Sriram Vaidyanathan

Treatment of Chronic Rhinosinusitis With Nasal Polyposis With Oral Steroids Followed by Topical Steroids: A Randomized Trial

BACKGROUND Chronic rhinosinusitis (CRS) with nasal polyposis is common. The long-term efficacy and safety of approaches to medical management are not well-known. OBJECTIVE 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. DESIGN Parallel randomized trial with computer-generated block randomization and central allocation. Patients and investigators were blinded to group assignment. (ClinicalTrials.gov registration number: NCT00788749) SETTING A specialty rhinology clinic in Tayside, Scotland. PATIENTS 60 adults with CRS and moderate-sized or larger nasal polyps who were referred by their primary physicians for specialty care. INTERVENTIONS 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. MEASUREMENTS Polyp grading (primary outcome), hyposmia score, quality of life, symptoms, nasal patency, adrenal function, and bone turnover. RESULTS 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. LIMITATIONS 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. CONCLUSION 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. PRIMARY FUNDING SOURCE Chief Scientist Office, Scotland; National Health Service Tayside Small Grants Scheme; and an Anonymous Trust grant from University of Dundee.

Fluticasone reverses oxymetazoline-induced tachyphylaxis of response and rebound congestion.

RATIONALE Chronic use of intranasal decongestants, such as oxymetazoline, leads to tachyphylaxis of response and rebound congestion, caused by alpha-adrenoceptor mediated down-regulation and desensitization of response. OBJECTIVES We evaluated if tachyphylaxis can be reversed by intranasal fluticasone propionate, and the relative alpha(1)- and alpha(2)-adrenoceptor components of tachyphylaxis using the alpha(1)-antagonist prazosin. METHODS In a randomized, double-blind, placebo-controlled, crossover design, 19 healthy subjects received intranasal oxymetazoline, 200 microg three times a day for 14 days, followed by the addition of fluticasone, 200 microg twice a day for a further 3 days. At Days 1, 14, and 17, participants received a single dose of oral prazosin, 1 mg, or placebo with measurements made before and 2 hours later. MEASUREMENTS AND MAIN RESULTS Outcomes evaluated were peak nasal inspiratory flow, nasal resistance, blood flow, and oxymetazoline dose-response curve (DRC). On Day 14 versus Day 1, inspiratory flow decreased (mean difference, 95% confidence interval) (-47.9 L x min(-1); -63.9 to -31.9; P < 0.001) and the DRC shifted downward (24.8 L x min(-1); 20.3-29.3; P < 0.001). On Day 17 versus Day 14, after fluticasone, inspiratory flow increased (45 L x min(-1); 30-61; P < 0.001) and the DRC shifted upward (26.2 L x min(-1); 21.7-30.7; P < 0.001). On Day 1, prazosin reduced inspiratory flow (-52.6 L x min(-1); -19.2 to -86) compared with baseline. This effect was abolished on Day 14 (7.9 L x in(-1); -41.3 to 25.5). CONCLUSIONS Oxymetazoline-induced tachyphylaxis and rebound congestion are reversed by intranasal fluticasone. Further studies are indicated to evaluate if combination nasal sprays of decongestant and corticosteroid are an effective strategy to obviate tachyphylaxis and rebound in rhinitis. Clinical trial registered with www.clinicaltrials.gov (NCT 00487032).

The minimal clinically important difference in allergic rhinitis

Background When presented with results from clinical measurements or research findings, clinicians must first make an interpretation of their importance, not only in statistical terms, but also the ‘clinical importance’ given the size of the change observed. To do this, they require an understanding of the relationship between their outcome measures, and the patients perception of change. The minimal clinically important difference (MCID) illustrates this relationship by calculating the smallest change in a given outcome that is meaningful to a patient. There are few reports of calculated MCIDs in the Rhinology literature.

Airway dysfunction in nasal polyposis: a spectrum of asthmatic disease?

