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Allergic fungal sinusitis
FUNGALRHlNOSINUSlTIS: A SPECTRUM OF DISEASE
0030-6665/00 $15.00 + .00
ALLERGIC FUNGAL SINUSITIS The Role of Immunotherapy Richard L. Mabry, MO, and Cynthia S. Mabry, RN, BSNi-
The role of surgery and antiinflammatory therapy (such as corticosteroids) in the management of allergic fungal sinusitis (AFS) is accepted fairly universally. Although once thought to be contraindicated in treating AFS, immunotherapy has now assumed an important role in attempting to control this recalcitrant disorder. IMMUNOLOGIC BASIS OF ALLERGIC FUNGAL SINUSITIS
Early workers described allergy as part of the clinical findings in AFS, but very little data were available to confirm this. Waxman et al 17 postulated that AFS resembled allergic bronchopulmonary aspergillosis (ABPA), and that both type I and III Gell and Coombs reactions were involved in the pathophysiology of the disease. More evidence for the immunologic basis for AFS has become available in recent years. Manning et al l S showed high levels of allergen-specific immunoglobulin E (lgE) for several fungal antigens in a large series of patients with AFS. In a series of 16 patients with Bipolaris AFS, Holman et al? demonstrated skin test positivity for Bipolaris in 100% and the presence of specific immunoglobulins E and G in 82% and 93% of the patients. Mabry and Manning» showed radioallergosorbent test (RAST) class II or higher responses for both fungal and nonfungal antigens, plus high levels of 19E, in a previously unreported series of patients with AFS. When 10 patients with AFS "Decaased
From the Department of Otorhinolaryngology, University of Texas Southwestern Medical Center, Dallas, Texas
OTOLARYNGOLOGIC CLINICSOF NORTH AMERICA VOLUME 33· NUMBER 2· APRil. 2000
433
434
MABRY & MABRY
were tested by skin test and in vitro methods for sensitivity to 11 moulds, the patients showed positive responses for virtually every antigen tested (Table 1),13 A word of explanation should be given regarding the difference between fungi and moulds. The term fungus is more inclusive, and embraces yeasts, smuts, rusts, and mushrooms. Fungi other than mushrooms generally are called collectively moulds. The moulds of allergenic significance are contained in the group called fungi imperfecta, and it is to this group that most allergists refer when they use the term mould. The organisms typically cultured in AFS, such as Bipolaris and Aspergillus, usually are called fungi. Although one most often speaks of fungi when dealing with a causative organism, and moulds when dealing with antigens for immunotherapy, the terms may be used interchangeably. The exact cause of AFS remains a matter of conjecture. The authors feel, however, that the schema suggested by Manning is the most likely (Fig. 1). The anatomic obstruction can be dealt with surgically, and little argument exists about the necessity for such intervention, Until a few years ago, the atopic component was addressed primarily by the use of systemic and topical glucocorticoids. The importance (and safety) of immunotherapy has only become apparent recently. HISTORY OF IMMUNOTHERAPY FOR ALLERGIC FUNGAL SINUSITIS
Because of the similarities between ABPA and AFS, immunotherapy traditionally was considered to be contraindicated in both conditions. This was because of the perceived risk that the antigens administered would provoke a Gell and Coombs type TIl (complex-mediated) reaction and worsen the patient's clinical status. A leading allergy text, however, indicates that such an adverse reaction would not necessarily occur, but suggests avoiding immunotherapy in this situation because of the uncertainties involved." The authors raise a valid concern, but one major difTable 1. POSITIVE RESPONSES TO FUNGAL ANTIGENS IN 10 PATIENTS WITH AFS Patients
Alternaria" Helminthosporium* Stemphyllium* Pullularia"
CUnJularia* Cladosporium" Epicoccum"
Penicillium Aapergillus Mucor Fusarium *Dematiaceous fungi
10 10
10 10 10
8 8 10 10 10
7
ALLERGIC FUNGALSINUSITIS
SURGERV~
INHALED FUNGUS
y
IMMUNOTHERAPV
ANATOMIC OBSTRUCTION
ATOPY
STASIS
IMMUNOLOGIC REACTIONS
~
MUCOSAL INFlAMMATION
435
J
STEROIDS
BACTERIAL RHINOSINUSITIS
Figure 1. Proposed pathophysiology of allergic fungal sinusitis and points of intervention. (Modified from Manning SC, Vuitch F, Weinberg AG, et al: Allergic aspergillosis: A newly recognized form of sinusitis in the pediatric population. Laryngoscope 99:681-685, 1989; with permission.)
