The Laryngoscope C 2013 The American Laryngological, V
Rhinological and Otological Society, Inc.
Systematic Review
Medical Management of Chronic Rhinosinusitis in Cystic Fibrosis: A Systematic Review Jonathan Liang, MD; Thomas Higgins, MD, MPH; Stacey L. Ishman, MD, MPH; Emily F. Boss, MD, MPH; James R. Benke, BS; Sandra Y. Lin, MD Objectives/Hypothesis: To systematically review existing literature on the effectiveness of medical management of chronic rhinosinusitis (CRS) in cystic fibrosis (CF) patients. Study Design: Systematic review. Methods: We performed a literature search of PubMed, Embase, and Cochrane CENTRAL from 1987 to 2012. Inclusion criteria included English language as containing original data, with five or more subjects, measurable clinical outcomes, and readily available interventions. Data were systematically collected on study design, patient demographics, clinical characteristics and outcomes, and level of evidence. Two investigators independently reviewed all manuscripts and performed a comprehensive quality assessment. Results: Of 415 abstracts identified, 12 articles were included. These 12 studies reported on 701 adult and pediatric CF patients who underwent medical therapy. Medical treatment included antibiotics (4/12), topical steroids (4/12), dornase alfa (3/12), and ibuprofen (1/12). Outcome measures included symptom scores (7/12), endoscopic findings (7/12), radiographic findings (4/12), pulmonary function testing (4/12), and rhinomanometry (2/12). Most studies found improvement in at least one of the outcome measures. There was statistical significance in clinical outcomes with dornase alfa, beclomethasone, and betamethasone. Most studies were level 3 or 4 evidence (9/12), but three studies were level 1 or 2 evidence (two dornase alfa studies, one betamethasone study). Conclusions: Dornase alfa and, to a lesser extent, topical steroids demonstrated significant benefits in the medical treatment CRS in CF. There was a lack of evidence to support antibiotic therapy in the outcomes assessed. Further high-quality studies should be carried out to determine the efficacy of various medical therapies for CRS in CF. Key Words: Chronic rhinosinusitis; cystic fibrosis; topical steroid; dornase alfa; medical. Level of Evidence: NA Laryngoscope, 124:1308–1313, 2014
INTRODUCTION Cystic fibrosis (CF) is a lethal autosomal recessive disease that affects the exocrine function of many organ systems. CF mainly affects the Caucasian population. The pathogenesis is due to a mutation of the q31 region of chromosome 7, which results in a defect in the transmembrane conductance regulator protein (CFTR). CFTR is located at the apical surface of the epithelial cells, and regulates the chloride ion transport. Defective chloride ion transport leads to increased absorption of sodium ion and water from the luminal surface of cells. As a result, the abnormal elec-
Department of Otolaryngology–Head and Neck Surgery, Johns Hopkins School of Medicine, Baltimore, Maryland, U.S.A. Editor’s Note: This Manuscript was accepted for publication October 30, 2013. Presented at the Triological Society Meeting of the Combined Otolaryngological Spring Meetings, Orlando, Florida, U.S.A., April 10–14, 2013. The authors have no funding, financial relationships, or conflicts of interest to disclose. Send correspondence to Sandra Y. Lin, MD, Department of Otolaryngology–Head and Neck Surgery, Johns Hopkins School of Medicine, 601 N. Caroline St., #6245, Baltimore, MD 21287-0910. E-mail: [email protected] DOI: 10.1002/lary.24503
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trolyte concentration in exocrine secretions leads to reduced water content of secretions and viscous mucus.1 Multisystem disease involves the upper and lower airway, ductal system of the pancreas, hepatobiliary ducts, and male reproductive tracts. On the surface of the respiratory mucosa, thick and viscous mucus surrounding the ciliary structures alters and impairs the normal mucociliary pattern. Chronic stasis of inspissated mucus and mucociliary clearance dysfunction predispose patients to subsequent chronic bacterial colonization and inflammation.2 Involvement of the sinonasal mucosa is observed in up to 100% of CF patients either by clinical or radiological examination. Up to two-thirds of patients with CF demonstrate nasal polyposis.3 It is thought that the paranasal sinuses may act as a reservoir for pathogens that are responsible for acute exacerbations of sinusitis and pulmonary spread of infection. Bronchoalveolar lavage fluid and nasal cavity cultures have been examined in CF patients with concordance rates reported as high as 80%.4–6 Management of CF rhinosinusitis includes both medical and surgical therapy. Medical therapy has evolved over the past few decades and includes nasal toilet, antimicrobial and anti-inflammatory medications (both systemic and topical forms), and newer recombinant enzymes– Liang et al.: Medical Management of CRS in CF
dornase alfa (Pulmozyme; Genentech, Inc., South San Francisco, CA). Although medical therapy is considered the mainstay of therapy, surgical therapy is an option for management when sinonasal disease fails to respond to maximal medical therapy. The objective of this study was to systematically review the literature to provide evidencebased recommendations regarding the effectiveness of medical treatment for CRS in CF patients.
MATERIALS AND METHODS A qualitative systematic review of the published English literature was conducted to broadly investigate the effectiveness of surgical therapy for CF rhinosinusitis. A quantitative metaanalysis was not performed due to the diverse study designs of the selected studies and the heterogeneity of the data. We adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis checklist and statement recommendations during the conduct of this qualitative systematic review.7 In March 2012, we searched PubMed, Embase, and the Cochrane CENTRAL database for relevant publications within the 25-year time period of January 1, 1987 through February 28, 2012. A principle electronic search strategy was designed for use in PubMed and then tailored for the other electronic databases in a similar fashion. The initial search included combined key terms and exploded Medical Subject Headings. The search focused on the following terms: cystic fibrosis, sinusitis, rhinosinusitis, nose, sinus, medical, medicine, steroid, corticosteroids, surgical, surgery, endoscopic sinus surgery, irrigation, rinse, lavage, DNase, antibiotics, macrolide. Additional publications were identified by reviewing reference lists and consulting expert review articles identified through the search from the last 10 years. A medical librarian helped to develop search strategies and review each for accuracy and thoroughness. Results of all electronic searches were imported into Endnote X3 (Thomas Reuters, New York, NY).
