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Over the past 2 decades, allergic fungal sinusitis (AFS) has become increasingly defined. Historically mistaken for a paranasal sinus tumor, allergic fungal sinusitis (AFS) now is believed to be an allergic reaction to aerosolized environmental fungi, usually of the dematiaceous species, in an immunocompetent host. This is in contrast to invasive fungal infections that affect immunocompromised hosts, such as patients with diabetes mellitus and patients with AIDS. Most patients with allergic fungal sinusitis (AFS) have a history of allergic rhinitis, and the exact timing of allergic fungal sinusitis (AFS) development can be difficult to discern. Thick fungal debris and mucin, as shown below, are developed in the sinus cavities and must be surgically removed so that the inciting allergen is no longer present. Recurrence is not uncommon once the disease is removed. Anti-inflammatory medical therapy and immunotherapy are being employed to help prevent recurrence
Total immunoglobulin E
Total IgE values generally are elevated in allergic fungal sinusitis (AFS), often to more than 1000 U/mL (normal values are < 50 U/mL).
Total IgE level traditionally has been used to monitor the clinical activity of allergic bronchopulmonary fungal disease.
On the basis of similar IgE behavior associated with recurrence of allergic fungal sinusitis (AFS), total IgE levels have been proposed as a useful indicator of allergic fungal sinusitis (AFS) clinical activity.
Immunologic testing for allergens
RAST versus skin testing
Patients with allergic fungal sinusitis (AFS) generally demonstrate positive skin tests and in vitro (RAST) responses to fungal and nonfungal antigens. Manning et al, who compared 16 patients with histologically confirmed allergic fungal sinusitis (AFS) with a control group of patients with chronic rhinosinusitis, first demonstrated the sensitivity of RAST. Levels of fungal-specific IgE were uniformly elevated in all patients with allergic fungal sinusitis (AFS) and corresponded to the results of fungal cultures. In contrast, levels of fungal-specific IgE were not elevated within the control group. Moreover, patients with allergic fungal sinusitis (AFS) appear to demonstrate a broad sensitivity to a number of fungal and nonfungal antigens. Mabry et al have reported their experience, which indicates that patients with allergic fungal sinusitis (AFS) are allergic to multiple fungal antigens and to many typical nonfungal antigens.
Preliminary information suggests that methods of quantitative skin testing (in vivo) may provide even greater sensitivity ratings than RAST in patients with allergic fungal sinusitis (AFS). RAST traditionally has been considered less sensitive than skin testing during the investigation of atopy involving fungi. This has been attributed to technical problems, such as difficulty in binding the mold antigen to the carrier substrate.
To study the validity of this concept, Mabry et al prospectively evaluated 10 patients with allergic fungal sinusitis (AFS) for sensitivity to 11 pertinent fungi by both RAST and dilutional intradermal testing. A predictable correlation between RAST and skin test scores was observed in many, but not all, patients. Most often, this disparity was in the form of greater sensitivity indicated by skin testing than by RAST, sometimes differing by as many as 3 classes.
The lack of concordance was not confined to testing for fungi cultured from the sinuses, nor was it more or less pronounced in the case of dematiaceous fungi. The most likely causes for the disparity were thought to involve subtle differences in antigens used in skin test material as compared to RAST standards. Additionally, skin testing allowed observation of delayed and late-phase reactions, a measure not possible by specific IgE testing with RAST. This study appears to emphasize the importance of both skin testing and specific IgE testing via RAST in initial evaluation of patients in whom allergic fungal sinusitis (AFS) is suspected.
Nonspecific allergy testing
Gell and Coombs type I hypersensitivity in patients with allergic fungal sinusitis (AFS) can be demonstrated by elevation of serum total and fungal-specific IgE and by positive skin test results for fungal and nonfungal antigens. However, this reaction does not appear to be fungal specific.
Sensitivity to numerous fungi has been indicated both by in vitro (RAST) and in vivo methods (skin testing), although generally, only a single fungus is isolated by culture of corresponding allergic fungal mucin. This previously has been thought to represent either a common fungal epitope or a genetic predisposition toward fungal allergy in allergic fungal sinusitis (AFS).
