Itraconazole in Medical Management of Patients with AFRS

Abstract

Allergic fungal rhinosinusitis is a non-invasive disease most commonly found in immunocompetent host. In present study we aim to study the role of itraconazole as primary medical management in Allergic Fungal rhinosinusitis in improving treatment outcome and its role in avoidance of surgery. Total of 50 patients of clinically diagnosed AFRS equally divided into 2 groups, one group receiving 3 months of itraconazole and other receiving steroids in tapering dose. Outcome measures used were—nasal endoscopy (Kupferberg score), symptom score (SNOT-20), NCCT-nose pns orbit (Lund-Mackay score) and biochemical, immunological markers with secondary outcomes of adverse effects and avoidance of surgery.

Introduction

Allergic fungal rhinosinusitis (AFRS) is a allergic disease of immunocompetent host in response to fungal elements present in sino-nasal cavity [1]. It is a non-invasive allergic process, mostly in young individuals with atopy in warm and humid climates [1]. High recurrence rates necessitate adjuvant treatment to defer recurrence and surgery. Specially in a situation of pandemic in which this study was done and the circumstances enforced delayed surgical scheduling, the role of primary medical management of diseases was researched by researchers, leading to the exploration of known entities already established for adjuvant treatment to be used in primary medical management.

Treatment of AFRS has always been a challenge, and recurrence is quite common so surgical debridement of polyp and mucin helps in the re-ventilation of sinuses, along with steroids which decrease the inflammatory response [2]. The search for other promising adjuvant medications led to the use of antifungals in the form of nasal sprays, lavages and oral formulation which has established the role of oral itraconazole in recalcitrant cases of AFRS. Studies conducted by Seiberling et al [3], Khalil et al [4], Chan et al [5] and Hashemi et al [6] have already shown that itraconazole when given in recalcitrant fungal sinusitis decreases the recurrence rate along with symptomatic improvement. Itraconazole given in the preoperative period followed by surgery results in better cavity condition and decreases recurrence in a long-term follow-up [7].

AFRS is considered as sino-nasal form of allergic bronchopulmonary aspergillosis (ABPA), where itraconazole is found to be effective in steroid resistant cases, even lower the steroid dose requirement and improves PFT [8]. The role of itraconazole in primary management of AFRS as a modality that can defer or substitute surgery still needs to be explored. Hence this RCT was planned to explore the feasibility of use of various available drugs such as steroids and itraconazole to see their role in primary medical management of AFRS.

Methodology

Study type: randomised controlled trial.

Site: Department of Otorhinolaryngology, Head and Neck Surgery, Radiodiagnosis, and Microbiology.

Duration: July 2020 to December 2021.

Sample size: 50 patients.

Inclusion and exclusion criteria: AFRS cases were diagnosed clinically, radiologically, and immunologically as per Bent and Kuhn criteria. Patients with chronic systemic illness, extensive intra-orbital or intracranial disease, evidence of invasive or granulomatous fungal disease, or those who did not consent to participation were excluded from the study.

Measuring Parameters:

1. SNOT-20 for symptomatology scoring [9] (baseline, during follow-up visits at 1, 2, and 3 months).

2. Kupferberg for nasal endoscopy grading [10] (baseline, during follow-up visits at 1, 2, and 3 months).

3. Lund-Mackay for radiological scoring using non-contrast computed tomography of the nose and paranasal sinuses (NCCT-PNS) [11](baseline and at the end of intervention).

4. Skin hypersensitivity test (Aspergillus flavus) 02 ml of aspergillin antigen was injected intra-dermally into one arm, and readings were taken every 15 min for the first hour to look for wheal and erythema.

5. Biochemical parameters like absolute eosinophilic count (AEC) and total IgE were monitored monthly.

6. Adverse effects.

Grouping method: randomization using computer-generated random number tables into groups A (receiving itraconazole) and B (receiving steroids).

In group A, 25 patients received itraconazole for 3 months (200 mg twice daily loading dose followed by 100 mg twice daily), and in group B, 25 patients received steroids in a tapering dose (1 mg/kg for 7 days, followed by 0.8 mg/kg for 6 days, then 0.6 mg/kg for 5 days, 0.4 mg/kg for 4 days, 0.2 mg/kg for 3 days, and 0.1 mg/kg for 2 days). A non-contrast CT scan with 0.6-mm cuts of the nose, paranasal sinuses, and orbit was done at the end of the treatment course in both groups, and a decision regarding surgery was taken.