Eligibility Criteria Only English-language studies with original data, including randomized controlled trials, cohort studies with or without comparison groups, and case series that included data on five or more patients with CF were included. Smaller series of four or fewer patients were excluded due to potential for bias. These criteria were used to exclude articles from analysis: published prior to 1987, no abstract present, not written in English, unpublished trials, review articles, technical reports, editorials, cadaver and animal studies, containing four or fewer patients with CF, and studies without measurable outcomes. Two team investigators independently reviewed the titles and abstracts for initial inclusion in the systematic review. Full publications were obtained following initial selection of titles and abstracts. Only articles focusing on medical management were used in this systematic review.
Data Extraction Data were extracted and reviewed independently by two investigators. A standardized worksheet for data extraction was developed and tested on five selected publications, following which the team revised and finalized the worksheet and data fields. Reviewers were privy to publication authors, journal titles, and institutions of origin. Any disagreement regarding study inclusion was addressed by rereview with both investigators until a consensus was met. Articles were assessed for study size, location, setting, main outcome measures, and conclusions. Quality was eval-
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Fig. 1. Literature search algorithm. [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.] uated for each article. The aggregate grade of evidence and the recommendations were assigned based on the available literature.7,8 Each article was reviewed for study design and assigned a level of evidence based on published guidelines by the Oxford Centre for Evidence-based Medicine-Levels of Evidence.9 Quality assessment for level 1 and 2 studies was performed using a modified Cochrane Collaboration Tool for Assessing Risk of Bias.10 This system assessed for potential sources of bias by evaluating for random allocation, allocation scheme concealment, concealment from study personnel and participants, incomplete data, and sponsoring company participation. Quality assessment for level 3 and 4 studies was performed utilizing the Newcastle-Ottawa Assessment Scale for assessing nonrandomized studies in systematic reviews.11 The scale assigned star ratings based on three categories: selection of cases and controls, comparability of controls on the basis of design/analysis, and methods of ascertaining exposure. A maximum of 10 stars can be awarded to case-control studies, whereas a maximum of 4 stars can be awarded to case series.
Summary Measures and Data Synthesis Articles were categorized based on pertinence to disease prevalence, diagnosis, evaluation, treatment, or sequelae. Data were synthesized through creation of detailed tables that summarized evidence relevant to the major categories. Given the qualitative nature of this systematic review, no additional analyses were performed.
RESULTS The study selection process is illustrated in Figure 1. The search strategy retrieved 416 abstracts, and 12 pertinent articles were selected for this systematic review (Table I).5,6,12–21 The systematic review included 701 patients, including both children and adults. Half of the Liang et al.: Medical Management of CRS in CF
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Liang et al.: Medical Management of CRS in CF
Retrospective casecontrol
Raynor et al.21 2000
1993
1995
2011
2007
1996
1998
2000
1988
1990
2005
1997
Year
11 to 29
4 to 28.5
mean 23.3
8 to 38
5 to 15
4 to 15
20 to 32
N/S (>16)
mean 15.2
mean 12.0
7–15
1–36
Age Range, yr
20
28
51
5
22
219
16
22
30
14
24
250
No.
Dornase alfa
Beclomethasone dipropionate
Serial antimicrobial lavage
Dornase alfa
Ibuprofen (high dose)
Antibiotics
Pulmonary toilet and antibiotics
Betamethasone
Beclomethasone dipropionate
Beclomethasone dipropionate
Dornase alfa
Antibiotics and topical drugs
Medical Treatment
PFTs, endoscopy, CT, need for surgery
Symptoms, rhinomanometry
Need for revision surgery
Symptoms, MRI volumetry, endoscopy, PFTs
Endoscopy
Labs, need for surgery
Symptoms, culture, PFT
Symptoms, endoscopy
Symptoms
Endoscopy, rhinomanometry
Symptoms, endoscopy, PFTs, CT, saccharine clearance test
Symptoms, endoscopy, CT, need for surgery
Outcomes
6 months
48 months
24 months
3 months
52.6 months
N/S
48 months
N/S
>48 months
2 months
12 months
N/S
Follow-up
CT 5computed tomography; MRI 5 magnetic resonance imaging; PFT 5 pulmonary function test; RCT 5randomized controlled trial; N/S 5 not specified.
Retrospective case series
Pignataro et al.20
Retrospective case series
Henriksson et al.17
Prospective case series
Retrospective case series
Halvorson et al.5
Moss et al.6
Prospective doubleblinded RCT
Hadfield et al.16
Prospective, doubleblinded, placebocontrolled, crossover study
Retrospective case series
Donaldson et al.15
Mainz et al.19
Retrospective case series
Costantini et al.14
Retrospective case series
Prospective doubleblinded RCT
Cimmino et al.13
Lindstrom et al.18
Prospective case series
Study Type
Brihaye et al.12
Author
TABLE I. Summary of Included Studies in the Systematic Review.
No
No
No
Yes
No
No
No
Yes
No
No
Yes
No
Statistical Analysis
Improved endoscopy score, fewer surgeries, no change in PFT, no change in CT.
Improved symptoms, improved nasal patency on rhinomanometry.
Both groups had surgical intervention; the group with surgery 1 antimicrobial lavage had a fewer number of patients who needed revision surgery.
Significant improvement in symptom scores; no significant change for other parameters.
All patients had absence of nasal polyps at some point during treatment.
Divided patients into acute vs. chronic sinusitis, suggested that patients with chronic sinusitis more likely to need surgery.
Descriptive results with no specific mention of improvement in outcome parameters.
Significant decreased polyp size on endoscopy; no difference in symptom scores.
Both groups had subjective symptom improvement.
Decreased nasal polys and nasal resistance.
Symptoms and endoscopic appearance improved in treatment group for longer (48 weeks) than in placebo group (24 weeks), significant improvement in PFT in treatment group.
Descriptive results with no specific mention of improvement in outcome parameters.
