You are in: eMedicine Specialties > Otolaryngology and Facial Plastic Surgery > ALLERGY Allergic Fungal SinusitisArticle Last Updated: Mar 30, 2006AUTHOR AND EDITOR INFORMATIONSection 1 of 12
  Author: John E McClay, MD, Assistant Professor, Department of Otolaryngology, Division of Pediatric Otolaryngology, Children's Medical Center, University of Texas Southwestern Medical School John E McClay is a member of the following medical societies: American Academy of Otolaryngic Allergy, American Academy of Otolaryngology-Head and Neck Surgery, American College of Surgeons, and American Medical Association Coauthor(s): Bradley Marple, MD, Vice Chairman, Department of Otolaryngology, University of Texas Southwestern Medical Center Editors: Lanny Garth Close, MD, Chair, Professor, Department of Otolaryngology-Head and Neck Surgery, Columbia University College of Physicians and Surgeons; Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine; Stephen G Batuello, MD, Consulting Staff, Colorado ENT Specialists; Christopher L Slack, MD, Otolaryngology-Facial Plastic Surgery, Private Practice, Associated Coastal ENT; Medical Director, Treasure Coast Sleep Disorders; Arlen D Meyers, MD, MBA, Professor, Department of Otolaryngology-Head and Neck Surgery, University of Colorado School of Medicine Author and Editor Disclosure Synonyms and related keywords: allergic fungal sinusitis, allergic Aspergillus sinusitis, allergic aspergillosis of paranasal sinuses, Aspergillus species, AFS, allergic mucin, allergic bronchopulmonary aspergillosis, ABPA, allergic fungal sinusitis, chronic rhinosinusitis, allergic rhinitis, chronic sinusitis, purulent rhinorrhea INTRODUCTIONSection 2 of 12
  Over the past 2 decades, allergic fungal sinusitis (AFS) has become increasingly defined. Historically mistaken for a paranasal sinus tumor, 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 AFS have a history of allergic rhinitis, and the exact timing of AFS development can be difficult to discern. Thick fungal debris and mucin 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. History of the ProcedureSeveral decades ago, fungal disease in the nose and paranasal sinuses represented an invasive deadly disease. Management consisted of extensive surgical debridement followed by therapy with systemic and topical antifungal agents. Early on, Aspergillus, a fungus known to cause invasive disease in the sinuses, was the only fungus recovered from the paranasal sinuses in patients with AFS because of the limitation of culture techniques and the lack of knowledge that dematiaceous fungi caused disease in the paranasal sinuses. Therefore, the disease was treated aggressively. In 1976, Safirstein noted that the combination of polyposis, crust formation, and sinus cultures yielding Aspergillus was similar to the constellation of findings observed in allergic bronchopulmonary aspergillosis (ABPA), a benign allergic process. Safirstein's description was duplicated and expanded on by reports of allergic aspergillosis of the paranasal sinuses and allergic Aspergillus sinusitis. In the late 1980s, the disease was more widely accepted as a benign fungal process and often confused with a paranasal sinus tumor on imaging studies because AFS creates expansion of affected sinus cavities. In 1989, Robson et al introduced the term allergic fungal sinusitis following reports that this condition could be caused by a number of different fungi, not only Aspergillus. Although the disease is becoming more recognized, confusion remains regarding diagnosis and treatment. ProblemNo consensus exists among rhinologists concerning diagnostic criteria for AFS. Several authors have made observations.
