INHALED MUCOACTIVE DRUGS FOR TREATING NON-CYSTIC FIBROSIS BRONCHIECTASIS IN CHILDREN

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1 I.iTER.iATlO.iAL JOl R:'I<AL OF IW\Il'iOPATHOLOG\ AND PHARMACOLOGY Vol. 26, no. 2, (2013) LETTER TO THE EDITOR INHALED MUCOACTIVE DRUGS FOR TREATING NON-CYSTIC FIBROSIS BRONCHIECTASIS IN CHILDREN D. SNIJDERS, S. CALGARO, I. BERTOZZI, S. QUARTESAN, I. KOZUH, F. LUNARDI and A. BARBATO Pediatrics Department, University ofpadua, Italy Received March 22, AcceptedApril 2, 2013 Non-cystic fibrosis bronchiectasis (ncfb) is an acquired condition of variable etiology. Medical treatment basically involves antibiotics and chest physiotherapy. An impaired mucociliary clearance seems to be one of the mechanisms behind ncfb, and inhaled therapy with mucoactive agents has frequently been used to try to correct it. The most often used mucoactive agents in this setting are N-acetylcysteine, hypertonic saline solution (US), mannitol powder and recombinant human DNase (rhdnase). Reviewing the international medical literature on the use of these drugs for patients with ncfb from 1992 to the present day, we retrieved 88 articles, only 12 of which met our selection criteria for this analysis. We found only 2 papers and 2 reviews on the use of rhdnase in children, and in adults 3 trials on US, 5 on mannitol powder and 2 on rhdnase.ln conclusion, no observational or randomized controlled trials (RCT) have been published on the use of these drugs in children with ncfb, while the few conducted on adult patients report some evidence of their effects. Further studies are needed on inhaled mucoactive drugs for the treatment of children with ncfb. Bronchiectasis is an abnormal dilation of the bronchi with thickening of the bronchial walls. It may be limited to the bronchi of a single lobe, or only a segment, or it may be diffuse and involve the bronchi of one or both lungs. It is characterized by inflammation, destruction of bronchial walls and chronic bacterial infection. Clinically, bronchiectasis causes chronic cough and chronic overproduction of sputum. Hypersecretion of viscous mucus can lead to recurrent infections, chronic inflammation and progressive airway obstruction (1). Depending on its etiology, bronchiectasis in children is usually classified according to whether or not it is related to cystic fibrosis (CF). In most cases of non-cystic fibrosis bronchiectasis (ncfb), the condition is acquired and may be the endpoint of a variety of chronic insults, such as recurrent lower respiratory infections, tuberculosis, congenital bronchial abnormalities, acquired bronchial obstruction, immunodeficiency, primary ciliary dyskinesia (PCD), allergic bronchopulmonary aspergillosis, or chronic systemic inflammatory disorders. When its etiology remains unclear, bronchiectasis is defined as idiopathic (I, 2). Cases of ncfb are considered rare in developed countries, but are nonetheless a major cause of chronic suppurative lung disease. Kapur and Karadag reported a prevalenceof 1:5,800 in children under 17 years ofage, a figure confirmed by the HRCT (3). Medical treatment involves antibiotics and chest physiotherapy in an effort to break the vicious circle of infection and prevent further airway destruction Key words: aerosol. hypertonic saline. Nsacetylcysteinc. mannitol. rhdnase. bronchiectasis, children :Huiling address: Prof. A. Barbato. Department of Pediatrics (SOB). Pediatric Endoscopy Unit, University of Padova, via Giustiniani S Padova, Italy rei Fax: barbato@pediatria.unipd.it (2013) Copynght,( by BIOLIFE. s.a.s. This publication and/or anicle is for individual use only and may not be further reproduced without written permission from the copyright holder. Unauthorized reproduction may result in financial and other penalties DISCLOSURE: ALL AUTHORS REPORT NO CONFLICTS OF INTEREST RELEVA:'I<T TO THIS ARTICLE.