Findings
TABLE II. Medical Therapy Outcome Assessment. Outcomes Therapy
Studies
Symptoms
Endoscopy
PFT
Radiography
Need for Surgery
Antibiotics
Brihaye et al.,12 Halvorson et al.,5 Henriksson et al.,17 Moss et al.6
0
0
0
0
1
Topical steroids
Costantini et al.,14 Donaldson et al.,15 Hadfield et al.,16 Pignataro et al.20
2
3
N/A
N/A
N/A
Dornase alfa
Cimmino et al.,13 Mainze et al.,19 Raynor et al.21
4
3
2
0
1
Ibuprofen
Lindstrom et al.18
N/A
1
N/A
N/A
N/A
One point for each study showing nonstatistical outcome improvement; two points for each study showing statistically significant outcome improvement. N/A 5 not applicable due to no study evaluating this outcome; PFT 5 pulmonary function test.
studies combined adult and pediatric patients, and thus no specific assessment can be made for each individual group. Therefore, these findings are representative for adult and pediatric CF patients as a group. Most articles (9 of 12) detailed follow-up time for the patients. The mean follow-up time of the included studies was 27.1 months. Two of the studies were level 1 evidence (e.g., randomized controlled trials). One study was level 2 evidence (e.g., cohort study). One study was level 3 evidence (e.g., case-control study). The remaining eight studies were level 4 evidence (e.g., case series). Three (25%) of the 12 articles used statistical analysis to assess outcome measures, with all of these showing a statistically significant difference in at least one of the outcomes measures. Nine (75%) of the 24 articles did not use statistical analysis to report outcome measures. Medical management included topical steroids in four studies (33%), antibiotics in four studies (33%), dornase alfa in three studies (25%), and high-dose ibuprofen in one study (8%). Outcome measures included symptom scores in seven studies (58%), endoscopic findings in seven studies (58%), radiographic findings in four studies (33%), pulmonary function testing in four studies (33%), rhinomanometry in two studies (17%), basic laboratory tests in one study (8%), microbial cultures in one study (8%), and saccharine clearance testing in one study (8%). To assess the outcomes, we evaluated the top five outcome measures: symptoms, endoscopy, pulmonary function test (PFT), need for revision surgery, and hospitalization by type of medical therapy (antibiotics, topical steroids, dornase alfa, and ibuprofen). We used a scoring system based on whether the study showed improvement and whether or not that finding was significant. Points were given to the articles as follows: one point for each study showing non-statistically significant outcome improvement, and two points for each study showing statically significant outcome improvement. Results of the outcome assessment are shown in Table II. Dornase Laryngoscope 124: June 2014
alfa and topical steroids were the only therapies that showed nonstatistically significant improvement in multiple studies or statistically significant improvement in at least one study. Furthermore, dornase alfa and topical steroids had the strongest evidence, showing improvement in multiple outcome measures. Risk of bias in the level 1 and 2 evidence studies was assessed using a modified Cochrane Collaboration Tool for Assessing Risk of Bias.10 All three studies in this category demonstrated low risk of bias after interpretation for potential sources of bias (Table III). The Newcastle-Ottawa Quality Assessment Scale11 was used to review the quality of the level 3 and 4 evidence studies. The mean score for case-control studies and case series was 5.0 out of 10 possible stars and 2.25 out of 4 possible stars, respectively (Table IV).
DISCUSSION This systematic review of the past 25 years of literature supports the potentially beneficial role of medical therapy for CF rhinosinusitis. The preponderance of evidence is based on level 3 to 4 evidence studies. Although the validity of an evidence-based medicine currently relies heavily on randomized controlled trials without biases, these can be difficult to carry out especially for surgical interventions due to ethical considerations and the inability to blind physicians and participants from the procedures. Bentsianov et al. stated that in the otolaryngology literature, 80% of therapeutic recommendations were forged based on data from level 4 evidence.22 Therefore, level 2 to 4 evidence studies were included along with level 1 evidence studies to provide the most meaningful aggregate of evidence and make current treatment recommendations. The two level 1 evidence studies examined betamethasone and dornase alfa, and demonstrated improvement in multiple outcome measures, primarily symptom and endoscopic scores. Dornase alfa efficacy was further supported by one level 2 evidence study and one level 3 evidence study, whereas the Liang et al.: Medical Management of CRS in CF
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TABLE III. Quality Assessment of Level 1 and 2 Evidence Studies (Modified Cochrane Collaboration Tool for Assessing Risk of Bias). Study Potential Source of Bias
Scoring Per Item
Cimmino et al.13
Hadfield et al.16
Mainz et al.19
Was there random allocation of subjects?
Random 5 0, nonrandom 5 1
0
0
0
Was the allocation scheme concealed? Were the interventions concealed from study personnel and participants? Was incomplete data adequately addresses?
Concealed 5 0, not concealed 5 1 Complete blinding 5 0, incomplete blinding 5 1
0
0
0
0
0
0
Addressed 5 0, not addressed 5 1
0
0
0
Did the sponsoring company participate in study design or interpretation?
No involvement 5 0, involvement 5 1
0
0
1
Were there any other important sources of bias?
None 5 0, yes 5 1
0
0
0
0
0
1
Total score
Interpretation of score (minimum possible score is 0, maximum possible score is 6): 0–1 point indicates low risk of bias (least bias, best quality study with valid results); 2–3 points indicate medium risk of bias (susceptible to some bias, but not enough to invalidate results); 4–6 points indicate high risk of bias (most bias, worst quality study with significant flaws).
remainder of support for topical steroids was from level 4 evidence studies. There is no strong evidence that antibiotics improve clinical outcomes. It is worth highlighting below the two level 1 evidence studies included in this systematic review, as they represent the soundest methodological investigation as to the effectiveness of medical therapy on rhinosinusitis for CF patients. Cimmino et al. performed a double-blinded, placebocontrolled trial to determine the benefit of nasally inhaled dornase alfa. Twenty-four pediatric patients with CF underwent endoscopic sinus surgery (ESS). Twelve patients were treated with dornase alfa, and 12 were treated with placebo postoperatively. Primary outcome measures were TABLE IV. Quality Assessment of Level 3 and 4 Evidence Studies (Newcastle-Ottawa Assessment Scale). Selection Grade (Maximum 4 Asterisks)
Comparability Grade (Maximum 2 Asterisks)
Exposure Grade (Maximum 4 Asterisks)
Total
Brihaye et al.12
*
N/A
*
**
Costantini et al.14
*
N/A
*
**
Donaldson et al.15 Halvorson et al.5
** **
N/A N/A
* *
** ***
Henriksson et al.17
*
N/A
**
***
Lindstrom et al.18 Moss et al.6
* *
N/A N/A
* *
** **
Pignataro et al.20
*
N/A
*
**
Raynor et al.21
**
*
**
*****
Author
Maximum possible total score for case control study is 10 asterisks, and maximum possible total score for case series is 4 asterisks. N/A 5 not applicable; for assessment of case series articles, questions regarding control group are not applicable.
