Efficacy of preoperative itraconazole in allergic fungal rhinosinusitis Sourabha K. Patro, M.S.,1 Roshan K. Verma, M.S., D.N.B.,1 Naresh K. Panda, M.S., F.R.C.S.,1 Arunaloke Chakrabarti, M.D.,2 and Paramjeet Singh, M.D.3
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ABSTRACT
Introduction: Criterion standard treatment of allergic fungal sinusitis (AFS) is primary surgery followed by adjuvant therapy. Even after good surgery, recurrence rates vary from 10 to 79%. Antifungals, e.g., itraconazole, and steroids have shown varying success rates in delaying recurrences given after surgery. Itraconazole decreases the need for steroids given as a primary treatment in allergic bronchopulmonary aspergillosis. This study investigated the efficacy of itraconazole given preoperatively for allergic fungal rhinosinusitis. Methodology: A prospective study was carried out from July 2011 to November 2013 with 27 patients with histologically proven AFS, who were given itraconazole for 1 month in the preoperative period and operated after completion of the course of itraconazole. They were compared with 25 matched controls of patients with AFS who were operated on directly without preoperative itraconazole. Both groups were given oral steroids in tapering doses for 6 weeks during the postoperative period and followed up at regular intervals. Evaluations were done by using symptomatic (Sino-Nasal Outcome Test [SNOT-20]), radiologic (Lund Mackay scores), and endoscopic (Kupferberg nasal endoscopic grades) parameters. Results: Symptomatology scores (SNOT-20) decreased significantly (p ⫽ 0.000) with itraconazole. There was a decrease (p ⫽ 0.007) in the Lund Mackay scores that reached up to 0. There was complete resolution of disease in 15% of the patients. Reductions in hyperdensities were noted on computed tomography in all the patients after preoperative itraconazole. Polyp sizes decreased and nasal endoscopic grades improved after itraconazole. Postoperative fungal cultures were positive in 60% of the patients in the preoperative itraconazole group compared with 76% of the patients in the control group, which indicated a decreased fungal burden. Conclusion: We found improvements in clinical, radiologic, and endoscopic parameters in AFS after preoperative itraconazole administration, which decreased the disease load significantly and also reduced the extent of surgery in the short-term follow-up. It may prove to be a good preoperative adjunct that needs further research (Am J Rhinol Allergy 29, 299 –304, 2015; doi: 10.2500/ajra.2015.29.4187)
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llergic fungal sinusitis (AFS) is a disease with a noninvasive allergic process to fungal antigens present in sinonasal cavities. It occurs mostly in young individuals with atopy and is associated with nasal polyposis and the presence of allergic mucin.1 It is commonly seen in warm and humid climates.2,3 Ninety percent of the patients with AFS show evidence of type I hypersensitivity with raised serum immunoglobulin (Ig) E levels and type III hypersensitivity by eosinophilia in sinus mucosa with fungal antigens.4,5 The primary treatment in AFS has always been surgery. The primary goal of surgery is to decrease the antigen load and improve the aeration of the sinuses.6 But treatment of AFS has always remained a challenge and required continuous follow up of patients because recurrence varies from 10 to 100%.7,8 Hence, adjuvant therapy plays a vital role in the management of AFS. The pathophysiologic similarities between AFS and allergic bronchopulmonary aspergillosis is the guide for adjuvant treatment of AFS.9 Topical steroids have been used by Kupferberg et al.7 and Marple and Mabry8 in their study, and they have been shown to delay recurrences in AFS. Oral steroids have also shown promising results in the postoperative period and have been shown to delay the recurrences.7,10 Immunotherapy as an adjuvant in postoperative period has been shown to reduce the recurrence and reliance on systemic steroids.11,12 However, use of preoperative immunotherapy in AFS have shown the disease to worsen.13,14 The search for a promising adjuvant led to the use of antifungals as adjuvant for AFS. Topical amphotericin B in the form of nasal spray
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From the 1Department of Otolaryngology, Head and Neck Surgery, 2Department of Microbiology, and 3Department of Radiodiagnosis, Post Graduate Institute of Medical Education and Research, Chandigarh, India The authors have no conflicts of interest to declare pertaining to this article Address correspondence to Roshan K. Verma, D.N.B., Department of Otolaryngology, Head and Neck Surgery, Post Graduate Institute of Medical Education and Research, Chandigarh, India 160012 E-mail address: [email protected] Copyright © 2015, OceanSide Publications, Inc., U.S.A.
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and nasal lavage in the postoperative period has been shown to produce symptomatic improvement but failed to show improvement in nasal endoscopic or radiologic scores.15,16 Rains and Mineck,17 Seiberling and Wormald,18 Chan et al.,19 Gupta et al.,20 Panda et al.21 in their studies have proven the role of itraconazole in AFS as a postoperative adjunct, which indicates that itraconazole is efficacious in delaying recurrences. Itraconazole has also been used in allergic bronchopulmonary aspergillosis and has been shown to reduce maintenance steroid requirements.22–24 Thus, we hypothesized that itraconazole may be effective in AFS given preoperatively because it has been found to be effective when given postoperatively and is also effective in cases of allergic bronchopulmonary aspergillosis which have a similar pathophysiology as that of AFS. This study was planned to study the role of itraconazole in AFS when given preoperatively.
METHODOLOGY A single-center, randomized, prospective study was done at our tertiary care hospital from July 2011 to November 2013. Institutional ethics and review committee approval was taken for the study, and informed consent was obtained from every patient for participation in the study. Information regarding the study and consent was explained to the patients in the language they understood. We included 52 patients with clinically and histologically diagnosed cases of AFS. All the cases were evaluated with a detailed clinical history, general physical examination, and complete head and neck examination, including anterior rhinoscopy. The symptomatology scores were evaluated as per Sino-Nasal Outcome Test (SNOT-20) scores. Computed tomography (CT) of nose and paranasal sinuses (PNS) in the axial and coronal planes was performed in all patients and were evaluated as per Lund Mackay scores. Diagnostic nasal endoscopy, along with punch biopsy from a nasal polyp, was done in all the patients for histologic conformation. Nasal endoscopy findings were graded based on Kupferberg grades. In addition, total serum IgE, absolute eosinophil counts, and Aspergillus skin hypersensitivity test
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were done in all patients. Skin-prick test that showed a wheal of diameter ⬎8 mm and an absolute eosinophil count of ⬎400 l were taken as significant. A final diagnosis was obtained by using Saravanan’s criteria25 before inclusion of the cases into the study. Patients with evidence of invasive or granulomatous fungal sinusitis, those who were allergic to itraconazole, patients presenting with extensive intraorbital or intracranial extension, and those who would not consent for participation were excluded from the study. All the patients included in the study were randomly divided into two groups, the study group and the control group. Group A patients received itraconazole preoperatively for 4 weeks. After itraconazole therapy, they were reevaluated by using SNOT-20 scores, Lund Mackay scores, and nasal endoscopic grade (Kupferberg grades), and then were taken for definitive surgery. Group B patients were taken directly for surgery after diagnosis and preliminary investigation. Postoperatively, both the groups were given 6 weeks of oral steroids in tapering doses. All the patients were followed up with regular nasal douching and nasal endoscopy. SNOT-20 scores and nasal endoscopic grades were determined at weeks 1, 6, 12, and 24 follow-up. Total IgE levels were assessed at 6 weeks postoperatively. CTs of nose and paranasal sinuses were done at the 12- and 24-week follow-ups. Both the groups were compared for the mentioned parameters to assess the effect of itraconazole. Patients in both groups are under our continuous follow-up to the present date. Statistical analysis was done by using the t-test with IBM SPSS Statistics version 20 (IBM Corp., Armonk, NY). A p value of ⬍0.05 was taken as the level of significance in each test.
