Fungal Rhinosinusitis
Robert T. Adelson
Bradley F. Marple
Matthew W. Ryan
FUNGAL RHINOSINUSITIS
Introduction
Fungi are increasingly recognized as etiologic agents in a diversity of disease states in the nose and paranasal sinuses. Over the past 30 years our enhanced understanding of the role of fungi in sinus disease and the complex interactions between host and pathogen has led to a logical classification of fungal rhinosinusitis with improvements in treatment outcomes. At the same time, the development of endoscopic surgical techniques has improved our diagnosis and treatment of all forms of rhinosinusitis. One distinction between fungal rhinosinusitis and other forms of rhinosinusitis is that all forms of fungal rhinosinusitis require some level of endoscopic assessment or surgery.
Basic Mycology
Fungi are eukaryotic organisms ubiquitous in our environment. Scientists estimate the total number of these different fungal species to be between 20,000 and 1.5 million, of which only a fraction of a percent are responsible for human illnesses, perhaps with only a few dozen species responsible for over 90% of infections (1,2). Fungi can exist either as yeast or molds. Characteristically, molds produce hyphae, multicellular, branching tubular extensions (2 to 10 µm in diameter), which coalesce as a colony known as a mycelium. Yeast are unicellular, from 3 to 15 µm in diameter, and reproduce asexually via budding. Failure of buds to detach can result in a characteristic chain of fungal cells known as pseudohyphae. The spore represents an evolutionary solution to fungal survival problems posed by unfavorable conditions. These derivatives of sexual or asexual fungal reproduction disperse easily into the environment, can withstand adverse surroundings, and retain their germinative abilities until a more receptive milieu is encountered. Inhalation of spores is thought to be the most common route by which fungal rhinosinusitis is initiated (3). Once the nasal mucosa has been accessed, development of a pathologic condition is determined not only by the inherent characteristics of the fungus, but by the host’s immune system and the complex host-pathogen interaction that ensues.
Classification of Fungal Rhinosinusitis
Fungal disease of the nose and paranasal sinuses can be classified based on the clinical, radiologic, and histologic manifestations of the host-pathogen relationship. Most classification schemes divide fungal rhinosinusitis into invasive and noninvasive diseases based on histopathologic evidence of fungus penetrating host tissue (4) (Table 37.1). Recent adjustments to the nomenclature regarding fungal rhinosinusitis reflect the evolving knowledge in this area of Rhinology (5). The full spectrum of invasive and noninvasive fungal rhinosinusitis is considered below.
Invasive Fungal Sinusitis
The unchecked incursion of omnipresent fungal pathogens are among the most impressive infections to which humans are susceptible. While an intact immune system provides sufficient defense against the development of invasive fungal disease, the proliferation of organ transplant procedures and the greater prevalence of diabetes mellitus have led to significant increases in the incidence of invasive fungal infections reported over the last 10 years (6). The growing population of patients with conditions that predispose them to invasive fungal disease, in combination with dramatic disease velocity and considerable morbidity and mortality, has made invasive fungal sinusitis (IFS) a topic of particular interest within the Otolaryngology literature. Previously, tissue-invasive fungal disease was commonly
referred to by a variety of terms including “zygomycosis,” “mucormycosis” and “invasive aspergillosis,” which encompassed almost all of the pathogens associated with human-invasive fungal disease. Revisions of the phylogenetic classification within the kingdom Fungi have eliminated the phylum Zygomycota and therefore the pathologic term Zygomycosis has been made obsolete (7). Mucor, Rhizopus, and many of the organisms responsible for invasive disease of the Order Mucorales are instead assigned to the subphylum Mucoromycotina until further study better delineates the relationship between these organisms (8). Finally, it has become clear that the various forms of fungal rhinosinusitis are primarily determined by host factors; thus the current classification scheme does not include the names of the organism.
referred to by a variety of terms including “zygomycosis,” “mucormycosis” and “invasive aspergillosis,” which encompassed almost all of the pathogens associated with human-invasive fungal disease. Revisions of the phylogenetic classification within the kingdom Fungi have eliminated the phylum Zygomycota and therefore the pathologic term Zygomycosis has been made obsolete (7). Mucor, Rhizopus, and many of the organisms responsible for invasive disease of the Order Mucorales are instead assigned to the subphylum Mucoromycotina until further study better delineates the relationship between these organisms (8). Finally, it has become clear that the various forms of fungal rhinosinusitis are primarily determined by host factors; thus the current classification scheme does not include the names of the organism.
