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Figure.

 Individual patients’ responses to medical therapy and sinus surgery. An improvement of at least 30% in nasal symptoms is judged clinically significant. Each point on the graph represents 1 patient.

Individual patients’ responses to medical therapy and sinus surgery. An improvement of at least 30% in nasal symptoms is judged clinically significant. Each point on the graph represents 1 patient.

Table 1. 
Baseline Characteristics of the Study Population*
Baseline Characteristics of the Study Population*
Table 2. 
Trial Outcomes From the Dornase Alfa and Placebo Groups*
Trial Outcomes From the Dornase Alfa and Placebo Groups*
1.
Davis  PBDrumm  MKonstan  MW Cystic fibrosis. Am J Respir Crit Care Med 1996;1541229- 1256
PubMedArticle
2.
Koch  CHoybi  N Pathogenesis of cystic fibrosis. Lancet 1993;3411065- 1074
PubMedArticle
3.
Shah  PLScott  SFKnight  RAMarriott  CRanasinha  CHodson  ME In vivo effects of recombinant human Dnase I on sputum in patients with cystic fibrosis. Thorax 1996;51119- 125
PubMedArticle
4.
Suri  RMetcalfe  CLees  B  et al.  Comparison of hypertonic saline and alternate-day or daily recombinant human deoxyribonuclease in children with cystic fibrosis: a randomised trial. Lancet 2001;3581316- 1321
PubMedArticle
5.
Davies  JTrindade  MTWallis  CRosenthal  MCrawford  OBush  A Retrospective review of the effects of rhDNase in children with cystic fibrosis. Pediatr Pulmonol 1997;23243- 248
PubMedArticle
6.
Hui  YGaffney  RCrysdale  WS Sinusitis in patients with cystic fibrosis. Eur Arch Otorhinolaryngol 1995;252191- 196
PubMedArticle
7.
King  V Upper respiratory disease, sinusitis, and polyposis. Clin Rev Allergy 1991;9143- 158
PubMed
8.
Gysin  CAlothman  GAPapsin  BC Sinonasal disease in cystic fibrosis: clinical characteristics, diagnosis, and management. Pediatr Pulmonol 2000;30481- 489
PubMedArticle
9.
Tomooka  LTMurphy  CDavidson  TM Clinical study and literature review of nasal irrigation. Laryngoscope 2000;1101189- 1193
PubMedArticle
10.
Raynor  EMButler  AGuill  MBent  PB Nasally inhaled dornase alfa in the postoperative management of chronic sinusitis due to cystic fibrosis. Arch Otolaryngol Head Neck Surg 2000;126581- 583
PubMedArticle
11.
Shwachman  HKulczycki  L Long-term study of one hundred five patients with cystic fibrosis. AJDC 1958;966- 15
12.
Lund  VJHolmstrom  MScadding  GK Functional endoscopic sinus surgery in the management of chronic rhino-sinusitis: an objective assessment. J Laryngol Otol 1991;105832- 835
PubMedArticle
13.
Klingbeil  PWiersbitzky  SBruns  RBallke  EH The saccarin test in the pediatric broncho-pneumologic outpatient: a non-invasive screening method for the assessment of ciliary function of the respiratory tract in children. Kinderarztl Prax 1990;58205- 210
PubMed
14.
Lund  VJKennedy  DWThe Staging and Therapy Group, Quantification for staging sinusitis. Ann Otol Rhinol Laryngol Suppl 1995;16717- 21
PubMed
15.
American Thoracic Society, Standardization of spirometry: 1987 update. Am Rev Respir Dis 1987;1361285- 1298
PubMedArticle
16.
Fuchs  HJBorowitz  DSChristiansen  DH  et al.  Effect of aerosolized recombinant human DNase on exacerbations of respiratory symptoms and on pulmonary function in patients with cystic fibrosis. N Engl J Med 1994;331637- 642
PubMedArticle
17.
Ballmann  MVon der Hardt  H Hypertonic saline and recombinant human DNase: a randomised cross-over pilot study in patients with cystic fibrosis. J Cyst Fibros 2002;135- 37
PubMedArticle
18.
Eng  PAMorton  JDouglass  JARiedler  JWilson  JRobertson  CF Short-term efficacy of ultrasonically nebulized hypertonic saline in cystic fibrosis. Pediatr Pulmonol 1996;2177- 83
PubMedArticle
19.
Umetsu  DTMoss  RBKing  VV  et al.  Sinus disease in patients with severe cystic fibrosis: relation to pulmonary exacerbation. Lancet 1990;3351077- 1078
PubMedArticle
20.
Madonna  DIsaacson  GRosenfeld  RMPanitch  H Effect of sinus surgery on pulmonary function in patients with cystic fibrosis. Laryngoscope 1997;107328- 331
PubMedArticle
21.
Nishioka  GJCook  PR Paranasal sinus disease in patients with cystic fibrosis. Otolaryngol Clin North Am 1996;29193- 204
PubMed
22.
Duplechain  JKWhite  JAMiller  RH Pediatric sinusitis: the role of endoscopic sinus surgery in cystic fibrosis and other form of sinonasal disease. Arch Otolaryngol Head Neck Surg 1991;117422- 426
PubMedArticle
23.
Cepero  RSmith  RCatlin  FBressler  KFuruta  GShandera  K Cystic fibrosis: an otorhinolaryngologic perspective. Otolaryngol Head Neck Surg 1987;97356- 360
PubMed
24.
Mygind  N Advances in the medical treatment of nasal polyps. Allergy 1999;5412- 16
PubMedArticle
25.
Barr  MBWeiss  STSegal  MRTager  IBSpeizer  FE The relationship of nasal disorders to lower respiratory tract symptoms and illness in a random sample of children. Pediatr Pulmonol 1992;1491- 94
PubMedArticle
Original Article
December 2005