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nasal symptom scores and endoscopic appearance. Secondary outcome measures were FEV1, computed tomography findings (graded using the Lund-Kennedy scale), and saccharine clearance test results. Pre- and post-treatment evaluation were performed in all patients. There was no difference in saccharine test scores pre- and post-treatment in both groups. There was improvement in the other outcome measures for both group, with effects in the dornase alfa group improving through 48 weeks versus only temporary improvement through 24 weeks followed by decline in the placebo group.13 Hadfield et al. performed a double-blinded, placebocontrolled trial to determine the benefit of betamethasone (50 lg) drops. Forty-six adult CF patients were divided into a treatment and placebo group, and 22 patients completed the study, with 10 patients in the betamethasone group and 12 patients in the placebo group. Outcome measures were symptoms and endoscopic polyp scores (scored with the Lund-Mackay scale). There was a statistically significant reduction in polyp size in the treatment group, which was not seen in the placebo group. However, there was no significant difference in symptom scores between the two groups. Furthermore, there was no difference between those subjects completing the study and those who dropped out.16 The major cause of mortality and morbidity in patients with CF is pulmonary deterioration. Frequent pulmonary exacerbations also lead to more frequent hospitalizations and increased medication use. This review identified four articles where PFT was used to measure treatment efficacy, and found inconclusive evidence as to whether medical therapy improves PFT or modifies lower airway function. Most studies demonstrated no significant improvement of PFT after medical treatment. Gains in PFT after ESS may be only temporary, because CF is a progressive disease. Overall, the role of medical Liang et al.: Medical Management of CRS in CF
therapy on modifying lower airway function is unclear. Higher level of evidence studies will be needed in the future to better define measures for pulmonary deterioration and assess the efficacy of treatment strategies for CF CRS. This is the first systematic review in the English literature of the medical management of CF CRS. Considering all of the literature, we found that there is a relatively small number of articles written on the topic that can be included in the review. Many studies had to be excluded because they did not have a clear definition of disease included in the article or lacked quantifiable outcome measures for comparison. Study heterogeneity was another limiting factor in this systematic review. Many of the studies that addressed the issue of rhinosinusitis were not favorably designed to compare between patients with comorbid diseases and utilized multiple outcome measures. During the review we identified several studies including CF patients within mixed rhinosinusitis populations, even though it was not available to extract their separate results for comparison. Furthermore, the heterogenous CF patient population—including a mixture of adult and pediatric patients—made it impossible to determine whether outcomes were different between the two groups. Variability also existed in medical therapy. The duration and dosage varies across studies, making comparability difficult. It is also difficult to rule out any confounding effects of previous or concurrent surgical therapy. The average follow-up period of the included studies was 27.1 months. This follow-up period allows for capturing early medical therapy failures, but longer follow-up may be beneficial for outcome assessment in this chronic and progressive disease. This systematic review was performed in conjunction with a systematic review of the surgical management of CF CRS.23 Liang et al. demonstrated that ESS was effective in treating CF CRS by improving symptoms and endoscopic scores.23 Taken together, both of these systematic reviews support both medical and surgical treatment of CF CRS. Deciding on when to pursue medical versus surgical management still varies considerably among otolaryngologist, and there is no strong evidence that one approach is superior to the other. The art of treatment of CF CRS likely combines both medical and surgical approaches tailored to the patient’s desires and expectations.
CONCLUSION Dornase alfa and, to a lesser extent, topical steroids, showed benefit in the medical treatment of CF CRS. There was a lack of evidence to support antibiotic therapy in the outcomes assessed. The primary outcome improvement is demonstrated by symptoms and endoscopic scores. Only level 1 evidence studies showed both symptom and endoscopic improvement with dornase alfa; beclomethasone treatment was associated with endoscopic improvement without clinical correlation. The efficacy of topical steroids for the medical treatment of CF CRS has yet to be clearly delineated. There is little evidence to claim that medical therapy modifies lower airway disease. The litera-
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ture includes level 1 to 4 evidence studies; the majority of studies were level 3 and 4 evidence. Due to the level and quality of evidence, the overall grade supporting the medical therapy in CF patients is B2. Future prospective studies with predetermined, objective, and validated outcome measures are needed to determine the effectiveness of surgical intervention for CF CRS.
Acknowledgments The authors acknowledge Stella Seal, medical librarian, who assisted us in the initial literature search; Bulent Ocal, MD, who assisted in the preparation of this article; and Jimmy Stanley, undergraduate research intern, who assisted in gathering the articles.
BIBLIOGRAPHY 1. Doull IJ. Recent advances in cystic fibrosis. Arch Dis Child 2001;85:62–66. 2. Hulka GF. Head and neck manifestations of cystic fibrosis and ciliary dyskinesia. Otolaryngol Clin North Am 2000;33:1333–1341, vii–viii. 3. Feuillet-Fieux MN, Lenoir G, Sermet I, et al. Nasal polyposis and cystic fibrosis (CF): review of the literature. Rhinology Aug 2011;49:347–355. 4. Wise SK, Kingdom TT, McKean L, DelGaudio JM, Venkatraman G. Presence of fungus in sinus cultures of cystic fibrosis patients. Am J Rhinol 2005;19:47–51. 5. Halvorson DJ, Dupree JR, Porubsky ES. Management of chronic sinusitis in the adult cystic fibrosis patient. Ann Otol Rhinol Laryngol 1998; 107(11 pt 1):946–952. 6. Moss RB, King VV. Management of sinusitis in cystic fibrosis by endoscopic surgery and serial antimicrobial lavage. Reduction in recurrence requiring surgery. Arch Otolaryngol Head Neck Surg 1995;121:566–572. 7. Liberati A, Altman DG, Tetzlaff J, et al. The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration. J Clin Epidemiol 2009;62:e1–e34. 8. American Academy of Pediatrics Steering Committee on Quality Improvement and Management. Classifying recommendations for clinical practice guidelines. Pediatrics 2004;114:874–877. 9. Phillips B, Ball C, Sackett D, et al. Levels of evidence and grades of recommendation. Oxford Centre for Evidence-based Medicine (March 2009). Available at: http://www.cebm.net/?o51025. Accessed on Feb 1, 2013. 10. Chandler J, Clarke M, Higgins J, eds. Cochrane Methods. Cochrane Database Syst Rev 2012;(suppl 1):1–56. 11. Wells G, O’Connel D, Peterson J, Welch V, Losos M, Tugwell P. The Newcasete-Ottawa Scale (NOS) for assessing the quality of nonrandomized studies in meta-analysis. Available at: http://www.ohri.ca/programs/ clinical_epidemiology/oxford.asp. Accessed on Feb 1, 2013. 