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Figure 1. SNOT scores of patients in the study group before and after therapy with itraconazole.
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RESULTS A total of 52 subjects were recruited during the study period: 27 in group A and 25 in group B. Two patients in group A refused surgery after taking itraconazole for 4 weeks due to personal reasons and were excluded from the study. Two patients in group A did not require surgery due to the complete disappearance of disease, but they were included in the analysis. Hence, 25 patients in group A were considered for final analysis. Group B included 25 patients, who were taken directly for surgery. The mean age was 30.60 years among the study group (group A) and 30.06 years among the control group (group B). Thirty-eight percent of the patients (19/50) were from the younger age group and were in their first and second decade of life. Nasal discharge, postnasal drip, and nasal obstruction, along with allergic symptoms, were the most common symptoms. Nasal polyposis was the most common sign (97.36%). Anterior ethmoids were the most common sinus involved, as seen on radiology. Erosion of ethmoidal cell septa was seen in 92.1%; posterior ethmoids, 84%; maxilla, 76%; sphenoid, 67%; and frontal sinus, 65%. Unilateral involvement of paranasal sinuses was seen in 23% of patients; 92.5% of patients showed multiple sinus involvement. Lamina papyraceae and the skull base were eroded in 13% and 5% of patients, respectively. On correlating the relationship between the Lund Mackay score and age, age had a negative correlation with disease extent, i.e., younger individuals had a propensity to have severe disease (p ⫽ 0.016). SNOT-20 scores, LM scores, and nasal endoscopic grades were compared before and after 1 month of itraconazole therapy in group A. The mean (⫾ SD) SNOT-20 scores decreased, from 31.28 ⫾ 13.79 to 15.72 ⫾ 9.34 (p ⫽ 0.000) (Fig. 1). The mean Lund Mackay radiologic scores decreased, from 18.04 ⫾ 6.04 to 15.24 ⫾ 7.37 (p ⫽ 0.007) (Fig. 2). It was also observed that the hyperdense areas in the sinuses on CTs reduced after itraconazole therapy and the scans became more homogenous. The nasal endoscopic grades were also decreased, from 2.9 ⫾ 0.27 to 2.68 ⫾ 0.85; however, this was not statistically significant (p ⫽ 0.161) (Fig. 3). In 8% (2/25) of patients in group A, dramatic improvement was seen after itraconazole therapy with complete disappearance of the disease in nasal endoscopy and decrease in the Lund Mackay scores from 12 and 21 to 0 and 1, respectively (Patients no. 12 and 20, Figs. 2, 4, 5). Reductions in hyperdensities were noted
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Figure 2. Lund Mackay scores of patients in the study group before and after therapy with itraconazole.
Figure 3. Kupferberg nasal endoscopic grades of patients in the study group before and after therapy with itraconazole.
on computed tomography in all the patients after preoperative itraconazole (Fig. 6). No major adverse effects were seen after or during itraconazole therapy. However, two patients had transient elevation of liver enzymes, which returned to normal 2 weeks after completion of itraconazole. A comparison of the cavity conditions on nasal endoscopy between group A and group B in the follow-up period at week 1, 6, 12, and 24 was done; for these follow-up times, the mean nasal endoscopic grades in group A were 0.04, 0.22, 0.84, and 0.64, respectively, and in
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group B, mean nasal endoscopic grades were 0.33, 0.28, 2.48, 0.32, respectively. On comparison of mean endoscopic grades between groups A and B, p values of 0.007, 0.062, 0.000, and 0.095 were obtained at 1, 6, 12, and 24 weeks, respectively, which reached levels of statistical significance at weeks 1 and 12; this indicates that cavity conditions during the postoperative period with preoperative itraconazole were significantly better compared with surgery and implicates a delay in the process of recurrence in patients treated with preoperative itraconazole compared with those who were directly taken for surgery (Table 1). Lund Mackay scores were obtained at 12- and 24-week follow-ups for both group A and group B: the mean Lund Mackay scores in group A were 0.24 ⫾ 0.43 and 1.40 ⫾ 1.41, respectively; whereas the mean (⫾ SD) Lund Mackay scores in group B were 2.20 ⫾ 1.84 and 2.32 ⫾ 1.34, respectively. On comparison between Lund Mackay scores at week 12 and 24 between group A and group B, the p values of 0.000 and 0.023 were obtained, which was statistically significant (p ⬍ .05). This indicates better cavity conditions in patients who were previously treated with itraconazole and again implicates a delay of the process of recurrences (Table 1). IgE values were acquired at the 6-week follow-up for both group A and group B. The mean IgE (IU/ml) value decreased significantly, from 4617 ⫾ 3420 to 1530 ⫾ 1133 in group A (p ⫽ 0.000), and from 4664 ⫾ 2566 to 857 ⫾ 737 in group B (p ⫽ 0.000) in the postoperative period at 6 weeks compared with those at the beginning of the study. The decrease in the mean IgE values between group A and group B was statistically similar (p ⫽ 0.251). Postoperative fungal cultures were positive in 60% of group A patients compared with 76% group B patients, which indicates a decreased fungal burden after itraconazole therapy, although it was not statistically significant (p ⫽ 0.292). The correlation between the decrease in the IgE values and the positive fungal cultures was sought, and a correlation coefficient of 0.143 was obtained in the group A compared with 0.078 in group B, which indicates that there was more chance of fungal culture being negative with a decrease in the IgE values with group A compared with those with group B. There was no significant difference between group A and group B in terms of intraoperative mucin (p ⫽ 0.353), fungal smear (p ⫽ 0.513), fungal culture (p ⫽ 0.355), and histopathologic characters such as the presence of mucin (p ⫽ .680), eosinophils (p ⫽ .490), and fungal hyphae between both groups (p ⫽ .500). Further analysis was done by comparing both group A and group B in terms of the difference in the nasal endoscopic grades between that obtained in follow up and that at the beginning of the study. Mean (⫾ SD) nasal endoscopic at the beginning of study was 2.92 ⫾ 0.277 and at follow up was 0.3 ⫾ 0.48 (week 1), 0.2 ⫾ 0.42 (week 6), 0.4 ⫾ 0.80 (week 12), and 0.4 ⫾ 0.81 (week 24) in group A. Whereas, in group B, it was 2.96 ⫾ 0.2 (at the beginning of the study) and, at follow-up, it was 0.4 ⫾ 0.2 (week 1), 0.8 ⫾ 0.45 (week 6), 2.48 ⫾ 1.55 (week 12), and 0.2 ⫾ 0.47 (week 24). The mean difference in the nasal