Dornase Alfa as Postoperative Therapy in Cystic Fibrosis Sinonasal Disease

Author Affiliations

Author Affiliations: Departments of Otorhinolaryngology (Drs Cimmino, Nardone, and Cavaliere) and Pediatrics (Drs Plantulli, Sepe, Esposito, Mazzarella, and Raia), University of Naples “Federico II,” Naples, Italy.

Arch Otolaryngol Head Neck Surg. 2005;131(12):1097-1101. doi:10.1001/archotol.131.12.1097
Abstract

Objective  To determine the benefit of nasally inhaled dornase alfa in patients with cystic fibrosis and nasal symptoms.

Design  Double-blind placebo-controlled trial.

Setting  Cystic Fibrosis Regional Center of Campania at the University of Naples “Federico II.”

Patients  A total of 24 patients with cystic fibrosis and chronic sinusitis.

Interventions  Patients underwent sinonasal surgery during a 3-year period and received once-daily doses of either dornase alfa (2.5 mg) or hypotonic saline solution (5 mL) beginning 1 month after surgery and for a 12-month period.

Main Outcome Measures  Primary outcomes were nasal-related symptoms and nasal endoscopic appearance; secondary outcomes were forced expiratory volume in 1 second, nasal computed tomography findings, and saccharine clearance test results. Patients were evaluated before and after treatment.

Results  After surgery, all outcomes were significantly improved for each treatment at 1 month (P<.05); primary outcomes were improved at 24 and 48 weeks in the group receiving dornase alfa (P<.05), and at 12 weeks in the group receiving placebo. Secondary outcomes were better in the dornase alfa group (P<.01) than in the placebo group at 12 months except for the saccharine clearance test results. In particular, median relative difference in forced expiratory volume in 1 second between dornase alfa and placebo was significantly improved in the dornase alfa group (P<.01).

Conclusions  Nasally inhaled dornase alfa can be effective in patients with cystic fibrosis and sinonasal disease who do not respond to conventional therapy after surgical treatment. Further studies should be carried out to determine the long-term effect on sinus disease, recurrence of polyps, and quality of life.