ference between ABPA and AFS is the ability of the surgeon to remove the fungal allergic load (allergic mucin) from the sinuses of the patient with AFS, whereas such a measure is not possible in patients with ABPA. It would seem reasonable that in the absence of a large and constant antigenic exposure, specific immunotherapy might achieve sufficient immunomodulation to have a positive effect on the patient's clinical course. Other than the authors' series, little published information about immunotherapy for AFS is available, but even these brief reports indicate that patients improved, rather than worsening, with such treatment. 2, 5, 16 The authors' interest was piqued by a report of Ferguson' in which she reviewed seven patients with AFS who received immunotherapy. Five of these patients did not improve or appeared to worsen while receiving this treatment. This group, however, received immunotherapy before they underwent surgery to free the involved sinuses of allergic mucin and fungal debris. On the other hand, two patients who received immunotherapy after initial control of their disease with surgery responded well to this modality. This sparked the authors' interest in a prospective study of immunotherapy with fungal antigens, administered after surgery, in patients withAFS. In August 1994 the authors received approval from the Investigational Review Board of the University of Texas Southwestern Medical Center to begin a prospective study of the effect of immunotherapy with multiple fungal antigens on the clinical course of patients with proven AFS. It was the authors' intention to offer this treatment to all patients with proven AFS, using the cohort who declined to participate as the control group. Because most patients coming to the authors did so after numerous operations for multiple recurrences of their disease, however,
436
MABRY & MABRY
the authors' only control group during the first 3 years consisted of three patients who initially enrolled but discontinued their immunotherapy after only a few weeks. The protocol initially followed involved testing for multiple fungal antigens and treating with all positive responders. Only after the first 6 months did the authors add to the treatment regimen the nonfungal antigens to which the patient was found to be positive (grasses, weeds, etc.). This was to allow the authors to more accurately study the effect of specific fungal immunotherapy. After the first year, the authors observed that not only were no adverse effects noted in the patients treated in this fashion, but the patients demonstrated a drastically improved clinical course compared with the authors' usual experience in treating AFS patients. Within 8 to 12 weeks of starting immunotherapy, the formation of nasal crusts had stopped, and no allergic mucin accumulation was noted. No systemic steroids were needed after immunotherapy was established, and topical steroid requirements were reduced drastically," By the second year of the study, it had become obvious that the treatment regimen was not detrimental, and appeared to be beneficial in an admittedly small series. By this time the authors were initiating immunotherapy simultaneously with all positive fungal and nonfungal antigens (in separate vials), combining them into a single vial when maintenance levels had been achieved. Two patients of the 11 treated by that time required revision surgery for frontoethmoid disease because of suppurative sinusitis (with no evidence of recurrent AFS), but otherwise no systemic corticosteroids were necessary, no polyp recurrence had been noted, and topical nasal steroids rarely were necessary. This was in comparison with the three patients who had opted out of the study within the first few weeks, all of whom had recurrent disease." As more experience has accrued in treating patients with allergic fungal sinusitis with a program that includes immunotherapy for fungal and nonfungal antigens, the authors have become convinced of the worth of such a regimen.> The authors subsequently were able to present a study comparing two groups of patients with AFS treated with the same regimen, with the exception of immunotherapy in one cohort.' The results were striking, with the group receiving immunotherapy showing statistically significant improvement in quality of life scores (Chronic Sinusitis Survey of Glicklich and Metson) and endoscopic mucosal staging (staging system of Kupferberg, Bent and Kuhn). All members of the control group required an average of two courses of systemic corticosteroids per year, whereas the treatment group required none. Based on the authors' continued success over more than 4 years, the authors strongly recommend consideration of fungal immunotherapy in patients with AFS.
