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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
Fungal allergy Invasive Fungus Fulminant Indolent Granulomatous Non-invasive fungus Mycetoma Saprophytic growth AFRS EFRS Allergic Fungal Rhinosinusitis Points to make: Fungus is currently considered a viable candidate as promoter of CRS Fungus is recognized to interact in a number of ways Range is wide: In some cases fungus can be present within the nose without contributing to disease. Saprophyte EFRS Marple, Laryngoscope 2001;111:

3 Clinical Observations
Concerning AFRS Need a clear picture of the disease that is at the center of this talk

4 Radiographic Characteristics: Bone Erosion
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 Histology - 0/142 demonstrated invasion The most notable aspect of the disease is the radiographic characteristices 1Radiology 1998; 207:417-22 2Oto HNS 2001;124:150-54 3Zinreich et al. Radiology 1988; 169:

5 Clinical Presentation: Mucin
Mucin is the hallmark of the disease As a brief review, those patients with AFRS present in a clinically characteristic fashion. Hallmarks of the disease in most cases are polyps, while the presence of gross mucin is present in all cases.

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

7 Diagnostic Criteria Bent and Kuhn Cody Allphin Lowry, Schaefer
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 Cody Allphin Lowry, Schaefer deShazo, Swain For the purposes of this presentation it is important to point out that up to a point there was no doubt of the association of allergy with AFRS Bent, Kuhn, Oto-HNS 1994;111:580-88 Meltzer, Hamilos, Hadley, Lanza, Marple, et. al. JACI 2004;114:S155-S212.

8 Eosinophilic Fungal Rhinosinusitis
Let us compare and contrast AFRS with another proposed clinical entity defined by the presence of both eosinophils and fungi…..EFRS

9 Mayo Experience – Evolution of a Pathogenesis
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 The story of EFRS begins in 1999 with the publication of the original article from the Mayo, which demonstrated that with sufficiently sensitive culture techniques fungi could be recovered from virtually all noses, diseased or not. Moreover, when the mucin from surgical patients with CRS was examined, 93% satisfied their histologic diagnosis of AFS. However, when these cases were studied for allergy, it did not vary from that which is recognized in the general CRS population. Given the lack of allergy, the name EFRS was proposed. That is all well and good, but what was really interesting was when Kita demonstrated that PBMC were exposed to Alternaria they produced significantly greater amounts of cytokines IL-5, IL-13, and IF gamma. This, in many’s opinion, is the most compelling piece of information regarding this that has been produced. Unfortunately, these data have yet to be published in a peer-reviewed fashion. Other studies by the Mayo have described their techniques for the resolution of histologic staining for fungus, and have demonstrated in a boyden chamber in vitro chemoattraction of eosinophils to mucus and tissue of patients with CRS. These studies have culminated in an uncontrolled study of Amphoterocin B irrigations for the treatment of CRS in which symptoms improved in response to treatments in 38 of 51, and endoscopic clearance in 35%. Ponikau. Mayo Clin Pro. 1999;74: Shin. JACI (abstract). Shin SH, Kita H et al . AAAAI NY, March 6, 2002 Taylor. Oto-HNS 2002;127: Wei. Laryngoscope 2003;113: Ponikau. JACI 2002;110:

10 Why the Difference? What are we calling “mucin”?
EFRS AFRS GMS It is interesting that when we find easily identified mucin, the GMS stains are effective. On the other hand, GMS stains are more frequently negative in the absence of easily recognized mucin, necessitating the use of chitin immunofluorenscence. The real question is whether these issues play a role in the interpretation of information? GMS Chitin GMS Courtesy of Ponikau

11 Impact of Clinical Findings upon Immunologic Data
67 20 87 In this slide, the I have plotted the immunologic findings produced by the Ponikau method versus all other papers that were used for this presentation. Skin or in vitro analysis for fungal antigens demonstrated differences. I applied no statistics, however. 179 179 Marple, presented Maryland CRS meeting 2003

12 AFRS vs EFRS: Why the Difference?
Are we looking at the same disease? 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:

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:

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:

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:

17 Types of Fungal Sinusitis
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) Perhaps rather than pitting the two diseases against one another, it would be more appropriate to classify these diseases in a manner that will be recommended in an upcoming consensus paper generated by representatives of the allergy and otolaryngology communities. This is based upon the prevailing recognition of the difference between the two diseases. Meltzer, Hamilos, Hadley, Lanza, Marple, et. al. Rhinosinusitis: Establishing Definitions for Clinical Research and Patient Care JACI 2004;114:

