Itraconazole Improved Bronchial Wall Thickness in Severe Persistent Asthma: A Double-blind Placebo-controlled Randomized Clinical Trial
-
Farnaz Aligolighasemabadi
,
Majid Mirsadraee
,
Mohammadamin Sadeghdoust
,
Shadi Ghaffari
,
Mohammad Sarafraz Yazdi
,
Saeed Naghibi
,
Amirhossein Hashemi Attar
Abstract
The purpose of this study was to evaluate the effect of 8 months of treatment with itraconazole on airway wall thickness in patients with severe persistent asthma.
It was a double-blind, randomized, placebo-controlled clinical trial (IRCT20091111002695N9). Seventy-five subjects with severe persistent asthma received itraconazole (100 mg), prednisolone (5 mg), or placebo twice a day for eight months in three treatment groups (n=25 in each group). The primary objective was to improve the right upper lobe apical segmental bronchus (RB1) wall thickness percentage measured by high-resolution computed tomography scan of the lungs. Other morphometric measurements of RB1, asthma control test (ACT) score, presence of wheezing, dyspnea severity, rate of asthma exacerbation, fractional exhaled nitric oxide (FeNO), and expiratory volume in 1 second (FEV1) were set as the secondary outcomes.
Wall thickness percentage reduced significantly from 46% to 43.7% from pre- to post-treatment in the itraconazole-treated subjects. Similarly, lumen area and radius increased significantly in both the prednisolone and itraconazole groups. Itraconazole led to a significant improvement in wheezing, dyspnea severity, FEV1, ACT score, and FeNO. Although prednisolone was also effective in improving pulmonary function tests and ACT scores, it was associated with significantly more side effects than itraconazole.
Long-term treatment with itraconazole resulted in a significant reduction in bronchial wall thickness and improvements in clinical findings and pulmonary function tests. Thus, itraconazole could be a helpful add-on treatment option for severe persistent asthma patients to achieve better disease control.
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25. Chong CR, Xu J, Lu J, Bhat S, Sullivan DJ, Jr., Liu JO. Inhibition of angiogenesis by the antifungal drug itraconazole. ACS Chem Biol. 2007;2(4):263-70.
26. Pounds R, Leonard S, Dawson C, Kehoe S. Repurposing itraconazole for the treatment of cancer. Oncol Lett. 2017;14(3):2587-97.
27. Head SA, Shi WQ, Yang EJ, Nacev BA, Hong SY, Pasunooti KK, et al. Simultaneous Targeting of NPC1 and VDAC1 by Itraconazole Leads to Synergistic Inhibition of mTOR Signaling and Angiogenesis. ACS Chem Biol. 2017;12(1):174-82.
28. Aftab BT, Dobromilskaya I, Liu JO, Rudin CM. Itraconazole Inhibits Angiogenesis and Tumor Growth in Non–Small Cell Lung CancerItraconazole in Lung Cancer. Cancer Res. 2011;71(21):6764-72.
29. Laddha AP, Kulkarni YA. VEGF and FGF-2: Promising targets for the treatment of respiratory disorders. Respir Med. 2019;156:33-46.
30. Kugler MC, Joyner AL, Loomis CA, Munger JS. Sonic hedgehog signaling in the lung. From development to disease. Am J Respir Cell Mol Biol. 2015;52(1):1-13.
31. Wang X, Xu C, Ji J, Cai Y, Shu Y, Chao Y, et al. IL-4/IL-13 upregulates Sonic hedgehog expression to induce allergic airway epithelial remodeling. Am J Physiol Lung Cell Mol Physiol. 2020;318(5):L888-L99.
32. Xu C, Zou C, Hussain M, Shi W, Shao Y, Jiang Z, et al. High expression of Sonic hedgehog in allergic airway epithelia contributes to goblet cell metaplasia. Mucosal Immunol. 2018;11(5):1306-15.
33. Kim J, Tang JY, Gong R, Kim J, Lee JJ, Clemons KV, et al. itraconazole, a commonly used antifungal that inhibits Hedgehog pathway activity and cancer growth. Cancer cell. 2010;17(4):388-99.
34. Agarwal R, Dhooria S, Singh Sehgal I, Aggarwal AN, Garg M, Saikia B, et al. A Randomized Trial of Itraconazole vs Prednisolone in Acute-Stage Allergic Bronchopulmonary Aspergillosis Complicating Asthma. Chest. 2018;153(3):656-64.