PROTOCOL FOR IMMUNOTHERAPY The authors have modified the methodology very little since commencing this project. Testing for allergy may be done either before or after
ALLERGIC FUNGAL SINUSmS
437
surgery. Immunotherapy, however, is never started until after surgery (generally 4 to 6 weeks afterward), and if surgery was done elsewhere and there is residual disease, this must be cleared before injections are commenced. The authors test for 12 index nonfungal antigens (grasses, weeds, trees, dust mites, cat, dog), generally by RAST, which is the authors' test method of choice. Because of the somewhat different sensitivities of skin test and in vitro methods in testing for moulds (see previous text), the authors have chosen to perform mould testing by the intradermal titration methods. The authors test for 11 common moulds (Table 2), including both dematiaceous and nondematiaceous fungi, and incorporate all positive reactors into a treatment vial. Because antigen for Bipolaris is not available commercially, the authors have chosen to use Helminthosporium, which is taxonomically quite similar. It is important to emphasize that one tests (and treats, when indicated) for multiple moulds, not just for the genus of fungus which may be cultured from the sinuses at surgery. The authors have shown that patients with AFS are sensitive to multiple moulds, and believe that it is important that they be treated for all positive reactors. The authors readily admit, however, that no studies are available confirming the efficacy of treating for all positive moulds rather than monotherapy. It is worth emphasizing again that a positive fungal culture is not a prerequisite for confirming the diagnosis of AFS, and Ferguson estimates that such cultures are negative in up to 40%of cases (BJFerguson, personal communication, 1999). An interesting report by Chrzanowski et al suggests that an 18-kd protein may represent a fungal panallergen, sensitivity to which could explain the tendency of patients with AFS to react to multiple fungal antigens.' The exact relevance of this finding to achieving successful immunomodulation in patients with AFS remains to be seen, but one looks forward to more information from this group of investigators. In addition to a vial containing fungal antigens, a separate vial is made for positive nonfungal antigens. The authors give one injection from each vial, in different arms, so as to be able to more accurately identify the source of any local reactions. Injections are administered weekly, with dose advancement according to the usual Indicators." As dosage strengths are increased, the antigens are combined into a single vial when possible, and immunotherapy is continued until a maximum tolerated dose is Table 2. FUNGAL ANTIGENS IN CURRENT TESTING AND TREATMENT PROTOCOL (IN APPROXIMATE RELATIVE ORDER OF IMPORTANCE, IN THE AUTHORS' TOTAL EXPERIENCE)
Helminthosporium Alternaria Stemphyllium Curuularia
Aspergillus
Fusarium Mucor Pullularia Cladosporium Penicillium
Epicoccum From Mabry RL, Marple BF, Folker RJ,et al: Immunotherapy for allergic fungal sinusitis: Three years' experience. Otolaryngol Head Neck Surg 119:648-651, 1998; with permission.
438
MABRY & MABRY
reached. Mer the patient has reached a maintenance level, injections are continued on a weekly basis for up to a year, and then the injection interval increased to every 2 weeks for the second year and every 2 to 3 weeks thereafter. A question that has not been answered yet is how long to continue the injections. The immunologic changes noted in patients with AFS who receive immunotherapy do not seem to follow the pattern generally expected with other types of immunotherapy. At present the authors are treating these patients in the same fashion as those with any type of inhalant allergy, aiming at a total of at least 3 years on immunotherapy. The authors experience in this regard is limited, but thus far they have not noted a tendency to recurrence in patients taken off injections after this interval." NURSING INTERVENTIONS
The nurse or allergy assistant plays an important role in dealing with patients with AF5. Testing may be done by either RAST or dilutional intradermal testing. Each has advantages and disadvantages," and the practitioner undoubtedly chooses the method with which he or she is most comfortable. Once immunotherapy is begun, doses are advanced in accordance with standard practice," keeping in mind that patients with AFS vary greatly in their ability to tolerate dosage advancement. Administration of fungal antigens is more likely to provoke delayed reactions, which necessitate careful dosage adjustment. The person administering immunotherapy has the most frequent contact with these patients. As a result, the allergy nurse or technician is able to monitor patient progress on a regular basis. This is an opportunity to act as a coach, encouraging patients to use their irrigation procedure (and instructing them in proper technique when necessary), and assisting them in using their medications properly. Many patients need repetition of the instruction to properly use nasal steroids, for example. Patients with AFS may tend to become discouraged when they develop complicating bacterial infections, or note crusting that requires frequent irrigation (especially early in their treatment course). They must be reminded that although the end result of this treatment has been shown to be extremely beneficial, it is neither magic nor immediate. FUTURE STUDIES
