Topical or systemic antifungal therapy for chronic rhinosinusitis

Review question

We reviewed the evidence for the benefits and harms of antifungal treatment in patients with chronic rhinosinusitis including those with allergic fungal rhinosinusitis (AFRS).

Background

Chronic rhinosinusitis is a common condition characterised by inflammation of the nose and paranasal sinuses (a group of air-filled spaces behind the nose, eyes and cheeks). Patients with chronic rhinosinusitis have at least two of the following symptoms for at least 12 weeks: either a blocked nose and/or discharge from their nose (runny nose) and one of either pain/pressure in their face or a reduced sense of smell (hyposmia). Some people also have nasal polyps, which are grape-like swellings of the normal nasal lining inside the nasal passage and sinuses. Some people with chronic rhinosinusitis with nasal polyps are allergic to airborne fungus and this can cause a specific type of condition called allergic fungal rhinosinusitis (AFRS).

Fungal spores are commonly found in the nose as they are in the air we breathe. It is not clear if fungus plays a role in all cases of chronic rhinosinusitis but there is evidence that it may have a role in a subset of patients. Antifungal treatments work to kill fungal spores or to stop them growing. Antifungal treatments for chronic rhinosinusitis are used either topically (put into the nose) or taken systemically (by mouth).

Study characteristics

We included eight studies (490 adult participants). Seven studies (437 participants) investigated topical antifungals (nasal sprays or irrigations) and one study (53 participants) investigated systemic antifungals (tablets). All studies compared antifungals to placebo or no treatment. Most studies were well conducted and there was a mix of patients with chronic rhinosinusitis both with, and without, nasal polyps.

Key results and quality of the evidence

At the end of at least four weeks treatment, none of the studies found that patients using antifungals (topical or systemic) had a better quality of life or less severe symptoms than patients who used placebo or had no treatment.

Not many participants in the studies reported having adverse effects. Topical antifungals may lead to more nasal irritation compared with placebo. It is uncertain if patients taking topical antifungals have more headaches or nosebleeds than with placebo.

For systemic antifungals, it is uncertain if patients using antifungals have more problems with their liver (hepatic toxicity) than with placebo. Systemic antifungals may lead to fewer patients with gastrointestinal disturbances compared to placebo.

We found no studies that compared antifungal treatment with other treatments for chronic rhinosinusitis.

We assessed the quality of the evidence as either low (further research is very likely to have an important impact on our confidence in the result) or very low (any estimate of the result is very uncertain), as some of the results are only from one or two studies, which do not have a lot of participants. Moreover, the different studies reported outcomes using different measurement scales making it difficult to draw conclusions.

Conclusions

Due to the very low quality of the evidence, it is uncertain whether or not the use of topical or systemic antifungals has an impact on patient outcomes in adults with chronic rhinosinusitis compared with placebo or no treatment. More trials are needed to assess well-defined patient populations (such as the AFRS subgroup) and to evaluate other antifungals that have not been assessed in randomised controlled trials.

Authors' conclusions: 

Due to the very low quality of the evidence, it is uncertain whether or not the use of topical or systemic antifungals has an impact on patient outcomes in adults with chronic rhinosinusitis compared with placebo or no treatment. Studies including specific subgroups (i.e. AFRS) are lacking.

Read the full abstract...
Background: 

This review adds to a series of reviews looking at primary medical management options for patients with chronic rhinosinusitis.

Chronic rhinosinusitis is common and characterised by inflammation of the lining of the nose and paranasal sinuses leading to nasal blockage, nasal discharge, facial pressure/pain and loss of sense of smell. The condition can occur with or without nasal polyps. Antifungals have been suggested as a treatment for chronic rhinosinusitis.

Objectives: 

To assess the effects of systemic and topical antifungal agents in patients with chronic rhinosinusitis, including those with allergic fungal rhinosinusitis (AFRS) and, if possible, AFRS exclusively.

Search strategy: 

The Cochrane ENT Information Specialist searched the Cochrane ENT Trials Register; Cochrane Central Register of Controlled Trials (CENTRAL); Ovid MEDLINE; Ovid Embase; CINAHL; Web of Science; ClinicalTrials.gov; ICTRP and additional sources for published and unpublished trials. The date of the search was 17 November 2017.

Selection criteria: 

Randomised controlled trials (RCTs) with at least a two-week follow-up period comparing topical or systemic antifungals with (a) placebo, (b) no treatment, (c) other pharmacological interventions or (d) a different antifungal agent. We did not include post-surgical antifungal use.

Data collection and analysis: 

We used the standard Cochrane methodological procedures. Our primary outcomes were disease-specific health-related quality of life (HRQL), patient-reported disease severity and the significant adverse effects of hepatic toxicity (systemic antifungals). Secondary outcomes included general HRQL, endoscopic nasal polyp score, computerised tomography (CT) scan score and the adverse effects of gastrointestinal disturbance (systemic antifungals) and epistaxis, headache or local discomfort (topical antifungals). We used GRADE to assess the quality of the evidence for each outcome; this is indicated in italics.

Main results: 

We included eight studies (490 adult participants). The presence of nasal polyps on examination was an inclusion criterion in three studies, an exclusion criterion in one study and the remaining studies included a mixed population. No studies specifically investigated the effect of antifungals in patients with AFRS.

Topical antifungal treatment versus placebo or no intervention

We included seven studies (437 participants) that used amphotericin B (six studies; 383 participants) and one that used fluconazole (54 participants). Different delivery methods, volumes and concentrations were used.

Four studies reported disease-specific health-related quality of life using a range of instruments. We did not meta-analyse the results due to differences in the instruments used, and measurement and reporting methods. At the end of treatment (one to six months) none of the studies reported statistically significant differences between the groups (low-quality evidence - we are uncertain about the result).

Two studies reported disease severity using patient-reported symptom scores. Meta-analysis was not possible. At the end of treatment (8 to 13 weeks) one study showed no difference and the second found that patients in the placebo group had less severe symptoms (very low-quality evidence - we are very uncertain about the result).

In terms of adverse effects, topical antifungals may lead to more local irritation compared with placebo (risk ratio (RR) 2.29, 95% confidence interval (CI) 0.61 to 8.62; 312 participants; 5 studies; low-quality evidence) but little or no difference in epistaxis (RR 0.97, 95% CI 0.14 to 6.63; 225 participants; 4 studies, low-quality evidence) or headache (RR 1.26, 95% CI 0.60 to 2.63; 195 participants; 3 studies; very low-quality evidence).

None of the studies found a difference in generic health-related quality of life (one study) or endoscopic score (five studies) between the treatment groups. Three studies investigated CT scan; two found no difference between the groups and one found a significant decrease in the mean percentage of air space occluded, favouring the antifungal group.

Systemic antifungal treatment versus placebo or no treatment

One study (53 participants) comparing terbinafine tablets against placebo reported that there may be little or no difference between the groups in disease-specific health-related quality of life or disease severity score (both low-quality evidence). Systemic antifungals may lead to more hepatic toxicity events (RR 3.35, 95% CI 0.14 to 78.60) but fewer gastrointestinal disturbances (RR 0.37, 95% CI 0.04 to 3.36), compared to placebo, although the evidence was of low quality.

This study did not find a difference in CT scan score between the groups. Generic health-related quality of life and endoscopic score were not measured.

Other comparisons

We found no studies that compared antifungal agents against other treatments for chronic rhinosinusitis.

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