Recent work by Chrzanowski et al identified the presence of an 18-kd protein in allergic mucin obtained from patients with allergic fungal sinusitis (AFS), which may represent such a pan-antigen.
On the basis of a postulated schema of the pathophysiology of allergic fungal sinusitis (AFS), a variety of treatment plans addressing its multiple contributing factors has emerged. Medical control of the disease has made use of various combinations of antifungal medications, corticosteroids, and immunotherapy, with varying degrees of disease control. Attempts to control this disease by only partially addressing the underlying causes likely have contributed to a high rate of recidivism. Successful treatment of allergic fungal sinusitis (AFS) requires that the treatment plan account for each factor responsible for the propagation of the disease.
The allergic fungal sinusitis (AFS) cycle suggests that atopy, continuous antigenic exposure, and inflammation all have key roles in the perpetuation of the disease. In theory, individually accounting for each of these factors provides for the best chance of long-term disease control. This comprehensive approach to management depends on complete removal of all fungal mucin (usually requiring surgery) and long-term prevention of recurrence through either immunomodulation (immunotherapy and/or corticosteroids) or fungistatic antimicrobials.
The origin of corticosteroid therapy for long-term management of allergic fungal sinusitis (AFS) arose directly from the success of this strategy in the treatment of ABPA. The potent anti-inflammatory and immunomodulatory effects of corticosteroids appear to be well suited to control recurrence of disease. This concept was emphasized by Bent and Kuhn, who noted eventual universal recurrence of allergic fungal sinusitis (AFS) in their patients who were not treated with systemic corticosteroids.
Schubert and Goetz further studied the role of systemic corticosteroids in postoperative management of allergic fungal sinusitis (AFS), demonstrating a significant increase in the time to revision sinus surgery in patients with allergic fungal sinusitis (AFS) who received prolonged courses of postoperative corticosteroids.[16, 17] Postoperative corticosteroid therapy in this study ranged from 2-12 months, with improved outcomes recorded among patients who were placed on longer courses of therapy. However, at present, the optimal dosing regimen and length of therapy remain unclear.
Topical corticosteroids are accepted as standard therapy in the postoperative treatment of allergic fungal sinusitis (AFS), but they possess a limited benefit before surgery because nasal access is restricted. However, after surgery, they may be effective in controlling local inflammation.
Complications of corticosteroids
The well-recognized benefits of systemic corticosteroids are counterbalanced by numerous potential adverse effects, including growth retardation, diabetes mellitus, hypertension, psychotropic effects, gastrointestinal side effects, cataracts, glaucoma, osteoporosis, and aseptic necrosis of the femoral head. Schubert and Goetz noted no adverse effects in their series of 67 patients with allergic fungal sinusitis (AFS) who were treated for up to 1 year with systemic corticosteroids, but long-term follow-up study for this form of therapy is lacking. The adverse effect profile of systemic corticosteroids warrants careful consideration when they are used in a long-term fashion to control allergic fungal sinusitis (AFS).
Topical corticosteroids generally present fewer adverse effects than systemic corticosteroids, based on their limited bioavailability. Long-term use, especially when topical corticosteroids are used at high dosages or in combination with inhaled corticosteroids, presents a risk of hypothalamic-pituitary-adrenal axis suppression, cataract formation, growth retardation, nasal bleeding, and nasal septal perforation in rare cases. As with individuals on any form of long-term therapy, patients using topical corticosteroid sprays should be monitored.
The similarity between allergic fungal sinusitis (AFS) and ABPA led to an empiric and theoretical concern that immunotherapy using specific fungal antigens in patients with either of these diseases might incite further allergic reactions by adding to the patient fungal antigenic stimulus. This concern specifically addressed the possible exacerbation of immune complex development and deposition. However, in allergic fungal sinusitis (AFS), surgery is able to remove the inciting fungal load from the paranasal sinuses. Therefore, it recently was postulated that immunotherapy may be beneficial, rather than harmful, as a component of treatment for allergic fungal sinusitis (AFS).