Cystic fibrosis (CF) is the most common lethal recessive disorder in white populations and is caused by a defective cystic fibrosis transmembrane conductance regulator, a chloride channel protein, leading to improper salt balance and thick tenacious secretions. Chronic bacterial infection and a vigorous host inflammatory response damage lungs and cause loss of pulmonary function.1 Large amounts of DNA coming from the degeneration of neutrophils lead to high viscosity of airway secretions in the sputum of patients with CF.2 It has been proposed that dornase alfa (recombinant human deoxyribonuclease) should cleave extracellular DNA in airway secretions and thus reduce in vivo sputum viscosity.3 Clinical trials and observational studies on the efficacy of dornase alfa inhalatory therapy have shown improvement in lung function (from 4.3% to 16% of median forced expiratory volume in 1 second [FEV1] increase) and a decrease of respiratory exacerbations in patients with CF and moderate lung disease.4,5

Sinonasal disease with or without nasal polyps is a common feature in patients with CF. Little information about its possible adverse effect on pulmonary function is currently available.6 It is suggested that mucus viscosity can lead to mechanical obstruction of sinus ostia, and impaired mucociliary clearance causes widespread inflammatory paranasal sinus disease and recurrent infections.7 The reestablishment of ventilation and drainage of sinonasal pathways are the goals of conventional treatment of CF.8 Nasal irrigation is used to clear secretions, debris, and crusts in the nose; furthermore, it may decongest nasal mucosa and improve mucociliary clearance and well-being.9 Moreover, inhaled topical therapy for sinonasal disease is generally no longer effective, and surgery is often required, especially for removing nasal polyps.8 Recently, the potential benefit of nasally inhaled dornase alfa in postoperative treatment of patients with CF and chronic sinusitis was considered in a preliminary study.10 The aim of the present study was to evaluate clinical response and long-term effects of nasally inhaled dornase alfa in patients with CF and surgically treated sinonasal disease.

METHODS
PATIENTS

Twenty-nine (11%) of 256 patients with CF who were surgically treated for chronic sinusitis with or without nasal polyps were consecutively enrolled during a 3-year period. Cystic fibrosis was diagnosed during regular follow-up at the CF Regional Center of Campania by the presence of typical clinical symptoms and repeatedly positive findings from the sweat test, according to guidelines.1 Five of 29 subjects withdrew from the study immediately before randomization without starting any treatment owing to a prolonged illness after surgery. Twenty-four patients with sinonasal disease (13 girls and 11 boys; mean ± SD age, 10.6 ± 2.7 years; age range, 7-15 years) were considered eligible for the study when they were clinically stable.

Disease severity was assessed by the clinical Shwachman-Kulczycki (SK) score based on general activity, physical examination, nutrition, and conventional chest radiographic findings. In general, SK scores rate the patient’s condition as excellent (86-100), good (71-85), fair (56-70), moderate (41-55), or severe (≤40).11 The mean SK score was 70 (range 55-80) in enrolled patients. At enrollment, lung function was assessed by standard spirometry with a compact spirometer: FEV1 ranged from about 57% to about 70% of predicted values.

Ten patients were considered to have chronic Pseudomonas aeruginosa (PA) infection on the basis of persistent isolation of PA from respiratory samples for at least 6 consecutive months. Ten (42%) of 24 patients had allergic rhinitis (determined by skinprick test) and did not respond to conventional topical therapy for allergy. The mean number of pulmonary exacerbations per year was 0.9 (range, 0-2) for patients with CF enrolled during the study.

Baseline characteristics of enrolled patients are summarized in Table 1. Ethics approval for this trial was obtained from the center, and written informed consent was obtained from the guardian of each child (and the patient when appropriate).

PROCEDURES

This prospective, randomized, double-blind trial was performed primarily to evaluate the beneficial therapeutic effect of aerosolized dornase alfa vs placebo in the postsurgical treatment of chronic sinusitis related to CF. Indications for sinus surgery included chronic nasal obstruction with mouth breathing, chronic purulent draining unresponsive to medical treatment for at least 6 consecutive months, and persistent headaches. No participants had received any investigational drug therapy within 4 months prior to nasal surgery.

Endoscopic sinus surgery consisted of nasal polypectomy, anterior and/or posterior ethmoidectomy, frontal recess surgery, middle meatal antrostomy, reduction of inferior and middle turbinate, sphenoidotomy, and uncinetomy.12 To ensure a clinically stable status prior to randomization, all patients received nasal lavages with 7% hypertonic saline solution for 2 weeks after surgery.