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 Fungus Surgery Immunomodulation Close follow-up AFS
Antifungals Fungus Surgery Complete removal of fungal antigen Tissue sparing Immunomodulation Perioperative steroids Immunotherapy Close follow-up Saline irrigation Office visits 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;

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

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

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% 1yr Steroids for <2 mo. - 55% 1yr Marple, Mabry - 42pts Immunotherapy - 10% mo. We are going to come back to this point, but what is important in this slide is that in the absence of further treatment the rate of disease recurrence is unacceptable high. Do not go into Allergy Asthma Proc 1996;17:259-68, Oto-HNS 1997;117:35-41, J Allergy Clin Immunol1998;102: , 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 , 1993. 2Ferguson, Abstract AAOA, 1993.

25 Could IT be used as a part of a comprehensive plan?
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 Mabry, Marple, Mabry Oto-HNS 1999;121:252-4

26 Cross-sectional study of 22 AFS pts Evaluation
Treatment of AFS: a comparison trial of postoperative IT with specific fungal antigens1 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) 1Folker, Marple, Mabry, Mabry, Laryngoscope 108: , 1998

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

28 Endoscopic Mucosal Staging
Folker, Marple, Mabry, Mabry, Laryngoscope 108: , 1998

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

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

31 Corticosteroids: Rationale
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

32 Corticosteroids Bent1 Schubert2 - 67 pts Corticosteroids < 2mo
Universal recurrence of AFS in following discontinuation of corticosteroids Schubert 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 1Bent, Kuhn, Allergy Asthma Proc 17:259-68, 1996 2Schubert, Goetz, J Allergy Clin Immun 103: , 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 Ferguson Rains Kennedy May limit
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: , 1998

35 Systemic Antifungals Alternate effect of antifungals Kanda
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 It is reported that anti-mycotic agents are effective for the treatment of patients with atopic dermatitis. We studied the in vitro effects of anti-mycotics on T-cell helper-1 (TH1) and T-cell helper-2 (TH2) cytokine production in anti-CD3 plus anti-CD28-stimulated T cells from atopic dermatitis patients and normal donors. The amounts of IL-4 and IL-5 secreted by anti-CD3/CD28-stimulated T cells were higher in atopic dermatitis patients than in normal donors. Azole derivatives, ketoconazole, itraconazole, miconazole, and nonazole terbinafine hydrochloride, and tolnaftate reduced IL-4 and IL-5 secretion without altering that of interferon-gamma and IL-2 in anti-CD3/CD28-stimulated T cells from both atopic dermatitis patients and normal donors. The azole derivatives were more inhibitory than nonazole anti-mycotics. These anti-mycotics reduced the anti-CD3/CD28-induced mRNA expression and promoter activities for IL-4 and IL-5. The 3',5'-cyclic adenosine monophosphate analog dibutyryl 3',5'-cyclic adenosine monophosphate reversed the inhibitory effects of the anti-mycotics on IL-4 and IL-5 secretion, mRNA expression, and promoter activities. Anti-CD3/CD28 transiently (<5 min) increased intracellular 3',5'-cyclic adenosine monophosphate in T cells, and the increase was greater in atopic dermatitis patients than in normal donors. The increase of 3',5'-cyclic adenosine monophosphate by anti-CD3/CD28 correlated with IL-4 and IL-5 secretion by anti-CD3/CD28. The transient 3',5'-cyclic adenosine monophosphate increase was suppressed by anti-mycotics, and azole derivatives were more suppressive than nonazoles. Azole derivatives inhibited the activity of cyclic adenosine monophosphate-synthesizing adenylate cyclase whereas terbinafine hydrochloride and tolnaftate enhanced the activity of 3',5'-cyclic adenosine monophosphate-hydrolyzing cyclic nucleotide phosphodiesterase in atopic dermatitis and normal T cells. These results suggest that the anti-mycotics may suppress IL-4 and IL-5 production by reducing 3',5'-cyclic adenosine monophosphate signal, and stress their potential use for the suppression of T helper-2-mediated inflammatory processes. Kanda N. Journal of Investigative Dermatology. 117(6): , 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 Background: Chronic rhinosinusitis (CRS) is one of the most common chronic diseases. Its etiology is unknown, and there is a paucity of effective medical treatments. Objective: We tested the hypothesis that intranasal antifungal treatment improves the objective computed tomography (CT) findings (inflammatory mucosal thickening), nasal endoscopy stages, and symptoms of CRS. Methods: A randomized, placebo-controlled, double-blind, single-center trial used amphotericin B to treat 30 randomly selected patients with CRS. Patients were instructed to instill 20 mL amphotericin B (250 mg/mL) or placebo to each nostril twice daily for 6 months. The primary outcome was a quantitative reduction in inflammatory mucosal thickening on CT scans of a standardized coronal cut. Secondary outcome measures were endoscopic scores, patient symptom scores, and levels of intranasal inflammatory mediators. Results: Twenty-four patients completed the 6 months of treatment. Patients receiving amphotericin B achieved a relative reduction in the percentage of mucosal thickening on CT scans (n = 10; 28.8%) compared with placebo (n = 14; 12.5%; P = .030). Likewise, the changes in the endoscopic scores improved in the amphotericin B group compared with placebo (P = .038). Between-group comparisons of the changes in the intranasal mucus levels of eosinophil-derived neurotoxin showed a reduction in the amphotericin B group and an increase in the placebo group (P = .046); levels of IL-5 showed similar tendencies (P = .082). Ponikau, et al. JACI 2005;115:

