Discussion:
Optimal medical management to prevent recurrence in post-operative patients of AFRS is still controversial. The International Consensus Statement on Allergy and Rhinology: Rhinosinusitis 2021 has recommended modest benefits from systemic antifungals in AFRS in improving endoscopic scoring and time to recurrence.8The dearth of well-designed trials for studying the efficacy of oral antifungals was also emphasized. Given the potential systemic toxicity with long-term systemic steroids, the possibility of utilizing Itraconazole in the post-operative care of AFRS, its repeatability, and safety in long-term use form the basis of the current study.
Though Bent and Kuhn’s criteria have been widely used since its inception for the diagnosis of AFRS, fungal detection could be problematic, attributing factors being the sparse distribution of fungus within mucin unless highly sensitive methods of detection are used.5,6In a study by Reda et al. only 6 out of 60 patients showed fungal hyphae and Charcot- Leyden crystals. A positive fungal culture was excluded by them, as it was inconclusive.9Similarly, Rains et al. had included patients without histologic evidence of fungus.10 In our study, allergic mucin was seen in 54 out of 57 patients, of which 28(96.5%) were from the Itraconazole group, and 26 (96.8%) were from the Methylprednisolone group. A positive fungal stain was seen in 31(54.3%) out of 57 patients, 13(72.4%) in the Itraconazole group, and 18(79.3%) in the Methylprednisolone group. Eosinophil with Charcot- Leyden crystals was seen in 48 out of 57 patients, twenty-three (79.3%) patients in the Itraconazole group, and 25 (89.2%) in the Itraconazole Methylprednisolone group. Culture positivity for fungus was seen only in 9 (15.8%) out of 57 patients, five patients in the Itraconazole group and 4 in the Methylprednisolone group. As reported by Tyler et al., neither a positive fungal culture confirmed the disease nor did a negative fungal culture exclude the diagnosis of AFRS because there is always a question of an isolated fungus being an air contaminant.11 This aspect was further explained in a study conducted by Buzina et al. in 233 patients, which showed that nasal mucus collected either by saline flushing or by endoscopic sinus surgery from both patients and healthy volunteers had the same proportion of fungal elements.12 Thus, many of the studies on AFRS have not strictly adhered to all the criteria mentioned in Bent and Kuhn.
Patients with AFRS should ideally have a raised IgE as this is an IgE-mediated immune response to an extra mucosal fungus. With surgery and adequate post-operative care, IgE should theoretically show a decreasing trend as the antigenic load decreases. All patients showed a reduction in IgE values after treatment (Table- 2). It was observed that 51.7% of Itraconazole and 64.3% of the Methylprednisolone group had normalized IgE (<500IU/ml) after treatment. However, the difference in pre-operative and post-operative IgE values between both groups was not significant. Moreover, all patients who recurred had an elevated IgE pre-operative value of more than 1000IU/ml, and post-operative value never decreased below 500IU/ml.
Serum eosinophilia is part of the minor criteria in AFRS.4 A raised eosinophil count can be seen associated with conditions like atopy; hence a high value in a patient need not be indicative of AFRS alone. Similarly, for the same reason, a fall in the absolute eosinophil count is not necessary with just the treatment for AFRS, and a patient can continue to have a persistent raised AEC even with treatment. In our study, AEC was raised in all patients pre-operatively, and 82.8% of patients who took Itraconazole and 89.3% who took Methylprednisolone had AEC<500 mm3 post-treatment. Though a definite decrement was seen in post-treatment patients in both groups, there was no statistically significant correlation between relapse and fall in AEC counts.
It is essential to slash down long-term or repeated usage of corticosteroids given the plethora of complications it can bring on, especially in the Asian population, where the metabolic syndrome is one of the leading causes of morbidity and mortality.13 In our study, we used oral Methylprednisolone in tapering doses of 16mg, 8mg, and 4mg over 2weeks each for six weeks. Twelve patients had transient weight gain, 8 had gastritis despite using proton pump inhibitors, and none developed steroid-induced DM. All our patients completed therapy without a treatment break.
A therapeutic dose of Itraconazole 400 mg once daily for six weeks was given in our study. All our patients had grade 3 polyps pre-operatively. In the Itraconazole group, 2 out of 29 (6.9%) patients had a recurrence. The rest who received Itraconazole had definite clinical improvement in QOL and endoscopy. Similar results in recurrence between the groups were observed by Rojita et al.14None of our patients on Itraconazole developed transaminitis or liver failure.
Rains et al. 10, in the retrospective analysis of patients with recurrent AFRS treated with high dose Itraconazole, topical nasal steroids, and low burst steroids, showed that only 20.5% of the patients with recurrence required revision surgery after this treatment. We followed up with patients for 24 months, and none required revision surgery. There was recurrence in terms of endoscopic staging, but SNOT- 20 score had reduced.
Not many studies have compared the effectiveness of both steroid and Itraconazole in AFRS. Though Kupferberg did compare steroids and antifungals in his trial, endoscopic evaluation was the only method employed as a comparison tool between the groups.7Also, the basis of division into groups was unclear. However, we had 30 patients in each arm and used subjective (QOL questionnaire) and objective outcome measures (IgE, AEC, Endoscopic grading).
In a study by Rojita et al., 14 patients received oral prednisolone 30 mg once daily for one month, followed by topical nasal steroids for six months. The other group received only Itraconazole 100 mg twice daily for six months. So topical nasal steroid was given only to the group that received oral steroids. Outcome parameters were measured at the end of 6 months, showing no statistical difference in the recurrence percentage. In contrast, our study compared oral steroids and Itraconazole as adjuncts to topical steroids. Hence all our patients (in both groups) received topical nasal sprays. Also, the drug regimen used in our study differed in that Itraconazole was given in a dose of 400 mg once daily and Methylprednisolone16 mg, 8 mg, and 4mg tapered over two weeks each for a total of 6 weeks. Our study evaluated outcome parameters at a shorter follow-up duration of 6 weeks, which was the decided study period planned for the study. However, we could follow up with 20 out of 29 patients in the Itraconazole group and 17 out of 28 patients from the Methylprednisolone group at six months. Recurrence was noticed in 6.9% (2 out of 20) and 14.3% (4 out of 17) of Itraconazole and Methylprednisolone groups, respectively, with no statistical significance between the two groups. In both groups, recurrence was treated by increasing the topical steroid dose. Efficacy of Itraconazole in refractory AFRS was cited by Chan et al. 15 and reported significant clinical improvement in 28% of cases. Some authors have reported no significant benefit with post-operative Itraconazole.16, 17 Lack of benefits may be due to the inability to identify fungi in the specimen or since Itraconazole may fail to reach the minimal inhibitory concentration in mucous when taken systemically.
In our experience, Itraconazole was found to be effective as a steroid-sparing agent in a distinct cohort of patients who underwent surgery. Further karyotyping and endotyping may be required to identify this subset. Robust studies with a longer duration of follow-up may be ideal for comparing the effectiveness in the long run.
Limitations:
The short duration of the follow-up period, small sample size, sinus surgery and concomitant use of topical steroid sprays are limiting factors. Also, in some patients whose pre-operative and post-operative IgE values showed a plateau trend with only a reduction in SNOT- 20 score raise the question of a possible overlap between AFRS and EMRS(Eosinophilic mucin rhinosinusitis) as the symptomatic relief could attributed to reduced antigenic load after surgery.