TABLE 37.1 CLASSIFICATION OF FUNGAL RHINOSINUSITIS | ||||||||||||||
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TABLE 37.2 FEATURES OF INVASIVE FUNGAL RHINOSINUSITIS | |||||||||||||||||||||||||||
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General Description of IFS
IFS is defined by fungal elements invading host sinonasal tissue. A diagnosis of IFS hinges upon histopathologic evidence of fungi invading nasal tissue: hyphal forms within sinus mucosa, submucosa, blood vessel, or bone. Specific histopathologic features, immunocompetence of the host, and disease progression allow further classification of invasive fungal sinus disease into three forms: acute invasive fungal rhinosinusitis (AIFR), chronic invasive fungal rhinosinusitis (CIFR), and granulomatous invasive fungal rhinosinusitis (GIFR) (see Table 37.1). In brief summary, a time course of 4 weeks separates acute from chronic disease, AIFR and CIFR typically occur in patients with some degree of immunocompromise while GIFR is limited to the apparently immunocompetent (see Table 37.2). Accurate classification of these different disease entities is an important step in discussing each with regard to their clinical presentation, pathogenesis, diagnosis, and treatment.
ACUTE INVASIVE FUNGAL RHINOSINUSITIS
Clinical Presentation and Diagnosis
AIFR is almost always seen in patients with some degree of compromised immune function, especially defective neutrophil numbers or function, though it has been reported rarely in patients with normal immune function (9). Ailments associated with impaired neutrophil numbers or function, such as hematologic malignancies, aplastic anemia, hemochromatosis, insulin-dependent diabetes, AIDS, organ transplantation, or those undergoing iatrogenic immunosuppression with systemic steroids
or chemotherapeutic agents, are particularly prone to development of AIFR (4,10). A high index of suspicion for invasive disease should be maintained in the immunocompromised patient with symptoms of rhinosinusitis, as early findings are often subtle.
or chemotherapeutic agents, are particularly prone to development of AIFR (4,10). A high index of suspicion for invasive disease should be maintained in the immunocompromised patient with symptoms of rhinosinusitis, as early findings are often subtle.
The presenting signs and symptoms of AIFR are not distinctly different from those associated with acute bacterial rhinosinusitis. Patients may complain of rhinorrhea, headache, nasal congestion, or facial pain; however, a fever is the most frequent finding, present in 50% to 90% of patients in the days prior to establishing a diagnosis of AIFR (11). The progression of AIFR leads to extrasinus extension by direct erosion through bone, perineural spread, or perivascular extension through communicating vessels in the surrounding bone (Figs. 37.1 and 37.2). Resultant nasal and/or palate mucosa necrosis, densely anesthetic regions of the face, proptosis, cranial nerve deficits, ophthalmoplegia, decreased vision, and mental status changes are ominous indications of aggressive vascular and neural invasion (12).
Several authors have examined the signs and symptoms of AIFR to better determine which patients will benefit from more aggressive diagnostic investigation. Within the immunocompromised patient population, the presence of a fever in combination with one additional symptom of sinonasal inflammation should prompt both imaging studies and nasal endoscopy (11). DelGaudio reported the success of a multidisciplinary approach for the early diagnosis and intervention for AIFR in neutropenic patients (13). Such patients presenting with fever of unknown origin or symptoms consistent with rhinosinusitis underwent sinus computed tomography (CT) scan and nasal endoscopy with appropriate biopsies in an effort to identify AIFR at an early stage. This surveillance protocol significantly reduced the number of surgical procedures required as well as the long-term morbidity of AIFR (13). Endoscopic findings will change dramatically as the disease progresses. Alterations in the visualized nasal mucosa are subtle early in the course of AIFR; however, nasal mucosal changes are the most consistent physical findings and should always be investigated by thorough endoscopy and biopsy in highrisk patients (13,14).