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endoscopic grades compared with the beginning of the study in group A was 2.60 ⫾ 0.50, 2.72 ⫾ 0.45, 2.08 ⫾ 0.81, 2.28 ⫾ 0.79 at week 1, 6, 12, and 24; in group B, was 2.92 ⫾ 0.27, 2.68 ⫾ 0.47, 1.20 ⫾ 0.1, 2.64 ⫾ 0.49 at week 1, 6, 12, and 24, respectively. The p values of 0.00, 0.76, 0.00, and 0.05 (Table 2) were obtained at week 1, 6, 12, and 24, respectively, postoperatively when these differences were compared between group A and group B. A similar comparison of differences was obtained in terms of Lund Mackay scores between those at the beginning of the study and at 12and 24-week postoperative follow-up. The mean Lund Mackay score at the beginning of study was 18.04 ⫾ 6.04 and, at follow-up, was 2.20 ⫾ 1.84 (12 weeks) and 1.40 ⫾ 1.41 (24 weeks) in group A, whereas, in group B, it was 16.52 ⫾ 3.78 (the beginning of the study) and at follow-up was 0.4 ⫾ 0.43 (12 weeks) and 2.32 ⫾ 1.34 (24 weeks). Intergroup comparison of mean Lund Mackay scores at week 12 and 24 after surgery revealed p values of 0.000 and 0.023 at week 12 and week 24, respectively (Table 1). This showed that there was a significant difference between the Lund Mackay scores between the groups in follow-up, which indicates better response to therapy and significantly better cavity conditions in the study group in terms of the radiologic findings. However, the mean of the differences in the Lund MacKay scores between those obtained during week-12 and week-24 follow-ups and those at the beginning of study in group A were 15.84 ⫾ 6.06 and 16.64 ⫾ 5.75 and, in group B, were 16.28 ⫾ 3.82 and 14.20 ⫾ 4.00, respectively. A comparison of these mean differences between both group A and group B revealed p values of 0.76 and 0.08 at week-12 and week-24, respectively (Table 3), which did not reach the levels of statistical significance. Similar intergroup comparison of differences obtained among scores at various intervals in follow-up and the beginning of the study in terms of SNOT-20 scores did not reveal any significant difference between the groups (Table 4) The effect of itraconazole on the SNOT-20 scores, LM scores, and nasal endoscopic grades in group A were obtained. All the surgeries were performed by a single surgeon (R.K.V.), and all the patients were from the same geographic location, i.e., north India, thus excluding the surgeon and the geographic confounding factors. Our analysis showed that there was statistically significant reduction in the SNOT scores (p ⫽ 0.000) and LM scores (p ⫽ 0.007), which could be attributed to the drug given, i.e., itraconazole, after excluding every other factor. Similar analysis for nasal endoscopic grades (p ⫽ 0.161) did not show any significant reduction that could be attributed to itraconazole. (Table 5) Recurrence was defined as an LM score of ⬎10 and a nasal endoscopic grade ⬎ ⫽ 2. None of the patients in group A and group B showed any evidence of recurrence until 6 months of follow-up. However, after the initial 24 weeks after surgery, all the patients were followed up at every 3-month interval to date. The recurrences for which repeated surgery was needed occurred between 8 and 14 months in 3 patients of group A and between 7 and 11 months in 6 patients of group B. The mean time to recurrence was 11.4 months in group A compared with
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Table 1 Mean values and p values for comparisons of different parameters obtained during follow-up NE Grade, Mean (ⴞ SD)
Week
1
6
12
LM Score, Mean (ⴞ SD) 24
12
24
SNOT-20 Score, Mean (ⴞ SD) 6
12
IgE Values (IU/ml), Mean (ⴞ SD) 24
6
Group A 0.33 ⫾ 0.48 0.22 ⫾ 0.42 0.84 ⫾ 0.80 0.64 ⫾ 0.81 2.20 ⫾ 1.84 1.40 ⫾ 1.41 5.26 ⫾ 3.18 5.0 ⫾ 3.24 4.24 ⫾ 2.94 1530.75 ⫾ 1133.14 Group B 0.04 ⫾ 0.20 0.28 ⫾ 0.45 2.48 ⫾ 1.55 0.32 ⫾ 0.47 0.24 ⫾ 0.43 2.32 ⫾ 1.34 5.56 ⫾ 1.47 5.72 ⫾ 1.94 5.32 ⫾ 2.61 857.72 ⫾ 737.50 Comparison 0.007 0.062 0.000 0.095 0.000 0.023 0.674 0.346 0.177 0.19 between the groups, p value NE ⫽ nasal endoscopy; LM ⫽ Lund Mackay; SNOT ⫽ Sino-Nasal Outcome Test
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Figure 4. CT and nasal endoscopic picture of patient nos. 12 and 20 before initiation of itraconazole, i.e., at the beginning of the study.
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Figure 5. CT and nasal endoscopic picture of patient nos. 12 and 20 after therapy of itraconazole for 1 month.
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9.6 months in group B. The difference in the time interval between both groups was not statistically significant (p ⫽ 0.092), although the recurrence rates were significantly less in the study group (group A) compared with the control group (group B).
DISCUSSION
AFS is common in young individuals who are immune competent and with predominant unilateral nasal polyposis with multiple sinus involvement. It has an equal male-to-female ratio.6,26,27 However, in our study, there was a predominance of bilateral disease, and unilateral disease was seen only in 23% of cases. Younger patients had more-severe disease, with extensive multiple sinus involvement than did older patients in our study. The management in cases of AFS has always been surgical. Recurrence rates vary from 13% to 100%.7 Bent and Kuhn27 rightly comment about allergic fungal sinusitis, “In AFS misdiagnosis is common, recurrence rates are high and proper treatment elusive.” Oral itraconazole has been used in the postoperative period as an adjunctive therapy and has been shown to decrease and delay the recurrences. This study is unique because we used itraconazole as preoperative adjunct in AFS and tried to analyze the effect of itraconazole on
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Figure 6. CT and nasal endoscopic picture of patient no. 13 before and after the therapy of itraconazole. Decrease in the number of areas of hyperdensities and size of the polyps can be seen, which indicates a decreased disease load and fungal burden.