12. Brihaye P, Jorissen M, Clement PA. Chronic rhinosinusitis in cystic fibrosis (mucoviscidosis). Acta Otorhinolaryngol Belg 1997;51:323–337. 13. Cimmino M, Nardone M, Cavaliere M, et al. Dornase alfa as postoperative therapy in cystic fibrosis sinonasal disease. Arch Otolaryngol Head Neck Surg 2005;131:1097–1101. 14. Costantini D, Di Cicco M, Giunta A, Amabile G. Nasal polyposis in cystic fibrosis treated by beclomethasone dipropionate. Acta Univ Carol Med (Praha) 1990;36:220–221. 15. Donaldson JD, Gillespie CT. Observations on the efficacy of intranasal beclomethasone dipropionate in cystic fibrosis patients. J Otolaryngol 1988;17:43–45. 16. Hadfield PJ, Rowe-Jones JM, Mackay IS. A prospective treatment trial of nasal polyps in adults with cystic fibrosis. Rhinology 2000;38:63–65. 17. Henriksson G, Westrin KM, Kumlien J, Stierna P. A 13-year report on childhood sinusitis: clinical presentations, predisposing factors and possible means of prevention. Rhinology 1996;34:171–175. 18. Lindstrom DR, Conley SF, Splaingard ML, Gershan WM. Ibuprofen therapy and nasal polyposis in cystic fibrosis patients. J Otolaryngol 2007; 36:309–314. 19. Mainz JG, Schiller I, Ritschel C, et al. Sinonasal inhalation of dornase alfa in CF: a double-blind placebo-controlled cross-over pilot trial. Auris Nasus Larynx 2011;38:220–227. 20. Pignataro LD, DiCicco M, Gaini RM, Amabile G, Costantini D. Beclomethasone dipropionate in the treatment of nasal polyps of cystic fibrosis patients: four years follow-up. Riv Orl Aud Fon 1993;13:65–66. 21. Raynor EM, Butler A, Guill M, Bent JP III. Nasally inhaled dornase alfa in the postoperative management of chronic sinusitis due to cystic fibrosis. Arch Otolaryngol Head Neck Surg 2000;126:581–583. 22. Bentsianov BL, Boruk M, Rosenfeld RM. Evidence-based medicine in otolaryngology journals. Otolaryngol Head Neck Surg 2002;126:371– 376. 23. Liang J, Higgins TS, Ishman SL, et al. Surgical management of chronic rhinosinusitis in cystic fibrosis: a systematic review. Int Forum Allergy Rhinol 2013;3:814–822.
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Rhinological and Otological Society, Inc.
Systematic Review
Medical Management of Chronic Rhinosinusitis in Cystic Fibrosis: A Systematic Review Jonathan Liang, MD; Thomas Higgins, MD, MPH; Stacey L. Ishman, MD, MPH; Emily F. Boss, MD, MPH; James R. Benke, BS; Sandra Y. Lin, MD Objectives/Hypothesis: To systematically review existing literature on the effectiveness of medical management of chronic rhinosinusitis (CRS) in cystic fibrosis (CF) patients. Study Design: Systematic review. Methods: We performed a literature search of PubMed, Embase, and Cochrane CENTRAL from 1987 to 2012. Inclusion criteria included English language as containing original data, with five or more subjects, measurable clinical outcomes, and readily available interventions. Data were systematically collected on study design, patient demographics, clinical characteristics and outcomes, and level of evidence. Two investigators independently reviewed all manuscripts and performed a comprehensive quality assessment. Results: Of 415 abstracts identified, 12 articles were included. These 12 studies reported on 701 adult and pediatric CF patients who underwent medical therapy. Medical treatment included antibiotics (4/12), topical steroids (4/12), dornase alfa (3/12), and ibuprofen (1/12). Outcome measures included symptom scores (7/12), endoscopic findings (7/12), radiographic findings (4/12), pulmonary function testing (4/12), and rhinomanometry (2/12). Most studies found improvement in at least one of the outcome measures. There was statistical significance in clinical outcomes with dornase alfa, beclomethasone, and betamethasone. Most studies were level 3 or 4 evidence (9/12), but three studies were level 1 or 2 evidence (two dornase alfa studies, one betamethasone study). Conclusions: Dornase alfa and, to a lesser extent, topical steroids demonstrated significant benefits in the medical treatment CRS in CF. There was a lack of evidence to support antibiotic therapy in the outcomes assessed. Further high-quality studies should be carried out to determine the efficacy of various medical therapies for CRS in CF. Key Words: Chronic rhinosinusitis; cystic fibrosis; topical steroid; dornase alfa; medical. Level of Evidence: NA Laryngoscope, 124:1308–1313, 2014
INTRODUCTION Cystic fibrosis (CF) is a lethal autosomal recessive disease that affects the exocrine function of many organ systems. CF mainly affects the Caucasian population. The pathogenesis is due to a mutation of the q31 region of chromosome 7, which results in a defect in the transmembrane conductance regulator protein (CFTR). CFTR is located at the apical surface of the epithelial cells, and regulates the chloride ion transport. Defective chloride ion transport leads to increased absorption of sodium ion and water from the luminal surface of cells. As a result, the abnormal elec-
Department of Otolaryngology–Head and Neck Surgery, Johns Hopkins School of Medicine, Baltimore, Maryland, U.S.A. Editor’s Note: This Manuscript was accepted for publication October 30, 2013. Presented at the Triological Society Meeting of the Combined Otolaryngological Spring Meetings, Orlando, Florida, U.S.A., April 10–14, 2013. The authors have no funding, financial relationships, or conflicts of interest to disclose. Send correspondence to Sandra Y. Lin, MD, Department of Otolaryngology–Head and Neck Surgery, Johns Hopkins School of Medicine, 601 N. Caroline St., #6245, Baltimore, MD 21287-0910. E-mail: [email protected] DOI: 10.1002/lary.24503
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trolyte concentration in exocrine secretions leads to reduced water content of secretions and viscous mucus.1 Multisystem disease involves the upper and lower airway, ductal system of the pancreas, hepatobiliary ducts, and male reproductive tracts. On the surface of the respiratory mucosa, thick and viscous mucus surrounding the ciliary structures alters and impairs the normal mucociliary pattern. Chronic stasis of inspissated mucus and mucociliary clearance dysfunction predispose patients to subsequent chronic bacterial colonization and inflammation.2 Involvement of the sinonasal mucosa is observed in up to 100% of CF patients either by clinical or radiological examination. Up to two-thirds of patients with CF demonstrate nasal polyposis.3 It is thought that the paranasal sinuses may act as a reservoir for pathogens that are responsible for acute exacerbations of sinusitis and pulmonary spread of infection. Bronchoalveolar lavage fluid and nasal cavity cultures have been examined in CF patients with concordance rates reported as high as 80%.4–6 Management of CF rhinosinusitis includes both medical and surgical therapy. Medical therapy has evolved over the past few decades and includes nasal toilet, antimicrobial and anti-inflammatory medications (both systemic and topical forms), and newer recombinant enzymes– Liang et al.: Medical Management of CRS in CF
dornase alfa (Pulmozyme; Genentech, Inc., South San Francisco, CA). Although medical therapy is considered the mainstay of therapy, surgical therapy is an option for management when sinonasal disease fails to respond to maximal medical therapy. The objective of this study was to systematically review the literature to provide evidencebased recommendations regarding the effectiveness of medical treatment for CRS in CF patients.