A positive fungal culture does not confirm the diagnosis of AFS, nor does a negative culture exclude it. For example, fungi may proliferate as saprophytic growth in diseased sinuses. Furthermore, mycology laboratories vary in capability, and specimen handling significantly influences the rate of positive fungal cultures in a clinical setting. Allergic mucin remains the most reliable indicator of AFS. Because nasal polyposis and fungal disease in the sinuses are not unique to AFS, other mycotic diseases in the differential diagnosis must be defined and include the following:
FrequencyIt is estimated that approximately 5-10% of patients affected by chronic rhinosinusitis actually carry a diagnosis of AFS. Atopy is characteristic of the disease; approximately two thirds of patients report a history of allergic rhinitis, and 90% of patients demonstrate elevated specific IgE to one or more fungal antigens. Approximately 50% of patients in a series by Manning et al had asthma. No linkage to aspirin sensitivity has been established. Incidence of AFS appears to be impacted by geographic factors. Review of world literature reveals that most sites reporting cases of AFS are located in temperate regions of relatively high humidity. However, incidence of AFS varied remarkably based on the location of reporting sites. AFS in the United States was encountered most commonly within the Mississippi basin, the Southeast, and the Southwest. The reason for this geographic difference remains unexplained. AFS is most common among adolescents and young adults; the mean age at diagnosis is 21.9 years. The male-to-female (M/F) ratio of AFS differs slightly between published reports but is believed to be equal when all ages are evaluated together. A literature review of 98 cases in the 1980s and early 1990s from 29 published journal articles reported an equal M/F incidence. A review by the author and colleagues of 151 patients at the University of Texas (UT) at Southwestern also revealed an equal M/F ratio, with ages ranging from 5-75 years. However, the M/F ratio may be age dependent and different in children and adults. In the review of patients at UT Southwestern, in children, males dominated (M/F ratio 2.1:1; average age, 13 y), and in adults, females dominated (M/F ratio 1:1.4; average age, 36 y). When evaluating the average ages and sex ratios of other studies, series with younger average ages are more likely to have a male predominance. The average ages in the male-dominated series were 25 and 27 years, while the average age in the female-dominated series was 33 years. The only other pediatric series consisted of 10 patients and had an M/F ratio of 1.5:1, with a mean age of 13.6 years. Interestingly, when 2 series of patients from a single institution were reviewed over time, an early study had an M/F ratio of 1.5:1, with an age range of 13-51 years (average age, 27.5 y), and a later review had an M/F ratio of 1:1.4, with an age range of 13-69 years (no average age given). EtiologyMost rhinologists believe that AFS is an allergic reaction to fungi, in which fungal debris, allergic mucin, and nasal polyposes are formed in the nasal cavity and paranasal sinuses. The causative fungi in AFS usually are dematiaceous fungi, consisting of the genera Bipolaris, Curvularia, Exserohilum, Alternaria, Drechslera, Helminthosporium, and Fusarium, with a small component of AFS caused by Aspergillus. In a 1996 review of English literature performed by Manning, 263 cases of AFS were identified, of which 168 cases yielded positive fungal cultures. Of these 168 positive cultures, 87% were from the dematiaceous genera, while only 13% yielded Aspergillus. The largest reported single institutional experience to date is at the UT Southwestern Medical Center in Dallas, Texas. The fungi recovered from the paranasal sinuses in that evaluation by the author and colleagues revealed that Bipolaris, followed by Curvularia, is the most common pathogen present, seen with similar incidence in adults and children (see Table 1). Most large reviews agree, indicating that Bipolaris and Curvularia species are the most common fungi recovered. When geographic location is specifically reviewed, the further west and inland the series, the more likely that Bipolaris species dominated the fungi recovered. When the series was performed in the Southeast, Curvularia species were more likely to be recovered. Interestingly, in the UT Southwestern experience, Aspergillus was recovered in 13% of adults but in no children. A report from India found only Aspergillus species identified in all 11 patients with AFS in whom fungus was recovered. Table 1. Causative Fungus Identified at UT Southwestern Medical Center