2 530 D. SNIJDERS ET AL. (2). An impaired mucociliary clearance seems to be one of the mechanisms causing and perpetuating ncfb, and inhaled therapy with mucoactive agents has frequently been used in an attempt to correct this impairment and alleviate symptoms (3). Many centers using this kind of therapy in ncfb patients follow the same treatment protocol as for CF patients, though there is no documented clinical evidence of its utility (2). The aim of the present review was to summarize the literature published in the last 20 years on the effect of inhaled drugs such as N-acetylcysteine (NAC), hypertonic saline solution (HS), mannitol powder and recombinant human DNase (rhdnase) in the treatment ofchildren with ncfb. MATERIALS AND METHODS We conducted a systematic search in the international medical literature ( ) in PubMed using the following medical subject headings (MeSH): "bronchiectasis/drug therapy" and "administration, inhalation"; then "bronchiectasis" was sequentially combined with "acetylcysteine", "mucolytics", "hypertonic solution", "mannitol", "hyperosrnolar", and "rhdnase". The Cochrane library was checked for any additional clinical trials. Analytical criteria Articles were considered relevant if they described randomized controlled trials (RCTs), uncontrolled observational studies, or case reports, reporting clinical data on children aged 0-18 years or on adults with ncfb. Only studies concerning drugs administrated by inhalation were considered. RESULTS In all, 88 relevant articles were retrievedfrom the adult and pediatric literature; 76 were rejected on the strength of our analytical criteria, while 12 papers on ncfb were considered for the purposes of this review (Fig. 1). The studies on the efficacy of HS inhalation in patients with ncfb (Table I) show that HS treatment Papers retrieved from systematic search in PubMed NAC US Mannitol powder rhdnase ~ 2 pediatric case report 2 trials on adults Fig. 1. Flow chart ofliterature review on pediatric ncfb. Results ofthe systematic PubMedsearch on pediatric ncfb in the English-language medical literature/rom 1992 to ncfb: non-cystic fibrosis bronchiectasis; NAC: N-acetylcysteine; HS: hypertonic saline solution; rhdnase: recombinant human DNase.

3 Int. J. ImmunopathoL Pharmacol. 531 Table I. Studies on the effect ofhypertonic saline in adults with ncfb. Year Method Patients Intervention Results 2005 RCT 24 Four single treatment schedules in random order: Significant effects of HS treatment: (4) (Adults) l. active cycle breathing technique (ACBT) - Higher sputum weight. alone; - Lower sputum viscosity after HS treatment. 2. nebulised terbutaline, nebulised HS (7%) - Lower Ease of expectoration with HS. then ACBT; - Increased FEVI and FVC. 3. nebulised terbutaline, nebulised IS (0.9%) then ACBT; 4. nebulised terbutaline, nebulised HS then ACBT RCT, single blind, 28 Patients were divided in two groups: Regular use of 7% HS improves lung function, (5) cross-over. (Adults) 1-4 weeks run-in of two distinct group; quality of life and health care utilisation in ncfb. 2- once daily inhalation of placebo (0.9% IS) or HS (7%) for 3 months; 3-4 weeks wash-out; 4- Cross-over of the treatment between the two groups for 3 months RCT 40 Inhalation of IS 0.9% or HS (6%) daily for 12 Inhalation of HS or IS has similar positive effects (6) (Adults) months. on exacerbations, quality of life, sputum colonization and respiratory function over twelve months in ncfb. HS: hypertonic saline; IS: isotonic saline; ACBT: active cycle breathing technique. Reference number in brackets under the year. Table II. Studies on the effect ofmannitol in adults with ncfb. Year Method Patients Intervention Results 1999 RCT cross- II Inhaled mannitol once, 320 (± 81) mg vs placebo. Inhalation of dry mannitol powder increased (7) over/open-labeled (Adults) clearance ofmucus and thus has the potential to benefit patients with bronchiectasis Controlled clinical 8 Inhaled mannitol once, 400 mg vs placebo. Mannitol inhalation acutely increases clearance (8) trial, open-labeled (Adults) of mucus, and this effect extends beyond the acute study period, resulting in decreased mucus retention at 24 h Controlled clinical 9 Inhaled mannitol 400 mg once daily for 12 days. Mannitol significantly improved health status (9) trial (Adults) over 12 days and the improvement was maintained for 6-10 days. Mannitol reduced mucus tenacity, increased mucus hydration acutely and improved cough clearability RCT, open-labeled 14 Inhaled mannitol in increasing doses Mucus clearance increases with increasing (10) (Adults) (160/320/480 mg) vs placebo. doses of mannitol and can be further increased by cough RCT, open-labeled 14 Inhaled mannitol increasing doses (160/320/480 Inhaled mannitol and voluntary repetitive (II) (Adults) mg) vs placebo. coughing improved the sputum's physical properties and this effect was not dosedependent. Changes in sputum properties did not predict efficacy of mucociliary and cough clearance. Reference number in brackets under the year.

