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AFRS: Current Approaches to Postoperative Management

AFRS: Current Approaches to Postoperative Management. Bradley F. Marple, MD Professor. Dept. of Otolaryngology Univ. of Texas Southwestern at Dallas. Potential Role for Fungus in CRS. Fungus Fungal allergy Invasive Fungus Fulminant Indolent Granulomatous Non-invasive fungus Mycetoma

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AFRS: Current Approaches to Postoperative Management

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  1. AFRS: Current Approaches to Postoperative Management Bradley F. Marple, MD Professor Dept. of Otolaryngology Univ. of Texas Southwestern at Dallas

  2. Potential Role for Fungus in CRS • Fungus • Fungal allergy • Invasive Fungus • Fulminant • Indolent • Granulomatous • Non-invasive fungus • Mycetoma • Saprophytic growth • AFRS • EFRS Allergic Fungal Rhinosinusitis Saprophyte EFRS Marple, Laryngoscope 2001;111:1006-19.

  3. Clinical Observations Concerning AFRS

  4. Radiographic Characteristics:Bone Erosion • CT1 • Allergic mucin mucocele • Associated obstructive sinusitis • Heterogeneous appearance3 • Ca • Chelated Fe, Mn • Mukherji1 • Reviewed 45 AFRS CTs • Bone erosion - 20% • Nussenbaum, Marple2 • Reviewed 142 AFRS CTs • Bone erosion - 20% • Histology - 0/142 demonstrated invasion 1Radiology 1998; 207:417-22 2OtoHNS 2001;124:150-54 3Zinreich et al.Radiology 1988; 169:439-44.

  5. Clinical Presentation: Mucin • Mucin is the hallmark of the disease

  6. Allergic Mucin • Gross findings - indistinguishable from ABPA • Thick viscosity • Tan, black, green • Histology • Non-invasive fungus • Grocott • Giemsa • PAS • Eosiniphils • Charcot-Leyden Crx

  7. Cody Allphin Lowry, Schaefer deShazo, Swain Bent and Kuhn Polyposis CT findings Eosinophilic mucus; no fungal invasion Gell & Coombs type I hypersensitivity JACI, Oto-HNS 2004 Eosinophilic mucin Histo – non invasive fungus Fungal specific IgE Diagnostic Criteria Bent, Kuhn, Oto-HNS 1994;111:580-88 Meltzer, Hamilos, Hadley, Lanza, Marple, et. al. JACI 2004;114:S155-S212.

  8. Eosinophilic Fungal Rhinosinusitis

  9. Ponikau – Improved ability to identify nasal fungus 94/101 clinical diagnosis of AFS 100% controls with fungus Allergy – no difference from general CRS population Proposed term “EFRS” Shin, Kita – PBMC + Alternaria IL-5, IL-13, IF-g Taylor – Fluorescein-labeled chitin stain Wei – Chemotaxis of eosinophils in presence of tissue/mucin of CRS Demonstrates chemoattractant effects Ponikau – Ampho B irrigation 38/51 symptoms improved 45 with prior surgery 35% endoscopically cleared No control group Mayo Experience – Evolution of a Pathogenesis Ponikau. Mayo Clin Pro. 1999;74:877-84. Shin. JACI (abstract). Shin SH, Kita H et al . AAAAI NY, March 6, 2002 Taylor. Oto-HNS 2002;127:377-383. Wei. Laryngoscope 2003;113:303-306. Ponikau. JACI 2002;110:862-866

  10. Why the Difference?What are we calling “mucin”? EFRS AFRS GMS Chitin GMS GMS Courtesy of Ponikau

  11. Impact of Clinical Findings upon Immunologic Data 67 20 87 179 179 Marple, presented Maryland CRS meeting 2003

  12. AFRS vs EFRS: Why the Difference? AFRS EFRS Patient selection Narrow Broad Definition of allergic mucin Gross Microscopic Incidence of atopy Near 100% Same as CRS Specificity vs sensitivity Too specific Too sensitive Marple, ARS Newsletter 2002;21

  13. Fungal Specific Humoral Response • Background • Literature to 2004: • Fungal allergy plays central role in pathogenesis of AFRS • Fungal specific IgE is a critical marker for AFRS • Inconsistent definitions for AFRS • Pant/Wormald • Sub-classified CRS in an attempt to better understand the role of humoral responses in the pathogenesis of the disease Pant H, Laryngoscope 2005;115:601-606.

  14. Fungal Specific Humoral Response • Design • 86 study subjects were enrolled • Sub-classified based upon following criteria • Presence of macroscopic eosinophilic mucin • Presence of fungal allergy • Histologic presence of fungi in eosinophiloc mucin • Cultures obtained from mucin • Serologic tests • Fungal specific IgE • Fungal specific IgG, IgM, IgA Pant H, Laryngoscope 2005;115:601-606.