Despite gaining a great deal of experience in the area, one still has no certain knowledge of the mechanism by which specific immunotherapy with fungal antigens benefits patients with AFS. The authors previously have studied and reported the changes in allergen-specific 19E and 19G noted over time in patients receiving such therapy. Instead of the expected eventual drop in specific 19E levels, they remain high throughout the pe-
ALLERGIC FUNGAL SINUSITIS
439
riod of treatment, despite excellent clinical responses. No consistent pattern to IgG levels has been observed. This leads one to question whether the treatment is affecting T cells, immune complexes, or other allergic mechanisms. Obviously, continued study in this regard is a priority. Despite reports from the authors' center of over 4 years' effectiveness, it is desirable for these results to be validated by work at other institutions, and they welcome such a challenge. A multicenter study, headed by Drs. Berrylin Ferguson and Bradley Marple, is in its early stage, and hopefully will provide more answers. Although the authors' work has involved testing by RAST and dilutional intradermal testing, they welcome head-tohead comparisons with treatment based on traditional prick and singledilution intradermal testing. The authors have detailed their technique for treating these patients, but welcome others to modify it and report their results. The authors need to determine what methodology provides the greatest benefit for their patients with this recalcitrant disease, and then attempt to widely disseminate their knowledge about employing it. CONCLUSION
Allergic fungal sinusitis appears to be the consequence of anatomic obstruction in patients with preexisting allergy. The treatment of patients with AFS involves thorough exenteration and marsupialization of involved sinuses, while sparing as much nondiseased mucosa as possible. Perioperative systemic corticosteroids, combined with topical steroids and nasal irrigation and cleaning, are a valuable part of the treatment regimen. Although at one time viewed skeptically because of the risk of its worsening the status of patients with AFS, specific immunotherapy with multiple relevant fungal and nonfungal antigens has reduced dramatically the necessity for corticosteroid therapy, while preventing recurrence of disease and the need for repeat surgery. Ongoing studies are desirable to continue to validate this work, but over 4 years' experience in treating these patients strongly supports the contention that this should be a standard part of the treatment regimen for patients with AFS. References 1. Chrzanowski RR, Rupp NT, Kuhn FA, et al: Allergenic fungi in allergic fungal sinusitis. Ann Allergy Asthma Immuno179:431-435, 1997 . 2. deShazo RD, Swain RE: Diagnostic criteria for allergic fungal sinusitis. J Allergy Clin Immuno196:24-35, 1995 3. Ferguson BJ: Immunotherapy and antifungal therapy in allergic fungal sinusitis. Presented at the 1993 Annual Meeting of the American Academy of Otolaryngic Allergy, Minneapolis, MN, Sept 1993 4. Folker RJ, Marple BF,Mabry RL, et al: Treatment of allergic fungal sinusitis: A comparison trial of postoperative immunotherapy with specific fungal antigens. Laryngoscope 108:1623-1627,1998 5. Goldstein MF, Dunsky EH, Dvorin OJ, et al: Allergic fungal sinusitis: A review with four illustrated cases. Am J Rhinol 8:13-18, 1994
440
MABRY &. MABRY
6. Greenberger P, Atkinson NF [r, Yunginger JW, et al: Allergic bronchopulmonary aspergillosis. In Middleton E, Reed C, Ellis E, et al (eds): Allergy Principles and Practice. St. Louis, Mosby, 1993, pp 1395-1414 7. Holman], Manning S, Gruchalla R: Immunologic characterization of allergic Bipolaris (fungal) sinusitis.] Allergy Clin Immuno195:201, 1995 8. King HC, Mabry RL, Mabry CS: Allergy in ENT Practice. New York, Thieme, 1998, pp 228-242 9. Mabry RL, Mabry CS: Immunotherapy for allergic fungal sinusitis: The second year. Otolaryngol Head Neck Surg 117:367-371, 1997 10. Mabry RL, Manning S: Radioallergosorbent microscreen and total immunoglobulin E in allergic fungal sinusitis. Otolaryngol Head Neck Surg 113:721-723, 1995 11. Mabry RL, Manning SC, Mabry CS: Immunotherapy in the treatment of allergic fungal sinusitis. Otolaryngo1 Head Neck Surg 116:31-35,1997 12. Mabry RL, Marple BF,Folker R], et al: Immunotherapy for allergic fungal sinusitis: Three years' experience. Otolaryngol Head Neck Surg 119:648-651, 1998 13. Mabry RL,Marple BF,Mabry CS: Mold testing by RASTand skin test methods in patients with allergic fungal sinusitis. Otolaryngol Head Neck Surg, 121:252-254, 1999 14. Mabry RL, Marple BF, Mabry CS: Outcomes after discontinuing immunotherapy for allergic fungal sinusitis. Otolaryngol Head Neck Surg 122:104-107, 2000 15. Manning SC, Mabry RL, Schaefer SD, et al: Evidence of IgE-mediated hypersensitivity in allergic fungal sinusitis. Laryngoscope 103:717-721, 1993 16. Quinn], Wickern G, Whisman B, et al: Immunotherapy in allergic Bipolaris sinusitis: A case report [abstract). ] Allergy Clin Immuno195:201, 1995 17. Waxman], Spector ], Sale S, et al: Allergic sinusitis: Concepts in diagnosis and treatment of a new clinical entity. Laryngoscope 97:261-266, 1987
