4.6.3.4.1. Summary of the evidence
This section aims to assess the efficacy of antibiotics in the post viral ARS group in children. Studies were included which involved children with ARS with symptoms of at least five days but less than 12 weeks (to exclude chronic rhinosinusitis). Only DBPCTs were included.
Studies were excluded if a significant proportion of the study population fulfilled the criteria for ABRS or if more than 20%
of the study population had symptoms for less than five days.
The minimum duration of five days was used as a cut-off to exclude patients with common cold. Studies without a placebo arm, and/or involving adults were also excluded. The primary outcome is number of patients who obtained cure/significant improvement at 10-14 days. The secondary outcomes assessed were number of days to cure and adverse effects.
Three studies were included: Garbutt, 2001; Kristo, 2005; and Khoshdel, 2014(244-246). The Garbutt study contained three arms.
Two studies evaluated amoxicillin(244, 246), one amoxicillin with clavulanic acid(244) and one cefuroxime(245). The antibiotics were taken for 10-14 days. All participants had symptoms of acute post-viral rhinosinusitis which fulfilled the EPOS criteria for at least at least five days (Table 4.6.3.).
Khoshdel et al.(246) found a higher cure rate in the amoxicillin group at day 3 (85 vs. 37.5% , p<0.01) but no difference at other time points. The other two studies did not find a significant dif-ference between antibiotics and placebo(244, 245).
The studies could be combined into a meta-analysis to deter-mine the cure rate at day 10-14 (366 patients in three studies)
(244-246). The use of antibiotics was not associated with greater
cure/significant improvement at day 10-14 (RR 1.02 95% CI .96-1.08, I2=0%) (Figure 4.6.11.).
Two studies could be combined and could not show that the pa-tients on antibiotics did have significantly more adverse events compared to the placebo group (RR 1.29 95% CI 0.69-4.38,
Figure 4.6.13. Consumption of antibiotics for systemic use in the com-munity by antibiotic group in 30 EU/EEA countries, 2013 (expressed in DDD per 1000 inhabitants and per day(251).
Figure 4.6.14. Proportion of macrolide Resistant (R) Streptococcus pneu-monia isolates in participating countries in 2013(250).
in symptoms. Three studies reported a reduced time to cure/
reduced symptoms(261, 264, 265), the other two did not. The data were insufficiently reported to meta-analyse. Three studies(263, 264)
evaluated the SNOT-20 score. The SNOT-20 is not validated for ARS but may give some impression of quality of life also in acute disease. The meta-analysis showed no significant difference between treatment with nasal corticosteroids and placebo alt-hough the data showed significant heterogeneity (MD 0.13, 95%
CI -0.04 to 0.31, p=0.14; 4 RCTs, n = 1120; Figure 4.6.14.).
Four studies reported on total symptom score(238, 260, 265, 266). The studies could be combined into a meta-analysis. Both the analyses of the studies where nasal corticosteroid was the single treatment (SMD 0.32, 95% CI 0.15 to 0.50, p=0.0003; two (two arms) RCTs, n = 1860; Figure 4.6.14.) and where nasal corticoste-roid was added to an antibiotic (that on its own has shown to be not effective (see paragraph 4.6.4.3.)) showed a significant effect over placebo (SMD 0.21, 95% CI 0.11 to 0.30, p<0.00001; two RCTs, n=1699; Figure 4.6.16.).
Some studies reported on separate symptoms where nasal congestion was often found to be significantly improved in the nasal corticosteroid group compared to placebo. No meta-ana-lysis was performed.
There was no difference in adverse events and/or in patients needing antibiotics in the studies that evaluated that parameter (Tables 4.6.6.-4.6.7.).
Finally, Svensson et al.(267) used a cost-effectiveness model to analyse the cost-effectiveness of mometasone furoate nasal spray (MFNS) compared with amoxicillin or placebo in the treatment of post-viral rhinosinusitis. Costs were reduced and quality-adjusted life years were increased with MFNS 200 µg twice daily compared with amoxicillin 500 mg three times daily.
MFNS was cost-saving or cost-effective compared with amoxicil-lin or non-active treatment in the sensitivity analyses regardless 4.6.4.1.1. Summary of the evidence
This section aims to assess the efficacy of nasal corticosteroids in adults with post-viral ARS. There are no studies evaluating the effect of nasal corticosteroids on ABRS. Studies were included if they involved adults with ARS with symptoms of at least five days but less than 12 weeks (to exclude chronic rhinosinusitis).