Statistical analysis was done using the student t test for unpaired data, to compare means. Mann–Whitney U test will be used to compare distributions between groups. Wilcoxon signed rank test will be used to compare ordinal data within each group over time. A two-tailed P value of less than 0.5 was considered significant in all tests for interpretation.

The consort chart is mentioned in Fig. 1.

Fig. 1.

Consort diagram

Results

After exclusion of assessed population, 50 patients included in the study: 25 in group A receiving itraconazole and 25 in group B receiving steroids. Two patients in group A and two in group B did not follow up, so a total of 46 patients were analysed, 23 in each group. Group A included 23 patients who continued itraconazole for 3 months with monthly monitoring.

Demography The mean age was 40.88 years (ranging from 16 to 72 years) in group A and 25.88 years in group B (ranging from 10 to 64 years). There was a male preponderance in both groups: 64 percent in group A and 60 percent in group B (Table 1).

Table 1.

Association between drug given and parameters

Parameters	Drug given		p value
	Itraconazole (n = 25)	Steroid (n = 25)
Age (years)***	40.88 ± 15.55	25.88 ± 14.41	0.0011
Gender			0.7713
Male	16 (64.0%)	15 (60.0%)
Female	9 (36.0%)	10 (40.0%)
Laterality			0.7473
Unilateral	6 (24.0%)	7 (28.0%)
Bilateral	19 (76.0%)	18 (72.0%)
Skin test (positive)	15 (60.0%)	20 (80.0%)	0.1233
Right nasal endoscopy (baseline)			0.3542
Grade 0	3 (12.0%)	2 (8.0%)
Grade 1	0 (0.0%)	3 (12.0%)
Grade 2	4 (16.0%)	2 (8.0%)
Grade 3	18 (72.0%)	18 (72.0%)
Left nasal endoscopy (baseline)			0.4212
Grade 0	3 (12.0%)	3 (12.0%)
Grade 1	0 (0.0%)	2 (8.0%)
Grade 2	5 (20.0%)	2 (8.0%)
Grade 3	17 (68.0%)	18 (72.0%)
SNOT-20 (baseline)	3.15 ± 0.58	3.14 ± 0.60	0.7691
LM Score (right) (baseline)	9.04 ± 4.10	9.80 ± 3.57	0.4221
LM Score (left) (baseline)	8.68 ± 4.21	8.64 ± 4.37	1.0001
Total IgE (baseline)***	581.48 ± 474.32	1145.00 ± 677.93	0.0011
Specific IgE (baseline)	1.70 ± 2.78	17.46 ± 77.05	0.1371
AEC (baseline)	534.88 ± 407.80	348.36 ± 186.77	0.2291
LM score (right)	7.17 ± 3.69	6.22 ± 3.72	0.3864
LM score (left)	6.83 ± 3.93	5.61 ± 3.58	0.2784
Surgery done (yes)	15 (60.0%)	10 (43.5%)	0.2523
Total surgeries			0.2462
None	9 (36.0%)	11 (47.8%)
Single	11 (44.0%)	11 (47.8%)
Multiple	5 (20.0%)	1 (4.3%)

***Significant at p < 0.05, 1: wilcoxon-mann–whitney U test, 2: fisher's exact test, 3: chi-squared test, 4: t-test

Clinical presentation Most patients presented with bilateral disease, 76% in group A and 72% in group B. 72% of patients in both groups presented with grade 3 nasal polyposis, the most common sign. SNOT-20 was compared in both groups; the mean SNOT-20 score (58%) in group A was 3.15 and 3.14 (60%) in group B. Nasal discharge and nasal obstruction were the most common symptoms. Skin hypersensitivity testing with Aspergillus flavus antigen was done; 60% in group A and 80% in group B showed positive skin tests.

The mean LM score in group A was 9.04 and 9.80 in group B, making the two groups comparable at baseline. A total of 40/46 (86.95%) patients (20 patients in group A and 22 patients in group B) have never undergone any sino-nasal surgery, while 6/46 (13%) patients (5 in group A and 1 in group B) have undergone functional endoscopic sinus surgery earlier and presented with recurrence. (Table 1).

Primary outcome of the intervention These patients were followed up monthly to look for any improvement in symptomatology and endoscopy scores. In group A, 23 patients completed a 3-month course of itraconazole; 3/23 (13.0%) patients moved from grade 2 to category 1, and 5/23 (21.7%) patients moved from grade 3 to grade 2 in nasal endoscopy. The overall change in nasal endoscopy grades over 3 months was statistically significant (Stuart-Maxwell test: χ2 = 8.000, p = 0.046). In group B receiving steroids, 8/23 (34.78%) patients improved from Kupferberg grade 3 to grade 2 (Table 2).

