power. Ethic aspect After planning the trial, it was presented to the Ethics Committee of Istanbul University, Istanbul Faculty of Medicine. After obtaining approval from The Ethics Committee, the trial was started. Statistical methods Categorical variants were analysed by chi-square test. Students t-test was used for comparing group scores. All statistical tests were performed using the SPSS 12.0 (licensed by Istanbul University) package for Windows (SPSS Inc, Chicago, IL, USA).

RESULTS During the course of the trial, 130 patients were diagnosed to have acute bacterial rhinosinusitis. Thirty-eight of these patients did not meet the inclusion criteria. Ninety-two eligible participants were randomized. Forty-nine participants were assigned to group 1 (erdosteine drug group), and 43 were assigned to group 2 (placebo group). During followup, eight patients in group 1 and three patients in group 2 were dropped out from the study protocol (Fig. 1). Fortyone participants from group 1 and 40 participants from

group 2 completed the clinical trial. Therefore, the data of 81 patients out of 92 enrolled were used in statistical analysis. The attrition rate was 12% (11 92). The basic demographic characteristics of participants are shown in Table 1. Forty-three percentage of the patients were women. Mean age was 8.5 3.2 years. In responses to treatment, clinical scores declined during the 14-day followup in both group 1 and group 2. Before the treatment, the mean scores of group 1 and group 2 were not signicantly different and were 11.0 5.4 (mean SD) and 12.1 4.5 respectively. On the 14th day of follow-up, mean scores were 3.1 4.1 in group 1 and 2.8 2.6 in group 2, and there was no statistically signicant difference (Table 1 and Fig. 2). When the patients were evaluated according to primary and secondary outcome criteria, 78% of the patients in group 1 achieved complete cure, while in group 2 this rate was 74.4%. The difference between the groups did not reach statistical signicance. Erdosteine created a difference in clinical improvement compared with placebo, although this was not statistically signicant. During the course of treatment, there were no complications requiring hospital administration in both groups.

Number of patients suitable for the trial n: 130

DISCUSSION The treatment of rhinosinutis in children and the efcacy of the medications are controversial. There are few randomized clinical drug efcacy trials about the treatment of sinusitis in the paediatric age group (19). These studies are particularly focused on the efcacy of antibiotics (5,6). The place and efcacy of adjuvants in the treatment of rhinosinusitis are also controversial, and there are very few randomized clinical drug efciency trials carried out in children. These are either about the efciency of topical
Table 1 General characteristics, S5 clinical scores and responses to treatment in erdosteine and placebo groups (n = 81)

Excluded patients n: 38 Not harboring inclusion criteria: 23 Not giving voluntary consent: 15

Variables Gender (number of girls, %) Age (years; mean SD) Weight (kg; mean SD) Height (cm; mean SD) Clinical S5 score* Onset of treatment Day 3 of treatment Day 14 of treatment Improvement rates Total cure (%) Improvement (%) No response (%) Complication (%)

Group 1 using erdosteine (n = 41) 21 (51.2) 9.4 2.8 25.6 10.2 124.0 19.0 11.0 5.4 7.5 6.0 3.1 4.1 78.0 19.6 2.4

Group 2 placebo (n = 40) 14 (35.0) 8.6 3.1 27.8 11.4 122.1 25.9 12.1 4.5 7.1 4.0 2.8 2.6 74.4 23.1 2.5

p 0.53 0.42 0.34 0.58 0.32 0.73 0.67 0.69 0.25 0.44

Entering randomization n: 92

Group-1: Receiving erdosteine n: 49

Group-2: Placebo n: 43

Leaving on followup n: 8

Leaving on followup n: 3

Entering analysis n: 41

Entering analysis n: 40

Figure 1 Flow chart of patients in the study.

= No case. *S5 clinical scoring system: 5 symptoms of rhinosinusitis (nasal obstruction, day cough, night cough, headache or facial ache and coloured nasal discharge) were taken as criteria in clinical scoring. In the scale, 0 no symptoms, 1 moderate problem, 2 severe condition and 3 extremely severe condition. The patients were asked to score their symptoms accordingly every day. Total scores were obtained for each day.

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14 12 10 8 6 4 2 0 0 1 2 3 4 5 6 7 8 Days 9 10 11 12 13 14
Placebo Erdosteine

The limitation of our study is the small number of patients in each group. If the study was carried out with more patients and was designed as a multicenter study, the external validity of our ndings would be higher and could be more generalized. However, when previous randomized clinical studies carried out in children are considered, the number of patients in our trial is not too small. In conclusion, the use of erdosteine as a mucolytic agent in children with acute rhinosinusitis does not directly affect the success of the treatment.

S5 clinical score

Figure 2 Comparison of trends of values obtained with the S5 scoring scale based on the information provided by the families during the treatment and the change with the treatment over the days among the erdosteine and placebo groups.

ACKNOWLEDGEMENTS We thank Prof.Dr. Mary Lu Angelilli for her contribution in the English adaptation of the article and we also thank Prof.Dr. Nermin Guler, Prof.Dr. Fatma Oguz and Prof.Dr. Mujgan Sdal for their cooperation.