symptom scores, endoscopic grades, CT scores, and the overall improvement in cavity condition and recurrence rates postoperatively. The mean SNOT-20 scores decreased from 31.28 to 15.72 after the patients received itraconazole for 1 month (p ⫽ 0.000), and the mean Lund Mackay scores decreased from 18.04 to 15.24 (p ⫽ 0.007). We also noticed a decrease in heterogeneity on CTs after itraconazole. Itraconazole given preoperatively improves the symptoms and the radiologic extent of disease. When the decrease in the IgE was compared with that of the fungal culture reports, higher correlation coefficient was seen in group A (0.143) compared with group B (0.078), which indicates decreased fungal burden with the use of itraconazole. Seiberling and Wormald18 in their study reported improvement in symptomatic and endoscopic parameters in 82.6% of the patients (19/23) with postoperative adjuvant itraconazole therapy. Although, in our study, we had symptomatic, endoscopic, and radiologic improvement with preoperative itraconazole therapy and also that the postoperative cavity was found to be better in patients who received preoperative itraconazole therapy than surgery alone. A statistically significant difference in nasal cavity conditions was seen between the nasal endoscopic grades at each follow-up compared with that of the beginning, except for cavity conditions at 12 weeks in the control group (Table 1). The final cavity status was significantly different between the two groups in the follow-up period, which indicates improvement in the cavity conditions and delay in the process of recurrence in the patients who had received itraconazole preoperatively. The differences obtained between the cavity conditions in follow-up and that at the beginning of the study also show a significant difference when compared between the groups (Table 2). Itraconazole helps in making the cavity conditions better compared with those in whom it was not administered. Seiberling and Wormald18 and Panda et al.21 also show a similar result of improved cavity conditions in established recurrences with the use of postoperative itraconazole in AFS. Rains and Mineck17 retrospectively evaluated 137 cases of recurrent disease in which patients were given high doses of itraconazole until the patients showed disappearance of the disease in nasal endoscopy and had found that once disappearance of disease in nasal endoscopy was achieved, 50.3% showed recurrence after average duration of 10.8 months of follow-up. The investigators showed that itraconazole decreases the need of oral steroids and the need for revision surgery.
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Table 2 Comparison of nasal endoscopic grades Mean Difference in NE Mean Difference in NE Mean Difference in NE Mean Difference in NE Grade at 1 Week After Grade at 6 Week After Grade at 12 Week After Grade at 24 Week After Surgery Compared With Surgery Compared With Surgery Compared With Surgery Compared With the Beginning the Beginning the Beginning the Beginning Group A Group B Intergroup comparison between the decrease in values obtained in group A and B, p value
2.60 ⫾ 0.50 2.92 ⫾ 0.27 0.00
2.72 ⫾ 0.45 2.68 ⫾ 0.47 0.76
2.08 ⫾ 0.81 1.20 ⫾ 0.1 0.00
2.28 ⫾ 0.79 2.64 ⫾ 0.49 0.05
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NE ⫽ nasal endoscopic.
Table 3 Results of intra- and intergroup comparison in terms of Lund Mackay scores
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Difference in Mean LM Scores at Week 12 Compared With the Beginning of the Study
Difference in Mean LM Scores at Week 24 Compared With the Beginning of the Study
15.84 ⫾ 6.06 16.28 ⫾ 3.82 0.76
16.64 ⫾ 5.75 14.20 ⫾ 4.00 0.08
Group A* Group B* Intergroup comparison between decrease in the values obtained in group A and B#
LM ⫽ Lund Mackay. *Intragroup comparison between values obtained at follow-up with that at the beginning of the study. #Comparison of the differences obtained in scores between preoperative and follow-up period.
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Table 4 Results of intragroup and intergroup comparison in terms of SNOT scores
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Week 6 Compared With the Beginning of the Study Group A* Group B* Intergroup comparison between the decrease in the values obtained in group A and B#
SNOT Score, Mean Difference Week 12 Compared With the Beginning of the Study
Week 24 Compared With the Beginning of the Study
26.28 ⫾ 12.30 27.92 ⫾ 7.18 0.56
27.04 ⫾ 12.35 28.32 ⫾ 7.12 0.65
26.44 ⫾ 13,11 28.08 ⫾ 7.86 0.59
*Intragroup comparison between the decrease in the values obtained in groups A and B (p value). #Comparison of the differences obtained in scores between the preoperative and follow-up period.
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Table 5 Effect of itraconazole in the study group after exclusion of other factors
Effect of itraconazole studied in group A after statistical exclusion of the other factors (surgeon, other treatment given common in both groups, geographic factors), p value
LM Score
SNOT-20 Score
NE Grade
0.007
0.000
0.161
LM ⫽ Lund Mackay; NE ⫽ nasal endoscopic.
However, in our study, we found that the time to recurrence in patients who received preoperative itraconazole therapy was 11.4 months and that 3 of 25 patients (12%) had recurrence, whereas patients with surgery alone had a recurrence of 6 of 25 (24%) at 9.6 months. Rupa et al.10 also showed that the cavity conditions were significantly (p ⫽ 0.0001) better when oral steroids are given along with itraconazole in the postoperative period compared with only itraconazole and placebo. The present study also included oral steroids postoperatively in both groups and showed that, despite postoperative steroid therapy, the cavity conditions were found to be
better in those patients who received preoperative itraconazole therapy. Hence, along with the benefits shown in previous studies by its postoperative use, the present study goes a step further to show that use of itraconazole as a preoperative adjunct could give similar benefits of delaying recurrences, along with improved symptom scores even in the preoperative period, which indicates an overall better quality of life for the patients, with the added benefits of an easier surgery with significantly decreased disease load as evidenced by the radiologic scores (Tables 1 and 3). Our study had limitations: the
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absence of placebo in the control group, a smaller sample size, and only one observer performed the grading.
13.
CONCLUSION
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The present study showed that itraconazole given preoperatively in patients with AFS improves the symptoms and quality of life, and decreases the disease load and decreases the extent of surgery. Preoperative itraconazole also improves the postoperative cavity conditions in nasal endoscopy along with steroids in the short term. Preoperative itraconazole with surgery also decreases recurrence rates when compared with surgery alone in short-term follow-up.
15.
16.
17.