4 532 D. SNIJDERS ET AL. Table III. Studies on the effect ofrhdnase in children and adults with ncfb. r Year Method Patients Intervention Results r 1995 Case report 14-year-old 2.5 mg rhdnase once daily Cough lessened and volume ofsputum decreased ( 12) girl with within 72 h. Spirometry after 4 weeks demonstrated Kartageners an improvement of20% in FEVI and 13% in FVC. 1 (PCD) These improvements were maintained after 4 I, I syndrome months. Double-blind 61 Group mg rhdnase twice daily for 2 weeks RhDNase produced no significant changes in ~96 ( 13) placebo-controlled (Adults) Group 2- rhdnase once daily for 2 weeks spirometry. subjective quality oflife. dyspnea. or study I Group 3- placebo for 2 weeks sputum transportability. il99x I Double~blind. 349 Aerosolized rhdnase or placebo twice daily for Pulmonary exacerbations were more frequent and ( I~), randomized, (Adults) 24 weeks FEV I decline was greater in patients who received, placebo- the rhdnase than in those given placebo., controlled. multicenter study! case reports a- a 13-year- 2.5 mg nebulized rhdnase once daily In both cases. rhdnase treatment improved ( 15) (brothers) old boy with a- as of26 months ofage respiratory symptoms and pulmonary function Kartagener's b- as of 7 years ofage (PFT). An exacerbation ofsymptoms and decline in (PCD) FEVI was recorded after terminating the therapy. I syndrome; b- a 17-yearold patient with PCD Reference number in brackets under the year. significantly improves lung function, quality of life, sputum output, viscosity and colonization in adults (4-6). We could find no studies on mannitol powder inhalation in children with ncfb. Table II shows 5 studies on the efficacy of mannitol treatment in terms of mucus clearance and sputum properties in adults (7-II). The use of rhdnase treatment in pediatric age is only described in 3 children with PCD/Kartagener's syndrome (Table III); these papers reported that it was effective in reducing mucus and improving pulmonary function test parameters. Two adult studies did not report the same results (12-15). We found no papers on the safety and efficacy of NAC, mannitol powder, HS or rhdnase in childhood, nor any observational studies or RCTs on the use ofnebulized NAC in adults with ncfb. DISCUSSION Among the mucoactive drugs considered, studies on NAC were unable to demonstrate their value in treating ncfb in children or adults. There are also no data available on the efficacy ofnac aerosol use in CF patients, or its efficacy after oral administration (17, 18). HS would appear to increase mucociliary clearance in CF (19), but only a few available studies concern ncfb, and its efficacy has only been tested in adult patients, showing positive effects on sputum properties and lung function (5-7). The use ofhs 3% has provedbeneficial in infants and childrenwith viral bronchiolitis (20), and in the treatment ofpulmonary atelectasis (21). The five studies considered in our review on the effect ofmannitol powder inhalation in adult patients with ncfb indicate that this treatment increases mucus clearance (7-11) and improves the physical properties of the sputum (9, 11). No side effects ofmannitol use have been reported, though bronchial hyper-responsiveness can occur (I, 10). Data on children are unavailable, partly because patient compliance is an issue when it comes to inhaling a dry-powder formulation. RhDNase is potentially capable of reducing lung secretion viscosity and increasing mucociliary transportability by hydrolyzing DNA polymers and reducing DNA length. There are numerous papers on the positive effect of aerosolized rhdnase in CF patients, with changes to the voice and rash emerging as the only side effects in RTCs (22). The available evidence of any positive effects of such a therapy on ncfb in childrencomes only from a few case reports (12, 15),