Only double-blind placebo-controlled randomized trials publis-hed after the year 1990, assessing the effects of nasal cortico-steroids for patients who fulfilled the criteria of post-viral acute rhinosinusitis are included. Patients with common cold and acute bacterial rhinosinusitis (ABRS), are excluded. Nasal corti-costeroids delivered into the nose and the paranasal sinuses by any delivery methods generally available in clinical practice are included. Outcomes included in this analysis are time to cure, quality of life, symptoms and adverse events.
Of the eight studies included in this section, five studies(238, 260-263)
were placebo-controlled trials assessing the effects of nasal cor-ticosteroids alone (Table 4.6.4.) and three were studies(264) evalu-ating the effect of the addition of nasal corticosteroids to treat-ment with antibiotics (Table 4.6.5.). The papers of Bachert(263) and Meltzer 2012(261) are post-hoc analyses of the data from Meltzer
2005(238). All studies mainly evaluated patients meeting the EPOS
criteria for acute post-viral rhinosinusitis although in the study of Dolor(264) duration of disease was not indicated. A number of studies evaluated more than one dosage of nasal corticoste-roids. These are analysed separately in the meta-analysis.
Five studies(260-262, 264, 265) reported on time to cure or reduction
Table 4.6.4. Nasal corticosteroids compared to placebo in adult patients with acute post-viral rhinosinusitis.
Study Methods Participants Interventions Outcomes Results
Keith
2012(260) DBPCT 737 patients (age >12y)
with acute post-viral rhinosinusitis
• FFNS 110μg once daily (n=240) for 2 weeks
• FFNS 110μg twice daily (n=252) for 2 weeks
• Placebo (n=245) for 2 weeks
During 1 month:
• SNOT-20
• Daily major symptom score (a composite before the morning and evening dose)
Treatment with FFNS vs.
placebo resulted in:
• No significant reduction in SNOT-20
• Significant reduction in major symptom score
• Significant reduction in congestion
• No significant difference in time to symptom improvement
• No difference in need for antibiotics
• No difference in adverse events
Meltzer
2012(261) DBPCT 728 patients (age >12y)
with post-viral ARS Post hoc analysis of Meltzer 2005(238)
• MFNS 200µg twice daily for 15 days (n=234)
• MFNS 200µg once daily for 15 days (n=243)
• Amoxicillin 500mg 3 times daily for 15 days (n=248)
• Placebo for 15 days (n=246)
• MSS
• The percentage of days with minimal MSS (defined as average am / pm MSS ≤4) for 1 month
• The percentage of days with minimal congestion percentage of days with minimal MSS
• Significantly reduced percentage of days with minimal congestion
• Significantly reduced time to first day with minimal symptoms Williamson
2007(262) DBPCT 240 adults post-viral ARS
(207 analysed) • 500mg of amoxicillin 3 times per day for 7 days and 200µg budesonide in each nostril once per day for 10 days (n=46)
• 500mg of amoxicillin 3 times per day for 7 days (n=54) 200µg budeso-nide in each nostril once per day for 10 days (n=56)
• Placebo (n=51)
• Proportion of patients having symptoms lasting 10 days or more
• Time to cure (graph)
• % cured at day 10
• Total symptom score
No significant effect in any treatment group compared to placebo for all outcomes
Bachert
2007(263) Post hoc analysis of
Meltzer 2005(238) although the dosa-ge indicated here are twice as high as in the original paper (200µg twice and four times daily compared to once and twice daily in Meltzer 2005(238)
340 patients (331
ana-lysed) with post-viral ARS • MFNS 200µg twice daily for 15 days (n=81)
• MFNS 200µg four times daily for 15 days (n=84)
• Amoxicillin 500mg 3 times daily for 10 days (n=84)
• Placebo nasal spray and tablets (n=82)
• SNOT-20
• Global scores Treatment with MFNS compared to placebo resulted in:
• Significant improve-ment in SNOT-20
• Significant improve-ment in global response to treatment
Study Methods Participants Interventions Outcomes Results Meltzer
2005(238) DBPCT Post-viral ARS (n=981) • MFNS 200µg once daily
for 15 days (n=243)
• MFNS 200µg twice daily for 15 days (n=235)
• Amoxicillin 500mg 3 times daily for 10 days (n=251)
• Placebo nasal spray and tablets (n=252)
• Mean am / pm MSS over days 2 to 15 of the treatment phase
• Mean major symptom score, total symptom score, and individual scores (average of am / pm scores) for each symptom averaged weekly and daily
• Safety assessments included disease recurrence during follow-up and adverse event monitoring
• MFNS 200mg twice daily produced significant symp-tom improvements versus amoxicillin and placebo
• MFNS 200mg once daily pro-duced significant symptom improvements versus placebo
• The incidence of treatment-emergent adverse events was similar among the treatment groups
ARS, acute rhinosinusitis; DBPCT, double blind placebo controlled trial; FFNS, fluticasone furoate nasal spray; MFNS, mometasone furoate nasal spray;
MSS, Mean Rhinosinusitis Major Symptom Score; SNOT-20, Sino-nasal Outcome Test-20; y, years.