  15. Fungal Specific Humoral Response • spIgE (Alternaria alternata and Aspergillus fumagatus) failed to differentiate • EMCRS from controls • Subsets within EMCRS • Culture results only partially matched those spIgE Pant H, Laryngoscope 2005;115:601-606

  16. Fungal Specific Humoral Response • Results • Alternaria alternata and Aspergillus fumigatus IgG3 marked the presence of EM (p=0.002, 0.004) • spIgG3 • Distinguished EMCRS from all other controls • May signify pathogenic significance of IgG3 Alternaria spIgG3 Pant H, Laryngoscope 2005;115:601-606

  17. Invasive Fulminant Indolent Granulomatous Non-granulomatous Non-invasive Fungal Ball (Mycetoma) Saprophytic growth Eosinophilic Fungal Inflammation IgE – dependent fungal inflammation Classic AFRS Non IgE-dependent fungal rhinosinusitis Eosinophilic Fungal Rhinosinusitis (EFRS) Types of Fungal Sinusitis Meltzer, Hamilos, Hadley, Lanza, Marple, et. al. Rhinosinusitis: Establishing Definitions for Clinical Research and Patient Care JACI 2004;114:155-212.

  18. 2006: Role of Fungus and Allergy in AFRS • AFRS is a distinct clinical entity that exists as a subset of CRS and is strongly associated with • Fungus • Allergy • The central role of allergy in the pathogenesis of AFS is now in question • But IgE-mediated sensitivity remains important identifier • It is reasonable to direct therapy based upon the presence of allergy and fungus • Evidence-based data is limited

  19. AFRS: Treatment Antifungals • Surgery • Complete removal of fungal antigen • Tissue sparing • Immunomodulation • Perioperative steroids • Immunotherapy • Close follow-up • Saline irrigation • Office visits Fungus Surgery Irrigation Proliferation Antigen Exposure Decreased Drainage Decreased Ventilation Stasis (Mucin) AFS Immune Response IgE/non-IgE Mast Cell Degranulation Mucosal Edema Inflammation Immunotherapy Steroids Marple,Mabry, AJR 1998:12;263-268

  20. Treatment Principles I.Elimination of Fungal Antigen (Surgery) II. Control of Recurrence Immunomodulation Antifungal Rx IT Steroids Topical Systemic Marple, Laryngoscope 2001;111:1006-19.

  21. Complete extirpation of mucin Fungi stimulate inflammation Permanent drainage & ventilation Preserve mucosa “Complete, but conservative” Post-operative access Surveillance Irrigation Goals of Surgery Marple,Mabry, AJR 1998:12;263-268

  22. Postoperative Recidivism Bent - Near 100% recurrence in absence of medical treatment Kupferberg - 19/24 patients recurred after d/c of steroids Schubert - 67pts Steroids for >2 mo. - 35% recurrence @ 1yr Steroids for <2 mo. - 55% recurrence @ 1yr Marple, Mabry - 42pts Immunotherapy - 10% recurrence @ 12 - 37 mo. Allergy Asthma Proc 1996;17:259-68, Oto-HNS 1997;117:35-41, J Allergy Clin Immunol1998;102:395-402, Am J Rhinology 2000;14:223-26

  23. Treatment Principles I.Elimination of Fungal Antigen (Surgery) II. Control of Recurrence Immunomodulation Antifungal Rx IT Steroids Topical Systemic

  24. Immunotherapy for AFS: Theory • Originally contraindicated • Analogies to ABPA • Theoretically contraindicated in treatment of ABPA “because of the uncertainties involved”1 • Specific IgG production may elicit immune complex reaction (G&C III) • Ferguson2 - concluded no effect • 7 AFS patients • 2 responded (surgery) • 5 no response 1Middleton & Reed, pp.1395-1414, 1993. 2Ferguson, Abstract AAOA, 1993.

  25. Surgery Remove antigenic load! Allergic evaluation RAST (or skin test) 3 most relevant fungal antigens Non-fungal antigens Skin test (or RAST) for additional fungi Allergy treatment Treat for all positive reactors Do not treat only cultured fungus Treat non-fungal reactive antigens Could IT be used as a part of a comprehensive plan? Mabry, Marple, Mabry Oto-HNS 1999;121:252-4

  26. Cross-sectional study of 22 AFS pts 2 groups matched for preop severity of disease (CT&PE) Similar surgery 11 tx’d with IT 11 no IT Evaluation Regular exam and endoscopic staging (Kupferberg) Chronic Sinusitis Survey (Glichlick & Metson) Treatment of AFS: a comparison trial of postoperative IT with specific fungal antigens1 1Folker, Marple, Mabry, Mabry, Laryngoscope 108:1623-27, 1998