To investigate the safety of fungal immunotherapy as an adjunct to allergic fungal sinusitis (AFS) treatment, a prospective study was performed to examine the response of patients with allergic fungal sinusitis (following adequate surgery) to immunotherapy with all fungal and nonfungal antigens to which the patients were sensitive. In the first year of this study, clinical status was not shown to worsen, patients did not require systemic corticosteroids, most patients were able to discontinue topical corticosteroid therapy, and allergic fungal sinusitis (AFS) recurrence was markedly diminished among patients compliant with the regimen. The follow-up study revealed similar findings at 2 and 3 years.
A complementary study retrospectively compared 11 patients treated in this manner with 11 age- and diseased-matched control subjects who received the same surgical and medical treatment but no immunotherapy. A statistically significant difference was noted between the 2 groups. The cohort receiving immunotherapy as part of their treatment performed better in quality-of-life scores and objective endoscopic measures of mucosal edema.
In a series of 8 patients in whom immunotherapy was given for 3-5 years and then discontinued, no recurrences were seen up to 17 months after discontinuation. Additional study is necessary, but initial work suggests that a role may exist for immunotherapy in the overall treatment strategy for allergic fungal sinusitis (AFS).
Technique of immunotherapy in allergic fungal sinusitis
In initial studies, only immunotherapy for positive fungal antigens was administered for the first 6 months to be certain that any effects (either positive or negative) on the disease process were caused by the administration of fungal antigens. Later, both fungal and nonfungal antigens to which the patient was found to be allergic were included in the treatment mix. However, administering these in 2 separate vials for the first several months of treatment remains advisable to more easily assess the source of any untoward local reaction and to more efficiently advance treatment dosage. After maintenance levels are achieved, the fungal and nonfungal antigens may be combined into one vial.
A common misconception is that only immunotherapy for those fungi identified by culture from allergic fungal mucin should be included in the testing/treatment regimen for a patient. Because of variability in mycology laboratories and circumstances, a positive culture is not obtained for all patients. Conversely, the presence of fungi on culture of sinus contents does not confirm the diagnosis of allergic fungal sinusitis (AFS). One successful approach has been to test for a wide variety of molds (the choice being dictated by experience gained in testing and treating allergy patients in the region) and to include all positive reactors in the treatment set.
Advancement and adjustment of dosage are performed in the usual fashion. Although late local reactions (induration of >30 mm in diameter occurring 24-48 h after an injection) are said to be more common when administering immunotherapy for molds than for other antigens, this has not been the reported experience in treating patients with allergic fungal sinusitis (AFS). Systemic reactions to immunotherapy likewise have not been observed in the UT Southwestern experience.
On the basis of experience, administration of immunotherapy to patients with allergic fungal sinusitis (AFS) is currently recommended for the same duration as that recommended for patients with allergies in general, ie, 3-5 years. Mabry and Marple's protocol at UT Southwestern is listed in Table 4 below. The antigens for which they test and treat are listed in Table 5 below.
Table 4. Protocol for Immunotherapy in Allergic Fungal Sinusitis (Open Table in a new window)
1. After successful surgical exenteration of sinuses and confirmation of diagnosis, perform allergy evaluation and testing (RAST or quantitative skin test) for typical panel of nonfungal antigens appropriate for the area. Test (RAST or quantitative skin test) for all relevant molds (fungi) available. Discuss treatment protocol with the patient and obtain informed consent.
2. Instruct the patient in avoidance measures for molds. Adjust pharmacotherapy as necessary.
3. Prepare a vial of all positive nonfungal antigens and a second vial of all positive fungal antigens. Perform a vial test with each.
4. Administer immunotherapy weekly, with dosage advancement as tolerated, placing 1 injection from each vial in a different arm. This allows for accurate recognition of the cause of any local reactions noted.
5. Observe the patient regularly and adjust dosage as necessary if local reactions or adverse changes in nasal signs/symptoms occur. Regularly examine the patient with endoscopy to detect reaccumulation of allergic mucin or reformation of polyps and to ensure that cleaning, medical management, etc, are carried out.