Background Chronic rhinosinusitis with nasal polyposis (CRSwNP) represents an interesting model to investigate the existence of a non‐allergic unified airway. The factors associated with airway dysfunction in CRSwNP are not fully understood.

Effects of chlorine and exercise on the unified airway in adolescent elite Scottish swimmers

To cite this article: Clearie KL, Vaidyanathan S, Williamson PA, Goudie A, Short P, Schembri S, Lipworth BJ. Effects of chlorine and exercise on the unified airway in adolescent elite Scottish swimmers.

Supervised step-down of inhaled corticosteroids in the community – An observational study

INTRODUCTION Current asthma guidelines recommend step-down of inhaled corticosteroids (ICS) to the minimum dose required for control of symptoms. AIM To determine if supervised step-down of (ICS) in the community has any effect on asthmatic inflammation. METHODS 119 Community based asthmatics underwent progressive step-down of therapy until they became unstable or reached an (ICS) dose of ≤200 μg beclomethasone dipropionate (BDP) or equivalent. Once unstable, participants stepped back up to the last stable dose of ICS. Exhaled nitric oxide (NO) and mannitol challenge were performed at the start and end of step-down. Asthma Quality of Life Questionnaire (AQLQ) and spirometry were recorded at each step-down visit. RESULTS The median (interquartile range) BDP equivalent dose was significantly higher pre vs. post step-down: 400 μg (400-800) and 250 μg (200-400) per day respectively (P < 0.05). Examination of change in PD(10) in individual patients revealed that 34% had an improvement (>+1 dd), 47% had no change (±-1 dd), and 19% had a worsening (<-1 dd). The geometric mean fold ratio in NO for pre vs. post was 0.96 (95% CI 0.87 to 1.06, P = 0.43). Mean (SEM) values for FEV(1) were 86.2% (1.51) vs. 84.5% (1.46) (P = 0.04). There was a significant improvement in AQLQ. CONCLUSIONS We have demonstrated that a significant reduction in ICS dose may be achieved in a community setting without any worsening of airways inflammation or lung function, and with an associated improvement quality of life in the majority of patients. This apparent disconnect may reflect enhanced adherence due to supervision of step-down.

Disconnect between standardized field-based testing and mannitol challenge in Scottish elite swimmers.

Background Elite swimmers have high rates of rhinoconjunctivitis and exercise‐induced bronchoconstriction. Moreover, exposure to chlorine and chlorine metabolites is known to induce bronchial hyper‐reactivity.

Relationship between fractional exhaled nitric oxide and nasal nitric oxide in airways disease

BACKGROUND Invasive techniques show evidence of a unified allergic airway. Nitric oxide is measured noninvasively from the lungs (fractional exhaled nitric oxide [FeNO]) and nose (nasal nitric oxide [nNO]). OBJECTIVE To investigate the relationship between FeNO and nNO in different airway conditions. METHODS A total of 227 participants were assessed: 41 healthy volunteers (HVs), 33 patients with asthma, 52 patients with allergic rhinitis (AR), 63 with unified airway disease (UAD), and 38 with nasal polyposis (NP). Correlation and multiple linear regression analyses were performed. RESULTS Geometric means (95% confidence intervals) for FeNO were as follows: 14.7 (12.4-17.5) ppb for HVs, 29.0 (22.5-37.4) ppb for asthma patients, 23.1 (19.0-28.1) for AR patients, 27.2 (23.0-32.4) for UAD patients, and 28.5 (21.5-37.8) for NP patients. For nNO, the values were as follows: 878.1 (807.0-955.6) ppb for HVs, 674.1 (557.4-815.1) for asthma patients, 853.3 (778.8-934.8) ppb for AR patients, 763.4 (694.1-839.5) for UAD patients, and 388.6 (317.9-474.9) for NP patients. The nNO was lower in the NP group than the other groups (P < .001). The nNO and FeNO were correlated in the AR patients (r = 0.56; P < .0001) and HVs (r = 0.44; P = .004) but not significantly in the other groups. Multiple linear regression of the whole cohort demonstrated that after diagnosis, age, sex, and inhaled corticosteroids were taken into account nNO had a significant association with FeNO (P = .02). CONCLUSION Reduced nNO in NP patients is due to ostiomeatal complex obstruction. FeNO is sensitive to suppression by inhaled corticosteroids. The AR and HV groups have no such confounders; hence, correlation is most evident. Exclusion of confounders reveals a correlation between upper and lower airway inflammation with noninvasive techniques.