Controversy has existed over whether the disease is infectious or allergic. Manning and Holman objectively addressed this controversy in 2 separate studies. In the first study, 8 patients with culture-positive Bipolaris AFS were prospectively compared with 10 control subjects who did not have AFS. Both groups were evaluated with (1) radioallergosorbent test (RAST) and enzyme-linked immunosorbent assay (ELISA) inhibition to Bipolaris-specific IgE and IgG antibodies and (2) skin testing with Bipolaris antigen. All 8 patients had positive skin test reactions to Bipolaris antigen and positive RAST and ELISA inhibition to Bipolaris-specific IgE and IgG. Eight of the 10 control subjects had negative results on both skin and serologic testing, implicating the importance of allergy to fungal antigens (both in vivo and in vitro) in the pathophysiology of AFS. In a complementary study, sinus mucosal specimens from 14 patients with AFS were compared with those from 10 control subjects who did not have AFS. Immunohistochemical analysis for eosinophilic mediators (major basic protein and eosinophilic-derived neurotoxin) and a neutrophil-derived mediator (neutrophil elastase) was performed to assess the underlying nature of inflammation. Eosinophilic-derived mediators were much more common (P< 0.00001) than neutrophil-derived mediators in the AFS group, whereas significant differences were not observed in the control group. The predominance of eosinophilic-derived mediators further supports the association between noninfectious (ie, allergic) inflammation and AFS. The concept of eosinophilic activation associated with AFS was further emphasized by Feger et al, who studied eosinophilic cationic protein levels in the serum and mucin of patients with AFS. No differences in serum eosinophilic cationic protein were detected between patients with AFS and control subjects, but eosinophilic cationic protein levels were significantly higher in the mucin of patients with AFS (P <0.01). Studies such as those by Manning et al and Feger et al offer strong immunologic and histologic data to support the argument that AFS represents an immunologically mediated disorder rather than a point on the spectrum of infectious fungal disease. PathophysiologyCurrently, the pathophysiology of AFS is postulated to be similar to that of allergic bronchopulmonary fungal disease (a term replacing bronchopulmonary aspergillosis). Manning and colleagues have suggested that several interrelated factors and events lead to the development and perpetuation of AFS. First, an atopic host is exposed to fungi, theoretically via normal nasal respiration, which provides the initial antigenic stimulus. An initial inflammatory response ensues as the result of both a Gell and Coombs type I (IgE-mediated) and type III (immune complex–mediated) reaction, causing subsequent tissue edema. The resulting obstruction of sinus ostia, which may be accentuated by anatomic factors such as septal deviation or turbinate hypertrophy, results in stasis within the sinuses. This creates an ideal environment for further proliferation of the fungus, thus increasing the antigenic exposure to which the host is allergic. At some point, the cycle becomes self-perpetuating, resulting in the eventual product of this process, allergic mucin, the material that fills the involved sinuses of patients with AFS. Accumulation of this debris obstructs the involved sinuses and propagates the process. The production of this allergic mucin and its eventual clinical, histologic, and radiographic characteristics are unique to AFS and serve as a hallmark of the disease. Grossly, allergic fungal mucin is thick, tenacious, and highly viscous. Its color may vary from light tan to brown or dark green (see Images 1-2). Its characteristic gross appearance has resulted in the use of such descriptive terms as peanut butter and axle grease when referring to allergic fungal mucin. ClinicalPatients with AFS normally present with signs and symptoms of nasal airway obstruction, allergic rhinitis, or chronic sinusitis that includes nasal congestion, purulent rhinorrhea, postnasal drainage, or headaches. Often, presentation of AFS is subtle. Patients typically complain of gradual nasal airway obstruction and production of semi-solid nasal crusts that, upon inquiry, match the gross description of allergic fungal mucin. Development of nasal airway obstruction may have been so gradual that the patient is unaware of its presence. Because of AFS's slow progression, if facial dysmorphia is present, its progression often is so slow that it is unrecognized by the patient and family members. Pain is uncommon among patients with AFS and suggests the concomitant presence of a bacterial rhinosinusitis. Patients with AFS are atopic, but generally their symptoms have been unresponsive to antihistamines, intranasal corticosteroids, and prior immunotherapy. Use of systemic corticosteroids may produce some relief of symptoms, but relapse is typical following completion of therapy. In contrast to patients who have invasive fungal sinusitis, patients with AFS always are immunocompetent. The range of physical findings on examination typically is broad, from nasal airway obstruction resulting from intranasal inflammation and polyposis (see Image 3) to gross facial disfigurement and orbital or ocular abnormalities. The author and colleagues reported that facial dysmorphism, consisting of proptosis (see Image 4), telecanthus (see Images 4-5), and malar flattening (see Image 4), more often was seen in children than in adults (42% vs 10%) in their series of 151 patients, including 107 adults aged 18 years or older and 44 children aged 17 years or younger (see Table 2). Usually, when proptosis was present in patients in this study, telecanthus and malar flattening could be identified (see Image 4), depending on the amount of proptosis. Because development of proptosis usually occurs over long periods, no diplopia or visual loss generally is seen. However, at times, extension of AFS into adjacent anatomic spaces can produce a dramatic clinical presentation, such as visual loss. Visual loss from AFS caused by compression of the ophthalmic nerve, described by Marple et al in 3 of 82 patients he encountered, was reversible with immediate surgical removal of fungal disease. Return occurred over weeks to months. Table 2. Facial Asymmetry Characteristics