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Mabry RL, Manning SC, and Mabry CS. Immunotherapy in the treatment of allergic fungal sinusitis. Otolaryngol Head Neck Surg 116:31–35, 1997. Doellman MS, Dion GR, Weitzel EK, and Reyes EG. Immunotherapy in allergic fungal sinusitis: The controversy continues. A recent review of literature. Allergy Rhinol (Providence) 4:e32–e35, 2013. Ponikau JU, Sherris DA, Kita H, and Kern EB. Intranasal antifungal treatment in 51 patients with chronic rhinosinusitis. J Allergy Clin Immunol 110:862–866, 2002. Ponikau JU, Sherris DA, Weaver A, and Kita H. Treatment of chronic rhinosinusitis with intranasal amphotericin B: A randomized, placebo-controlled, double-blind pilot trial. J Allergy Clin Immunol 115: 125–131, 2005. Rains BM III, and Mineck CW. Treatment of allergic fungal sinusitis with high-dose itraconazole. Am J Rhinol 17:1–8, 2003. Seiberling K, and Wormald PJ. The role of itraconazole in recalcitrant fungal sinusitis. Am J Rhinol Allergy 23:303–306, 2009. Chan KO, Genoway KA, and Javer AR. Effectiveness of itraconazole in the management of refractory allergic fungal rhinosinusitis. J Otolaryngol Head Neck Surg 37:870–874, 2008. Gupta RP, Bahadur S, Thakar A, et al. Management protocols of Allergic Fungal Sinusitis. Indian J Otolaryngol Head Neck Surg 59:35–40, 2007. Panda NK, Francis AA, Chakrabarti A and Virk RS. Oral itraconazole as an adjunct to steroids in AFS. Otolaryngol Head Neck Surg 147: 114, 2012. Denning DW, Van Wye JE, Lewiston NJ, and Stevens DA. Adjunctive therapy of allergic bronchopulmonary aspergillosis with itraconazole. Chest 100:813–819, 1991. Wark PA, Hensley MJ, Saltos N, et al. Anti-inflammatory effect of itraconazole in stable allergic bronchopulmonary aspergillosis: A randomized controlled trial. J Allergy Clin Immunol 111:952–957, 2003. Santos A, Loureiro G, Faria E, and Chieira C. Itraconazole, an effective adjunctive treatment for allergic bronchopulmonary aspergillosis. J Investig Allergol Clin Immunol 19:404–408, 2009. Saravanan K, Panda NK, Chakrabarti A, et al. AFS: An attempt to resolve the diagnostic dilemma. Arch Otolaryngol Head Neck Surg 132:173–178, 2006. Manning SC, and Holman M. Further evidence for allergic pathophysiology in allergic fungal sinusitis. Laryngoscope 108:1485–1496, 1998. Bent JP III, and Kuhn FA. Diagnosis of allergic fungal sinusitis. Otolaryngol Head Neck Surg 111:580–588, 1994. e
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ABSTRACT
Introduction: Criterion standard treatment of allergic fungal sinusitis (AFS) is primary surgery followed by adjuvant therapy. Even after good surgery, recurrence rates vary from 10 to 79%. Antifungals, e.g., itraconazole, and steroids have shown varying success rates in delaying recurrences given after surgery. Itraconazole decreases the need for steroids given as a primary treatment in allergic bronchopulmonary aspergillosis. This study investigated the efficacy of itraconazole given preoperatively for allergic fungal rhinosinusitis. Methodology: A prospective study was carried out from July 2011 to November 2013 with 27 patients with histologically proven AFS, who were given itraconazole for 1 month in the preoperative period and operated after completion of the course of itraconazole. They were compared with 25 matched controls of patients with AFS who were operated on directly without preoperative itraconazole. Both groups were given oral steroids in tapering doses for 6 weeks during the postoperative period and followed up at regular intervals. Evaluations were done by using symptomatic (Sino-Nasal Outcome Test [SNOT-20]), radiologic (Lund Mackay scores), and endoscopic (Kupferberg nasal endoscopic grades) parameters. Results: Symptomatology scores (SNOT-20) decreased significantly (p ⫽ 0.000) with itraconazole. There was a decrease (p ⫽ 0.007) in the Lund Mackay scores that reached up to 0. There was complete resolution of disease in 15% of the patients. Reductions in hyperdensities were noted on computed tomography in all the patients after preoperative itraconazole. Polyp sizes decreased and nasal endoscopic grades improved after itraconazole. Postoperative fungal cultures were positive in 60% of the patients in the preoperative itraconazole group compared with 76% of the patients in the control group, which indicated a decreased fungal burden. Conclusion: We found improvements in clinical, radiologic, and endoscopic parameters in AFS after preoperative itraconazole administration, which decreased the disease load significantly and also reduced the extent of surgery in the short-term follow-up. It may prove to be a good preoperative adjunct that needs further research (Am J Rhinol Allergy 29, 299 –304, 2015; doi: 10.2500/ajra.2015.29.4187)
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llergic fungal sinusitis (AFS) is a disease with a noninvasive allergic process to fungal antigens present in sinonasal cavities. It occurs mostly in young individuals with atopy and is associated with nasal polyposis and the presence of allergic mucin.1 It is commonly seen in warm and humid climates.2,3 Ninety percent of the patients with AFS show evidence of type I hypersensitivity with raised serum immunoglobulin (Ig) E levels and type III hypersensitivity by eosinophilia in sinus mucosa with fungal antigens.4,5 The primary treatment in AFS has always been surgery. The primary goal of surgery is to decrease the antigen load and improve the aeration of the sinuses.6 But treatment of AFS has always remained a challenge and required continuous follow up of patients because recurrence varies from 10 to 100%.7,8 Hence, adjuvant therapy plays a vital role in the management of AFS. The pathophysiologic similarities between AFS and allergic bronchopulmonary aspergillosis is the guide for adjuvant treatment of AFS.9 Topical steroids have been used by Kupferberg et al.7 and Marple and Mabry8 in their study, and they have been shown to delay recurrences in AFS. Oral steroids have also shown promising results in the postoperative period and have been shown to delay the recurrences.7,10 Immunotherapy as an adjuvant in postoperative period has been shown to reduce the recurrence and reliance on systemic steroids.11,12 However, use of preoperative immunotherapy in AFS have shown the disease to worsen.13,14 The search for a promising adjuvant led to the use of antifungals as adjuvant for AFS. Topical amphotericin B in the form of nasal spray
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From the 1Department of Otolaryngology, Head and Neck Surgery, 2Department of Microbiology, and 3Department of Radiodiagnosis, Post Graduate Institute of Medical Education and Research, Chandigarh, India The authors have no conflicts of interest to declare pertaining to this article Address correspondence to Roshan K. Verma, D.N.B., Department of Otolaryngology, Head and Neck Surgery, Post Graduate Institute of Medical Education and Research, Chandigarh, India 160012 E-mail address: [email protected] Copyright © 2015, OceanSide Publications, Inc., U.S.A.
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and nasal lavage in the postoperative period has been shown to produce symptomatic improvement but failed to show improvement in nasal endoscopic or radiologic scores.15,16 Rains and Mineck,17 Seiberling and Wormald,18 Chan et al.,19 Gupta et al.,20 Panda et al.21 in their studies have proven the role of itraconazole in AFS as a postoperative adjunct, which indicates that itraconazole is efficacious in delaying recurrences. Itraconazole has also been used in allergic bronchopulmonary aspergillosis and has been shown to reduce maintenance steroid requirements.22–24 Thus, we hypothesized that itraconazole may be effective in AFS given preoperatively because it has been found to be effective when given postoperatively and is also effective in cases of allergic bronchopulmonary aspergillosis which have a similar pathophysiology as that of AFS. This study was planned to study the role of itraconazole in AFS when given preoperatively.