MATERIALS AND METHODS A qualitative systematic review of the published English literature was conducted to broadly investigate the effectiveness of surgical therapy for CF rhinosinusitis. A quantitative metaanalysis was not performed due to the diverse study designs of the selected studies and the heterogeneity of the data. We adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis checklist and statement recommendations during the conduct of this qualitative systematic review.7 In March 2012, we searched PubMed, Embase, and the Cochrane CENTRAL database for relevant publications within the 25-year time period of January 1, 1987 through February 28, 2012. A principle electronic search strategy was designed for use in PubMed and then tailored for the other electronic databases in a similar fashion. The initial search included combined key terms and exploded Medical Subject Headings. The search focused on the following terms: cystic fibrosis, sinusitis, rhinosinusitis, nose, sinus, medical, medicine, steroid, corticosteroids, surgical, surgery, endoscopic sinus surgery, irrigation, rinse, lavage, DNase, antibiotics, macrolide. Additional publications were identified by reviewing reference lists and consulting expert review articles identified through the search from the last 10 years. A medical librarian helped to develop search strategies and review each for accuracy and thoroughness. Results of all electronic searches were imported into Endnote X3 (Thomas Reuters, New York, NY).
Eligibility Criteria Only English-language studies with original data, including randomized controlled trials, cohort studies with or without comparison groups, and case series that included data on five or more patients with CF were included. Smaller series of four or fewer patients were excluded due to potential for bias. These criteria were used to exclude articles from analysis: published prior to 1987, no abstract present, not written in English, unpublished trials, review articles, technical reports, editorials, cadaver and animal studies, containing four or fewer patients with CF, and studies without measurable outcomes. Two team investigators independently reviewed the titles and abstracts for initial inclusion in the systematic review. Full publications were obtained following initial selection of titles and abstracts. Only articles focusing on medical management were used in this systematic review.
Data Extraction Data were extracted and reviewed independently by two investigators. A standardized worksheet for data extraction was developed and tested on five selected publications, following which the team revised and finalized the worksheet and data fields. Reviewers were privy to publication authors, journal titles, and institutions of origin. Any disagreement regarding study inclusion was addressed by rereview with both investigators until a consensus was met. Articles were assessed for study size, location, setting, main outcome measures, and conclusions. Quality was eval-
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Fig. 1. Literature search algorithm. [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.] uated for each article. The aggregate grade of evidence and the recommendations were assigned based on the available literature.7,8 Each article was reviewed for study design and assigned a level of evidence based on published guidelines by the Oxford Centre for Evidence-based Medicine-Levels of Evidence.9 Quality assessment for level 1 and 2 studies was performed using a modified Cochrane Collaboration Tool for Assessing Risk of Bias.10 This system assessed for potential sources of bias by evaluating for random allocation, allocation scheme concealment, concealment from study personnel and participants, incomplete data, and sponsoring company participation. Quality assessment for level 3 and 4 studies was performed utilizing the Newcastle-Ottawa Assessment Scale for assessing nonrandomized studies in systematic reviews.11 The scale assigned star ratings based on three categories: selection of cases and controls, comparability of controls on the basis of design/analysis, and methods of ascertaining exposure. A maximum of 10 stars can be awarded to case-control studies, whereas a maximum of 4 stars can be awarded to case series.
Summary Measures and Data Synthesis Articles were categorized based on pertinence to disease prevalence, diagnosis, evaluation, treatment, or sequelae. Data were synthesized through creation of detailed tables that summarized evidence relevant to the major categories. Given the qualitative nature of this systematic review, no additional analyses were performed.
RESULTS The study selection process is illustrated in Figure 1. The search strategy retrieved 416 abstracts, and 12 pertinent articles were selected for this systematic review (Table I).5,6,12–21 The systematic review included 701 patients, including both children and adults. Half of the Liang et al.: Medical Management of CRS in CF
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Liang et al.: Medical Management of CRS in CF
Retrospective casecontrol
Raynor et al.21 2000
1993
1995
2011
2007
1996
1998
2000
1988
1990
2005
1997
Year
11 to 29
4 to 28.5
mean 23.3
8 to 38
5 to 15
4 to 15
20 to 32
N/S (>16)
mean 15.2
mean 12.0
7–15
1–36
Age Range, yr
20
28
51
5
22
219
16
22
30
14
24
250
No.
Dornase alfa
Beclomethasone dipropionate
Serial antimicrobial lavage
Dornase alfa
Ibuprofen (high dose)
Antibiotics
Pulmonary toilet and antibiotics
Betamethasone
Beclomethasone dipropionate
Beclomethasone dipropionate
Dornase alfa
Antibiotics and topical drugs
Medical Treatment
PFTs, endoscopy, CT, need for surgery
Symptoms, rhinomanometry
Need for revision surgery
Symptoms, MRI volumetry, endoscopy, PFTs
Endoscopy
Labs, need for surgery
Symptoms, culture, PFT
Symptoms, endoscopy
Symptoms
Endoscopy, rhinomanometry
Symptoms, endoscopy, PFTs, CT, saccharine clearance test
Symptoms, endoscopy, CT, need for surgery
Outcomes
6 months
48 months
24 months
3 months
52.6 months
N/S
48 months
N/S
>48 months
2 months
12 months
N/S
Follow-up
CT 5computed tomography; MRI 5 magnetic resonance imaging; PFT 5 pulmonary function test; RCT 5randomized controlled trial; N/S 5 not specified.
