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\begin{document}

\title{A prospective study comparing Itraconazole and systemic steroids as an
adjunct to topical steroids in the post-operative management of Allergic
fungal rhinosinusitis}



\author[1]{Amala Salil}%
\author[1]{Nedha Joy}%
\author[1]{Bini Faizal}%
\affil[1]{Amrita Institute of Medical Sciences and Research Centre}%


\vspace{-1em}



  
  \date{May 29, 2024}


\begingroup
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\selectlanguage{english}
\begin{abstract}
Title: A prospective study comparing Itraconazole and systemic steroids
as an adjunct to topical steroids in the post-operative management of
Allergic fungal rhinosinusitis ABSTRACT Objectives The objective of this
study was to compare the efficacy of Itraconazole and systemic steroids
as an adjuvant to topical steroids in post-operative patients with
Allergic Fungal Rhinosinusitis (AFRS) using both subjective and
objective outcome measurements. Methods A prospective comparative study
was conducted in a tertiary care center on 60 patients diagnosed with
AFRS. Patients with chronic systemic illness and those undergoing
revision surgery were excluded. Post-operative patients were divided
into two groups of 30 each which received Itraconazole 400 mg OD or
Methylprednisolone in tapering doses over six weeks. The outcomes were
measured at the end of 6 weeks -Kupferberg endoscopic staging, Absolute
Eosinophilic Count (AEC), Serum Immunoglobulin (IgE), and Sino Nasal
Outcome Test - 20 scores. Results Our study showed no statistical
significance in outcomes between the two groups treated with
Itraconazole and Methylprednisolone regarding recurrence, AEC, IgE, and
Quality of Life Assessment (p\textless{}0.01). Conclusion Itraconazole
was comparable to Methylprednisolone in preventing disease recurrence in
the post-operative management of AFRS. It may be a viable alternative to
replacing systemic steroids where the latter may be contraindicated.
Itraconazole given at a dose of 400 mg once daily for six weeks was a
safe dose. Keywords: Allergic Fungal Rhinosinusitis, Itraconazole,
endoscopy, Quality of Life, Methylprednisolone Key points: *
Itraconazole was comparable to systemic steroid (Methylprednisolone) in
preventing disease recurrence in the post-operative management of AFRS.
* It may be a viable alternative to replacing systemic steroids where
the latter may be contraindicated. * Itraconazole given at a dose of 400
mg once daily for six weeks was a safe dose. * Recurrence may be treated
safely with Itraconazole than with steroids. * The course may be
repeated in case of recurrence with close monitoring.%
\end{abstract}%



\sloppy


\textbf{Title:} A prospective study comparing Itraconazole and systemic
steroids as an adjunct to topical steroids in the post-operative
management of Allergic fungal rhinosinusitis

\textbf{ABSTRACT}

\textbf{Objectives}

The objective of this study was to compare the efficacy of Itraconazole
and systemic steroids as an adjuvant to topical steroids in
post-operative patients with Allergic Fungal Rhinosinusitis (AFRS) using
both subjective and objective outcome measurements.

\textbf{Methods}

A prospective comparative study was conducted in a tertiary care center
on 60 patients diagnosed with AFRS. Patients with chronic systemic
illness and those undergoing revision surgery were excluded.
Post-operative patients were divided into two groups of 30 each which
received Itraconazole 400 mg OD or Methylprednisolone in tapering doses
over six weeks. The outcomes were measured at the end of 6 weeks
-Kupferberg endoscopic staging, Absolute Eosinophilic Count (AEC), Serum
Immunoglobulin (IgE), and Sino Nasal Outcome Test - 20 scores.

\textbf{Results}

Our study showed no statistical significance in outcomes between the two
groups treated with Itraconazole and Methylprednisolone regarding
recurrence, AEC, IgE, and Quality of Life Assessment (p\textless{}0.01).

\textbf{Conclusion}

Itraconazole was comparable to Methylprednisolone in preventing disease
recurrence in the post-operative management of AFRS. It may be a viable
alternative to replacing systemic steroids where the latter may be
contraindicated. Itraconazole given at a dose of 400 mg once daily for
six weeks was a safe dose.

\textbf{Keywords} : Allergic Fungal Rhinosinusitis, Itraconazole,
endoscopy, Quality of Life, Methylprednisolone

\textbf{Key points} :

\begin{itemize}
\tightlist
\item
  Itraconazole was comparable to systemic steroid (Methylprednisolone)
  in preventing disease recurrence in the post-operative management of
  AFRS.
\item
  It may be a viable alternative to replacing systemic steroids where
  the latter may be contraindicated.
\item
  Itraconazole given at a dose of 400 mg once daily for six weeks was a
  safe dose.
\item
  Recurrence may be treated safely with Itraconazole than with steroids.
\item
  The course may be repeated in case of recurrence with close
  monitoring.
\end{itemize}