  27. Follow-up Overall mean f/u 33 mos. IT group Mean - 30 mos. Range - 12-43 mos. Non-IT group Mean - 35 mos. Range - 12-50 mos. Corticosteroids IT group Systemic - 0% Non-IT group Systemic - averaged 2 courses per year Treatment of AFS: a comparison trial of postoperative IT with specific fungal antigens1 1Folker, Marple, Mabry, Mabry, Laryngoscope 108:1623-27, 1998

  28. Endoscopic Mucosal Staging P<0.02 Folker, Marple, Mabry, Mabry, Laryngoscope 108:1623-27, 1998

  29. Chronic Sinusitis Survey p<0.05 Folker, Marple, Mabry, Mabry, Laryngoscope 108:1623-27, 1998

  30. Treatment Principles I.Elimination of Fungal Antigen (Surgery) II. Control of Recurrence Immunomodulation Antifungal Rx IT Steroids Topical Systemic

  31. Concept originates from the treatment of ABPA Anti-inflammatory Immunomodulation Systemic Used in some form for all patients with AFS Topical Standard therapy No published evidence of effect in AFS Effect demonstrated in NP Corticosteroids: Rationale

  32. Bent1 Universal recurrence of AFS in following discontinuation of corticosteroids Schubert2 - 67 pts Corticosteroids < 2mo 55% recurrence at 1yr Shorter time to recurrence Higher total IgE Corticosteroids > 2mo 35% recurrence at 1yr Longer time to recurrence Lower total IgE Corticosteroids 1Bent, Kuhn, Allergy Asthma Proc 17:259-68, 1996 2Schubert, Goetz, J Allergy Clin Immun 103:395-402, 1998

  33. Treatment Principles I.Elimination of Fungal Antigen (Surgery) II. Control of Recurrence Immunomodulation Antifungal Rx IT Steroids Topical Systemic

  34. Systemic Antifungals • Denning • Use of itraconazole for ABPA • Decrease in total IgE • Decrease in systemic corticosteroid use • Ferguson • Limited available data • Potential drug related morbidity • Cost of treatment • Rains • Safety of itraconazole • Kennedy • Terbenifine offered no benefit to the treatment of CRS May limit usefulness of therapy 1Denning, et al, Chest 100:813-19, 1991 2Ferguson, Arch Otolaryngol Head Neck Surg 124:1174-77, 1998

  35. Systemic Antifungals • Alternate effect of antifungals • Kanda et.al • CD3/CD28 cells from atopic derm and controls • In vitro T-cell helper-1 (TH1) and T-cell helper-2 (TH2) cytokines studied in response to antimycotics • Results • Azole derivatives suppressed expression of IL-4 and IL-5 by reducing 3,5 cAMP signal Kanda N. Journal of Investigative Dermatology. 117(6):1635-46, 2001 Dec.

  36. Topical Antifungals • Test of fungal hypothesis • Methods • Double blind placebo controlled • 24 CRS subjects randomized • Ampho B irrigation - 10 • Saline control - 14 • Results • CT scores • SNOT – 20 – no sig change • Endoscopy (7/10, 5/14) • IL-5 – no sig change • Eosinophils – no sig change • Alternaria – no change • Conclusion – Ampho B works Ponikau, et al. JACI 2005;115:125-31.

  37. StratificationIssues • Alternaria • No change over 6 months • Does this support hypothesis? • Stratification Issues • Demographics • Inflammatory Mediators • EDN • IL-5 Ponikau, et al. JACI 2005;115:125-31

  38. Topical Antifungals • Test of fungal hypothesis • Methods • Double blind placebo controlled • 74 CRS subjects randomized • Ampho B spray • Saline control • Results • 60 completed the study • Conclusion – no effect • Controversy in delivery Weshta, et al. JACI 2004;113:1122-28.

  39. Recidivism after treatment Bent - Near 100% recurrence in absence of medical treatment Kupferberg - 19/24 patients recurred after d/c of steroids Schubert - 67pts Steroids for >2 mo. - 35% recurrence @ 1yr Steroids for <2 mo. - 55% recurrence @ 1yr Marple, Mabry - 42pts Immunotherapy - 10% recurrence @ 12 - 37 mo. Marple, Newcomer - 17pts followed 4 - 11yrs. 1/17 with recurrence of AFS No decrease in fungal IgE No difference in treatment arms Allergy Asthma Proc 1996;17:259-68, Oto-HNS 1997;117:35-41, J Allergy Clin Immunol1998;102:395-402, Am J Rhinology 2000;14:223-26 Oto-HNS: 2002 127(5) 361-6

  40. Conclusion • AFS remains intriguing • Subset of CRS • Surgery • Crucial part of treatment • Medical follow-up appears crucial to long-term success • Need for evidence-based studies Elimination of Fungal Antigen Control of Recurrence Immunomodulation Antifungal Rx IT Steroids Topical Systemic

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