*Not all initial clinical records mention the presence or absence of facial asymmetry or vision problems. INDICATIONSSection 3 of 12
All patients with AFS should undergo surgical debridement of their sinuses. The inciting fungal antigen must be removed for immunotherapy to be successful. Any recurrent disease also should be surgically removed. RELEVANT ANATOMYSection 4 of 12
Relevant anatomy is the same as in any endoscopic sinus surgery procedure. Often, anatomy is distorted because of expansion of the sinuses secondary to the disease process. The lateral nasal wall is pushed medially, obliterating the nasal cavity on the affected side (see Image 4), and the inferior and middle turbinates are pushed inferomedially (see Images 5-6). If the ethmoid sinuses are involved, the roof often is expanded superiorly into the anterior cranial fossa, and the lateral wall is expanded into the orbit (see Image 7). CONTRAINDICATIONSSection 5 of 12
No specific contraindications exist to surgical removal of fungal debris and polyps in patients with AFS. Normally, these patients are healthy immunocompetent individuals. WORKUPSection 6 of 12
Lab Studies
Imaging Studies
Histologic FindingsAllergic fungal mucin (see Images 1-2) normally is first encountered at surgery. Therefore, recognition of its presence is the initial step in establishing an accurate diagnosis of AFS. Realizing that mucin, rather than paranasal sinus mucosa, demonstrates the histologic appearance consistent with AFS is important. Examination of mucosa and polyps obtained from involved paranasal sinuses reveals findings consistent with the inflammation of a chronic inflammatory process and should be performed to exclude fungal invasion. Once mucin is collected, culture and pathologic examination are undertaken. Initially described by Millar and Lamb and Katzenstein et al, histologic examination of allergic mucin reveals a constellation of characteristic findings. Branching noninvasive fungal hyphae are identified within sheets of eosinophils and elongated eosinophilic bodies (Charcot-Leyden crystals), which represent the product of eosinophilic degradation. Use of various histologic staining techniques helps to identify the variety of components within allergic fungal mucin. Hematoxylin and eosin (H&E) staining accentuates the mucin and cellular components of allergic fungal mucin. Using this stain, background mucin often takes on a chondroid appearance, while eosinophils and Charcot-Leyden crystals are heavily stained and become easily detectable. Fungi fail to stain using this technique and therefore may be difficult to identify. The presence of fungi may be implicated on H&E stain by the resulting negative image against an otherwise stained background. However, fungal hyphae and elements are often rare, scattered, and fragmented within allergic mucin, rendering identification difficult unless specific histologic stains are used. Fungal elements are recognized for a unique ability to absorb silver. This property is the basis for various silver stains, such as the Grocott-Gomori methenamine silver (GMS) stain, which turns fungi black or dark brown. The use of a fungal stain complements the findings of initial H&E stain and is extremely important in the identification of fungi. TREATMENTSection 7 of 12
Medical therapyOn the basis of a postulated schema of the pathophysiology of 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 AFS requires that the treatment plan account for each factor responsible for the propagation of the disease. The 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. Corticosteroids The origin of corticosteroid therapy for long-term management of 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 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 AFS, demonstrating a significant increase in the time to revision sinus surgery in patients with AFS who received prolonged courses of postoperative corticosteroids. 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 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 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 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. Immunotherapy The similarity between 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 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 AFS. To investigate the safety of fungal immunotherapy as an adjunct to AFS treatment, a prospective study was performed to examine the response of patients with AFS (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 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 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 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 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 AFS currently is 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. The antigens for which they test and treat are listed in Table 5. Table 4. Protocol for Immunotherapy in Allergic Fungal Sinusitis