METHODOLOGY A single-center, randomized, prospective study was done at our tertiary care hospital from July 2011 to November 2013. Institutional ethics and review committee approval was taken for the study, and informed consent was obtained from every patient for participation in the study. Information regarding the study and consent was explained to the patients in the language they understood. We included 52 patients with clinically and histologically diagnosed cases of AFS. All the cases were evaluated with a detailed clinical history, general physical examination, and complete head and neck examination, including anterior rhinoscopy. The symptomatology scores were evaluated as per Sino-Nasal Outcome Test (SNOT-20) scores. Computed tomography (CT) of nose and paranasal sinuses (PNS) in the axial and coronal planes was performed in all patients and were evaluated as per Lund Mackay scores. Diagnostic nasal endoscopy, along with punch biopsy from a nasal polyp, was done in all the patients for histologic conformation. Nasal endoscopy findings were graded based on Kupferberg grades. In addition, total serum IgE, absolute eosinophil counts, and Aspergillus skin hypersensitivity test
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were done in all patients. Skin-prick test that showed a wheal of diameter ⬎8 mm and an absolute eosinophil count of ⬎400 l were taken as significant. A final diagnosis was obtained by using Saravanan’s criteria25 before inclusion of the cases into the study. Patients with evidence of invasive or granulomatous fungal sinusitis, those who were allergic to itraconazole, patients presenting with extensive intraorbital or intracranial extension, and those who would not consent for participation were excluded from the study. All the patients included in the study were randomly divided into two groups, the study group and the control group. Group A patients received itraconazole preoperatively for 4 weeks. After itraconazole therapy, they were reevaluated by using SNOT-20 scores, Lund Mackay scores, and nasal endoscopic grade (Kupferberg grades), and then were taken for definitive surgery. Group B patients were taken directly for surgery after diagnosis and preliminary investigation. Postoperatively, both the groups were given 6 weeks of oral steroids in tapering doses. All the patients were followed up with regular nasal douching and nasal endoscopy. SNOT-20 scores and nasal endoscopic grades were determined at weeks 1, 6, 12, and 24 follow-up. Total IgE levels were assessed at 6 weeks postoperatively. CTs of nose and paranasal sinuses were done at the 12- and 24-week follow-ups. Both the groups were compared for the mentioned parameters to assess the effect of itraconazole. Patients in both groups are under our continuous follow-up to the present date. Statistical analysis was done by using the t-test with IBM SPSS Statistics version 20 (IBM Corp., Armonk, NY). A p value of ⬍0.05 was taken as the level of significance in each test.
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Figure 1. SNOT scores of patients in the study group before and after therapy with itraconazole.
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RESULTS A total of 52 subjects were recruited during the study period: 27 in group A and 25 in group B. Two patients in group A refused surgery after taking itraconazole for 4 weeks due to personal reasons and were excluded from the study. Two patients in group A did not require surgery due to the complete disappearance of disease, but they were included in the analysis. Hence, 25 patients in group A were considered for final analysis. Group B included 25 patients, who were taken directly for surgery. The mean age was 30.60 years among the study group (group A) and 30.06 years among the control group (group B). Thirty-eight percent of the patients (19/50) were from the younger age group and were in their first and second decade of life. Nasal discharge, postnasal drip, and nasal obstruction, along with allergic symptoms, were the most common symptoms. Nasal polyposis was the most common sign (97.36%). Anterior ethmoids were the most common sinus involved, as seen on radiology. Erosion of ethmoidal cell septa was seen in 92.1%; posterior ethmoids, 84%; maxilla, 76%; sphenoid, 67%; and frontal sinus, 65%. Unilateral involvement of paranasal sinuses was seen in 23% of patients; 92.5% of patients showed multiple sinus involvement. Lamina papyraceae and the skull base were eroded in 13% and 5% of patients, respectively. On correlating the relationship between the Lund Mackay score and age, age had a negative correlation with disease extent, i.e., younger individuals had a propensity to have severe disease (p ⫽ 0.016). SNOT-20 scores, LM scores, and nasal endoscopic grades were compared before and after 1 month of itraconazole therapy in group A. The mean (⫾ SD) SNOT-20 scores decreased, from 31.28 ⫾ 13.79 to 15.72 ⫾ 9.34 (p ⫽ 0.000) (Fig. 1). The mean Lund Mackay radiologic scores decreased, from 18.04 ⫾ 6.04 to 15.24 ⫾ 7.37 (p ⫽ 0.007) (Fig. 2). It was also observed that the hyperdense areas in the sinuses on CTs reduced after itraconazole therapy and the scans became more homogenous. The nasal endoscopic grades were also decreased, from 2.9 ⫾ 0.27 to 2.68 ⫾ 0.85; however, this was not statistically significant (p ⫽ 0.161) (Fig. 3). In 8% (2/25) of patients in group A, dramatic improvement was seen after itraconazole therapy with complete disappearance of the disease in nasal endoscopy and decrease in the Lund Mackay scores from 12 and 21 to 0 and 1, respectively (Patients no. 12 and 20, Figs. 2, 4, 5). Reductions in hyperdensities were noted
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Figure 2. Lund Mackay scores of patients in the study group before and after therapy with itraconazole.
Figure 3. Kupferberg nasal endoscopic grades of patients in the study group before and after therapy with itraconazole.
on computed tomography in all the patients after preoperative itraconazole (Fig. 6). No major adverse effects were seen after or during itraconazole therapy. However, two patients had transient elevation of liver enzymes, which returned to normal 2 weeks after completion of itraconazole. A comparison of the cavity conditions on nasal endoscopy between group A and group B in the follow-up period at week 1, 6, 12, and 24 was done; for these follow-up times, the mean nasal endoscopic grades in group A were 0.04, 0.22, 0.84, and 0.64, respectively, and in