\textbf{Introduction:}

Allergic Fungal Rhinosinusitis (AFRS) is a type I and type III mediated
hypersensitivity reaction to inhaled fungal antigens, notably
Aspergillus species and dematiaceous fungi present in the nasal cavity
of immunocompetent individuals.\textsuperscript{1}This non-invasive form
of fungal sinusitis is notorious for high recurrence rates and is often
a topic of intrigue to the treating clinician. Multimodality treatment
with primary surgery followed by medical management is the usual norm.
The aim of surgery in these cases is to remove the antigenic fungal load
and improve the aeration of sinuses. Surgery would facilitate easy
access to topical sprays and lavages. Medical therapy with topical and
systemic corticosteroids plays a vital role in preventing disease
recurrence. However, a steroid-sparing agent with a better side effect
profile may be a welcome alternative. The favorable outcomes in patients
with Allergic Broncho Pulmonary Aspergillosis(ABPA) treated with
Itraconazole have prompted rhinologists to add Itraconazole to the
armamentarium against AFRS.\textsuperscript{2, 3} However, there is a
paucity of studies comparing the effectiveness of Itraconazole and
systemic steroids as an adjuvant to topical steroids in post-operative
patients, in preventing disease recurrence in AFRS, which was the
objective of our study.

\textbf{Materials and Methods:}

The study was approved by the Institutional Ethics committee of our
institute and conformed to the ethical standards laid down in the
Declaration of Helsinki. This manuscript preparation followed the
principles of COPE (Committee on Publication Ethics) and guidelines of
STROBE (The Strengthening the Reporting of Observational Studies in
Epidemiology) statement. Informed consent was taken from all patients
recruited for the study.

The study was a prospective observational study on AFRS patients in a
tertiary care teaching hospital. Patients with chronic systemic illness
and those undergoing revision surgery were excluded. AFRS was diagnosed
based on Bent and Kuhn's criteria.\textsuperscript{4} Based on the
literature, as it was difficult to fulfill all criteria, especially a
positive fungal culture, we came to a diagnosis based on clinical,
radiological, and histopathological reports.\textsuperscript{5, 6}

\emph{Pre-operative assessment:}

Complete blood counts, Absolute Eosinophil Count (AEC), and total Serum
Immunoglobulin (IgE) levels were assessed, along with a Quality-of-life
questionnaire-Sino- nasal Outcome Test (SNOT- 20). The standard
reference level of serum IgE in our institute was 0-100 IU/ml, and in
AFRS, as per standard,\textgreater{}500 IU/ml was considered elevated.
The standard reference range for AEC in our Institute was 40 -440
mm\textsuperscript{3}. In AFRS, as per standard, a value of more than
500mm\textsuperscript{3} was considered elevated. Nasal polyps were
graded by endoscopy according to Kupferberg's grading
system.\textsuperscript{7}Patients were given a course of antibiotics
(Roxithromycin 150 mg twice a day for ten days) and a short course of
oral steroid (8 mg Methylprednisolone for five days followed by 4 mg
methylprednisolone for five days) one week prior to endoscopic sinus
surgery.

\emph{Intraoperative assessment:}

Nasal polyp, fungal debris, and allergic mucin were sampled separately
and sent for fungal smear, fungal culture, and histopathology (HPE) to
look for Charcot-Leyden crystals, fungal hyphae, allergic mucin, and
eosinophils.

\emph{Post-operative assessment:}

After one week of surgery, patients were divided into two groups by a
closed envelope technique of randomization, but no blinding was
involved. The Itraconazole group was given oral Itraconazole 400 mg once
daily for six weeks. The Methylprednisolone group was given tapering
doses of 16mg, 8mg, and 4mg of Methylprednisolone, each taken for two
weeks. Both groups were given topical fluticasone nasal spray, one puff
(50mcg) each nostril once daily and saline nasal douching for six weeks.

The Itraconazole group had a baseline liver function test repeated every
two weeks. In case of alteration of values, the drug was withdrawn.
Similarly, in the Methylprednisolone group, baseline blood sugar levels
(Fasting Blood Sugar {[}FBS{]}, Post Prandial Blood Sugar {[}PPBS{]},
and Glycosylated Hemoglobin {[}HbA1c{]}) were checked. People with
diabetes receiving Methylprednisolone were monitored every two weeks. In
case of poor glycemic control, the drug was withdrawn. At the end of 6
weeks, patients were assessed for post-operative SNOT- 20 scores,
Kupferberg endoscopic staging, AEC, and Serum IgE.

The patients who were available for follow-up were followed up at twelve
weeks and twenty four weeks even after the study period of six weeks.
After six weeks, patients in both groups continued to use Fluticasone
nasal spray.