Address reprint requests to Richard 1. Mabry, MD Department of Otorhinolaryngology University of Texas Southwestern Medical Center 5323 Harry Hines Boulevard, Room G7. 228 Dallas, TX 75235-9035
0030-6665/00 $15.00 + .00
ALLERGIC FUNGAL SINUSITIS The Role of Immunotherapy Richard L. Mabry, MO, and Cynthia S. Mabry, RN, BSNi-
The role of surgery and antiinflammatory therapy (such as corticosteroids) in the management of allergic fungal sinusitis (AFS) is accepted fairly universally. Although once thought to be contraindicated in treating AFS, immunotherapy has now assumed an important role in attempting to control this recalcitrant disorder. IMMUNOLOGIC BASIS OF ALLERGIC FUNGAL SINUSITIS
Early workers described allergy as part of the clinical findings in AFS, but very little data were available to confirm this. Waxman et al 17 postulated that AFS resembled allergic bronchopulmonary aspergillosis (ABPA), and that both type I and III Gell and Coombs reactions were involved in the pathophysiology of the disease. More evidence for the immunologic basis for AFS has become available in recent years. Manning et al l S showed high levels of allergen-specific immunoglobulin E (lgE) for several fungal antigens in a large series of patients with AFS. In a series of 16 patients with Bipolaris AFS, Holman et al? demonstrated skin test positivity for Bipolaris in 100% and the presence of specific immunoglobulins E and G in 82% and 93% of the patients. Mabry and Manning» showed radioallergosorbent test (RAST) class II or higher responses for both fungal and nonfungal antigens, plus high levels of 19E, in a previously unreported series of patients with AFS. When 10 patients with AFS "Decaased
From the Department of Otorhinolaryngology, University of Texas Southwestern Medical Center, Dallas, Texas
OTOLARYNGOLOGIC CLINICSOF NORTH AMERICA VOLUME 33· NUMBER 2· APRil. 2000
433
434
MABRY & MABRY
were tested by skin test and in vitro methods for sensitivity to 11 moulds, the patients showed positive responses for virtually every antigen tested (Table 1),13 A word of explanation should be given regarding the difference between fungi and moulds. The term fungus is more inclusive, and embraces yeasts, smuts, rusts, and mushrooms. Fungi other than mushrooms generally are called collectively moulds. The moulds of allergenic significance are contained in the group called fungi imperfecta, and it is to this group that most allergists refer when they use the term mould. The organisms typically cultured in AFS, such as Bipolaris and Aspergillus, usually are called fungi. Although one most often speaks of fungi when dealing with a causative organism, and moulds when dealing with antigens for immunotherapy, the terms may be used interchangeably. The exact cause of AFS remains a matter of conjecture. The authors feel, however, that the schema suggested by Manning is the most likely (Fig. 1). The anatomic obstruction can be dealt with surgically, and little argument exists about the necessity for such intervention, Until a few years ago, the atopic component was addressed primarily by the use of systemic and topical glucocorticoids. The importance (and safety) of immunotherapy has only become apparent recently. HISTORY OF IMMUNOTHERAPY FOR ALLERGIC FUNGAL SINUSITIS
Because of the similarities between ABPA and AFS, immunotherapy traditionally was considered to be contraindicated in both conditions. This was because of the perceived risk that the antigens administered would provoke a Gell and Coombs type TIl (complex-mediated) reaction and worsen the patient's clinical status. A leading allergy text, however, indicates that such an adverse reaction would not necessarily occur, but suggests avoiding immunotherapy in this situation because of the uncertainties involved." The authors raise a valid concern, but one major difTable 1. POSITIVE RESPONSES TO FUNGAL ANTIGENS IN 10 PATIENTS WITH AFS Patients
Alternaria" Helminthosporium* Stemphyllium* Pullularia"
CUnJularia* Cladosporium" Epicoccum"
Penicillium Aapergillus Mucor Fusarium *Dematiaceous fungi
10 10
10 10 10
8 8 10 10 10
7
ALLERGIC FUNGALSINUSITIS
SURGERV~
INHALED FUNGUS
y
IMMUNOTHERAPV
ANATOMIC OBSTRUCTION
ATOPY
STASIS
IMMUNOLOGIC REACTIONS
~
MUCOSAL INFlAMMATION
435
J
STEROIDS
BACTERIAL RHINOSINUSITIS
Figure 1. Proposed pathophysiology of allergic fungal sinusitis and points of intervention. (Modified from Manning SC, Vuitch F, Weinberg AG, et al: Allergic aspergillosis: A newly recognized form of sinusitis in the pediatric population. Laryngoscope 99:681-685, 1989; with permission.)