One month after surgery, patients were randomly assigned to receive for 1 year either dornase alfa or placebo. The first group of 12 patients underwent 4 consecutive treatment cycles, each cycle consisting of 8 weeks of therapy with once-daily 2.5-mg doses of dornase alfa (in 2.5 mL of vehicle; Genentech, San Francisco, Calif) separated by 4-week washout periods. The second group followed the same dosing schedule with once-daily placebo inhalation (21.9 mg of sodium chloride and 0.38 mg of calcium chloride in 2.5 mL of water for inhalation) (Genentech). Both therapies were iso-osmolar and administered into both nostrils in the morning via a Sidestream nebulizer and Portaneb compressor (Medic-Aid Ltd, West Sussex, England), with a mean daily inhalation time of 11 minutes.

No patient discontinued treatment. Vials were assigned by an operator not participating in the study, returned, and counted at the end of each treatment course as a measure of compliance. The patients, investigators, and all study participants remained blinded to the treatment assignment until the study was completed. The follow-up visits were performed before surgery and 4, 12, 24, and 48 weeks after surgery for both groups of patients. Routine medication and physiotherapy were continued throughout the study.

The protocol-defined primary outcome was the assessment of nasal-related symptoms and nasal endoscopic appearance. Secondary outcome measures were results of nasal radiologic examination, saccharine clearance test,13 and FEV1. At each visit, the severity of 6 symptoms was evaluated on a well-established scale12 of 0 to 10, with 10 being the most severe: (1) facial pain or pressure, (2) headache, (3) nasal blockage and congestion, (4) nasal discharge, (5) olfactory disturbance, and (6) overall discomfort.

Endoscopic investigations were performed with the patient in a sitting position by a 2.7-mm flexible endoscope. No decongestant or local anesthesia was used. Nasal endoscopic appearance was scored by 2 otorhinolaryngologists using the postoperative criteria described by Lund and Kennedy.14 In particular, the presence of residual polyps, edema, discharge, scarring, and crusting of both nasal cavities was scored as follows: absence of polyps, 0; presence of polyps confined to the middle meatus, 1; presence of polyps beyond the middle meatus, 2; no discharge, 0; clear and thin discharge, 1; thick and purulent discharge, 2; the absence and presence of edema, scarring, and crusting were scored at 0 and 1, respectively.14

Mucociliary clearance was assessed at each visit by performing a saccharine test.13 A fragment of saccharin tablet was placed 1 cm behind the anterior margin of the inferior turbinate, and the patient was instructed to sit with his head inclined forward by 10 degrees. During the test, the patient had to frequently swallow (every 30 seconds) and avoid blowing the nose. Mucociliary transport time under endoscopic control was investigated.

Axial and coronal computed tomographic (CT) scans of the nose and paranasal sinuses were performed, mostly using the limited-slice CT method before surgery and at weeks 24 and 48 after surgery. The CT findings were scored by 2 otorhinolaryngologists according to well-defined radiologic staging standards.14 Each sinus (maxillary sinus, anterior ethmoid, posterior ethmoid, sphenoid sinus, and frontal sinus) was graded as 0 (no abnormality), 1 (partial opacification), or 2 (total opacification). The osteomeatal complex was scored only as 0 (not occluded) or 2 (occluded). Before surgery and at the end of the trial, spirograms were assessed by a compact spirometer (Vitalograph, Buckingham, England). Forced vital capacity (FVC), FEV1, FEV1/FVC ratio, and the forced expiratory flow during the middle half of the FVC (FEF25%-75%) were recorded and expressed as a percentage of predicted values based on sex, height, and age according to American Thoracic Society standards.15

A standard costing method was not used to assess the total health care cost for therapy.

STATISTICAL ANALYSIS

Data analysis of the 2 groups in the clinical trial are presented as mean ± SD and percentages. Findings for each parameter were compared within the groups by 1-way analysis of variance for repeated measures. The null hypothesis tested for each outcome measure was that the mean values were equal at all time points. If a significant difference was found either after surgery or during therapy, pairwise comparisons were performed using the Newman-Keuls method.