Effect of systemic steroids on humming nasal nitric oxide in chronic rhinosinusitis with nasal polyposis

BACKGROUND Increased nasal nitric oxide (NO) is a marker for paranasal sinus ostial patency. However, there are no data evaluating the effect of systemic steroids on humming nasal NO in chronic rhinosinusitis with nasal polyposis (CRSNP). OBJECTIVES To assess whether 2 weeks of oral steroids in CRSNP increases humming nasal NO, whether humming is a more sensitive indicator of this increase than other methods of measuring NO, and whether it correlates with improvements in clinical parameters for sinonasal disease. METHODS Adults with CRSNP (grade 2 and above) were treated with oral prednisolone, 25 mg/d for 2 weeks. Nasal NO was measured by aspiration, exhalation at 0.2 L·s⁻¹, and humming methods. Peak nasal inspiratory flow, Sinonasal Outcomes Test 20 score, symptoms, olfaction, and polyp grade were also measured before and after treatment. RESULTS Twelve patients (mean age, 49 years) completed the treatment. The differences in nasal NO before and after steroid treatment were significantly less pronounced as measured by geometric mean-fold ratio with aspiration (1.5; 95% confidence interval [CI], 1.1 to 1.9; P = .009) and exhalation (2.1; 95% CI, 1.2 to 3.9; P = .02) compared with the humming technique (4.9; 95% CI, 2.2 to 10.7; P = .001). The standardized response means for the methods of NO estimation were 0.97 for aspiration, 1.05 for exhalation, and 1.61 for humming. CONCLUSIONS This study demonstrates that humming nasal NO increases after 2 weeks of oral steroid therapy for CRSNP. Humming NO is more sensitive than aspiration and exhalation and is associated with improvements in symptoms, polyp size, and quality of life. Humming NO may fill the niche for a noninvasive marker of sinus ostial patency.

Systemic bioavailability of hydrofluoroalkane (HFA) formulations of fluticasone/salmeterol in healthy volunteers via pMDI alone and spacer

AIM To compare a test version of HFA fluticasone/salmeterol (FP/SM) combination inhaler (Neolab, UK) with the reference product Seretide (GlaxoSmithKline, UK). METHODS An in vitro Anderson cascade impactor was used to compare the fine particle dose (<4.7 microm). Two separate randomized cross-over studies were performed to compare the systemic bioavailability of test vs. reference (T vs. R) formulations of FP/SM 250/25 microg pMDI in healthy volunteers. In study 1 blood pharmacokinetic analysis using oral charcoal block was performed over 24 h following a single dose of four puffs via pMDI alone. In study 2 systemic bioactivity was measured following single doses of four and eight puffs via a spacer device: serum potassium (K(+)) to reflect SM, and overnight urinary cortisol : creatinine (OUCC) for FP. An early pharmacokinetic profile was also assessed over 120 min. RESULTS The in vitro fine particle dose was similar for test vs. reference pMDI alone and via spacer. The results of both studies were consistent: No significant differences between formulations were seen in terms of FP kinetics. Analysis of SM kinetics revealed superiority of the test product. No significant dose-response or difference in T : R ratio was noted for OUCC. Fall in K(+) revealed a significant dose-response with a non-significant T : R ratio. CONCLUSIONS The in vitro fine particle dose may not predict pharmacokinetic and systemic pharmacodynamic outcomes. Single dosing studies with fluticasone/salmeterol 250/25 microg via pMDI or with spacer showed pharmacokinetic equivalence with FP, but not SM. No significant difference between formulations was seen with either adrenal suppression or hypokalaemia.