ference between ABPA and AFS is the ability of the surgeon to remove the fungal allergic load (allergic mucin) from the sinuses of the patient with AFS, whereas such a measure is not possible in patients with ABPA. It would seem reasonable that in the absence of a large and constant antigenic exposure, specific immunotherapy might achieve sufficient immunomodulation to have a positive effect on the patient's clinical course. Other than the authors' series, little published information about immunotherapy for AFS is available, but even these brief reports indicate that patients improved, rather than worsening, with such treatment. 2, 5, 16 The authors' interest was piqued by a report of Ferguson' in which she reviewed seven patients with AFS who received immunotherapy. Five of these patients did not improve or appeared to worsen while receiving this treatment. This group, however, received immunotherapy before they underwent surgery to free the involved sinuses of allergic mucin and fungal debris. On the other hand, two patients who received immunotherapy after initial control of their disease with surgery responded well to this modality. This sparked the authors' interest in a prospective study of immunotherapy with fungal antigens, administered after surgery, in patients withAFS. In August 1994 the authors received approval from the Investigational Review Board of the University of Texas Southwestern Medical Center to begin a prospective study of the effect of immunotherapy with multiple fungal antigens on the clinical course of patients with proven AFS. It was the authors' intention to offer this treatment to all patients with proven AFS, using the cohort who declined to participate as the control group. Because most patients coming to the authors did so after numerous operations for multiple recurrences of their disease, however,
436
MABRY & MABRY
the authors' only control group during the first 3 years consisted of three patients who initially enrolled but discontinued their immunotherapy after only a few weeks. The protocol initially followed involved testing for multiple fungal antigens and treating with all positive responders. Only after the first 6 months did the authors add to the treatment regimen the nonfungal antigens to which the patient was found to be positive (grasses, weeds, etc.). This was to allow the authors to more accurately study the effect of specific fungal immunotherapy. After the first year, the authors observed that not only were no adverse effects noted in the patients treated in this fashion, but the patients demonstrated a drastically improved clinical course compared with the authors' usual experience in treating AFS patients. Within 8 to 12 weeks of starting immunotherapy, the formation of nasal crusts had stopped, and no allergic mucin accumulation was noted. No systemic steroids were needed after immunotherapy was established, and topical steroid requirements were reduced drastically," By the second year of the study, it had become obvious that the treatment regimen was not detrimental, and appeared to be beneficial in an admittedly small series. By this time the authors were initiating immunotherapy simultaneously with all positive fungal and nonfungal antigens (in separate vials), combining them into a single vial when maintenance levels had been achieved. Two patients of the 11 treated by that time required revision surgery for frontoethmoid disease because of suppurative sinusitis (with no evidence of recurrent AFS), but otherwise no systemic corticosteroids were necessary, no polyp recurrence had been noted, and topical nasal steroids rarely were necessary. This was in comparison with the three patients who had opted out of the study within the first few weeks, all of whom had recurrent disease." As more experience has accrued in treating patients with allergic fungal sinusitis with a program that includes immunotherapy for fungal and nonfungal antigens, the authors have become convinced of the worth of such a regimen.> The authors subsequently were able to present a study comparing two groups of patients with AFS treated with the same regimen, with the exception of immunotherapy in one cohort.' The results were striking, with the group receiving immunotherapy showing statistically significant improvement in quality of life scores (Chronic Sinusitis Survey of Glicklich and Metson) and endoscopic mucosal staging (staging system of Kupferberg, Bent and Kuhn). All members of the control group required an average of two courses of systemic corticosteroids per year, whereas the treatment group required none. Based on the authors' continued success over more than 4 years, the authors strongly recommend consideration of fungal immunotherapy in patients with AFS.
