Sriram Vaidyanathan, MBBS; Martyn Barnes, MBChB; Peter Williamson, MBChB; Pippa Hopkinson; Peter T. Donnan, MD; Brian Lipworth, MD
Chronic rhinosinusitis (CRS) with nasal polyposis is common. The long-term efficacy and safety of approaches to medical management are not well-known.
To evaluate the efficacy and safety of a 2-week regimen of oral steroid therapy followed by 26 weeks of sequential topical steroid maintenance therapy.
Parallel randomized trial with computer-generated block randomization and central allocation. Patients and investigators were blinded to group assignment. (ClinicalTrials.gov registration number: NCT00788749)
A specialty rhinology clinic in Tayside, Scotland.
60 adults with CRS and moderate-sized or larger nasal polyps who were referred by their primary physicians for specialty care.
Patients were randomly assigned in a 1:1 ratio to receive oral prednisolone, 25 mg/d, or placebo for 2 weeks, followed in both groups by fluticasone propionate nasal drops, 400 µg twice daily, for 8 weeks and then fluticasone propionate nasal spray, 200 µg twice daily, for 18 weeks.
Polyp grading (primary outcome), hyposmia score, quality of life, symptoms, nasal patency, adrenal function, and bone turnover.
The mean decrease in polyp grade from baseline to 2 weeks was 2.1 units (SD, 1.1) in the prednisolone group and 0.1 unit (SD, 1.0) in the placebo group (mean difference between groups, −1.8 units [95% CI, −2.4 to −1.2 units]; P < 0.001). The difference between groups was −1.08 units (CI, −1.74 to −0.42 unit; P = 0.001) at 10 weeks and −0.8 unit (CI, −1.8 to 0.2 unit; P = 0.11) at 28 weeks. The mean decrease in hyposmia score from baseline to 2 weeks was 31.12 mm (SD, 30.1) in the prednisolone group and 1.41 mm (SD, 30.6) in the placebo group (mean difference between groups, −28.33 mm [CI, −42.71 to −13.96 mm]; P = 0.002). The difference between groups was −16.06 mm (CI, −30.99 to −1.13 mm; P = 0.03) at 10 weeks and −12.13 mm (CI, −30.55 to 6.29 mm; P = 0.19) at 28 weeks. Prednisolone therapy resulted in transient suppression of adrenal function and increase in bone turnover after 2 weeks, with a return to baseline at 10 and 28 weeks.
Patients were referred from primary care to a single-center rhinology clinic, which limits the generalizability of results. Serial measurements of surrogates of nasal inflammation (such as nitric oxide or cytokine levels) were not performed.
Initial oral steroid therapy followed by topical steroid therapy seems to be more effective over 6 months than topical steroid therapy alone in decreasing polyp size and improving olfaction in patients referred for specialty care of CRS with at least moderate nasal polyposis.
Chief Scientist Office, Scotland; National Health Service Tayside Small Grants Scheme; and an Anonymous Trust grant from University of Dundee.
Chronic rhinosinusitis with nasal polyposis is a common problem resulting in nasal blockage, facial pain, and hyposmia. Responses to therapy are frequently incomplete, and relapses are common. Although oral steroids are recommended only when specialty care is required, little is known about their efficacy.
Patients with at least moderate-sized nasal polyps and chronic rhinosinusitis were randomly assigned to receive 2 weeks of therapy with oral steroids or placebo, followed in both groups by sequential steroid nasal drops and spray. Over 28 weeks of therapy, a greater reduction in the size of polyps and greater improvement in olfaction were observed after induction therapy with oral steroids.
The diagnosis of chronic rhinosinusitis with nasal polyposis was made by otorhinolaryngologists at a specialty clinic, and the applicability of these findings to patients seen only in primary care is unclear.
An initial course of oral steroids seems to be effective in reducing polyp size and improving olfaction in some patients with chronic rhinosinusitis and nasal polyps.
Appendix Table 1.
Appendix Table 2.
Panels A and B show mean values (±SE) for efficacy variables. Panels C and D show mean values (±SE) for safety variables (basal and dynamic adrenocortical function). ACTH = adrenocorticotropic hormone; VAS = visual analogue scale.