Retrospective case series
Pignataro et al.20
Retrospective case series
Henriksson et al.17
Prospective case series
Retrospective case series
Halvorson et al.5
Moss et al.6
Prospective doubleblinded RCT
Hadfield et al.16
Prospective, doubleblinded, placebocontrolled, crossover study
Retrospective case series
Donaldson et al.15
Mainz et al.19
Retrospective case series
Costantini et al.14
Retrospective case series
Prospective doubleblinded RCT
Cimmino et al.13
Lindstrom et al.18
Prospective case series
Study Type
Brihaye et al.12
Author
TABLE I. Summary of Included Studies in the Systematic Review.
No
No
No
Yes
No
No
No
Yes
No
No
Yes
No
Statistical Analysis
Improved endoscopy score, fewer surgeries, no change in PFT, no change in CT.
Improved symptoms, improved nasal patency on rhinomanometry.
Both groups had surgical intervention; the group with surgery 1 antimicrobial lavage had a fewer number of patients who needed revision surgery.
Significant improvement in symptom scores; no significant change for other parameters.
All patients had absence of nasal polyps at some point during treatment.
Divided patients into acute vs. chronic sinusitis, suggested that patients with chronic sinusitis more likely to need surgery.
Descriptive results with no specific mention of improvement in outcome parameters.
Significant decreased polyp size on endoscopy; no difference in symptom scores.
Both groups had subjective symptom improvement.
Decreased nasal polys and nasal resistance.
Symptoms and endoscopic appearance improved in treatment group for longer (48 weeks) than in placebo group (24 weeks), significant improvement in PFT in treatment group.
Descriptive results with no specific mention of improvement in outcome parameters.
Findings
TABLE II. Medical Therapy Outcome Assessment. Outcomes Therapy
Studies
Symptoms
Endoscopy
PFT
Radiography
Need for Surgery
Antibiotics
Brihaye et al.,12 Halvorson et al.,5 Henriksson et al.,17 Moss et al.6
0
0
0
0
1
Topical steroids
Costantini et al.,14 Donaldson et al.,15 Hadfield et al.,16 Pignataro et al.20
2
3
N/A
N/A
N/A
Dornase alfa
Cimmino et al.,13 Mainze et al.,19 Raynor et al.21
4
3
2
0
1
Ibuprofen
Lindstrom et al.18
N/A
1
N/A
N/A
N/A
One point for each study showing nonstatistical outcome improvement; two points for each study showing statistically significant outcome improvement. N/A 5 not applicable due to no study evaluating this outcome; PFT 5 pulmonary function test.
studies combined adult and pediatric patients, and thus no specific assessment can be made for each individual group. Therefore, these findings are representative for adult and pediatric CF patients as a group. Most articles (9 of 12) detailed follow-up time for the patients. The mean follow-up time of the included studies was 27.1 months. Two of the studies were level 1 evidence (e.g., randomized controlled trials). One study was level 2 evidence (e.g., cohort study). One study was level 3 evidence (e.g., case-control study). The remaining eight studies were level 4 evidence (e.g., case series). Three (25%) of the 12 articles used statistical analysis to assess outcome measures, with all of these showing a statistically significant difference in at least one of the outcomes measures. Nine (75%) of the 24 articles did not use statistical analysis to report outcome measures. Medical management included topical steroids in four studies (33%), antibiotics in four studies (33%), dornase alfa in three studies (25%), and high-dose ibuprofen in one study (8%). Outcome measures included symptom scores in seven studies (58%), endoscopic findings in seven studies (58%), radiographic findings in four studies (33%), pulmonary function testing in four studies (33%), rhinomanometry in two studies (17%), basic laboratory tests in one study (8%), microbial cultures in one study (8%), and saccharine clearance testing in one study (8%). To assess the outcomes, we evaluated the top five outcome measures: symptoms, endoscopy, pulmonary function test (PFT), need for revision surgery, and hospitalization by type of medical therapy (antibiotics, topical steroids, dornase alfa, and ibuprofen). We used a scoring system based on whether the study showed improvement and whether or not that finding was significant. Points were given to the articles as follows: one point for each study showing non-statistically significant outcome improvement, and two points for each study showing statically significant outcome improvement. Results of the outcome assessment are shown in Table II. Dornase Laryngoscope 124: June 2014
alfa and topical steroids were the only therapies that showed nonstatistically significant improvement in multiple studies or statistically significant improvement in at least one study. Furthermore, dornase alfa and topical steroids had the strongest evidence, showing improvement in multiple outcome measures. Risk of bias in the level 1 and 2 evidence studies was assessed using a modified Cochrane Collaboration Tool for Assessing Risk of Bias.10 All three studies in this category demonstrated low risk of bias after interpretation for potential sources of bias (Table III). The Newcastle-Ottawa Quality Assessment Scale11 was used to review the quality of the level 3 and 4 evidence studies. The mean score for case-control studies and case series was 5.0 out of 10 possible stars and 2.25 out of 4 possible stars, respectively (Table IV).
DISCUSSION This systematic review of the past 25 years of literature supports the potentially beneficial role of medical therapy for CF rhinosinusitis. The preponderance of evidence is based on level 3 to 4 evidence studies. Although the validity of an evidence-based medicine currently relies heavily on randomized controlled trials without biases, these can be difficult to carry out especially for surgical interventions due to ethical considerations and the inability to blind physicians and participants from the procedures. Bentsianov et al. stated that in the otolaryngology literature, 80% of therapeutic recommendations were forged based on data from level 4 evidence.22 Therefore, level 2 to 4 evidence studies were included along with level 1 evidence studies to provide the most meaningful aggregate of evidence and make current treatment recommendations. The two level 1 evidence studies examined betamethasone and dornase alfa, and demonstrated improvement in multiple outcome measures, primarily symptom and endoscopic scores. Dornase alfa efficacy was further supported by one level 2 evidence study and one level 3 evidence study, whereas the Liang et al.: Medical Management of CRS in CF
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TABLE III. Quality Assessment of Level 1 and 2 Evidence Studies (Modified Cochrane Collaboration Tool for Assessing Risk of Bias). Study Potential Source of Bias
Scoring Per Item
Cimmino et al.13
Hadfield et al.16
Mainz et al.19
Was there random allocation of subjects?
Random 5 0, nonrandom 5 1
0
0
0
Was the allocation scheme concealed? Were the interventions concealed from study personnel and participants? Was incomplete data adequately addresses?
Concealed 5 0, not concealed 5 1 Complete blinding 5 0, incomplete blinding 5 1
0
0
0
0
0
0
Addressed 5 0, not addressed 5 1
0
0
0
Did the sponsoring company participate in study design or interpretation?