Table 2.

Change in nasal endoscopy over time (n = 23)

Nasal endoscopy		Baseline					Stuart-Maxwell test
		Grade 0	Grade 1	Grade 2	Grade 3	Total	χ2	P value
3 months	Grade 0	3 (13.0%)	0 (0.0%)	0 (0.0%)	0 (0.0%)	3 (13.0%)	8.000	0.046
	Grade 1	0 (0.0%)	0 (0.0%)	3 (13.0%)	0 (0.0%)	3 (13.0%)
	Grade 2	0 (0.0%)	0 (0.0%)	0 (0.0%)	5 (21.7%)	5 (21.7%)
	Grade 3	0 (0.0%)	0 (0.0%)	0 (0.0%)	12 (52.2%)	12 (52.2%)
	Total	3 (13.0%)	0 (0.0%)	3 (13.0%)	17 (73.9%)	23 (100.0%)

The uncolored cells on the diagonal represent patients whose category did not change. The bold shaded cells represent patients who moved to a lower category. The italic shaded cells represent patients who moved to a higher category

The SNOT-20 score was used to look for symptomatology scoring. In group A, the mean baseline SNOT-20 score was 3.15, and in the follow-up period, the mean SNOT-20 score was 2.94, 2.67, and 2.46 at the end of 1, 2, and 3 months, respectively. The overall improvement was statistically significant (Friedman Test: χ2 = 65.1, p =  < 0.001). In group B receiving steroids, the mean baseline SNOT-20 was 3.14, which decreased to 2.03 after completing the course of steroids. During the follow-up period of 1 month of treatment, the mean of SNOT-20 was 2.94 and 2.03 in groups A and B, respectively, thus a significant difference between the 2 groups in terms of SNOT-20 (1 month) (W = 447.500, p =  < 0.001). As per the observation the amount of decrease in SNOT-20 scores were similar in both the groups, but with significant duration of therapy, being 1 month and 3 months of steroids and itraconazole respectively (Table 3).

Table 3.

Assessment of change in total IgE over time (n = 23) in itraconazole

Timepoint	Total IgE			Friedman test
	Mean (SD)	Median (IQR)	Range	χ2	P value
Baseline	581.48 (474.32)	467.00 (543.00)	75.00–1748.00	27.6	< 0.001
1 month	558.45 (518.78)	350.00 (556.00)	52.00–1705.00
2 months	486.47 (436.03)	350.00 (521.00)	31.20–1440.00

A similar comparison of differences was obtained in terms of Lund Mackay scores between those at the beginning of the study and at the end of treatment during follow-up. The mean LM score in group A decreased from 9.04 at baseline to 7.17 on the right side and 8.68 to 6.83 on the left side at the end of 3 months (overall change statistically significant, p = 0.001). Similarly, in group A, the mean LM score was reduced from 9.80 to 6.22 on the right side and 8.6 to 5.6 on the left side. When both groups were compared at the end of their treatment, no significant difference was found in the LM score (p = 0.386) (Fig. 2).

Fig. 2.

The following is a line diagram depicting the change in SNOT-20 over time in itraconazole

AFRS is considered an immunological response to fungus, so inflammatory markers like total IgE and AEC were studied to look for any reduction in these markers with treatment. The mean of total IgE was 581.48 and 1145 in groups A and B, respectively. There was a statistically significant reduction in total IgE from 581.48 to 486.47 in group A and 1145 to 735.78 in group B (Friedman Test: χ2 = 27.6, p =  < 0.001). Similarly, when AEC was compared, mean AEC decreased from 534.88 to 397.65 at the end of treatment. Thus, the fall in total IgE and AEC throughout treatment with itraconazole suggests some anti-inflammatory role of itraconazole in the pathogenesis of AFRS (Table 3).

Adverse effects Prolonged antifungal treatment needs regular monitoring of side effects with monthly LFT. The mean ALP increased from 104.96 to 108.52, the mean ALT increased from 27.14 to 30.47, and the mean AST increased from 25.68 to 24.93 at the end of itraconazole treatment (statistically insignificant, p > 0.005). None of the patients had any major side effects. Two patients complained of gastrointestinal side effects and discontinued therapy. Also, with a short course of steroids, patients complained of weight gain, acne, muscle cramps, and hyperglycaemia.