* Overall significant mean difference between groups.
† Scale of 0 to 100 mm.
Appendix Table 3.
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Asthma and Allergy Research Group, Division of Cardiovascular and Lung Biology, University of Dundee
March 1, 2011
Incorrect assumptions in the editorial
We thank Mullol and colleague for bringing to prominence a much ignored but debilitating illness. We would like to take the opportunity to discuss several points raised by the editorial.
First, the editorial proposes that differences between groups in the co-primary outcomes of polyp size and olfaction do not endure at 28 weeks. Our interpretation of the data is that there are significant overall differences over the 28 week period of -1.1 units (-1.5, -0.6; <0.001) for polyp score and 15.40mm (-25.85, -4.95; 0.004) for hyposmia score (Table 2). These differences were calculated post hoc as requested by the journal using a longitudinal mixed model analysis (see methods). Moreover, this interpretation was supported using the a priori analysis of an ANCOVA: the differences between groups at 28 weeks were -0.9 units (-1.7 - - -0.1; 0.04) and P < 0.02 for hyposmia score (95%CI not calculable as a square-root transform was applied). We feel it is imperative not to ignore the significant overall trend between groups over the entire treatment period due to a P value falling on the 'wrong' side of an arbitrary numeral. Of course further research is needed before generalizability of this study can be fully understood. But the data show a significant difference over the entire study period.
Second, our study did not evaluate combined oral and topical steroids but sequential therapy. While combined therapy in patients with nasal polyposis may cause significant side-effects due to additive overall steroid burden, we have demonstrated there is no lasting effect on HPA axis or osteoblastic activity in patients treated sequentially. Indeed, almost 50% of our subjects had asthma and were on inhaled corticosteroids. With this in mind, it is unclear why the editorial recommends a 3 month trial of intranasal corticosteroids in patients with moderate to large sized nasal polyps. This approach was not supported by our data and we believe patients with this severity of disease will inevitable have some degree of ostiomeatal complex obstruction, which is the principal cause for disease perpetuation. Nasal steroid sprays do not relieve this obstruction and we routinely and safely treat patients with grade 2 and 3 polyps with an initial oral steroid burst followed by sequential topical therapy in the form of nasal drops and then spray. Using a tapered oral dosing regimen may not provide any benefit as there is a long experience in the UK of treating patients with asthma and COPD with a single daily dose of 25-50 mg without tapering. If anything, a tapering approach could lead to prolonged steroid exposure with increased risk of long term harm. Of course, no trial result will or should replace judicious clinical assessment of each individual patient by their physician. We also acknowledge that our patients were a selected cohort from a specialty clinic and that approach may not be applicable to patients with milder disease.
Third, we agree that there may be a loss of efficacy when switching from drops to nasal spray. While availability of nasal drops is not universal and they are more expensive; in our clinical practice in patients with severe disease we routinely step down therapy from fluticasone nasal drops 400 mcg bid to 200 mcg bid rather than switching to sprays. Nasal drops have been shown in cadaveric studies to access the middle meatus rather than nasal spray which mainly deposits on the inferior turbinates. Nasal drops also have lower systemic bioavailability in head to head comparison with nasal sprays.
Authors of the above article.
Adrian G. Letz
Mike O'Callaghan Federal Hospital
March 10, 2011
Suggestion for More Rigorous Allergy Testing and More Information Concerning Aspirin-Allergic Patients
TO THE EDITOR: Vaidyanathan and colleagues have provided useful information showing the efficacy of providing a burst of systemic corticosteroids for chronic rhinosinusitis (CRS) with nasal polyps along with continuing intranasal corticosteroids.
As a specialist who sees many CRS patients who have already had > 12 weeks of symptoms by the time they see me, providing a burst of oral corticosteroids, in addition to intranasal corticosteroids, has been my practice. It is reassuring to see that this approach is safe and efficacious in a double-blinded, randomized trial.