 Figure 37.1 AIFR High Magnification (1200×) H&E stained section demonstrates necrotic material between trabeculae of bone removed from the ethmoid sinuses. Invasive septated fungal hyphae are seen penetrating the tissue. Image and Caption: Anthony T. Yachnis, MD; Department of Pathology, University of Florida College of Medicine, Gainesville, FL. |
 Figure 37.2 AIFR Low Magnification (600×) Gomori Methenamine Stain (GMS) section demonstrates an abundance of invasive fungal hyphae penetrating the bony sinus trabeculae. Image and Caption: Anthony T. Yachnis, MD; Department of Pathology, University of Florida College of Medicine, Gainesville, FL. |
If biopsy of obvious mucosal abnormalities fail to confirm the expected diagnosis, then directed biopsies should be obtained from sites commonly involved in AIFR, such as the middle turbinate (62%) and nasal septum (24%), as well as any other areas of mucosal edema (11). Pale mucosa that does not bleed normally or elicit painful reactions upon biopsy is indicative of tissue ischemia and incipient fungal angioinvasion. The risks of nasal biopsy are small and several authors emphasize the role of early nasal biopsy in the absence of specific mucosal abnormalities as one method of initiating treatment at the earliest stages of disease (14). The risk of hemorrhage from nasal biopsy can be diminished in patients with an underlying bleeding diathesis by replacing any deficient coagulation factors and correcting the thrombocytopenia to a platelet count of greater than 60 × 109/L. Cutting biopsy forceps will limit the resultant mucosal defect and allow the surgeon to accurately sample the leading edges of ischemic or necrotic mucosal lesions, as biopsies from areas of frank necrosis are less likely to provide a histopathologic diagnosis. Middle turbinate biopsy has been shown to have an overall sensitivity of 75% and a specificity of 100% in diagnosing AIFR on frozen section, and this lower-than-desired sensitivity may reflect the inherent difficulties with frozen section studies of fungal disease processes (15).
The utility of frozen section studies in surgery is twofold: to establish a diagnosis and to guide surgical decision making. Management of AIFR with frozen sections has been
studied by several authors, yet a clear consensus is lacking for the role of this type of histopathologic analysis in intraoperative management. Ghadiali et al. report the largest series to date for frozen section analysis in AIFR with an overall sensitivity of 84% for frozen section studies of biopsies to establish disease with no significant difference between the sensitivities of frozen section identification for Mucor when compared to that for Aspergillus (16). However, the use of histopathologic controls for surgical margins can be misleading and probably does not offer any additional assurance of disease eradication greater than the clinical appreciation of freely bleeding tissue margins (16). Tissue processing during preparation of the frozen section can be compromised by necrosis, hemorrhage, and distortion of the fungi such that even in cases where invasive fungi are identified, morphologic features that allow speciation cannot be appreciated (16,17). While fungal culture remains the gold standard for identifying the culprit fungi and guiding the choice of antifungal therapy, such cultures remain negative in 30% to 50% of cases (18,19), and prior or concomitant administration of antifungal agents also decrease yield on fungal culture. Newer methods such as in situ hybridization technology with oligonucleotide probes to identify fungus-specific ribosomal RNA sequences hold promise. This technique has advantages over traditional fungal culture of both greater speed and higher sensitivity in determining the involved fungal species, allowing more rapid institution of targeted antifungal therapy (20).