To determine the effect of sinus surgery and drug therapy on pulmonary function, FEV1 was compared by the t test for paired data. Comparisons between treatment groups were analyzed by unpaired t tests. In keeping with the aim of the study, multiple regression was used to account for potential confounding factors that might have introduced bias (number of operations, the child’s age at first operation, presence of allergic rhinitis, and extent of the operation as assessed by surgery score). In this analysis, the primary outcomes, symptom score, and endoscopic appearance score were expressed as percentage differences between the examination at 1 month and at 12 months after surgery. All hypothesis tests were set with an alpha level of .05. A computerized statistical package was used to perform all statistical analyses (SPSS version 10.0; SPSS Inc, Chicago, Ill).

RESULTS

Twelve patients were randomized to receive dornase alfa, and 12 placebo. None of the enrolled patients without chronic colonization acquired PA during the study. On the basis of returned treatment packs, the estimated adherence (average proportion of medication taken) was 94% for placebo and 98% for dornase alfa. At baseline, there were no significant differences between the treatment groups and no order of randomization effect on either primary outcomes (symptom score, P = .93; endoscopic appearance score, P = .28) or secondary outcomes (surgery score, P = .75; radiologic score, P = .72; saccharine clearance test, P = .78).

Surgical treatment followed by medical therapy with either dornase alfa or placebo produced a significant improvement in all the parameters within both groups (P<.01), and it appeared to be the most effective therapy after 4 weeks. The Figure shows individual patient responses to medical therapy and sinus surgery. An improvement of at least 30% in nasal symptoms was judged clinically significant.

In the treatment group, all outcomes (ie, nasal symptoms score, endoscopic appearance score, radiologic score, and saccharine clearance test score) improved at each visit. The greatest improvement was observed 24 weeks after surgery for primary outcomes, as confirmed by the analysis of comparison between each treatment period (Table 2). In the placebo group, the greatest improvement in the primary outcomes was observed 12 weeks after surgery, with a mild worsening in the last 24 weeks of therapy, while the mucociliary transport appeared to improve at each measurement (Table 2). In particular, the placebo group showed a mean improvement in nasal symptoms score of 23.1% at 24 weeks after surgery and a worsening of 3% between weeks 24 and 48 after surgery. Conversely, the dornase alfa group showed a persistent improvement throughout the study in both nasal symptoms (up to a mean of 32.5%) and endoscopic appearance (43.5%) by 48 weeks after surgery. The overall increase in FEV1 was significant (8.9%; P<.05) for the dornase alfa group but not for the placebo group (3.03%; P = .08).

There were significant differences between the 2 groups for all the outcomes at the end of trial except for saccharine clearance test scores, which did not achieve a statistically significant difference. The efficacy of medical therapy, expressed as percentage differences of either symptoms score (adjusted R2 = 0.87) or endoscopic appearance score (adjusted R2 = 0.93) and adjusted for potential confounders with the multiple regression procedure, showed a very significant benefit in patients who received dornase alfa (P<.001). No patient treated with dornase alfa showed specific adverse events.

COMMENT

This randomized, prospective, double-blind trial compared the effects of placebo and dornase alfa in patients with CF surgically treated for chronic rhinosinusitis. In recent years, dornase alfa has been widely used in the treatment of patients with CF and moderate pulmonary disease, but there are still unclear issues associated with a wide variation in individual response.4,16,17 Recently, a preliminary report suggested the potential impact of nasally inhaled dornase alfa in controlling postoperative symptoms and decreasing the recurrence rate of nasal polyps in patients with CF and chronic sinusitis.10 In our study, aerosolized dornase alfa treatment significantly improved all outcome measures over placebo; furthermore, improvement of clinical findings was demonstrated to increase over the 48 weeks after surgery. Nebulized placebo showed a significant effectiveness for the medium term (Table 2).

Generally, symptoms and health status of patients with sinonasal disease appear to be improved under placebo irrigation.9 In our CF placebo group, we observed an improvement in the nasal symptoms score in the first 24 weeks after surgery and then a worsening between weeks 24 and 48 after surgery. Conversely, our data show a persistent improvement in the nasal symptoms score at 48 weeks after surgery with dornase alfa therapy.