PROTOCOL FOR IMMUNOTHERAPY The authors have modified the methodology very little since commencing this project. Testing for allergy may be done either before or after
ALLERGIC FUNGAL SINUSmS
437
surgery. Immunotherapy, however, is never started until after surgery (generally 4 to 6 weeks afterward), and if surgery was done elsewhere and there is residual disease, this must be cleared before injections are commenced. The authors test for 12 index nonfungal antigens (grasses, weeds, trees, dust mites, cat, dog), generally by RAST, which is the authors' test method of choice. Because of the somewhat different sensitivities of skin test and in vitro methods in testing for moulds (see previous text), the authors have chosen to perform mould testing by the intradermal titration methods. The authors test for 11 common moulds (Table 2), including both dematiaceous and nondematiaceous fungi, and incorporate all positive reactors into a treatment vial. Because antigen for Bipolaris is not available commercially, the authors have chosen to use Helminthosporium, which is taxonomically quite similar. It is important to emphasize that one tests (and treats, when indicated) for multiple moulds, not just for the genus of fungus which may be cultured from the sinuses at surgery. The authors have shown that patients with AFS are sensitive to multiple moulds, and believe that it is important that they be treated for all positive reactors. The authors readily admit, however, that no studies are available confirming the efficacy of treating for all positive moulds rather than monotherapy. It is worth emphasizing again that a positive fungal culture is not a prerequisite for confirming the diagnosis of AFS, and Ferguson estimates that such cultures are negative in up to 40%of cases (BJFerguson, personal communication, 1999). An interesting report by Chrzanowski et al suggests that an 18-kd protein may represent a fungal panallergen, sensitivity to which could explain the tendency of patients with AFS to react to multiple fungal antigens.' The exact relevance of this finding to achieving successful immunomodulation in patients with AFS remains to be seen, but one looks forward to more information from this group of investigators. In addition to a vial containing fungal antigens, a separate vial is made for positive nonfungal antigens. The authors give one injection from each vial, in different arms, so as to be able to more accurately identify the source of any local reactions. Injections are administered weekly, with dose advancement according to the usual Indicators." As dosage strengths are increased, the antigens are combined into a single vial when possible, and immunotherapy is continued until a maximum tolerated dose is Table 2. FUNGAL ANTIGENS IN CURRENT TESTING AND TREATMENT PROTOCOL (IN APPROXIMATE RELATIVE ORDER OF IMPORTANCE, IN THE AUTHORS' TOTAL EXPERIENCE)
Helminthosporium Alternaria Stemphyllium Curuularia
Aspergillus
Fusarium Mucor Pullularia Cladosporium Penicillium
Epicoccum From Mabry RL, Marple BF, Folker RJ,et al: Immunotherapy for allergic fungal sinusitis: Three years' experience. Otolaryngol Head Neck Surg 119:648-651, 1998; with permission.
438
MABRY & MABRY
reached. Mer the patient has reached a maintenance level, injections are continued on a weekly basis for up to a year, and then the injection interval increased to every 2 weeks for the second year and every 2 to 3 weeks thereafter. A question that has not been answered yet is how long to continue the injections. The immunologic changes noted in patients with AFS who receive immunotherapy do not seem to follow the pattern generally expected with other types of immunotherapy. At present the authors are treating these patients in the same fashion as those with any type of inhalant allergy, aiming at a total of at least 3 years on immunotherapy. The authors experience in this regard is limited, but thus far they have not noted a tendency to recurrence in patients taken off injections after this interval." NURSING INTERVENTIONS
The nurse or allergy assistant plays an important role in dealing with patients with AF5. Testing may be done by either RAST or dilutional intradermal testing. Each has advantages and disadvantages," and the practitioner undoubtedly chooses the method with which he or she is most comfortable. Once immunotherapy is begun, doses are advanced in accordance with standard practice," keeping in mind that patients with AFS vary greatly in their ability to tolerate dosage advancement. Administration of fungal antigens is more likely to provoke delayed reactions, which necessitate careful dosage adjustment. The person administering immunotherapy has the most frequent contact with these patients. As a result, the allergy nurse or technician is able to monitor patient progress on a regular basis. This is an opportunity to act as a coach, encouraging patients to use their irrigation procedure (and instructing them in proper technique when necessary), and assisting them in using their medications properly. Many patients need repetition of the instruction to properly use nasal steroids, for example. Patients with AFS may tend to become discouraged when they develop complicating bacterial infections, or note crusting that requires frequent irrigation (especially early in their treatment course). They must be reminded that although the end result of this treatment has been shown to be extremely beneficial, it is neither magic nor immediate. FUTURE STUDIES