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group B, mean nasal endoscopic grades were 0.33, 0.28, 2.48, 0.32, respectively. On comparison of mean endoscopic grades between groups A and B, p values of 0.007, 0.062, 0.000, and 0.095 were obtained at 1, 6, 12, and 24 weeks, respectively, which reached levels of statistical significance at weeks 1 and 12; this indicates that cavity conditions during the postoperative period with preoperative itraconazole were significantly better compared with surgery and implicates a delay in the process of recurrence in patients treated with preoperative itraconazole compared with those who were directly taken for surgery (Table 1). Lund Mackay scores were obtained at 12- and 24-week follow-ups for both group A and group B: the mean Lund Mackay scores in group A were 0.24 ⫾ 0.43 and 1.40 ⫾ 1.41, respectively; whereas the mean (⫾ SD) Lund Mackay scores in group B were 2.20 ⫾ 1.84 and 2.32 ⫾ 1.34, respectively. On comparison between Lund Mackay scores at week 12 and 24 between group A and group B, the p values of 0.000 and 0.023 were obtained, which was statistically significant (p ⬍ .05). This indicates better cavity conditions in patients who were previously treated with itraconazole and again implicates a delay of the process of recurrences (Table 1). IgE values were acquired at the 6-week follow-up for both group A and group B. The mean IgE (IU/ml) value decreased significantly, from 4617 ⫾ 3420 to 1530 ⫾ 1133 in group A (p ⫽ 0.000), and from 4664 ⫾ 2566 to 857 ⫾ 737 in group B (p ⫽ 0.000) in the postoperative period at 6 weeks compared with those at the beginning of the study. The decrease in the mean IgE values between group A and group B was statistically similar (p ⫽ 0.251). Postoperative fungal cultures were positive in 60% of group A patients compared with 76% group B patients, which indicates a decreased fungal burden after itraconazole therapy, although it was not statistically significant (p ⫽ 0.292). The correlation between the decrease in the IgE values and the positive fungal cultures was sought, and a correlation coefficient of 0.143 was obtained in the group A compared with 0.078 in group B, which indicates that there was more chance of fungal culture being negative with a decrease in the IgE values with group A compared with those with group B. There was no significant difference between group A and group B in terms of intraoperative mucin (p ⫽ 0.353), fungal smear (p ⫽ 0.513), fungal culture (p ⫽ 0.355), and histopathologic characters such as the presence of mucin (p ⫽ .680), eosinophils (p ⫽ .490), and fungal hyphae between both groups (p ⫽ .500). Further analysis was done by comparing both group A and group B in terms of the difference in the nasal endoscopic grades between that obtained in follow up and that at the beginning of the study. Mean (⫾ SD) nasal endoscopic at the beginning of study was 2.92 ⫾ 0.277 and at follow up was 0.3 ⫾ 0.48 (week 1), 0.2 ⫾ 0.42 (week 6), 0.4 ⫾ 0.80 (week 12), and 0.4 ⫾ 0.81 (week 24) in group A. Whereas, in group B, it was 2.96 ⫾ 0.2 (at the beginning of the study) and, at follow-up, it was 0.4 ⫾ 0.2 (week 1), 0.8 ⫾ 0.45 (week 6), 2.48 ⫾ 1.55 (week 12), and 0.2 ⫾ 0.47 (week 24). The mean difference in the nasal
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endoscopic grades compared with the beginning of the study in group A was 2.60 ⫾ 0.50, 2.72 ⫾ 0.45, 2.08 ⫾ 0.81, 2.28 ⫾ 0.79 at week 1, 6, 12, and 24; in group B, was 2.92 ⫾ 0.27, 2.68 ⫾ 0.47, 1.20 ⫾ 0.1, 2.64 ⫾ 0.49 at week 1, 6, 12, and 24, respectively. The p values of 0.00, 0.76, 0.00, and 0.05 (Table 2) were obtained at week 1, 6, 12, and 24, respectively, postoperatively when these differences were compared between group A and group B. A similar comparison of differences was obtained in terms of Lund Mackay scores between those at the beginning of the study and at 12and 24-week postoperative follow-up. The mean Lund Mackay score at the beginning of study was 18.04 ⫾ 6.04 and, at follow-up, was 2.20 ⫾ 1.84 (12 weeks) and 1.40 ⫾ 1.41 (24 weeks) in group A, whereas, in group B, it was 16.52 ⫾ 3.78 (the beginning of the study) and at follow-up was 0.4 ⫾ 0.43 (12 weeks) and 2.32 ⫾ 1.34 (24 weeks). Intergroup comparison of mean Lund Mackay scores at week 12 and 24 after surgery revealed p values of 0.000 and 0.023 at week 12 and week 24, respectively (Table 1). This showed that there was a significant difference between the Lund Mackay scores between the groups in follow-up, which indicates better response to therapy and significantly better cavity conditions in the study group in terms of the radiologic findings. However, the mean of the differences in the Lund MacKay scores between those obtained during week-12 and week-24 follow-ups and those at the beginning of study in group A were 15.84 ⫾ 6.06 and 16.64 ⫾ 5.75 and, in group B, were 16.28 ⫾ 3.82 and 14.20 ⫾ 4.00, respectively. A comparison of these mean differences between both group A and group B revealed p values of 0.76 and 0.08 at week-12 and week-24, respectively (Table 3), which did not reach the levels of statistical significance. Similar intergroup comparison of differences obtained among scores at various intervals in follow-up and the beginning of the study in terms of SNOT-20 scores did not reveal any significant difference between the groups (Table 4) The effect of itraconazole on the SNOT-20 scores, LM scores, and nasal endoscopic grades in group A were obtained. All the surgeries were performed by a single surgeon (R.K.V.), and all the patients were from the same geographic location, i.e., north India, thus excluding the surgeon and the geographic confounding factors. Our analysis showed that there was statistically significant reduction in the SNOT scores (p ⫽ 0.000) and LM scores (p ⫽ 0.007), which could be attributed to the drug given, i.e., itraconazole, after excluding every other factor. Similar analysis for nasal endoscopic grades (p ⫽ 0.161) did not show any significant reduction that could be attributed to itraconazole. (Table 5) Recurrence was defined as an LM score of ⬎10 and a nasal endoscopic grade ⬎ ⫽ 2. None of the patients in group A and group B showed any evidence of recurrence until 6 months of follow-up. However, after the initial 24 weeks after surgery, all the patients were followed up at every 3-month interval to date. The recurrences for which repeated surgery was needed occurred between 8 and 14 months in 3 patients of group A and between 7 and 11 months in 6 patients of group B. The mean time to recurrence was 11.4 months in group A compared with
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Table 1 Mean values and p values for comparisons of different parameters obtained during follow-up NE Grade, Mean (ⴞ SD)
Week
1
6
12
LM Score, Mean (ⴞ SD) 24
12
24
SNOT-20 Score, Mean (ⴞ SD) 6
12
IgE Values (IU/ml), Mean (ⴞ SD) 24
6
Group A 0.33 ⫾ 0.48 0.22 ⫾ 0.42 0.84 ⫾ 0.80 0.64 ⫾ 0.81 2.20 ⫾ 1.84 1.40 ⫾ 1.41 5.26 ⫾ 3.18 5.0 ⫾ 3.24 4.24 ⫾ 2.94 1530.75 ⫾ 1133.14 Group B 0.04 ⫾ 0.20 0.28 ⫾ 0.45 2.48 ⫾ 1.55 0.32 ⫾ 0.47 0.24 ⫾ 0.43 2.32 ⫾ 1.34 5.56 ⫾ 1.47 5.72 ⫾ 1.94 5.32 ⫾ 2.61 857.72 ⫾ 737.50 Comparison 0.007 0.062 0.000 0.095 0.000 0.023 0.674 0.346 0.177 0.19 between the groups, p value NE ⫽ nasal endoscopy; LM ⫽ Lund Mackay; SNOT ⫽ Sino-Nasal Outcome Test
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Figure 4. CT and nasal endoscopic picture of patient nos. 12 and 20 before initiation of itraconazole, i.e., at the beginning of the study.
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Figure 5. CT and nasal endoscopic picture of patient nos. 12 and 20 after therapy of itraconazole for 1 month.
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9.6 months in group B. The difference in the time interval between both groups was not statistically significant (p ⫽ 0.092), although the recurrence rates were significantly less in the study group (group A) compared with the control group (group B).