No involvement 5 0, involvement 5 1
0
0
1
Were there any other important sources of bias?
None 5 0, yes 5 1
0
0
0
0
0
1
Total score
Interpretation of score (minimum possible score is 0, maximum possible score is 6): 0–1 point indicates low risk of bias (least bias, best quality study with valid results); 2–3 points indicate medium risk of bias (susceptible to some bias, but not enough to invalidate results); 4–6 points indicate high risk of bias (most bias, worst quality study with significant flaws).
remainder of support for topical steroids was from level 4 evidence studies. There is no strong evidence that antibiotics improve clinical outcomes. It is worth highlighting below the two level 1 evidence studies included in this systematic review, as they represent the soundest methodological investigation as to the effectiveness of medical therapy on rhinosinusitis for CF patients. Cimmino et al. performed a double-blinded, placebocontrolled trial to determine the benefit of nasally inhaled dornase alfa. Twenty-four pediatric patients with CF underwent endoscopic sinus surgery (ESS). Twelve patients were treated with dornase alfa, and 12 were treated with placebo postoperatively. Primary outcome measures were TABLE IV. Quality Assessment of Level 3 and 4 Evidence Studies (Newcastle-Ottawa Assessment Scale). Selection Grade (Maximum 4 Asterisks)
Comparability Grade (Maximum 2 Asterisks)
Exposure Grade (Maximum 4 Asterisks)
Total
Brihaye et al.12
*
N/A
*
**
Costantini et al.14
*
N/A
*
**
Donaldson et al.15 Halvorson et al.5
** **
N/A N/A
* *
** ***
Henriksson et al.17
*
N/A
**
***
Lindstrom et al.18 Moss et al.6
* *
N/A N/A
* *
** **
Pignataro et al.20
*
N/A
*
**
Raynor et al.21
**
*
**
*****
Author
Maximum possible total score for case control study is 10 asterisks, and maximum possible total score for case series is 4 asterisks. N/A 5 not applicable; for assessment of case series articles, questions regarding control group are not applicable.
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nasal symptom scores and endoscopic appearance. Secondary outcome measures were FEV1, computed tomography findings (graded using the Lund-Kennedy scale), and saccharine clearance test results. Pre- and post-treatment evaluation were performed in all patients. There was no difference in saccharine test scores pre- and post-treatment in both groups. There was improvement in the other outcome measures for both group, with effects in the dornase alfa group improving through 48 weeks versus only temporary improvement through 24 weeks followed by decline in the placebo group.13 Hadfield et al. performed a double-blinded, placebocontrolled trial to determine the benefit of betamethasone (50 lg) drops. Forty-six adult CF patients were divided into a treatment and placebo group, and 22 patients completed the study, with 10 patients in the betamethasone group and 12 patients in the placebo group. Outcome measures were symptoms and endoscopic polyp scores (scored with the Lund-Mackay scale). There was a statistically significant reduction in polyp size in the treatment group, which was not seen in the placebo group. However, there was no significant difference in symptom scores between the two groups. Furthermore, there was no difference between those subjects completing the study and those who dropped out.16 The major cause of mortality and morbidity in patients with CF is pulmonary deterioration. Frequent pulmonary exacerbations also lead to more frequent hospitalizations and increased medication use. This review identified four articles where PFT was used to measure treatment efficacy, and found inconclusive evidence as to whether medical therapy improves PFT or modifies lower airway function. Most studies demonstrated no significant improvement of PFT after medical treatment. Gains in PFT after ESS may be only temporary, because CF is a progressive disease. Overall, the role of medical Liang et al.: Medical Management of CRS in CF
therapy on modifying lower airway function is unclear. Higher level of evidence studies will be needed in the future to better define measures for pulmonary deterioration and assess the efficacy of treatment strategies for CF CRS. This is the first systematic review in the English literature of the medical management of CF CRS. Considering all of the literature, we found that there is a relatively small number of articles written on the topic that can be included in the review. Many studies had to be excluded because they did not have a clear definition of disease included in the article or lacked quantifiable outcome measures for comparison. Study heterogeneity was another limiting factor in this systematic review. Many of the studies that addressed the issue of rhinosinusitis were not favorably designed to compare between patients with comorbid diseases and utilized multiple outcome measures. During the review we identified several studies including CF patients within mixed rhinosinusitis populations, even though it was not available to extract their separate results for comparison. Furthermore, the heterogenous CF patient population—including a mixture of adult and pediatric patients—made it impossible to determine whether outcomes were different between the two groups. Variability also existed in medical therapy. The duration and dosage varies across studies, making comparability difficult. It is also difficult to rule out any confounding effects of previous or concurrent surgical therapy. The average follow-up period of the included studies was 27.1 months. This follow-up period allows for capturing early medical therapy failures, but longer follow-up may be beneficial for outcome assessment in this chronic and progressive disease. This systematic review was performed in conjunction with a systematic review of the surgical management of CF CRS.23 Liang et al. demonstrated that ESS was effective in treating CF CRS by improving symptoms and endoscopic scores.23 Taken together, both of these systematic reviews support both medical and surgical treatment of CF CRS. Deciding on when to pursue medical versus surgical management still varies considerably among otolaryngologist, and there is no strong evidence that one approach is superior to the other. The art of treatment of CF CRS likely combines both medical and surgical approaches tailored to the patient’s desires and expectations.
CONCLUSION Dornase alfa and, to a lesser extent, topical steroids, showed benefit in the medical treatment of CF CRS. There was a lack of evidence to support antibiotic therapy in the outcomes assessed. The primary outcome improvement is demonstrated by symptoms and endoscopic scores. Only level 1 evidence studies showed both symptom and endoscopic improvement with dornase alfa; beclomethasone treatment was associated with endoscopic improvement without clinical correlation. The efficacy of topical steroids for the medical treatment of CF CRS has yet to be clearly delineated. There is little evidence to claim that medical therapy modifies lower airway disease. The litera-
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ture includes level 1 to 4 evidence studies; the majority of studies were level 3 and 4 evidence. Due to the level and quality of evidence, the overall grade supporting the medical therapy in CF patients is B2. Future prospective studies with predetermined, objective, and validated outcome measures are needed to determine the effectiveness of surgical intervention for CF CRS.
Acknowledgments The authors acknowledge Stella Seal, medical librarian, who assisted us in the initial literature search; Bulent Ocal, MD, who assisted in the preparation of this article; and Jimmy Stanley, undergraduate research intern, who assisted in gathering the articles.
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