Secondary outcome (avoidance of surgery) At the end of treatment, patients with a relatively decreased burden of disease and significant improvement in nasal symptoms, 10/23 (43.37%) and 13/23 (56.5%) in groups A and B, respectively, did not undergo surgical intervention. Thus, itraconazole is effective as a primary modality of treatment and is comparable to steroids in avoiding surgery as the primary modality of treatment. It was believed that the fungistatic or fungicidal action of antifungals decrease the fungus load noted on pre and post therapy non contrast CT scans of nose and PNS, and this forms the main driving force in pathogenesis (Fig. 3).

Fig. 3.

A Pretreatment scans of CT PNS showing heterogenous soft tissue density in bilateral maxillary, anterior and posterior ethmoids. B Post treatment with 3 months of itraconazole in same patient showing decrease in disease load

Discussion

AFRS is an allergic reaction to fungus in the sinuses, mainly affecting immunocompetent hosts, where fungus stimulates the immune system and results in a chronic inflammatory response. The role of antifungals in the treatment of AFRS has evolved over time, starting with intranasal sprays, nasal irrigations, and oral drugs. Patro et al. conducted a prospective study where 52 patients were divided into two groups: 27 received itraconazole for one month in the preoperative period, and the control group was taken directly to surgery [7]. Postoperatively, all patients received steroids and were followed up for 12 weeks, with better cavity conditions and fewer recurrence rates in the preoperative itraconazole group. Two patients receiving itraconazole did not undergo any surgical procedures due to the complete disappearance of the disease. We also observed significant improvements in symptomatology, clinical, radiological, and biochemical parameters comparable to steroids.

Roshan et al. compared preoperative and postoperative itraconazole in AFRS in a prospective study where 100 patients were included, 50 received itraconazole (25 in the preoperative and 25 in the postoperative period for 4 weeks), and a control group of 50 patients did not receive itraconazole [12]. Postoperatively, all patients received a short course of steroids. They concluded that itraconazole, either in the preoperative or postoperative period, delays recurrence and improves postoperative cavity conditions with no significant difference. All these trials studied primarily the effect of itraconazole on postoperative cavity conditions and recurrence rates; our study explored the effects of itraconazole in medical management.

Shah et al. studied prolonged use of itraconazole, 200 mg twice daily for a minimum period of 3 months, in 34 patients with AFRS and observed a significant improvement in clinical, SNOT-22 score, Meltzer endoscopy score, and LM score. 21/34 (61.76%) patients did not require surgery and concluded that itraconazole can be given as sole therapy in AFRS patients [13]. The main limitation of the study was the absence of a control arm to compare the results. We have also found similar results for itraconazole in medical management, which is comparable to steroids.

In the Cochrane review by Head K et al., to study the effect of topical and systemic antifungal therapy in CRS, they included 8 studies, of which 7 studied the effect of topical antifungal therapy and 1 study included systemic antifungal therapy in CRS with or without nasal polyposis. Perioperative studies to investigate the surgical outcome were excluded. They did not conclude any impact of systemic or topical antifungals on patient outcomes due to the very low quality of the evidence, which warrants the need for more randomised trials, especially in AFRS patients [14].

In a study conducted by Kennedy et al., where CRS was treated with a high dose of terbinafine, concluded that fungus resides in mucin rather than the mucosa of the nasal mucosa [15]. Whether systemic antifungal acts in this mucin is not well known. Also, Kennedy et al., isolated naïve CD45RA T cells from healthy volunteers, Th1 & Th2 type cells were differentiated in presence of varying concentration of itraconazole [16]. They found no effect of itraconazole on proliferation of Th1 & Th2 cells, also on interleukins and interferons, thus predicted antifungal treatments failed in the treatment of eosinophilic chronic rhinosinusitis. In our study, the decline in IgE with itraconazole supports the idea that a decline in fungus load reduces inflammation and the vicious cycle in the pathogenesis of AFRS, or whether there is some anti-inflammatory action of itraconazole that is yet to be explored.

Comparison of studies comparing the effect of antifungal therapy both topical and oral in AFRS patients is given in Table 4.

Table 4.

Comparison of studies comparing the effect of antifungal therapy both topical and oral in AFRS patients