37 Stratification Issues
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 Background: Recently, fungal elements were suspected to be the causative agent of chronic rhinosinusitis, and benefits of topical amphotericin B therapy have been reported. Objective: The effects of amphotericin B versus control nasal spray on chronic rhinosinusitis were compared in a doubleblind, randomized clinical trial. Methods: Patients with chronic rhinosinusitis were administered 200 mL per nostril amphotericin B (3 mg/mL) or saline nasal spray 4 times daily over a period of 8 weeks. The response rate, defined as a 50% reduction of pretreatment computed tomography score, was the primary outcome variable. Additional outcome variables included a symptom score, a quality of life score, and an endoscopy score. Before and after treatment, nasal lavages were pretreated with dithiothreitol and examined for fungal elements by PCR and standard culture techniques. Results: Seventy-eight patients were included, and 60 patients finished the study per protocol. In the control group, no positive response (0 of 32) was observed, and 2 of 28 patients responded in the amphotericin B group (P > .2). The symptom scores were distinctly worse after amphotericin B therapy (P < .005). The other parameters investigated did not differ remarkably between the treatment groups. Conclusion: Nasal amphotericin B spray in the described dosing and time schedule is ineffective and deteriorates patient symptoms. (J Allergy Clin Immunol 2004;113: ) Weshta, et al. JACI 2004;113:

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% 1yr Steroids for <2 mo. - 55% 1yr Marple, Mabry - 42pts Immunotherapy - 10% mo. Marple, Newcomer - 17pts followed yrs. 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: , Am J Rhinology 2000;14:223-26 Oto-HNS: (5) 361-6

40 Conclusion AFS remains intriguing Elimination of Fungal Antigen
Control of Recurrence Immunomodulation Antifungal Rx IT Steroids Topical Systemic 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

41 Experience of Others Braun – 92 patients with CRS
Replicated findings of 1999 Ponikau paper Richetti – 74 patients with nasal polyps Ampho B irrigation for 4 weeks 47% experienced complete resolution of polyps Proposed mechanism of effect Ampho B antifungal effect, OR Ampho B possesses well-known anti-inflammatory effect!!! These findings are not unique to the Mayo. Braun. Laryngoscope 2003;113: Richetti. J of Laryngol & Otol 2002;116:

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

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

44 Treatment of AFS: a comparison trial of postoperative IT with specific fungal antigens1
Conclusion - “We report our experience dating to Aug 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.” 1Folker, Marple, Mabry, Mabry, Laryngoscope 108: , 1998

45 Controversies Surrounding Fungal Rhinosinusitis
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 it diminish the association with sIgE? Two amongst the controversies.

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

47 Antifungal antimicrobials
Used initially to arrest the potential progression to invasive fungal disease Next used in an attempt to control recidivism of disease Amphoterocin B Toxicity limits use Ketoconazole, itraconazole, fluconazole Poor in vitro activity to dematiaceous fungi1 1Manning, et al, Laryngoscope 108; ,1998

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

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