Despite gaining a great deal of experience in the area, one still has no certain knowledge of the mechanism by which specific immunotherapy with fungal antigens benefits patients with AFS. The authors previously have studied and reported the changes in allergen-specific 19E and 19G noted over time in patients receiving such therapy. Instead of the expected eventual drop in specific 19E levels, they remain high throughout the pe-
ALLERGIC FUNGAL SINUSITIS
439
riod of treatment, despite excellent clinical responses. No consistent pattern to IgG levels has been observed. This leads one to question whether the treatment is affecting T cells, immune complexes, or other allergic mechanisms. Obviously, continued study in this regard is a priority. Despite reports from the authors' center of over 4 years' effectiveness, it is desirable for these results to be validated by work at other institutions, and they welcome such a challenge. A multicenter study, headed by Drs. Berrylin Ferguson and Bradley Marple, is in its early stage, and hopefully will provide more answers. Although the authors' work has involved testing by RAST and dilutional intradermal testing, they welcome head-tohead comparisons with treatment based on traditional prick and singledilution intradermal testing. The authors have detailed their technique for treating these patients, but welcome others to modify it and report their results. The authors need to determine what methodology provides the greatest benefit for their patients with this recalcitrant disease, and then attempt to widely disseminate their knowledge about employing it. CONCLUSION
Allergic fungal sinusitis appears to be the consequence of anatomic obstruction in patients with preexisting allergy. The treatment of patients with AFS involves thorough exenteration and marsupialization of involved sinuses, while sparing as much nondiseased mucosa as possible. Perioperative systemic corticosteroids, combined with topical steroids and nasal irrigation and cleaning, are a valuable part of the treatment regimen. Although at one time viewed skeptically because of the risk of its worsening the status of patients with AFS, specific immunotherapy with multiple relevant fungal and nonfungal antigens has reduced dramatically the necessity for corticosteroid therapy, while preventing recurrence of disease and the need for repeat surgery. Ongoing studies are desirable to continue to validate this work, but over 4 years' experience in treating these patients strongly supports the contention that this should be a standard part of the treatment regimen for patients with AFS. References 1. Chrzanowski RR, Rupp NT, Kuhn FA, et al: Allergenic fungi in allergic fungal sinusitis. Ann Allergy Asthma Immuno179:431-435, 1997 . 2. deShazo RD, Swain RE: Diagnostic criteria for allergic fungal sinusitis. J Allergy Clin Immuno196:24-35, 1995 3. Ferguson BJ: Immunotherapy and antifungal therapy in allergic fungal sinusitis. Presented at the 1993 Annual Meeting of the American Academy of Otolaryngic Allergy, Minneapolis, MN, Sept 1993 4. Folker RJ, Marple BF,Mabry RL, et al: Treatment of allergic fungal sinusitis: A comparison trial of postoperative immunotherapy with specific fungal antigens. Laryngoscope 108:1623-1627,1998 5. Goldstein MF, Dunsky EH, Dvorin OJ, et al: Allergic fungal sinusitis: A review with four illustrated cases. Am J Rhinol 8:13-18, 1994
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6. Greenberger P, Atkinson NF [r, Yunginger JW, et al: Allergic bronchopulmonary aspergillosis. In Middleton E, Reed C, Ellis E, et al (eds): Allergy Principles and Practice. St. Louis, Mosby, 1993, pp 1395-1414 7. Holman], Manning S, Gruchalla R: Immunologic characterization of allergic Bipolaris (fungal) sinusitis.] Allergy Clin Immuno195:201, 1995 8. King HC, Mabry RL, Mabry CS: Allergy in ENT Practice. New York, Thieme, 1998, pp 228-242 9. Mabry RL, Mabry CS: Immunotherapy for allergic fungal sinusitis: The second year. Otolaryngol Head Neck Surg 117:367-371, 1997 10. Mabry RL, Manning S: Radioallergosorbent microscreen and total immunoglobulin E in allergic fungal sinusitis. Otolaryngol Head Neck Surg 113:721-723, 1995 11. Mabry RL, Manning SC, Mabry CS: Immunotherapy in the treatment of allergic fungal sinusitis. Otolaryngo1 Head Neck Surg 116:31-35,1997 12. Mabry RL, Marple BF,Folker R], et al: Immunotherapy for allergic fungal sinusitis: Three years' experience. Otolaryngol Head Neck Surg 119:648-651, 1998 13. Mabry RL,Marple BF,Mabry CS: Mold testing by RASTand skin test methods in patients with allergic fungal sinusitis. Otolaryngol Head Neck Surg, 121:252-254, 1999 14. Mabry RL, Marple BF, Mabry CS: Outcomes after discontinuing immunotherapy for allergic fungal sinusitis. Otolaryngol Head Neck Surg 122:104-107, 2000 15. Manning SC, Mabry RL, Schaefer SD, et al: Evidence of IgE-mediated hypersensitivity in allergic fungal sinusitis. Laryngoscope 103:717-721, 1993 16. Quinn], Wickern G, Whisman B, et al: Immunotherapy in allergic Bipolaris sinusitis: A case report [abstract). ] Allergy Clin Immuno195:201, 1995 17. Waxman], Spector ], Sale S, et al: Allergic sinusitis: Concepts in diagnosis and treatment of a new clinical entity. Laryngoscope 97:261-266, 1987
Address reprint requests to Richard 1. Mabry, MD Department of Otorhinolaryngology University of Texas Southwestern Medical Center 5323 Harry Hines Boulevard, Room G7. 228 Dallas, TX 75235-9035