Table 4.6.5. Nasal corticosteroid as addition to oral antibiotics in adult patients with acute post-viral rhinosinusitis.
Study Methods Participants Interventions Outcomes Results
Nayak 2002(265)
DBPCT 967 post-viral rhinosinusitis patients
• MFNS 400µg nasal spray twice daily for 21 days (n=324)
• MFNS 200µg nasal spray twice daily for 21 days (n=318)
• Placebo nasal spray for 21 days (n=325)
All patients: amoxicillin/cla-vulanate potassium 875mg, twice daily, for 21 days
• Mean improvement in daily symptom scores (0-3) for total symptoms, heada-che, facial pain, congestion, purulent rhinorrhoea, postnasal drip, and cough over 15 days
• Overall therapeutic response to treatment (0-5) at day 21
Treatment with MFNS 400 and 200 twice daily compa-red to placebo resulted in a significantly:
• Larger mean reduction in total symptom scores and congestion than placebo
• Larger mean reduction in facial pain, rhinorrhoea and post-nasal drip than placebo
• Significantly better overall therapeutic response at day 21 compared to placebo
• Significant faster onset of relief
• Comparable adverse events No differences in CT scans, adverse events and plasma cortisol
Dolor 2001(264)
DBPCT 95 ARS patients with acute sinonasal symptoms and history of recurrent rhino-sinusitis or chronic rhinitis (92 analyzed) (duration of disease unclear)
• FPNS 2 puffs twice daisy
• Placebo nasal spray in each nostril once daily for 21 days (n=48)
All received 250mg of ce-furoxime axetil twice daily for 10 days and 2 puffs of xylo zoline hydrochloride in each nostril twice daily for 3 days
• Time to clinical success (patient reported cured or much improved)
• Significantly shortened time to clinical success
• Significantly shorter time to clinical success
• Improved work performance
• No significant differences in rhinosinusitis symptom
Meltzer 2000(266)
DBPCT 407 post-viral ARS patients • MFNS 400µg, twice daily (n=200)
• Placebo spray twice daily for 21 days (n=207) All patients:
Augmentin, 875 mg twice daily
• Daily symptom scores (0-3) for headache, facial pain, congestion, purulent rhinorrhoea, postnasal drip, and cough
• Overall therapeutic response to treatment (0-5) at day 21
• CT scan at day 21
• Adverse events
• Significantly greater decre-ase in total symptom score and headache, congestion, and facial pain compared with placebo.
• No differences in other outcomes
• No difference in therapy-related local adverse events
CT, computed tomography; DBPCT, double blind placebo controlled trial; FPNS: fluticasone propionate nasal spray; MFNS, mometasone furoate nasal spray; SF-12, Short Form-12 (12-item short form QOL survey; SNOT-20, Sino-nasal Outcome Test-20.
Table 4.6.4. Nasal corticosteroids compared to placebo in adult patients with acute post-viral rhinosinusitis. (continued)
Figure 4.6.15. Forest plot of the effect of intranasal corticosteroids versus placebo on change from baseline SNOT-20 score in acute post-viral rhinosi-nusitis.
Figure 4.6.16. Forest plot of the effect of intranasal corticosteroids versus placebo on change from baseline of total symptom score in acute post-viral rhinosinusitis.
CI, confidence interval; M-H, Mantel Haenszel.
CI, confidence interval; M-H, Mantel Haenszel.
of the HRQOL measurement used.
4.6.4.1.2. Conclusion
Nasal corticosteroids are effective in reducing total symptom score in adults suffering from acute post-viral rhinosinusitis.
However, the effect is small. Nasal corticosteroids have not been shown to have an effect on QOL. We downgraded the evidence because of high heterogeneity. Acute post-viral rhinosinusitis is a self-limiting disease. Based on the moderate quality of the evidence and the small effect size the EPOS2020 steering com-mittee advises only to prescribe a nasal corticosteroid when reduction of the symptoms of the acute post-viral rhinosinusitis is considered necessary.
4.6.4.2. Nasal corticosteroid in acute post-viral rhinosinusitis