The authors completed a thorough investigation of baseline characteristics, but I would suggest that more rigorous allergy testing would have provided even more useful information. The presence of atopy was assessed by total serum IgE level along with radioallergosorbent testing for specific IgE to grass pollen, house dust mite, cat, and dog. True allergic rhinitis requires both the presence of symptoms elicited by a specific substance (for example, rhinitis during grass pollen season or perennial symptoms if allergic to house dust mite) along with specific IgE demonstrated to that substance. Individual patient histories with attention to seasonality of symptoms along with allergen skin prick testing would have better delineated any allergic component of these patients' CRS (1).
The presence of aspirin allergy was studied, and I am curious how history of aspirin intolerance was assessed. Approximately 50% in each study group had a positive nasal lysine-aspirin challenge, but only 23% in the prednisolone group and 20% in the placebo group had a "history of aspirin intolerance." Aspirin-exacerbated respiratory disease (or Samter's triad) is important to address in CRS patients, because formal aspirin challenge and desensitization with continuation of aspirin therapy can afford long-term symptom relief and reduction of courses of oral corticosteroids (2). Cystic fibrosis is another important condition to rule-out in patients with CRS with nasal polyps.
In conclusion, despite the European guidelines cited by the authors, it is entirely reasonable for a primary care physician to provide a course of oral corticosteroids for CRS patients while they are waiting to see a specialist.
1. Bernstein IL, Li JT, Bernstein DI, Hamilton R, Spector SL, Tan R, et al. Allergy diagnostic testing: an updated practice parameter. Ann Allergy Asthma Immunol. 2008;100:S1-148.
2. Berges-Gimeno MP, Simon RA, Stevenson, DD. Long-term treatment with aspirin desensitization in asthmatic patients with aspirin-exacerbated respiratory disease. J Allergy Clin Immuol 2003;111:180-86.
Asthma and Allergy Research Group, University of Dundee
March 11, 2011
Re:Suggestion for More Rigorous Allergy Testing and More Information Concerning Aspirin-Allergic Patients
To The Editor
We would like to thank Dr Letz for his comment and agree completely that it is not only safe but also important to commence a short burst of oral steroids in patients with nasal polyposis at the outset to improve the efficacy of subsequent topical therapy.
All our patients underwent a comprehensive assessment including a full history, medical examination, total nasal symptoms score, Juniper mini-RQLQ, RAST for the four common aeroallergens, Aspergillus IgG, total serum IgE, Staphylococcus aureus enterotoxin levels. (Methods) While skin prick testing is more sensitive than serum specific IgE, it is less specific. Thus in nasal polyposis, where traditionally the role of allergy has been questioned, skin prick testing on its own adds nothing to RAST testing. Moreover, the role of allergen immunotherapy and anti- histamines in the treatment of polyps is not established.
Our patients were classed as having a positive history only in the presence of clear symptoms suggestive of aspirin intolerance or medical records to prove the same. The role of routine aspirin sensitivity testing in the absence of clear symptoms of intolerance is unclear i.e. it is unlikely that an asymptomatic patient with a positive aspirin challenge would be treated with desensitization.
In a study (unpublished) we conducted in 75 patients with known aspirin intolerance and a positive aspirin challenge test, we found no increase in disease severity in those with a positive test but absent symptoms. We also found that in symptomatic patients with a history of aspirin intolerance, a longer duration of rhinitis and low FEF25-75 were more likely to have a positive challenge test.
Lastly, our patients were too old to have cystic fibrosis, although we didn't test for CF genes per se.
1. Bousquet PJ, Chatzi L, Jarvis D, Burney P. Assessing skin prick tests reliability in ECRHS-I. Allergy. Mar 2008;63(3):341-346.
2. Fokkens W, Lund V, Mullol J. European position paper on rhinosinusitis and nasal polyps 2007. Rhinol Suppl. 2007(20):1-136.
authors of main article.
Vaidyanathan S, Barnes M, Williamson P, Hopkinson P, Donnan PT, Lipworth B. Treatment of Chronic Rhinosinusitis With Nasal Polyposis With Oral Steroids Followed by Topical Steroids: A Randomized Trial. Ann Intern Med. ;154:293–302. doi: 10.7326/0003-4819-154-5-201103010-00003
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Published: Ann Intern Med. 2011;154(5):293-302.
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