References
1. Subcommittee on Management of Sinusitis and Committee on Quality Improvement. Clinical practice guideline: management of sinusitis. American Academy of Pediatrics. Pediatrics 2001; 108: 798808. 2. Espesito S, Principi N. Guidelines fort he diagnosis and treatment of acute and subacute rhinosinusitis in children. J Chemother 2008; 20: 14757. 3. Principi N, Esposito S. New insights into pediatric rhinosinusitis. Pediatr Allergy Immunol 2007; 18 Suppl 18: 79. 4. Leung AK, Keller JD. Acute sinusitis in children: diagnosis and management. J Pediatr Health Care 2004; 18: 726. 5. Wald ER, Chiponis D, Ledesma-Medina J. Comparative effectiveness of amoxicillin and amoxicillin-clavulanate potassium in acute paranazal sinus infactions in children: a double-blind, placebo-controlled trial. Pediatrics 1986; 77: 795800. 6. Wald ER, Nash D, Eickhoff J. Effectiveness of amoxicillin clavulanate potassium in treatment of acute bacterial sinusitis in children. Pediatrics 2009; 124: 915. 7. Garbutt JM, Goldstein M, Gellman E, Shannon W, Littenberg B. A randomized, placebo-controlled trial of antimicrobial treatment for children with clinically diagnosed acute sinusitis. Pediatrics 2001; 107: 61925. 8. Zacharisen M, Casper R. Pediatric sinusitis. Immunol Allergy Clin North Am 2005; 25: 31332. 9. Morris P, Leach A. Antibiotics for persistent nasal discharge (rhinosinusitis) in children. Cochrane Database Syst Rev 2007; CD001094. DOI: 10.1002/14651858.CD001094. pub2. 10. De Sutter A, Lemiengre M, Van Maele G, van Driel M, De Meyere M, Christiaens T, et al. Predicting prognosis and effect of antibiotic treatment in rhinosinusitis. Ann Fam Med 2006; 4: 48693. 11. Tan R, Spector S. Pediatric sinusitis. Curr Allergy Asthma Rep 2007; 7: 4216. 12. Harvey R, Hannan SA, Badia L, Scadding G. Nasal saline irrigations for the symptoms of chronic rhinosinusitis. Cochrane Database Syst Rev 2007; 18: CD006394. 13. Novembre E, Mori F, Pucci N, Bernardini R, Vierucci A, deMartino M. Systemic treatment of rhinosinusitis in children. Pediatr Allergy Immunol 2007; 18 Suppl 18: 5661. 14. Fiocchi A, Sarratud T, Bouygue GR, Ghiglioni D, Bernardo L, Terracciano L. Topical treatment of rhinosinusitis. Pediatr Allergy Immunol 2007; 18 Suppl 18: 627.

corticosteroids or normal saline (14,20). To our knowledge, our research is the rst randomized clinical trial investigating the efcacy of mucolytic agents like erdosteine in the treatment of rhinosinusitis in children. The reason for choosing erdosteine was its anti-inammatory and antioxidant effects in addition to its mucolytic effect, and evidence of its benecial effect in minimizing mucosal damage (17,19). Furthermore, twice daily dosing, availability of a suspension form and a favourable taste were the other reasons for our choice. The randomized, placebo controlled and double blinded nature of our trial increases its validity. The S5 clinical scoring system, which has been used in previous trials, was used in the evaluation of our patients. The limitation of our and the previous studies was the determination of clinical success in sinusitis with a rather subjective evaluation like S5 that was only based on the information from the families. However, another method has not been used as the standard so far. Apart from using this method known as the standard, the patients were also evaluated by a physician during their follow-up and not only those assessed by the family but also the clinical ndings observed by the physician were taken into evaluation. When S5 clinical scoring values were taken into consideration during the follow-up of the patients, there was a difference between the values on day 14 among the groups using the placebo and the drug, but this was not statistically significant (3.1 vs. 2.8). The mucolytic agent does not seem to have a signicant contribution to the success of treatment. There are no signicant differences among the groups regarding possible drug adverse effects. There were no cases with clinically relevant serious adverse effects and consequent hospitalization. No change was noted in the coughing symptom that was predicted to worsen because of the mucolytic effect. Vomiting or bronchospasm were not observed in either group.

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15. CONSORT statement. Available at: http://www.consort-statement.org, connections date: July 23, 2008. 16. Ylmaz HR, Iraz M, Sogut S, Ozyurt H, Yldrm Z, Akyol O, et al. The effects of erdosteine on the activities of some metabolic enzymes during cisplatin-induced nephrotoxicity in rats. Pharmacol Res 2004; 50: 28790. 17. Braga PC, Dal Sasso M, Zucotti T. Assessment of the antioxidant activity of the SH metabolite I of erdosteine on human neutrophil oxidative bursts. Arzneimittelforschung Drug Res 2000; 50: 73946.

18. Balli F, Bergamini B, Calistru P, Ciofu EP, Domenici R, Doros G, et al. Clinical effects of erdosteine in the treatment of acute respiratory tract diseases in children. Int J Clin Pharmacol Ther 2007; 45: 1622. 19. Wald ER. Sinusitis in children. N Engl J Med 1992; 326: 31923. 20. Karadag A, Kurtaran H, Tekin O, Uraldi C, Aydogan T. Isotonic saline or hypertonic saline: which is the best for sinusitis? J Fam Pract 2004; 53: 637.

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