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
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 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 AFS presents concomitantly with ABPA. Unlike in 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 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. Antifungals Systemic antifungal therapy for 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 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 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 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 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. Surgical therapyThe invariable components of combination therapy still are surgical removal of the inciting fungal allergic mucin and marsupialization of the involved sinuses. For this reason, surgery has played an important role in the management of AFS since its earliest reports. An aggressive surgical posture initially was adopted because of a perceived risk of fungal invasion. This frequently was accomplished through the use of open antrostomies with radical removal of mucosa, intranasal sphenoethmoidectomies, and Lynch frontoethmoidectomies. Despite such aggressive therapy, recidivism remained high, and most patients required multiple surgical procedures. Clinical appearance of the disease often confused the underlying diagnosis, further influencing surgeons to adopt a more radical stance. Radiographic evidence of invasion (which really was extension) into adjacent spaces (eg, orbit, intracranial cavity) frequently was interpreted as evidence of malignancy or invasive fungal disease. It logically followed that surgical approaches appropriate for these serious conditions (eg, lateral rhinotomy, facial degloving approaches, craniofacial resection) would be performed. Increased acceptance of specific immunologic hypersensitivity as the cause of AFS has led to changes in its management. These changes have involved the medical and surgical arms of therapy. While systemic use of antifungal medications largely has been replaced by immunomodulation, radical surgery for AFS has given way to more conservative tissue-sparing approaches. Mabry et al refer to this surgery as conservative but complete, relying almost completely on endoscopic techniques. Preoperative detailsTo minimize recurrence of disease, treatment of AFS is directed at removal of the inciting antigenic material via complete surgical removal of allergic mucin and debris while also ameliorating the underlying inflammatory process through the use of limited systemic and topical steroid preparations. One accepted preoperative medical regimen is to initiate systemic corticosteroid therapy (prednisone dosed at 0.5-1 mg/kg/d) approximately 1 week before surgery to decrease intranasal inflammation and nasal polyp volume. Bleeding encountered at surgery following preoperative steroids also is reduced. Additionally, preoperative antibiotics are instituted because of the frequency of concomitant postobstructive bacterial sinusitis. Intraoperative detailsAt surgery, 3 surgical goals should be achieved: (1) complete extirpation of all allergic mucin and fungal debris, (2) permanent drainage and ventilation of the affected sinuses while preserving the integrity of the underlying mucosa, and (3) postoperative access to the previously diseased areas. First, surgery should result in complete extirpation of all allergic mucin and fungal debris, thus greatly reducing or eliminating the antigenic inciting factor within the atopic individual (see Image 10). At times, this may be challenging because the nasal polyposis inherent in AFS can range from subtle to extensive, causing distortion of local anatomy and loss of useful surgical landmarks. Bleeding often occurs in response to surgical manipulation of the polyps, increasing the potential for disorientation. The operating surgeon must recognize that these factors, in combination with the high likelihood of bony dehiscence, increase the risk of iatrogenic injury. Aside from these problems, polyps can provide an important intraoperative role by serving as a marker of disease. AFS causes a relatively consistent configuration of disease. The involved paranasal sinus, acting as a reservoir for allergic fungal mucin, is the epicenter of the disease process. Allergic fungal mucin completely occupies the sinus cavity and almost always is mixed with fungal elements (see Images 11-13), while the lining mucosa, demonstrating only mild-to-moderate inflammation, remains an intact barrier to the fungus. More significant inflammation located at the sinus ostia gives rise to polyps that extend into the infundibulum, middle meatus, sphenoethmoid recess, and nasal cavity. Recognition of this allows the surgeon to follow the polyps to the disease. The allergic mucin, not the polyps, should be sent to a pathologist to confirm the diagnosis of AFS (see Histologic Findings). The fungal elements and mucin can be sent for culture and pathologic stain to help make the diagnosis and identify the fungus responsible for the disease. Fungal stains are positive more often than fungal cultures, but both should be attempted. Resulting nasal polyposis also can facilitate surgical treatment of AFS in another fashion. The expansile behavior of AFS increases access to involved paranasal sinuses. As revealed radiographically, the combination of slowly growing nasal polyps and accumulating allergic fungal mucin expands the involved paranasal sinuses and the surgical route to the involved sinuses. Enlargement of the nasal cavity, middle meatus, and frontal recess provides the surgeon with access adequate to address the disease, even in the most difficult areas, such as the lateral area of the frontal sinus, which once was thought to require a traditional nonendoscopic approach (see Image 6, Image 14). After surgical access to the involved sinus is achieved, a dilated cavity filled with allergic fungal mucin is encountered. This material is thick, tenacious, and viscous and may vary in color from light tan to black. Because of its noninvasive behavior, it may be removed in a blunt fashion, leaving the involved sinus completely lined with intact mucosa. Preservation of mucosa provides protection of adjacent anatomic structures, even in the face of large areas of bony dehiscence. The next goal of surgery is to produce permanent drainage and ventilation of the affected sinuses while preserving the integrity of the underlying mucosa. This has been aided greatly by the recent advent of tissue-sparing instrumentation. Even in the setting of significant dissolution of the fovea ethmoidalis, lamina papyracea, clivus, and sphenoid planum, wide marsupialization of diseased areas can be achieved without causing trauma to the underlying mucosa. Careful preservation of mucosa ensures that underlying periosteum, dura, and/or periorbita remain free of penetrating injury. Sinonasal polyposis initially may preclude orientation, but removal in a controlled fashion using powered microdissection provides the operating surgeon with eventual access to areas of fungal presence. After adequate ventilation and drainage are achieved, the preserved underlying mucosa is able to revert to its normal state. Adequate ventilation and drainage also provide for the final goal of surgery, postoperative access to the previously diseased areas. Even under ideal conditions, small residua of fungus may remain in situ, inciting recurrence if not controlled postoperatively. Surgery should be performed with facilitation of postsurgical care in mind. This goal can be attained reliably in most patients while preserving the integrity of important intranasal structures, such as the middle and inferior turbinates. These surgical goals can be accomplished through a number of approaches and techniques, the choice of which ultimately is influenced by the experience and training of the surgeon. Endoscopic powered instrumentation has demonstrated its effectiveness; this technique allows for removal of soft tissue and thin bone while maintaining superb visibility. Exercise great care when using powered instrumentation because the well-recognized bone dissolution associated with AFS increases the potential risk of inadvertent orbital and/or intracranial penetration. In the event of extensive remodeling or bone erosion, image-guided systems (eg, Stealth, InstaTrak) may be of benefit. Postoperative detailsPostoperative care begins immediately following surgery with nasal saline irrigation with bulb irrigations or Water-Pic, with or without the Grossan adaptor. Sinus packing usually is not needed, but the need is evaluated on an individual basis. Weekly clinic visits for about a month initially are required to allow regular inspection of the operative site and debridement of crusts and retained fungal debris. Systemic corticosteroids, which were initiated before surgery, are continued during the postoperative period and slowly tapered during the process of healing. The length of corticosteroid treatment and the form of postoperative adjunctive medical management used to further control the disease are at the discretion of the managing physician. The authors typically treat the patients with 3-4 weeks of steroids postoperatively, starting with a similar dose of steroids received preoperatively for 10-14 days. The steroids then are tapered over the next 10-14 days. Topical nasal steroids are started at the first postoperative visit, continued until immunotherapy is well established, and used thereafter as needed. Follow-upPostoperative follow-up care for the first month is noted above. No set interval is established for follow-up visits after the postoperative regimen. However, the author has started requesting patient follow-up visits at 3-month intervals to detect recurrences early because recurrence is not uncommon. Immunotherapy is always recommended for these patients, thus they are monitored closely by the physician, usually an allergist, who is instituting the injections. If symptoms of sinusitis or nasal airway obstruction return, rigid or flexible rhinoscopy in the clinic or CT should be performed to evaluate for recurrent disease. COMPLICATIONSSection 8 of 12
In most patients, surgery is performed without incident, but the pathologic behavior of AFS theoretically increases surgical risk. Nasal polyposis, expansile accumulations of allergic mucin, and poor intraoperative hemostasis may increase spatial disorientation. Additionally, areas of bony dehiscence may confuse or distort anatomic boundaries while offering little protection to the orbit and intracranial cavities. Conversely, a less than complete surgical procedure (in an attempt to decrease iatrogenic injury) is likely to lead to incomplete retrieval of allergic fungal mucin and rapid recurrence of AFS. On the basis of currently accepted pathophysiology of AFS, little risk of fungal invasion into adjacent tissues should exist in an immunocompetent host. However, rare exceptions may occur. Tsimikas et al report a single case of an Aspergillus frontal lobe abscess that occurred following surgical treatment of AFS that had expanded into the anterior cranial fossa. This case may represent seeding of the intracranial cavity as a result of inadvertent dural penetration, and it emphasizes the importance of mucosal preservation. In addition to fungal or bacterial seeding, penetration of the dura or periorbita iatrogenically during surgery may result in injury of structures within the orbit or intracranial cavities. Such transgressions can cause diplopia, blindness, hemorrhage, stroke, intracranial hemorrhage, encephalocele, and/or cerebrospinal fluid (CSF) rhinorrhea (see the eMedicine article Pediatric Sinusitis, Surgical Treatment). Erosion by AFS of the osseous boundaries separating the intracranial fossa from the sinonasal cavities may increase the risk of subsequent encephalocele formation. The otologic community commonly accepts that dural exposure in the absence of dural injury along the tegmen mastoideum rarely results in development of an encephalocele. Unfortunately, no analogous information within the rhinologic literature exists. However, it is logical to assume that eventual encephalocele formation may occur as a result of a combination of factors, including dural injury, location of bony dehiscence, and/or size of the bony dehiscence. In rare cases, accumulations of allergic fungal mucin actually may appear to support intracranial structures. Monitoring for development of encephaloceles is important, because their occurrence may require subsequent repair of bony dehiscence. OUTCOME AND PROGNOSISSection 9 of 12
The potential for AFS recidivism is well respected and ranges from 10% to nearly 100%. Recurrence can be in the form of mucosal edema (see Image 15), polyps (see Image 16), scarring, allergic mucin, or fungal debris. However, published rates of AFS recurrence can be misleading and are highly dependent on length of follow-up study. To emphasize the importance of long-term surveillance, Bent and Kuhn pointed out that, in their experience, the often-dramatic initial response to surgical therapy eventually was replaced by recurrence of AFS in the absence of ongoing therapy. Similarly, Kupferburg et al monitored the appearance of sinonasal mucosa of 24 patients treated with combined medical and surgical therapy for AFS. Of the 24 patients, 19 eventually developed recurrence of disease after discontinuation of systemic corticosteroids, but the authors observed thatendoscopic evidence of disease generally preceded return of subjective symptoms. AFS recidivism appears to be influenced by long-term postoperative therapy. Schubert and Goetz reported the long-term clinical outcome of 67 patients following initial surgical therapy for AFS. Patients treated with at least 2 months of oral corticosteroids were compared to those who received no corticosteroids. At 1 year following initial surgery, patients treated with oral corticosteroids were significantly less likely to have experienced recurrent AFS (35%) than those who had not (55%). However, AFS recidivism remains high despite appropriate postoperative medical therapy. Fungal and nonfungal specific immunotherapy holds some potential as a form of postoperative treatment in patients with AFS, but clinical failures can arise during immunotherapy. In a review of 42 patients who had received immunotherapy following surgery, Marple et al reported 4 recurrences of disease, which were attributed to noncompliance with immunotherapy or inadequate operative extirpation of allergic fungal mucin. FUTURE AND CONTROVERSIESSection 10 of 12
Controversy still exists regarding the exact criteria for diagnosis and the exact regimen for treatment. Although not perfected, recent evidence supports the theory that AFS represents an immunologic, rather than infectious, disease process. An improved understanding of this underlying disease process has led to an evolution in the treatment of AFS. Medical therapy has begun to shift from an emphasis on systemic antifungal therapy to various forms of topical treatment and immunomodulation. Likewise, surgical treatment of AFS, still a crucial component of the overall treatment plan of the patient, has shifted from radical to a more conservative but complete, usually endoscopic, approach. Although important, surgery alone does not lead to a long-term disease-free state. A comprehensive management plan incorporating medical, surgical, and immunologic care remains the most likely means of providing long-term disease control for AFS. The exact combination continues to be debated strongly. MULTIMEDIASection 11 of 12
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