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

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Presentation on theme: "AFRS: Current Approaches to Postoperative Management Bradley F. Marple, MD Professor Dept. of Otolaryngology Univ. of Texas Southwestern at Dallas."— Presentation transcript:

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

3 Clinical Observations Concerning AFRS Clinical Observations Concerning AFRS

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

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

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

7 Diagnostic Criteria Cody Cody Allphin Allphin Lowry, Schaefer Lowry, Schaefer deShazo, Swain 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 Bent, Kuhn, Oto-HNS 1994;111:580-88 Meltzer, Hamilos, Hadley, Lanza, Marple, et. al. JACI 2004;114:S155-S212. Bent, Kuhn, Oto-HNS 1994;111:580-88 Meltzer, Hamilos, Hadley, Lanza, Marple, et. al. JACI 2004;114:S155-S212.

8 Eosinophilic Fungal Rhinosinusitis Eosinophilic Fungal Rhinosinusitis

9 Mayo Experience – Evolution of a Pathogenesis Ponikau – Improved ability to identify nasal fungus Ponikau – Improved ability to identify nasal fungus 94/101 clinical diagnosis of AFS 94/101 clinical diagnosis of AFS 100% controls with fungus 100% controls with fungus Allergy – no difference from general CRS population Allergy – no difference from general CRS population Proposed term EFRS Proposed term EFRS Shin, Kita – PBMC + Alternaria Shin, Kita – PBMC + Alternaria IL-5, IL-13, IF- IL-5, IL-13, IF- Taylor – Fluorescein-labeled chitin stain 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 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 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? Chitin GMS EFRSAFRS GMS Courtesy of Ponikau

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

12 AFRS vs EFRS: Why the Difference? AFRSEFRS Patient selection NarrowBroad Definition of allergic mucinGrossMicroscopic Incidence of atopyNear 100%Same as CRS Specificity vs sensitivityToo specificToo sensitive Marple, ARS Newsletter 2002;21

13 Fungal Specific Humoral Response Background Background Literature to 2004: Literature to 2004: Fungal allergy plays central role in pathogenesis of AFRS Fungal allergy plays central role in pathogenesis of AFRS Fungal specific IgE is a critical marker for AFRS Fungal specific IgE is a critical marker for AFRS Inconsistent definitions for AFRS Inconsistent definitions for AFRS Pant/Wormald Pant/Wormald Sub-classified CRS in an attempt to better understand the role of humoral responses in the pathogenesis of the disease 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 Design 86 study subjects were enrolled 86 study subjects were enrolled Sub-classified based upon following criteria Sub-classified based upon following criteria Presence of macroscopic eosinophilic mucin Presence of macroscopic eosinophilic mucin Presence of fungal allergy Presence of fungal allergy Histologic presence of fungi in eosinophiloc mucin Histologic presence of fungi in eosinophiloc mucin Cultures obtained from mucin Cultures obtained from mucin Serologic tests Serologic tests Fungal specific IgE Fungal specific IgE Fungal specific IgG, IgM, IgA 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 spIgE (Alternaria alternata and Aspergillus fumagatus) failed to differentiate EMCRS from controls EMCRS from controls Subsets within EMCRS Subsets within EMCRS Culture results only partially matched those spIgE Culture results only partially matched those spIgE Pant H, Laryngoscope 2005;115:601-606

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

17 Types of Fungal Sinusitis Invasive Invasive Fulminant Fulminant Indolent Indolent Granulomatous Granulomatous Non-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) 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 AFRS is a distinct clinical entity that exists as a subset of CRS and is strongly associated with Fungus Fungus Allergy Allergy The central role of allergy in the pathogenesis of AFS is now in question The central role of allergy in the pathogenesis of AFS is now in question But IgE-mediated sensitivity remains important identifier But IgE-mediated sensitivity remains important identifier It is reasonable to direct therapy based upon the presence of allergy and fungus It is reasonable to direct therapy based upon the presence of allergy and fungus Evidence-based data is limited Evidence-based data is limited