Dornase alfa efficacy on impaired mucociliary transport in patients with CF is reported herein and elsewhere.4,5 It seems that improvements in the radiologic picture 6 months after surgery in both groups is the result of sinus surgery rather than of medical treatment. In the dornase alfa group, we believe that persistence in improved radiologic findings at 48 weeks after surgery could be related to the effect of this therapy. The extent of surgery, number of surgical procedures, and presence of nasal allergy did not interfere with dornase alfa efficacy in improving the primary outcomes such as symptoms score and endoscopic appearance score.

An increase in pulmonary function is thought to be related both to medical therapy and surgery. Results of previous studies have shown that hypertonic saline solution improves sputum clearance and pulmonary function, with a mean FEV1 improvement ranging from 3% to 15% in the short term.4,18 The effect of dornase alfa on lung function, well-being, and airway viscosity in patients with CF is well demonstrated in several longer-term trials.4,5,16 Umetsu et al19 suggested a positive effect of sinus surgery in controlling pulmonary exacerbations, although no improvement in lung function test was observed in this study, nor in that by Madonna et al.20

Nevertheless, surgery plays the most important role in the management of sinonasal disease. Nasal polyposis occurs at a rate ranging from 6% to 48% in CF and shows either a high recurrence rate after nasal polypectomy or frequent spontaneous resolution by late adolescence.21,22 In our study, surgery seems to result in the greatest improvement (Figure) and to enhance the efficacy of subsequent medical therapy. Nasal polypectomy with intranasal ethmoidectomy represents the procedure of choice, showing a lower recurrence rate than polypectomy alone.23 Dornase alfa could be considered a tool for reducing nasal complaints and extending the effects of surgery.

However, a longer follow-up period is needed to establish the role of dornase alfa in preventing recurrence of nasal polyps after sinus surgery and its cost-effectiveness (considering the high long-term cost of this daily therapy). Investigations should verify the effect of other medical therapies compared with dornase alfa either in improving rhinitis symptoms and nasal airway patency or in reducing both size and recurrence rates of polyps.24

Several studies have suggested a relationship between sinusitis and chronic pulmonary disease.19,25 In CF, an association of sinus disease with lung worsening has not been clearly demonstrated; however, sinus disease could play a significant role in quality of life and morbidity. Furthermore, chronic mouth breathing and anosmia related to nasal obstruction and rhinorrhea, often complained of by patients with CF and sinus disease, may affect appetite. We have recorded (data not shown) a significant reversal of weight loss after 6 months of dornase alfa therapy in all patients.

The present study is a clinical pilot investigation. Longer-duration trials should be carried out to determine the effect of inhaled dornase alfa on recurrence rate of polyps after sinus surgery, on quality of life, and pulmonary function, and prospectively to assess dornase alfa as an alternative therapy to surgery.

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Article Information

Correspondence: Valeria Raia, MD, Department of Pediatrics; University of Naples “Federico II,” via S. Pansini, 5-80131 Naples, Italy (raia@unina.it).

Submitted for Publication: March 29, 2005; final revision received July 13, 2005; accepted July 25, 2005.

Financial Disclosure: None.