DISCUSSION
AFS is common in young individuals who are immune competent and with predominant unilateral nasal polyposis with multiple sinus involvement. It has an equal male-to-female ratio.6,26,27 However, in our study, there was a predominance of bilateral disease, and unilateral disease was seen only in 23% of cases. Younger patients had more-severe disease, with extensive multiple sinus involvement than did older patients in our study. The management in cases of AFS has always been surgical. Recurrence rates vary from 13% to 100%.7 Bent and Kuhn27 rightly comment about allergic fungal sinusitis, “In AFS misdiagnosis is common, recurrence rates are high and proper treatment elusive.” Oral itraconazole has been used in the postoperative period as an adjunctive therapy and has been shown to decrease and delay the recurrences. This study is unique because we used itraconazole as preoperative adjunct in AFS and tried to analyze the effect of itraconazole on
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Figure 6. CT and nasal endoscopic picture of patient no. 13 before and after the therapy of itraconazole. Decrease in the number of areas of hyperdensities and size of the polyps can be seen, which indicates a decreased disease load and fungal burden.
symptom scores, endoscopic grades, CT scores, and the overall improvement in cavity condition and recurrence rates postoperatively. The mean SNOT-20 scores decreased from 31.28 to 15.72 after the patients received itraconazole for 1 month (p ⫽ 0.000), and the mean Lund Mackay scores decreased from 18.04 to 15.24 (p ⫽ 0.007). We also noticed a decrease in heterogeneity on CTs after itraconazole. Itraconazole given preoperatively improves the symptoms and the radiologic extent of disease. When the decrease in the IgE was compared with that of the fungal culture reports, higher correlation coefficient was seen in group A (0.143) compared with group B (0.078), which indicates decreased fungal burden with the use of itraconazole. Seiberling and Wormald18 in their study reported improvement in symptomatic and endoscopic parameters in 82.6% of the patients (19/23) with postoperative adjuvant itraconazole therapy. Although, in our study, we had symptomatic, endoscopic, and radiologic improvement with preoperative itraconazole therapy and also that the postoperative cavity was found to be better in patients who received preoperative itraconazole therapy than surgery alone. A statistically significant difference in nasal cavity conditions was seen between the nasal endoscopic grades at each follow-up compared with that of the beginning, except for cavity conditions at 12 weeks in the control group (Table 1). The final cavity status was significantly different between the two groups in the follow-up period, which indicates improvement in the cavity conditions and delay in the process of recurrence in the patients who had received itraconazole preoperatively. The differences obtained between the cavity conditions in follow-up and that at the beginning of the study also show a significant difference when compared between the groups (Table 2). Itraconazole helps in making the cavity conditions better compared with those in whom it was not administered. Seiberling and Wormald18 and Panda et al.21 also show a similar result of improved cavity conditions in established recurrences with the use of postoperative itraconazole in AFS. Rains and Mineck17 retrospectively evaluated 137 cases of recurrent disease in which patients were given high doses of itraconazole until the patients showed disappearance of the disease in nasal endoscopy and had found that once disappearance of disease in nasal endoscopy was achieved, 50.3% showed recurrence after average duration of 10.8 months of follow-up. The investigators showed that itraconazole decreases the need of oral steroids and the need for revision surgery.
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Table 2 Comparison of nasal endoscopic grades Mean Difference in NE Mean Difference in NE Mean Difference in NE Mean Difference in NE Grade at 1 Week After Grade at 6 Week After Grade at 12 Week After Grade at 24 Week After Surgery Compared With Surgery Compared With Surgery Compared With Surgery Compared With the Beginning the Beginning the Beginning the Beginning Group A Group B Intergroup comparison between the decrease in values obtained in group A and B, p value
2.60 ⫾ 0.50 2.92 ⫾ 0.27 0.00
2.72 ⫾ 0.45 2.68 ⫾ 0.47 0.76
2.08 ⫾ 0.81 1.20 ⫾ 0.1 0.00
2.28 ⫾ 0.79 2.64 ⫾ 0.49 0.05
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NE ⫽ nasal endoscopic.
Table 3 Results of intra- and intergroup comparison in terms of Lund Mackay scores
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Difference in Mean LM Scores at Week 12 Compared With the Beginning of the Study
Difference in Mean LM Scores at Week 24 Compared With the Beginning of the Study
15.84 ⫾ 6.06 16.28 ⫾ 3.82 0.76
16.64 ⫾ 5.75 14.20 ⫾ 4.00 0.08
Group A* Group B* Intergroup comparison between decrease in the values obtained in group A and B#
LM ⫽ Lund Mackay. *Intragroup comparison between values obtained at follow-up with that at the beginning of the study. #Comparison of the differences obtained in scores between preoperative and follow-up period.
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Table 4 Results of intragroup and intergroup comparison in terms of SNOT scores
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Week 6 Compared With the Beginning of the Study Group A* Group B* Intergroup comparison between the decrease in the values obtained in group A and B#
SNOT Score, Mean Difference Week 12 Compared With the Beginning of the Study
Week 24 Compared With the Beginning of the Study
26.28 ⫾ 12.30 27.92 ⫾ 7.18 0.56
27.04 ⫾ 12.35 28.32 ⫾ 7.12 0.65
26.44 ⫾ 13,11 28.08 ⫾ 7.86 0.59
*Intragroup comparison between the decrease in the values obtained in groups A and B (p value). #Comparison of the differences obtained in scores between the preoperative and follow-up period.
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Table 5 Effect of itraconazole in the study group after exclusion of other factors
Effect of itraconazole studied in group A after statistical exclusion of the other factors (surgeon, other treatment given common in both groups, geographic factors), p value
LM Score
SNOT-20 Score
NE Grade
0.007
0.000
0.161
LM ⫽ Lund Mackay; NE ⫽ nasal endoscopic.
However, in our study, we found that the time to recurrence in patients who received preoperative itraconazole therapy was 11.4 months and that 3 of 25 patients (12%) had recurrence, whereas patients with surgery alone had a recurrence of 6 of 25 (24%) at 9.6 months. Rupa et al.10 also showed that the cavity conditions were significantly (p ⫽ 0.0001) better when oral steroids are given along with itraconazole in the postoperative period compared with only itraconazole and placebo. The present study also included oral steroids postoperatively in both groups and showed that, despite postoperative steroid therapy, the cavity conditions were found to be
better in those patients who received preoperative itraconazole therapy. Hence, along with the benefits shown in previous studies by its postoperative use, the present study goes a step further to show that use of itraconazole as a preoperative adjunct could give similar benefits of delaying recurrences, along with improved symptom scores even in the preoperative period, which indicates an overall better quality of life for the patients, with the added benefits of an easier surgery with significantly decreased disease load as evidenced by the radiologic scores (Tables 1 and 3). Our study had limitations: the
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absence of placebo in the control group, a smaller sample size, and only one observer performed the grading.
13.
CONCLUSION
14.
The present study showed that itraconazole given preoperatively in patients with AFS improves the symptoms and quality of life, and decreases the disease load and decreases the extent of surgery. Preoperative itraconazole also improves the postoperative cavity conditions in nasal endoscopy along with steroids in the short term. Preoperative itraconazole with surgery also decreases recurrence rates when compared with surgery alone in short-term follow-up.
15.
16.
17.
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July–August 2015, Vol. 29, No. 4
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