studied by several authors, yet a clear consensus is lacking for the role of this type of histopathologic analysis in intraoperative management. Ghadiali et al. report the largest series to date for frozen section analysis in AIFR with an overall sensitivity of 84% for frozen section studies of biopsies to establish disease with no significant difference between the sensitivities of frozen section identification for Mucor when compared to that for Aspergillus (16). However, the use of histopathologic controls for surgical margins can be misleading and probably does not offer any additional assurance of disease eradication greater than the clinical appreciation of freely bleeding tissue margins (16). Tissue processing during preparation of the frozen section can be compromised by necrosis, hemorrhage, and distortion of the fungi such that even in cases where invasive fungi are identified, morphologic features that allow speciation cannot be appreciated (16,17). While fungal culture remains the gold standard for identifying the culprit fungi and guiding the choice of antifungal therapy, such cultures remain negative in 30% to 50% of cases (18,19), and prior or concomitant administration of antifungal agents also decrease yield on fungal culture. Newer methods such as in situ hybridization technology with oligonucleotide probes to identify fungus-specific ribosomal RNA sequences hold promise. This technique has advantages over traditional fungal culture of both greater speed and higher sensitivity in determining the involved fungal species, allowing more rapid institution of targeted antifungal therapy (20).
Radiology
Diagnostic imaging of the paranasal sinuses is often performed in the workup of patients with presumed or proven AIFR. Although no radiographic imaging findings have been found to be pathognomonic for AIFR, such studies assist in the differential diagnosis, treatment planning, and monitoring of the condition. CT images will document the presence of radiographic changes consistent with sinus disease and define the sinonasal anatomy both for surgery and as a baseline exam for future comparison. Fine-cut, noncontrasted CT scans of the sinuses in axial and coronal planes can detect paranasal sinus bony erosion and screen for extrasinus soft tissue involvement. Magnetic resonance imaging (MRI) (with or without gadolinium) delineates the degree of orbital involvement and/or intracranial spread. These findings provide key information regarding the feasibility of surgery and ultimately patient prognosis.
Although bone erosion and extrasinus extension are often cited as classic radiographic findings of AIFR, these results are not typically found in the incipient case of AIFR but instead are ominous signs of advanced disease. The radiographic findings with the greatest positive predictive values are also those that are indicative of late and often irreversible disease: osseous erosion, facial soft tissue thickening, extrasinus involvement. Soft tissue infiltration with loss of the fat planes anterior and posterior to the maxillary sinus is considered an early indicator of AIFR (21). Another subtle finding, severe sinonasal edema without evidence of bone erosion, is emerging as a consistent and early radiographic finding amongst many cases of invasive disease (16,22). Severe unilateral thickening of nasal cavity mucosa is the most consistent CT characteristic suggestive of early IFS, albeit nonspecific for invasive fungal disease (23) (Fig. 37.3).
Physicians should not become overly dependent upon radiographic information alone when considering the diagnosis of AIFR. AIFR may present without significant radiographic evidence of sinusitis and there is poor correlation between surgical specimens and radiographic demonstration of the extent of disease (23). While some studies report a normal CT scan in 12% of patients with histopathologic evidence of IFS, other reviews found no patient afflicted with the disease to have a normal CT scan (11,16). Care should be taken in the interpretation of CT scans in cases suspicious for AIFR as imaging studies are supportive, but not diagnostic, of AIFR.
Pathology
Aspergillus and the members of the Subphylum Mucoromycotina (Mucor, Rhizomucor, Absidia) are the fungi most frequently implicated in AIFR, though unusual cases involving Candida, Bipolaris, Cunninghamella, Conidiobolus, Scytalidium, Fusarium, and Exserohilum have been reported (2,12).
The clinical manifestations of AIFR develop as a result of the propagation of angioinvasive and neuroinvasive fungi within the sinonasal cavity and facial tissues. AIFR
is defined by fungal forms invading into the submucosal tissue, often associated with angioinvasion resulting in vascular thrombosis, infarction, and necrosis. Areas of coagulative tissue necrosis are extensive and the total numbers of hyphae can be relatively sparse at times, with an associated neutrophilic infiltration (9). The acidotic environment of tissue ischemia and necrosis provide an ideal medium for fungal growth and further propagation of the fungal infestation (12).
is defined by fungal forms invading into the submucosal tissue, often associated with angioinvasion resulting in vascular thrombosis, infarction, and necrosis. Areas of coagulative tissue necrosis are extensive and the total numbers of hyphae can be relatively sparse at times, with an associated neutrophilic infiltration (9). The acidotic environment of tissue ischemia and necrosis provide an ideal medium for fungal growth and further propagation of the fungal infestation (12).
