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.