6. As dosage advancement permits (generally by second vial), antigens may be combined into 1 vial; continue for a 3- to 5-year regimen according to standard practice.
Reproduced from Mabry RL, 1998.
Table 5. Fungal Antigens in Current Testing and Treatment Protocol at the University of Texas Southwestern Medical Center at Dallas (Open Table in a new window)
Fungal Antigens in Approximate Relative Order of Local (Dallas, TX) Importance
Reproduced from Mabry RL, 1998.
Complications of immunotherapy
Currently, no treatment-related complications have been identified when immunotherapy follows appropriate surgical extirpation of all allergic mucin. However, this finding should not promote a sense of false security concerning this form of therapy because immunotherapy continues to represent a new and incompletely understood treatment modality. In general terms, immunotherapy may lead to worsening of local or systemic disease, specifically if the patient continues to be exposed to a significant antigenic load.
Ferguson reported 7 patients who received immunotherapy for the treatment of allergic fungal sinusitis (AFS). The 5 patients who received immunotherapy before surgical removal of all allergic mucin either symptomatically worsened or failed to improve in response to therapy. In contrast to these findings, the 2 patients who underwent surgery before initiation of immunotherapy responded well to this treatment modality. This small study supports the concept that immunotherapy administered in the presence of an ongoing antigenic load (in this case, fungus) raises the risk of untoward complications of therapy (eg, immune complex deposition, delayed or late-phase reactions, local reactions).
Another permutation of this concern occurs when allergic fungal sinusitis (AFS) presents concomitantly with ABPA. Unlike in allergic fungal sinusitis (AFS), the fungi within the lower respiratory tract of patients with ABPA cannot be surgically removed, thereby resulting in a retained antigenic load. Moreover, while clinical manifestations of allergic fungal sinusitis (AFS) sometimes are dramatic, they rarely are life threatening. The threat of ABPA potentially is much greater. Given the lack of information regarding the effects of immunotherapy on ABPA, great care should be taken when immunotherapy is given in this situation.
Systemic antifungal therapy for allergic fungal sinusitis (AFS) initially was proposed to control the theoretical potential for progression to invasive forms of fungal sinusitis. As the unacceptably high rate of recidivism following surgery alone was recognized, antifungal therapy often was used in an attempt to provide some degree of control over recurrence of allergic fungal sinusitis (AFS). Early use of amphotericin B yielded to the use of less toxic agents, such as ketoconazole, itraconazole, and fluconazole, but the poor in vivo activity of these agents against dematiaceous fungi soon was discovered.
Objective data on the effects of this form of therapy for allergic fungal sinusitis (AFS) have been limited. Denning et al studied the effect of systemic itraconazole in patients with ABPA and demonstrated a decrease in total IgE (used as a marker of disease severity) and in systemic corticosteroid requirements. Anecdotal reports of systemic itraconazole to prevent allergic fungal sinusitis (AFS) recurrence offer mixed results. Ferguson points out that the expense, limited available data, and potential drug-related morbidity of systemic antifungal therapy may limit the usefulness of this form of treatment for noninvasive fungal disease.
Topical application of antifungal agents may hold some benefit in the control of postoperative recurrence, and studies of this form of treatment currently are underway. Bent and Kuhn studied the in vitro susceptibility of fungi commonly encountered in patients with allergic fungal sinusitis (AFS) and determined that minimal inhibitory concentrations can be exceeded with certain antifungal agents when applied topically. Similarly, Ponikau et al support the use of topical antifungal agents. Supportive data are pending.
Complications of antifungal therapy
Antifungal medications are recognized for some potentially serious adverse effects, which warrant consideration when these medications are used as a form of treatment for AFS. The well-known complications associated with amphotericin B include acute renal failure, anemia, agranulocytosis, acute liver failure, cardiopulmonary hypertension, and hemorrhagic gastroenteritis. Itraconazole and fluconazole offer a slightly safer form of antifungal therapy but still may give rise to drug-induced cardiac dysrhythmias, hepatic dysfunction, urticaria, and anaphylaxis.