\emph{Sample size:}

Due to the sparsity of similar studies, a pilot study was conducted in
the department on 20 patients. Based on the results of recurrence
percentage among patients receiving Itraconazole (10\%) and
Methylprednisolone (30\%) observed in the pilot study and with 80\%
power and 95\% confidence, the minimum sample size required was 62.
Sixty patients were recruited (30 in each arm).

\emph{Statistical analysis:}

The data were analyzed using IBM SPSS version 20.0 software. Categorical
variables were expressed using frequency and percentage and numericals
using mean and standard deviation. An independent sample t-test was used
to test the statistical significance of comparing mean change from
baseline of SNOT- 20, Serum IgE, and AEC at one month between two
groups. A Chi-square test with continuity correction was used to test
the statistical significance of the association of all categorical
variables (Predominant symptoms, histopathological findings, and nasal
endoscopic grading) between both the groups. P-value \textless{} 0.05
was considered to be statistically significant.

\textbf{Results:}

At the end of six weeks, one patient from Itraconazole and two from
Methylprednisolone groups were lost for follow-up, leaving behind 57
patients. Hence, out of 57 patients, 29 (50.9 \%) belonged to the
Itraconazole group, and the rest, 28(49.1\%) Methylprednisolone group.
Both groups were comparable (Table- 1).

After six weeks of treatment, serum IgE was found to be normalized
(\textless{} 500 IU/mL) in 51.7\% and 64.3\% of Itraconazole and
Methylprednisolone groups, with no statistical difference between both
groups. (p=0.34). The AEC was normalized in 82.8\% and 89.3\% in
Itraconazole and Methylprednisolone groups with no statistical
difference between both groups(p=0.74) (Tables- 2, 3). Pre-operatively,
all patients had grade 3 nasal polyps on nasal endoscopy. At six weeks
after surgery, recurrence (Kupferberg Grade more than 1) was seen in 2
patients (6.9 \%) in the Itraconazole group and 4(14.3\%) patients in
the Methylprednisolone group. The difference was not statistically
significant (p=0.6).

At 12 weeks, 24 out of 29 from the Itraconazole group and 17 out of 28
from the Methylprednisolone group were available for follow-up. Of
which, 5(20.8\%) in the itraconazole group and 6(35.3\%) in the
methylprednisolone group showed recurrence in endoscopy, which was not
statistically significant (p=0.6).

At 24 weeks, 20 of the 29 patients in the Itraconazole group and 17 of
the 28 patients in the Methylprednisolone group were available for
follow-up. Of which, 5(25 \%) in the itraconazole group and 7(41.2\%) in
the methylprednisolone group showed recurrence in nasal endoscopy
(p=0.3).

\textbf{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.\textsuperscript{8}The 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.\textsuperscript{5,6}In 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.\textsuperscript{9}Similarly, Rains et al. had included
patients without histologic evidence of fungus.\textsuperscript{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.\textsuperscript{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.\textsuperscript{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 (\textless{}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.\textsuperscript{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\textless{}500
mm\textsuperscript{3} 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.\textsuperscript{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.\textsuperscript{14}None 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.\textsuperscript{7}Also, 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.\textsuperscript{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.

\textbf{Conclusions:}

Itraconazole was comparable to Methylprednisolone in preventing disease
recurrence in the post-operative management of AFRS. It may be a viable
alternative to replace systemic steroids where the latter may be
contraindicated. An oral dose of 400 mg once daily of Itraconazole given
for six weeks was safe.

\textbf{Funding Source} : There was no funding from any external agency.

\textbf{Conflict of interest:} None to declare.

\textbf{Data Availability Statement:}

The data supporting this study's findings is available from the
corresponding author at reasonable request.

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\textbf{Legends for tables}

Table- 1: The baseline characteristics of both the study groups are
comparable.

Table 2: Both study groups showed similar improvement in terms of
symptoms, SNOT- 20, AEC, and serum IgE in the first week

Table 3: At the end of 6 weeks, both the Itraconazole and steroid groups
had similar scores in SNOT- 20. The AEC and serum IgE had become normal
in a majority of patients.

\textbf{Hosted file}

\verb`Table- 1.docx`  available at \url{https://authorea.com/users/486637/articles/571531-a-prospective-study-comparing-itraconazole-and-systemic-steroids-as-an-adjunct-to-topical-steroids-in-the-post-operative-management-of-allergic-fungal-rhinosinusitis}

\textbf{Hosted file}

\verb`Table- 2.docx`  available at \url{https://authorea.com/users/486637/articles/571531-a-prospective-study-comparing-itraconazole-and-systemic-steroids-as-an-adjunct-to-topical-steroids-in-the-post-operative-management-of-allergic-fungal-rhinosinusitis}

\textbf{Hosted file}

\verb`Table- 3.docx`  available at \url{https://authorea.com/users/486637/articles/571531-a-prospective-study-comparing-itraconazole-and-systemic-steroids-as-an-adjunct-to-topical-steroids-in-the-post-operative-management-of-allergic-fungal-rhinosinusitis}

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