2. Chung KF, Wenzel SE, Brozek JL, Bush A, Castro M, Sterk PJ, et al. Erratum: International ERS/ATS guidelines on definition, evaluation and treatment of severe asthma (European Respiratory Journal (2014) 43 (343-373)). Eur Respir J. 2014;43(4):1216.
3. Heffler E, Madeira LNG, Ferrando M, Puggioni F, Racca F, Malvezzi L, et al. Inhaled Corticosteroids Safety and Adverse Effects in Patients with Asthma. J Allergy Clin Immunol Pract. 2018;6(3):776-81.
4. Volmer T, Effenberger T, Trautner C, Buhl R. Consequences of long-term oral corticosteroid therapy and its side-effects in severe asthma in adults: a focused review of the impact data in the literature. Eur Respir J. 2018;52(4).
5. Cecchi L, Annesi-Maesano I, d'Amato G. News on climate change, air pollution, and allergic triggers of asthma. J Investig Allergol Clin Immunol. 2018;28(2):91-7.
6. Poole JA, Barnes CS, Demain JG, Bernstein JA, Padukudru MA, Sheehan WJ, et al. Impact of weather and climate change with indoor and outdoor air quality in asthma: A Work Group Report of the AAAAI Environmental Exposure and Respiratory Health Committee. J Allergy Clin Immunol. 2019;143(5):1702-10.
7. Fraczek MG, Chishimba L, Niven RM, Bromley M, Simpson A, Smyth L, et al. Corticosteroid treatment is associated with increased filamentous fungal burden in allergic fungal disease. J Allergy Clin Immunol. 2018;142(2):407-14.
8. Kauffman HF. Immunopathogenesis of allergic bronchopulmonary aspergillosis and airway remodeling. Front Biosci. 2003;8(5):e190-6.
9. Kauffman HF, Tomee JF, van de Riet MA, Timmerman AJ, Borger P. Protease-dependent activation of epithelial cells by fungal allergens leads to morphologic changes and cytokine production. J Allergy Clin Immunol. 2000;105(6 Pt 1):1185-93.
10. Fehrenbach H, Wagner C, Wegmann M. Airway remodeling in asthma: what really matters. Cell Tissue Res. 2017;367(3):551-69.
11. Bergeron C, Tulic MK, Hamid Q. Airway remodelling in asthma: from benchside to clinical practice. Can Respir J. 2010;17(4):e85-93.
12. Bergeron C, Tulic M, Hamid Q. Tools used to measure airway remodelling in research. Eur Respir J. 2007;29(3):596-604.
13. Pepe C, Foley S, Shannon J, Lemiere C, Olivenstein R, Ernst P, et al. Differences in airway remodeling between subjects with severe and moderate asthma. J Allergy Clin Immunol. 2005;116(3):544-9.
14. Denning DW, O'Driscoll BR, Powell G, Chew F, Atherton GT, Vyas A, et al. Randomized controlled trial of oral antifungal treatment for severe asthma with fungal sensitization: The Fungal Asthma Sensitization Trial (FAST) study. Am J Respir Crit Care Med. 2009;179(1):11-8.
15. Pasqualotto AC, Powell G, Niven R, Denning DW. The effects of antifungal therapy on severe asthma with fungal sensitization and allergic bronchopulmonary aspergillosis. Respirology. 2009;14(8):1121-7.
16. Moss RB. Treatment options in severe fungal asthma and allergic bronchopulmonary aspergillosis. Eur Respir J. 2014;43(5):1487-500.
17. Global Initiative for Asthma. Global Strategy for Asthma Management and Prevention.; 2020. https://ginasthma.org/reports/.
18. Pasqualotto AC, Powell G, Niven R, Denning DW. The effects of antifungal therapy on severe asthma with fungal sensitization and allergic bronchopulmonary aspergillosis. Respirology. 2009;14(8):1121-7.
19. Agarwal R. Severe asthma with fungal sensitization. Current allergy and asthma reports. 2011;11(5):403-13.
20. Agarwal R, Dhooria S, Sehgal IS, Aggarwal AN, Garg M, Saikia B, et al. A randomized trial of itraconazole vs prednisolone in acute-stage allergic bronchopulmonary aspergillosis complicating asthma. Chest. 2018;153(3):656-64.