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

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

21 Goals of Surgery Complete extirpation of mucin Complete extirpation of mucin Fungi stimulate inflammation Fungi stimulate inflammation Permanent drainage & ventilation Permanent drainage & ventilation Preserve mucosa Preserve mucosa Complete, but conservative Complete, but conservative Post-operative access Surveillance Irrigation 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 R x IT Steroids Topical Systemic I. Elimination of Fungal Antigen (Surgery) II. Control of Recurrence Immunomodulation Antifungal R x IT Steroids Topical Systemic

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

25 Could IT be used as a part of a comprehensive plan? Surgery Surgery Remove antigenic load! Remove antigenic load! Allergic evaluation Allergic evaluation RAST (or skin test) RAST (or skin test) 3 most relevant fungal antigens 3 most relevant fungal antigens Non-fungal antigens Non-fungal antigens Skin test (or RAST) for additional fungi 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 Mabry, Marple, Mabry Oto-HNS 1999;121:252-4

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

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

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

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

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

31 Corticosteroids: Rationale Concept originates from the treatment of ABPA Concept originates from the treatment of ABPA Anti-inflammatory Anti-inflammatory Immunomodulation 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

32 Corticosteroids Bent 1 Bent 1 Universal recurrence of AFS in following discontinuation of corticosteroids Universal recurrence of AFS in following discontinuation of corticosteroids Schubert 2 - 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 1 Bent, Kuhn, Allergy Asthma Proc 17:259-68, 1996 2 Schubert, Goetz, J Allergy Clin Immun 103:395-402, 1998

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

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

35 Systemic Antifungals Alternate effect of antifungals Alternate effect of antifungals Kanda et.al Kanda et.al CD 3 /CD 28 cells from atopic derm and controls CD 3 /CD 28 cells from atopic derm and controls In vitro T-cell helper-1 (T H 1) and T-cell helper-2 (T H 2) cytokines studied in response to antimycotics In vitro T-cell helper-1 (T H 1) and T-cell helper-2 (T H 2) cytokines studied in response to antimycotics Results Results Azole derivatives suppressed expression of IL-4 and IL-5 by reducing 3,5 cAMP signal 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 Test of fungal hypothesis Methods Methods Double blind placebo controlled Double blind placebo controlled 24 CRS subjects randomized 24 CRS subjects randomized Ampho B irrigation - 10 Ampho B irrigation - 10 Saline control - 14 Saline control - 14 Results Results CT scores CT scores SNOT – 20 – no sig change SNOT – 20 – no sig change Endoscopy (7/10, 5/14) Endoscopy (7/10, 5/14) IL-5 – no sig change IL-5 – no sig change Eosinophils – no sig change Eosinophils – no sig change Alternaria – no change Alternaria – no change Conclusion – Ampho B works Conclusion – Ampho B works Ponikau, et al. JACI 2005;115:125-31.

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

38 Topical Antifungals Test of fungal hypothesis Test of fungal hypothesis Methods Methods Double blind placebo controlled Double blind placebo controlled 74 CRS subjects randomized 74 CRS subjects randomized Ampho B spray Ampho B spray Saline control Saline control Results Results 60 completed the study 60 completed the study Conclusion – no effect Conclusion – no effect Controversy in delivery 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 Elimination of Fungal Antigen Control of Recurrence Immunomodulation Antifungal R x IT Steroids Topical Systemic Elimination of Fungal Antigen Control of Recurrence Immunomodulation Antifungal R x IT Steroids Topical Systemic Conclusion AFS remains intriguing AFS remains intriguing Subset of CRS Subset of CRS Surgery Surgery Crucial part of treatment Crucial part of treatment Medical follow-up appears crucial to long- term success Medical follow-up appears crucial to long- term success Need for evidence- based studies Need for evidence- based studies

41 Experience of Others Braun – 92 patients with CRS Braun – 92 patients with CRS Replicated findings of 1999 Ponikau paper Replicated findings of 1999 Ponikau paper Richetti – 74 patients with nasal polyps Richetti – 74 patients with nasal polyps Ampho B irrigation for 4 weeks Ampho B irrigation for 4 weeks 47% experienced complete resolution of polyps 47% experienced complete resolution of polyps Proposed mechanism of effect Proposed mechanism of effect Ampho B antifungal effect, OR Ampho B antifungal effect, OR Ampho B possesses well-known anti-inflammatory effect!!! Ampho B possesses well-known anti-inflammatory effect!!! Braun. Laryngoscope 2003;113:264-269. Richetti. J of Laryngol & Otol 2002;116:261-263.