Study and year	Title of the study	Methodology	Comments
Ponikau et al., 2005 [17]	Treatment of chronic rhinosinusitis with intranasal amphotericin B	In a randomised, placebo-controlled, double-blind pilot trial, 30 patients were instructed to instil 20 ml of amphotericin B or placebo intranasally	Patients using intranasal amphotericin have reduced inflammatory thickening, both radiologically and endoscopically
Isaac et al., 2011 [18]	Meta-analysis of topical amphotericin B for the treatment of chronic sinusitis	Included were 6 studies from 2002 to 2009 on use of the amphotericin either lavage or spray	Did not reveal any significant effect when compared to control, and a systematic review of the literature did not support the use of topical amphotericin
Khalil et al.,2008 [4]	Role of antifungal therapy in prevention of recurrent AFRS after FESS	The prospective study included 50 patients with AFRS, all of whom underwent surgery. Postoperatively, all received oral steroids and topical steroids. In addition, it is divided into 5 groups: A (oral itraconazole for 3 months), B (topical fluconazole nasal sprays), C (combined systemic and topical antifungal), D (fluconazole nasal irrigation for 6 weeks), and E (no antifungal therapy)	They concluded itraconazole is ineffective to delay recurrence. Topical antifungals in the form of nasal sprays and irrigation have the least recurrence rate
Chan et al., 2008 [5]	Effectiveness of itraconazole in management of refractory AFRS	32 patients with AFRS post-surgery and refractory to steroids and amphotericin nasal sprays were treated with itraconazole for 3 months	Itraconazole was discovered to be helpful in refractory cases of AFRS and that it may extend the time until the next treatment for people with recalcitrant fungal sinusitis, dramatically reduce the risk of relapse. Also helps to reduce or discontinue using oral steroids
Seiberling et al., 2009 [3]	Role of itraconazole in recalcitrant fungal sinusitis	In the retrospective study, 23 patients with recalcitrant fungal sinusitis were included. All patients were treated with surgery, followed by a 3-week course of steroids. Any recurrence after that was treated with itraconazole for a minimum period of 6 months	Patients with recalcitrant FRS who have tried medical and surgical treatment may benefit from taking itraconazole. Itraconazole may increase the interval between recurrences, allowing the patient to drastically reduce or discontinue taking steroids
Hashemi et al., 2014 [6]	Effectiveness of itraconazole on clinical symptoms and radiological finding in patients with recurrent chronic rhinosinusitis and nasal polyposis	22 patients, post-surgery, were given itraconazole for 3 months	Itraconazole has shown beneficial effect on clinical symptoms, radiological findings, and quality of life with recurrent chronic rhinosinusitis and nasal polyposis
Rojita et al.,2017 [19]	Comparison of steroid and itraconazole for prevention of recurrence in AFRS, a RCT	In the prospective study, 60 patients were divided into 2 groups: A received systemic steroids for 1 month and topical steroid sprays for 6 months postoperatively and B received oral itraconazole for 6 months postoperatively	For the postoperative care of AFRS, itraconazole is a viable therapeutic option to steroids. Even though there was no discernible difference between the two groups, patients receiving itraconazole experienced improved symptom alleviation and endoscopic disease clearance

The present study differs from existing literature in that we studied primarily the effect of itraconazole on patients’ symptomatology and endoscopy findings, not focusing on surgical outcome. Also, itraconazole has already shown a promising role in recalcitrant cases not responding to other therapy or in preventing recurrence. But till now, no study has compared itraconazole in the primary treatment of AFRS to steroids, especially in patients who did not undergo any surgical procedure.

Literature is replete with its role in avoiding recurrences, a better cavity in the post-op period, and in recalcitrant cases of AFRS. Though the established criterion standard treatment for AFRS is surgery and steroids, moreover, as per the findings of this study, itraconazole achieves similar results to steroids with 3 months of therapy compared to 1 month of steroid therapy. We strongly recommend itraconazole therapy to patients who are not willing for surgery or are unfit for surgery, patients in whom the use of a steroid is contraindicated, and itraconazole can be used as primary therapy in AFRS. The present study has added to its (itraconazole) role even as primary treatment in selected cases and added one more drug to the armamentarium of AFRS. Itraconazole does have a good safety profile, though the cost of therapy is higher.

Limitations and Future Directions

This study had 23 patients in both arms, which is an adequate sample size considering the incidence of the study. However, a multicentric study of this type with a larger sample size will validate our findings in a profound way. Long-term follow-up still needs to be investigated, though short-term results are promising in this study.

Conclusion

In present study significant improvement was noted in nasal endoscopy, symptomatology, and radiological scores in patients of AFRS receiving itraconazole, comparable to steroids, thus making it a safe alternative in primary medical management of AFRS in patients in whom steroids are either not tolerated or are contraindicated.

Funding

None.

Data Availability

All the data related to current study is with corresponding author and can be shared upon request.

Declarations

Conflict of interest

No competing interest.

Ethical Approval and Consent to Participate

Before commencing the study ethical approval was taken from post graduate institute of medical education and research ethical committee. Written informed consent/assent were taken from all the participants before including in our study.

Consent for Publication

Written consent/assent were taken from the involved participants for publishing their data, images and details.