21. Fedorov A, Beichel R, Kalpathy-Cramer J, Finet J, Fillion-Robin J-C, Pujol S, et al. 3D Slicer as an image computing platform for the Quantitative Imaging Network. Magn Reson Imaging. 2012;30(9):1323-41.
22. Sadeghdoust M, Mirsadraee M, Aligolighasemabadi F, Khakzad MR, Hashemi Attar A, Naghibi S. Effect of azithromycin on bronchial wall thickness in severe persistent asthma: A double-blind placebo-controlled randomized clinical trial. Respir Med. 2021;185:106494.
23. De Beule K, Van Gestel J. Pharmacology of itraconazole. Drugs. 2001;61 Suppl 1(1):27-37.
24. Vincent M, Percier P, De Prins S, Huygen K, Potemberg G, Muraille E, et al. Investigation of inflammatory and allergic responses to common mold species: Results from in vitro experiments, from a mouse model of asthma, and from a group of asthmatic patients. Indoor Air. 2017;27(5):933-45.
25. Chong CR, Xu J, Lu J, Bhat S, Sullivan DJ, Jr., Liu JO. Inhibition of angiogenesis by the antifungal drug itraconazole. ACS Chem Biol. 2007;2(4):263-70.
26. Pounds R, Leonard S, Dawson C, Kehoe S. Repurposing itraconazole for the treatment of cancer. Oncol Lett. 2017;14(3):2587-97.
27. Head SA, Shi WQ, Yang EJ, Nacev BA, Hong SY, Pasunooti KK, et al. Simultaneous Targeting of NPC1 and VDAC1 by Itraconazole Leads to Synergistic Inhibition of mTOR Signaling and Angiogenesis. ACS Chem Biol. 2017;12(1):174-82.
28. Aftab BT, Dobromilskaya I, Liu JO, Rudin CM. Itraconazole Inhibits Angiogenesis and Tumor Growth in Non–Small Cell Lung CancerItraconazole in Lung Cancer. Cancer Res. 2011;71(21):6764-72.
29. Laddha AP, Kulkarni YA. VEGF and FGF-2: Promising targets for the treatment of respiratory disorders. Respir Med. 2019;156:33-46.
30. Kugler MC, Joyner AL, Loomis CA, Munger JS. Sonic hedgehog signaling in the lung. From development to disease. Am J Respir Cell Mol Biol. 2015;52(1):1-13.
31. Wang X, Xu C, Ji J, Cai Y, Shu Y, Chao Y, et al. IL-4/IL-13 upregulates Sonic hedgehog expression to induce allergic airway epithelial remodeling. Am J Physiol Lung Cell Mol Physiol. 2020;318(5):L888-L99.
32. Xu C, Zou C, Hussain M, Shi W, Shao Y, Jiang Z, et al. High expression of Sonic hedgehog in allergic airway epithelia contributes to goblet cell metaplasia. Mucosal Immunol. 2018;11(5):1306-15.
33. Kim J, Tang JY, Gong R, Kim J, Lee JJ, Clemons KV, et al. itraconazole, a commonly used antifungal that inhibits Hedgehog pathway activity and cancer growth. Cancer cell. 2010;17(4):388-99.
34. Agarwal R, Dhooria S, Singh Sehgal I, Aggarwal AN, Garg M, Saikia B, et al. A Randomized Trial of Itraconazole vs Prednisolone in Acute-Stage Allergic Bronchopulmonary Aspergillosis Complicating Asthma. Chest. 2018;153(3):656-64.
| Files | ||
| Issue | Vol 22 No 1 (2023) | |
| Section | Original Article(s) | |
| DOI | https://doi.org/10.18502/ijaai.v22i1.12000 | |
| Keywords | ||
| Airway remodeling Asthma Itraconazole X-ray computed tomography | ||
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How to Cite
1.
Aligolighasemabadi F, Mirsadraee M, Sadeghdoust M, Ghaffari S, Sarafraz Yazdi M, Naghibi S, Hashemi Attar A. Itraconazole Improved Bronchial Wall Thickness in Severe Persistent Asthma: A Double-blind Placebo-controlled Randomized Clinical Trial. Iran J Allergy Asthma Immunol. 2023;22(1):1-11.