References
1.
Davis  PBDrumm  MKonstan  MW Cystic fibrosis. Am J Respir Crit Care Med 1996;1541229- 1256
PubMedArticle
2.
Koch  CHoybi  N Pathogenesis of cystic fibrosis. Lancet 1993;3411065- 1074
PubMedArticle
3.
Shah  PLScott  SFKnight  RAMarriott  CRanasinha  CHodson  ME In vivo effects of recombinant human Dnase I on sputum in patients with cystic fibrosis. Thorax 1996;51119- 125
PubMedArticle
4.
Suri  RMetcalfe  CLees  B  et al.  Comparison of hypertonic saline and alternate-day or daily recombinant human deoxyribonuclease in children with cystic fibrosis: a randomised trial. Lancet 2001;3581316- 1321
PubMedArticle
5.
Davies  JTrindade  MTWallis  CRosenthal  MCrawford  OBush  A Retrospective review of the effects of rhDNase in children with cystic fibrosis. Pediatr Pulmonol 1997;23243- 248
PubMedArticle
6.
Hui  YGaffney  RCrysdale  WS Sinusitis in patients with cystic fibrosis. Eur Arch Otorhinolaryngol 1995;252191- 196
PubMedArticle
7.
King  V Upper respiratory disease, sinusitis, and polyposis. Clin Rev Allergy 1991;9143- 158
PubMed
8.
Gysin  CAlothman  GAPapsin  BC Sinonasal disease in cystic fibrosis: clinical characteristics, diagnosis, and management. Pediatr Pulmonol 2000;30481- 489
PubMedArticle
9.
Tomooka  LTMurphy  CDavidson  TM Clinical study and literature review of nasal irrigation. Laryngoscope 2000;1101189- 1193
PubMedArticle
10.
Raynor  EMButler  AGuill  MBent  PB Nasally inhaled dornase alfa in the postoperative management of chronic sinusitis due to cystic fibrosis. Arch Otolaryngol Head Neck Surg 2000;126581- 583
PubMedArticle
11.
Shwachman  HKulczycki  L Long-term study of one hundred five patients with cystic fibrosis. AJDC 1958;966- 15
12.
Lund  VJHolmstrom  MScadding  GK Functional endoscopic sinus surgery in the management of chronic rhino-sinusitis: an objective assessment. J Laryngol Otol 1991;105832- 835
PubMedArticle
13.
Klingbeil  PWiersbitzky  SBruns  RBallke  EH The saccarin test in the pediatric broncho-pneumologic outpatient: a non-invasive screening method for the assessment of ciliary function of the respiratory tract in children. Kinderarztl Prax 1990;58205- 210
PubMed
14.
Lund  VJKennedy  DWThe Staging and Therapy Group, Quantification for staging sinusitis. Ann Otol Rhinol Laryngol Suppl 1995;16717- 21
PubMed
15.
American Thoracic Society, Standardization of spirometry: 1987 update. Am Rev Respir Dis 1987;1361285- 1298
PubMedArticle
16.
Fuchs  HJBorowitz  DSChristiansen  DH  et al.  Effect of aerosolized recombinant human DNase on exacerbations of respiratory symptoms and on pulmonary function in patients with cystic fibrosis. N Engl J Med 1994;331637- 642
PubMedArticle
17.
Ballmann  MVon der Hardt  H Hypertonic saline and recombinant human DNase: a randomised cross-over pilot study in patients with cystic fibrosis. J Cyst Fibros 2002;135- 37
PubMedArticle
18.
Eng  PAMorton  JDouglass  JARiedler  JWilson  JRobertson  CF Short-term efficacy of ultrasonically nebulized hypertonic saline in cystic fibrosis. Pediatr Pulmonol 1996;2177- 83
PubMedArticle
19.
Umetsu  DTMoss  RBKing  VV  et al.  Sinus disease in patients with severe cystic fibrosis: relation to pulmonary exacerbation. Lancet 1990;3351077- 1078
PubMedArticle
20.
Madonna  DIsaacson  GRosenfeld  RMPanitch  H Effect of sinus surgery on pulmonary function in patients with cystic fibrosis. Laryngoscope 1997;107328- 331
PubMedArticle
21.
Nishioka  GJCook  PR Paranasal sinus disease in patients with cystic fibrosis. Otolaryngol Clin North Am 1996;29193- 204
PubMed
22.
Duplechain  JKWhite  JAMiller  RH Pediatric sinusitis: the role of endoscopic sinus surgery in cystic fibrosis and other form of sinonasal disease. Arch Otolaryngol Head Neck Surg 1991;117422- 426
PubMedArticle
23.
Cepero  RSmith  RCatlin  FBressler  KFuruta  GShandera  K Cystic fibrosis: an otorhinolaryngologic perspective. Otolaryngol Head Neck Surg 1987;97356- 360
PubMed
24.
Mygind  N Advances in the medical treatment of nasal polyps. Allergy 1999;5412- 16
PubMedArticle
25.
Barr  MBWeiss  STSegal  MRTager  IBSpeizer  FE The relationship of nasal disorders to lower respiratory tract symptoms and illness in a random sample of children. Pediatr Pulmonol 1992;1491- 94
PubMedArticle
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