42 Fungal Specific Humoral Response Classification of Diseases EMCRS Controls CRS ARFA HV CRS ARFA HV n=15 n=26 n=15 n=15 n=26 n=15 AFS AFS-Like NAFES NANFES n=12 n=5 n=8 n=5 Pant H, Laryngoscope 2005;115:601-606.

43 Clinical classification of CRS Chronic rhinosinusitis (CRS) CRS without NPCRS with NP Eosinophilic mucin with fungal hyphae (and positive fungal skin tests) classic AFS Vaso- motor rhinitis GERDSarcoid- osis With eosinophilic Inflammatory features With eosinophilic Inflammatory features Without fungal hyphae ASA sensitive ASA tolerant ASA sensitive ASA tolerant Allergic rhinitis With other Inflammatory features With other inflammatory features Anatomic abnormalities, humoral immune deficiency, abnormal mucociliary function Bacterial Infection Non- allergic rhinitis Non- allergic rhinitis Meltzer, Hamilos, Hadley, Lanza, Marple, et. al. Rhinosinusitis: Establishing Definitions for Clinical Research and Patient Care. JACI 2004;114:155-212.

44 Treatment of AFS: a comparison trial of postoperative IT with specific fungal antigens 1 Conclusion - We report our experience dating to Aug. 1993 in the management of AFS. Based upon endoscopic staging, quality of life assessment, and comparison with the usual course of AFS, immunotherapy with relevant fungal antigens is not harmful, and appears to be beneficial. 1 Folker, Marple, Mabry, Mabry, Laryngoscope 108:1623-27, 1998

45 Controversies Surrounding Fungal Rhinosinusitis Does the data presented prove fungus as the sole cause of CRS? Does the data presented prove fungus as the sole cause of CRS? Does the existence of EFRS negate that of AFRS (or all other causes of CRS)? Does the existence of EFRS negate that of AFRS (or all other causes of CRS)? Does it diminish the association with sIgE? Does it diminish the association with sIgE?

46 Corticosteroids: How to use (Marple, Mabry, Am J Rhinol 12:263-68,1998) Preop Preop Start 0.5-1.0 mg/kg/day to start 1 week prior to surgery Start 0.5-1.0 mg/kg/day to start 1 week prior to surgery Postop Postop Resume 0.5-1.0 mg/kg/day Resume 0.5-1.0 mg/kg/day Taper over 4 weeks Taper over 4 weeks Continue low dose, alternate day therapy, or Continue low dose, alternate day therapy, or Start immunotherapy, or Start immunotherapy, or Start antifungal therapy Start antifungal therapy

47 Antifungal antimicrobials Used initially to arrest the potential progression to invasive fungal disease Used initially to arrest the potential progression to invasive fungal disease Next used in an attempt to control recidivism of disease Next used in an attempt to control recidivism of disease Amphoterocin B Amphoterocin B Toxicity limits use Toxicity limits use Ketoconazole, itraconazole, fluconazole Ketoconazole, itraconazole, fluconazole Poor in vitro activity to dematiaceous fungi 1 Poor in vitro activity to dematiaceous fungi 1 1 Manning, et al, Laryngoscope 108;1485-96,1998

48 Fungal Specific Humoral Response Conclusions of study Conclusions of study Fungal spIgE fails to differentiate AFS Fungal spIgE fails to differentiate AFS Fails to support central pathogenic role of spIgE Fails to support central pathogenic role of spIgE spIgE may simply be involved in exacerbation of underlying inflammation in some forms of EMCSF spIgE may simply be involved in exacerbation of underlying inflammation in some forms of EMCSF Fungal spIgG3 Fungal spIgG3 Served as marker of EM production Served as marker of EM production Separated EMCRS from CRS Separated EMCRS from CRS Pant H, Laryngoscope 2005;115:601-606.


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