5 lot. J. Immuoopathol. Pharmacol. 533 while some small, uncontrolled trials reported that the treatment was of no benefit to adults with ncfb (13, 14). One explanation for this discrepancy might be that rhdnase would only be effective in patients with thick secretions that cannot be mobilized by standard treatment (23). A limitation of our analysis lies in that we only searched the literature in the PubMed database and Cochrane library, an approach that may have been too restrictive. In conclusion, while inhaled drugs influencing mucociliary clearance in pediatric CF patients have been amply studied to ascertain their safety and effectiveness, there is no such evidence available in the literature for children with ncfb. RCTs are needed to clarify the effectiveness of mucoactive agents in these patients. REFERENCES I. Wills P, Greenstone M. Inhaled hyperosmolar agents for bronchiectasis. Cochrane Database Syst Rev 2006; 2:CD Ilowite J, Spiegler P, Kessler H. Pharmacological treatment options for bronchiectasis: focus on antimicrobial and anti-inflammatory agents. Drugs 2009; 69: Kapur N, Karadag B. Differences and similarities in non-cystic fibrosis bronchiectasis between developing and affluent countries. Paediatr Respir Rev 2011; 12: Kellett F, Redfern J, Niven RM. Evaluation of nebulised hypertonic saline (7%) as an adjunct to physiotherapy in patients with stable bronchiectasis. Respir Med 2005; 99: Kellett F, Robert NM. Nebulised 7% hypertonic saline improves lung function and quality of life in bronchiectasis. Respir Med 2011; 105: Nicolson CH, Stirling RG, Borg BM, Button BM, Wilson JW, Holland AE. The long-term effect of inhaled hypertonic saline 6% in non-cystic fibrosis bronchiectasis. Respir Med 2012; 106: Daviskas E, Anderson SD, Eberl S, Chan HK, Bautovich G. Inhalation of dry powder mannitol improves clearance of mucus in patients with bronchiectasis. Am J Respir Crit Care Med 1999; 159: Daviskas E, Anderson SD, Eberl S, Chan HK, Young IH. The 24-h effect of mannitol on the clearance of mucus in patients with bronchiectasis. Chest 2001; 119: Daviskas E, Anderson SD, Gomes K, Briffa P. Cochrane B, Chan HK, Young IH, Rubin BK. Inhaled mannitol for the treatment of mucociliary dysfunction in patients with bronchiectasis: effect on lung function, health status and sputum. Respirology 2005; 10: Daviskas E, Anderson SD, Eberl S, Young IH. Effect of increasing doses of mannitol on mucus clearance in patients with bronchiectasis. Eur Respir J 2008; 31: Daviskas E, Anderson SD, Young IH. Effect of mannitol and repetitive coughing on the sputum properties in bronchiectasis. Respir Med 2010; 104: Desai M, Weller PH, Spencer DA. Clinical benefit from nebulized human recombinant DNase in Kartagener's syndrome. Pediatr Pulmonol 1995: 20: Wills PJ, Wodehouse T, Corkery K, Mallon K. Wilson R, Cole PJ. Short-term recombinant human DNase in bronchiectasis. Effect on clinical state and in vitro sputum transportability. Am J Respir Crit Care Med 1996; 154: O'Donnell AE, Barker AF, Ilowite JS, Fick RB. Treatment of idiopathic bronchiectasis with aerosolized recombinant human DNase 1. rhdnasc Study Group. Chest 1998; 113: EI-Abiad NM, Clifton S, Nasr SZ. Long-term use of nebulized human recombinant DNase I in two siblings with primary ciliary dyskinesia. Respir Med 2007; 101: Randell SH, Boucher RC. Effective mucus clearance is essential for respiratory health. Am J Respir Cell Mol Bioi 2006; 35: Henke MO, Ratjen F. Mucolytics in cystic fibrosis. Paediatr Respir Rev 2007; 8: Nash EF, Stephenson A, Ratjen F, Tullis E. Nebulized and oral thiol derivatives for pulmonary disease in cystic fibrosis. Cochrane Database Syst Rev 2009; 1:CD Elkins MR, Robinson M, Rose BR, et al: National Hypertonic Saline in Cystic Fibrosis (NHSCF) Study Group. A controlled trial oflong-term inhaled

6 534 D. SNIJDERS ET AL. hypertonic saline in patients with cystic fibrosis. N Engl J Med 2006; 3543: Kuzik BA, AI-Qadhi SA, Kent S, Flavin MP, Hopman W, Hotte S, Gander S. Nebulized hypertonic saline in the treatment of viral bronchiolitis in infants. J Pediatr 2007; 151: Oilmen U, Karagol BS, Oguz SS. Nebulised hypertonic saline and recombinant human DNase in the treatment of pulmonary atelectasis in newborns. Pediatr Int 2011; 53: Jones AP, Wallis C. Dornase alpha for cystic fibrosis. Cochrane Database Syst Rev 2010; 3:CDOO1l Ratjen F. Dornase in non-cf. Pediatr Pulmonol 2004; 26: