Allergic fungal rhinosinusitis: A review of clinical manifestations and current treatment strategies

Transcription

1 Medical Mycology September 2006, 44, S277 S284 Allergic fungal rhinosinusitis: A review of clinical manifestations and current treatment strategies BRADLEY F. MARPLE Department of Otolaryngology, Head and Neck Surgery, University of Texas Southwestern Medical Center, Dallas, Texas, USA Allergic fungal rhinosinusitis is a relatively newly characterized disease entity that commands a great deal of interest. Large amounts of information are being generated addressing the underlying etiology of the disease, its clinical presentation, and forms of treatment. Although controversy still exists, recent evidence supports the theory that AFRS 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 AFRS. Keywords Introduction: the role of fungus in chronic rhinosinusitis While the overall impact that fungus plays in the etiology and pathogenesis of chronic inflammatory rhinosinusitis may be argued, there is little disagreement that fungus does play some role in selected cases. The currently recognized forms of fungal diseases of the paranasal sinuses can be broadly classified as either invasive or non-invasive. Invasive forms of fungal rhinosinusitis, including indolent, fulminant, and granulomatous variants, are fortunately rare and confined to relatively well-defined groups of patients who are frequently immunocompromised. In such cases, failure to appropriately identify and treat the disease can potentially lead to death or disfigurement. In contrast to the danger posed by invasive forms of fungal disease, in some cases fungi appear to have the ability to incite varying degrees of chronic inflammatory sinonasal disease. The degree to which non-invasive fungi impact local inflammation may vary according to the disease. Fungal balls (previously referred to as mycetomas) are recognized as self-limited collections of matted fungal hyphae confined most commonly to the maxillary sinus, and while they may be locally destructive, Correspondence: Bradley F. Marple, Department of Otolaryngology, Head and Neck Surgery, University of Texas Southwestern, 5323 Harry Hines Blvd, Dallas, Texas , USA. Bradley.Marple@UTSouthwestern.edu Mycosis, fungus, rhinosinusitis, AFRS they represent the mildest trigger of regional inflammation. At the opposite end of the inflammatory spectrum, under certain circumstances small amounts of fungal exposure appear to have the ability to stimulate a relatively robust regional reaction. One such example is that of allergic rhinitis caused by exposure to fungal allergens. While the concept of allergy to fungus is not new, the potential for fungus to serve as a non-invasive stimulus of mucosal inflammation was realized with the recognition of allergic fungal rhinosinusitis (AFRS) over two decades ago [1]. AFRS was first recognized in the late 1970s by pulmonologists and pathologists who noted the distinct clinical and immunologic similarities that it shared with allergic bronchopulmonary aspergillosis (ABPA) [2 4]. As general awareness of AFRS has grown, an increasing amount of corroborative literature has followed describing its clinical appearance, immunologic characteristics, incidence, geographic distribution, and response (or lack thereof) to various forms of therapy. Despite the differing designs and conclusions of each of these studies, all share one important feature: patients who were selected for study were identified based upon the clinical manifestations of their disease. Pathogenesis: historical controversies The mere presence of fungus within the paranasal sinuses historically has raised questions concerning its potential for tissue invasion. Early attempts to treat AFRS were often dictated by the fear that fungi within 2006 ISHAM DOI: /

2 S278 Marple the paranasal sinuses represented a precursor to invasive fungal sinusitis [5]. It is not surprising, therefore, that extensive surgical debridement followed by the use of systemic antifungal agents was initially commonplace. Eventually this notion was challenged by the theory that AFRS represented an immunologic response to presentation of a fungal antigen within a susceptible host. Manning and Holman [6] helped to clarify this controversy in two separate studies. In the first, eight patients with culture-positive Bipolaris AFRS were prospectively compared with ten controls with chronic rhinosinusitis. All eight patients with AFRS had positive skin test reactions to Bipolaris antigen, as well as significant levels of Bipolaris specific IgE and IgG by in vitro testing. Eight of the ten controls demonstrated negative results to both skin and serologic testing, suggesting that the presence of allergy to fungus as being important in the pathogenesis of AFRS. In a complementary study [6], sinus mucosal specimens from 14 patients with AFRS were compared with those from 10 controls with chronic rhinosinusitis. Immunohistochemical analysis for eosinophilic mediators (major basic protein and eosinophilic derived neurotoxin) and a neutrophil-derived mediator (neutrophil elastase) was performed to compare the underlying inflammatory processes within each cohort. Inflammatory mediators derived from eosinophils predominated over neutrophil-derived mediators (P B ) in the AFRS group, whereas significant differences were not present within the control group. The relative predominance of eosinophil-derived inflammatory mediators as compared to neutrophilderived inflammatory mediators further support the Edema Obstruction Decreased ventilation Stasis Allergy Fungal sensitization Exposure Fungal proliferation Antigen exposure Inflammation Eosinophils (MBP, ECP) Inflammatory Trigger Gell & Coombs Type I/III Other association between non-infectious (i.e., immunologically mediated) inflammation and AFRS, and helps to differentiate this disease from other forms of chronic rhinosinusitis. The concept of eosinophilic activation associated with AFRS was further supported by Feger et al. [7], who studied eosinophilic cationic protein levels (ECP) in the serum and mucin of patients with AFRS. No differences in serum ECP were detected between patients with AFRS and controls, but ECP levels were significantly higher in mucin recovered from patients with AFRS as compared to controls (P B0.01). Studies such as those by Manning et al. [6] and Feger et al. [7] offered immunologic and histologic data to support the argument that AFRS represents an immunologically-mediated disorder rather than an early stage of invasive fungal disease. Further, these observations led to speculation regarding the pathophysiology of AFRS. A theory proposed by Manning and colleagues is based upon the assumption that AFRS exists as the nasal correlate of ABPA, and suggests that several inter-related factors and events lead to the development and perpetuation of the disease [8] (Fig. 1). Controversy: the role of fungus in chronic rhinosinusitis a matter of perspective? In 1999 a unifying hypothesis of CRS was proposed by Ponikau et al. [9]. This hypothesis suggested that colonizing fungi in sinus mucus might play a much broader role in the pathogenesis of chronic rhinosinusitis. Using a specially designed culture technique, 93% of 101 consecutive patients with CRS demonstrated the Fig. 1 AFRS: a combination of predisposing factors occurring simultaneously is most likely necessary to initiate the cyclic inflammatory cascade responsible for the clinical expression of the disease.

3 Allergic fungal rhinosinusitis: a review S279 presence of fungi obtained from nasal lavage. Examination of surgically-obtained specimens from these patients also revealed eosinophils and fungal hyphae in the sinus mucus of nearly all study patients. In contrast to prior AFRS studies, conventional IgE-mediated allergy to fungi was not consistently observed. It was therefore proposed that virtually all cases of chronic rhinosinusitis were associated with sensitization to colonizing fungi. It was further suggested that the term allergic fungal rhinosinusitis be replaced with eosinophilic fungal rhinosinusitis [9]. One potential problem with the common etiology that was proposed by the authors was the fact that fungi were also observed in 100% of normal control subjects. At initial glance the differences between the findings of the Mayo clinic and those supported by already published data appeared dramatic. The differences may, however, simply represent a definitional difference of perspective. In the case of the large volume of existing peer-reviewed data concerning AFRS, authors have identified patients based upon a recognized set of clinical criteria. When this is done, AFRS reliably emerges as a distinct clinical entity that differs from chronic rhinosinusitis in terms of its immunologic, clinical and histologic features. In contrast, it logically follows that reliance upon the combination of extremely sensitive fungal culture techniques and the common histologic presence of eosinophilic inflammation as diagnostic criteria will result in the convergence of the majority of chronic inflammatory sinonasal diseases into a single homogeneous group. These important observations by the Mayo group have engendered interest in the broader potential role of fungus as an inflammatory stimulus, and have further served to focus attention upon chronic rhinosinusitis as an inflammatory disease. Unfortunately, given the vast definitional differences and resultant patient selection, at the present time it appears that no valid comparisons can be made between AFRS and EFRS [10,11]. Associated fungi: the role of dematiaceous fungi in AFRS Early reports, which implied that Aspergillus sp. was the primary causative fungus associated with AFRS, were based largely upon the morphologic appearance of the fungal hyphae identified histologically, as well as the recognized clinical and immunologic similarities shared between AFRS and allergic bronchopulmonary aspergillosis (ABPA). This notion was further supported by early serologic testing, published by Katzenstein, demonstrating elevated specific IgE to Aspergillus flavus in two patients afflicted with AFRS [4]. As the availability of culture-specific AFRS information increased, however, it became apparent that many fungal species could be associated with development of the disease [12]. In a 1996 review of the English literature performed by Manning, 263 cases of AFRS were identified, of which 168 cases yielded positive fungal cultures. Of those 168 positive cultures, 87% were dematiaceous genera while only 13% yielded Aspergillus [6]. Although not typically associated with invasive forms of fungal disease, dematiaceous fungi are recognized for the role they play in inhalant allergy. Specific genera within the dematiaceous family include Bipolaris, Curvularia, Exserohilum, Alternaria, Drechslera, Helminthosporium, andfusarium. Epidemiology of AFRS Allergic fungal rhinosinusitis is recognized as a disease distinct from other fungal forms of sinusitis [11]. Most common among adolescents and young adults (mean age at diagnosis 21.9 years) [6], it is invariably associated with nasal polyposis and the presence of allergic fungal mucin. It is estimated that approximately 510% of those patients suffering from chronic rhinosinusitis actually carries a diagnosis of AFRS [13 15]. Atopy is characteristic of the disease: roughly 70% of patients report a history of allergic rhinitis, and 90% show elevated specific IgE to one or more fungal antigens. Approximately 50% of the patients in a series by Manning et al. suffered asthma. No linkage to aspirin sensitivity has been established [6]. The incidence of AFRS appears to vary by geographical region. Review of the world s literature reveals that the majority of sites reporting cases of AFRS are located in more temperate regions where relative humidity is high [5,15]. Ferguson et al. [16] performed a questionnaire-based study within the United States in order to assess variations in the regional incidence of AFRS. Results of this study indicated that the incidence of AFRS varied remarkably according to the location of reporting sites, and was most commonly encountered within the Mississippi basin, the southeast, and the southwest. The reason for this geographic difference remains unexplained. Clinical presentation of AFRS History and physical Occasionally, the presentation of AFRS may be dramatic, giving rise to acute visual loss, gross facial dysmorphia, or complete nasal obstruction [8,17,18],

4 S280 Marple but more often the presentation of AFRS is subtle. Patients typically complain of gradual nasal airway obstruction and production of semisolid nasal crusts that match the gross description of allergic fungal mucin. Nasal airway obstruction may have developed so gradually that the patient is unaware of its presence. Pain is uncommon among patients with AFRS and when present suggests the concomitant presence of a bacterial rhinosinusitis [8,19]. In contrast to the often subtle symptoms of AFRS, physical findings are often more remarkable. The range of physical findings on examination is typically broad, ranging from nasal airway obstruction resulting from intranasal inflammation and polyposis to gross facial disfigurement and orbital or ocular abnormalities [17,24]. Radiologic findings The gradual accumulation of allergic fungal mucin produces the unique and rather predictable characteristics of the disease. Allergic fungal mucin sequestered within involved paranasal sinus cavities slowly increases in quantity and eventually leads to the recognizable radiographic findings characteristic of AFRS (Table 1). In a 1998 report of CT findings from 45 patients with AFRS, Mukherji et al. provided objective support for several previous clinical observations [20]. AFRS, although bilateral in 51% of the cases reviewed, caused asymmetric involvement of the paranasal sinuses in 78% of the cases. Bone erosion and extension of disease into adjacent anatomic areas was encountered in 20% of the patients and was more likely to occur in the presence of bilateral, advanced disease. Expansion, remodeling, or thinning of involved sinus walls was common (and was thought to be due to the expansile nature of the accumulating mucin). These findings were corroborated by Nussenbaum et al., who reviewed CT scans of 142 patients treated for AFRS at a single institution and also found demineralization of bone in approximately 20% of the subjects [21]. Areas of heterogeneous signal intensity within paranasal sinuses filled with allergic fungal mucin are frequently identified on computerized tomographic Table 1 CT findings associated with AFRS Complete opacification of at least one paranasal sinus Expansion of involved sinuses Attenuation/erosion of the bone bordering involved sinus Heterogeneity of signal within involved sinus Unilateral or asymmetric distribution of disease Displacement of adjacent anatomic compartments Fig. 2 Coronal CT scan demonstrating areas of signal heterogeneity within ethmoid sinuses filled with allergic fungal mucin. Note lateral displacement of the lamina papyracea. scans (Fig. 2). Although these findings are not specific for AFRS, they are relatively characteristic of the disease, and may provide preoperative information suggestive of a diagnosis of AFRS [22]. Current evidence supports accumulations of heavy metals (e.g., iron and manganese) and calcium salt precipitation within inspissated allergic fungal mucin as the most likely cause of these radiographic findings [22,23]. Desiccation of sinus contents may also contribute to the hyperdense areas seen on CT scans. Magnetic resonance imaging can also provide information useful in preoperative identification of allergic fungal mucin. This effect is more pronounced on T2-weighted images as a result of prolonged magnetic field relaxation times. The high protein and low water concentration of allergic fungal mucin, coupled with the high water content within surrounding edematous paranasal sinus mucosa, gives rise to rather specific MR characteristics. The combined CT and MRI findings provides a radiographic appearance that is highly suggestive of AFRS [23]. Immunologic testing The total IgE level has served as a useful tool commonly used to follow the clinical activity of allergic

5 Allergic fungal rhinosinusitis: a review S281 bronchopulmonary aspergillosis. Based upon similar IgE behavior associated with recurrence of ABPA, total IgE levels have been proposed as a useful indicator of AFRS clinical activity. Total IgE values are generally elevated in AFRS, often to more than 1000 units per milliliter [7,25,26]. The wide range of values for total IgE across populations of patients, however, limits its use as a screening tool [27]. Several studies have also demonstrated a positive correlation between skin test and in vitro responses both to fungal and non-fungal antigens and patients with AFRS [28,30]. Moreover, patients with AFRS appear to demonstrate a broad sensitivity to a number of fungal and non-fungal antigens [28]. Based on these and other studies, it is generally agreed that patients with AFRS will have positive evidence of fungal allergy to the fungus colonizing their allergic mucin in the majority of cases. Sensitivity to numerous fungi has been indicated by both 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 has been previously thought to be the result of either a common fungal epitope or a genetic predisposition toward fungal allergy in AFRS. Chrzanowski et al. identified the presence of an 18-kD protein in allergic mucin obtained from patients with AFRS, which may represent a fungal pan-antigen [31]; however, no further corroborative studies to support this finding have emerged. Histology of allergic fungal mucin It is the production of allergic mucin as defined by its clinical, histologic, and radiographic characteristics that is unique to AFRS, and serves as a hallmark of the disease. Grossly, allergic fungal mucin is thick, tenacious, and highly viscous in consistency; its color may vary from light tan to brown or dark green [14,32]. This characteristic gross appearance has led to the use of such descriptive terms as peanut-butter and axlegrease. Given both the location of this mucin within the paranasal sinuses as well as its thick consistency, it is common that allergic fungal mucin is initially encountered at the time of surgery. As a result of this, the diagnosis of AFRS is frequently delayed until such time [1]. Initially described by Millar [33], Lamb [3] and Katzenstein [4], histologic examination of allergic mucin reveals a constellation of characteristic findings. Branching noninvasive fungal hyphae are identified within sheets of eosinophils and CharcotLeyden crystals. Complete appreciation of all components of the mucin, however, is dependent upon appropriate histologic staining techniques. Hematoxylin and eosin (H&E) staining accentuates the mucin and cellular components of allergic fungal mucin. Using this stain, background mucin will often take on a chondroid appearance, while eosinophils and CharcotLeyden crystals are heavily stained and become easily detected. Fungi fail to stain with H&E, however, and may be implicated only by their resulting negative image against an otherwise stained background. Given that fungal hyphae are frequently rare, scattered, and fragmented within allergic mucin, identification is extremely 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 Grocott s or Gomori s methamine silver (GMS) stain, which turn 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. Culture of fungi Fungal cultures of allergic fungal mucin may provide some supportive evidence helpful in the diagnosis and subsequent treatment of AFRS, but must be interpreted with caution. It is important to realize that the diagnosis of AFRS is not established, nor eliminated based upon the results of these cultures. The variable yield of fungal cultures (64 100% [6]) renders AFRS in the presence of a negative fungal culture quite possible. Conversely, a positive fungal culture fails to confirm the diagnosis of AFRS, as it may merely represent the presence of saprophytic fungal growth. It is for this reason that the histologic appearance of allergic mucin remains the most reliable indicator of AFRS [1]. Diagnostic criteria Given that nasal polyposis is not unique to AFRS, and that fungi may be present within the nose and paranasal sinuses in multiple diseases, AFRS must be differentiated from other diseases of the sinuses. Other recognized sinonasal processes that must be differentiated from AFRS include saprophytic fungal growth in an otherwise normal nose [34], fungal ball (formerly referred to as mycetoma) [35], eosinophilic mucin sinusitis [36,37], and invasive fungal sinusitis. A number of different attempts at establishment of diagnostic criteria have been proposed, most of which focus upon some combination of the radiologic, immunologic, clinical, and histologic manifestations of the disease. As an example, Allphin and colleagues [38] felt that the combination of opacified paranasal

6 S282 Marple sinuses on radiography, characteristic histologic findings of allergic mucin, and laboratory evidence of allergy was sufficient to differentiate AFRS from other forms of rhinosinusitis. Lowery and Schaefer [39] proposed a more specific set of diagnostic criteria, which included eosinophilia, immediate skin reactivity or serum IgE antibodies to fungal antigen, elevated total IgE level, nasal mucosal edema or polyposis, histopathologic findings of allergic mucin containing non-invasive fungal hyphae, and characteristic CT or MRI findings. Bent and Kuhn [13] demonstrated five common characteristics: Gell and Coombs type I (IgE mediated), hypersensitivity, nasal polyposis, characteristic radiographic findings, eosinophilic mucin without fungal invasion into sinus tissue, and positive fungal stain of sinus contents removed at the time of surgery. In 2004, a panel of international experts was convened for the purposes of establishing working diagnoses for a variety of categories of chronic rhinosinusitis. Among the diagnoses that were approved was one for AFRS. The panel discussed and acknowledged the impact of the clinical characteristics of AFRS upon the presence of an IgE-mediated sensitivity to fungus. As such, the diagnostic criteria approved by this panel reflected those that had been previously proposed, and was based upon a combination of histologic, immunologic, clinical, and radiologic factors [11] (Table 2). Table 2 Symptoms Objective findings Radiographic findings Other diagnostic measures Diagnostic criteria for AFRS Requires]one of the following: Anterior and/or posterior nasal drainage Nasal obstruction Decreased sense of smell Facial pain-pressure-fullness Requires all of the following: Presence of allergic mucin (pathology showing fungal hyphae with degranulating eosinophils) Evidence of fungal specific IgE (skin test of in vitro test) No histologic evidence of invasive fungal disease Highly recommended: Sinus CT demonstrating Bone erosion Sinus expansion Extension of disease into adjacent anatomic areas Possible, but not required: Fungal culture Total serum IgE Imaging by more than one technique (CT or MRI) Treatment The treatment of AFRS continues to evolve. As the natural course of the disease has become better recognized, radical surgery that was the norm initially has been replaced by a combination of conservative surgery and adjunctive medical therapy. The cornerstone of this treatment, however, continues to be surgery. The goals of surgical intervention are to eradicate all allergic mucin, while simultaneously providing permanent drainage and ventilation for the affected sinuses. Despite the controversy over the actual initiating factor, it appears that AFRS is an inflammatory response to fungi that leads to the production of mucin. The accumulation of mucin appears to play a role in the cyclic recurrence of the disease by way of perpetuating antigenic exposure [8]. In theory, complete surgical removal of mucin breaks this cycle. Unfortunately, despite the most complete surgery AFRS recidivism remains unacceptably high when surgery is used as the sole form of therapy. Hence, many have come to support the use of adjunctive forms of medical therapy in attempts to better control this problem. With evidence supporting fungal hypersensitivity in the pathogenesis of AFRS, fungal immunotherapy appeared a strong potential for benefit. Initial studies addressing the safety of adjunctive immunotherapy for the treatment of AFRS revealed not only that this practice appeared safe, but surprisingly led to a remarkable decrease in disease recurrence. In one such study, patients treated with fungal immunotherapy for a period of three years following surgery showed a significant decrease in their rate of recurrence [29]. In addition, patients receiving immunotherapy statistically had less mucosal edema as noted on endoscopy and reported better quality of life [40]. Immunomodulation can also be achieved by means other than immunotherapy. The use of postoperative corticosteroids has demonstrated similar results in the management of AFRS recurrence rates. Patients treated with a prolonged course of systemic corticosteroids demonstrate a significant increase in time before revision sinus surgery [25]. Although no published studies have specifically evaluated the role of nasal steroids in the control of AFRS, they have been accepted as standard postoperative treatment. Given the potential drug-related morbidity, systemic antifungals have not enjoyed similar use for the management of AFRS recurrence as other medical treatment options [41]. However, similar to other medical therapies, systemic antifungals have demonstrated improved outcome [42].

7 Allergic fungal rhinosinusitis: a review S283 A recent look at the long-term outcome, 4 to 10 years, of 17 patients with AFRS reported a low rate of recidivism regardless of the postoperative management [27]. Aggressive medical management within the first three postoperative years resulted in control of AFRS recurrence, but after this period, a majority of patients enjoyed a period of disease quiescence. Conclusion Allergic fungal sinusitis is a relatively newly characterized disease entity that commands a great deal of interest. Large amounts of information are being generated addressing the underlying etiology of the disease, its clinical presentation, and forms of treatment. Although controversy still exists, recent evidence supports the theory that AFRS 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 AFRS. 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