 Figure 37.3 AIFR Axial on contrast CT scan shows right maxillary sinus opacification and right nasal cavity mucosal thickening. There is loss of normal fat planes within the pterygopalatine fossa, a sign of invasive disease. Image and caption: Jeffrey Bennett, MD. Department of Radiology, University of Florida College of Medicine, Gainesville, FL. |
Treatment
AIFR is a condition specific to a well-defined patient population, and as such, a high index of suspicion for disease and preventive measures constitute the first step in management in the at-risk population. The most closely monitored of the high-risk population, those with hematologic malignancies or post-transplant patients (AIFR incidence rates from 1.7% to 2.6%), are also most amenable to methods of decreasing environmental exposure to fungi, administration of prophylactic antifungal drugs, and hospital-based screening protocols for IFS. Hospital rooms equipped with high-efficiency particulate air filtration have been shown to reduce fungal burdens, thereby intervening at the initial stage of fungal inhalation (10,14).
Prophylaxis with antifungal medications in high-risk patients should be used with caution, as their side effect profiles, toxicity, and the potential for augmenting drug resistance remain important concerns (10). Nevertheless, prophylaxis is frequently initiated in high-risk patients undergoing additional immunosuppressive therapy. Similarly, prophylactic antifungal medications are indicated for patients with a known history of invasive fungal disease who will require further immunosuppressive therapy (7,10,24).
While secondary prophylaxis with amphotericin B deoxycholate (ABD) is well established and demonstrates a reduction in the rate of recurrent infection, newer, less toxic antifungal agents have supplanted ABD in this role (10). Posaconazole, a second-generation extended spectrum triazole, has been shown to be superior to standard azole therapy in preventing invasive fungal infections in immunocompromised hosts and may soon play a primary antifungal role in the treatment of AIFR (25). While there are no studies that compare prophylaxis regimens with regard solely to AIFR, there is evidence that severely immunocompromised patients, with neutropenia have improved outcomes with posaconazole over earlier generation azoles in the prevention of fungal infections (26). AIFR treatment is most successful when aggressive multimodality therapy can be instituted in the earliest stages of disease. Some hospital-based protocols initiate CT scans of the sinuses in high-risk patients with sinonasal symptoms or unexplained fever, followed by endoscopic examination and intranasal biopsy of all patients with radiographic abnormalities (14,22,23).
Treatment of AIFR relies on medical and surgical therapy directed against the offending fungal pathogen in addition to reversal of the patient’s underlying state of immunocompromise. Systemic antifungal medication is instituted immediately while treatment of diabetic ketoacidosis (DKA) or restoration of neutropenia is undertaken. Correction of acidosis and underlying dehydration is associated with an 80% survival rate in AIFR with concomitant DKA (7,9). In transplant patients or those with hematologic malignancies, an absolute neutrophil count (ANC) less than 1,000/mm3 has been associated with both the onset of disease and reduced survival. White blood cell transfusions and administration of granulocyte colony-stimulating factor that increase the ANC above 1,000 mm3 have been shown to improve survival in neutropenic patients (14,18).
Systemic antifungal therapy is routinely employed in AIFR. ABD, a polyene macrolide, has been the drug of choice for the systemic treatment of invasive and disseminated fungal infections since its introduction into clinical practice in the 1960s (27). Amphotericin B exhibits fungicidal activity against a wide spectrum of pathogenic fungi; however, its side effects are multiple, serious, and can limit both dosage and duration of therapy in critically ill patients (27). Infusion-related symptoms including fever, chills, headache, nausea, vomiting, thrombophlebitis, and hyperkalemia are seen in 50% of patients and can be managed acutely; however, long-term myelosuppression, ototoxicity, and nephrotoxicity are more problematic (18,27,28). Nephrotoxicity, which occurs in 80% of patients treated with amphotericin B, and the resultant azotemia and electrolyte disturbances (hypokalemia) ultimately mandates halting therapy or switching antifungal agents (27). The negative impact of ABD on the general medical condition of these typically compromised patients has increasingly favored the use of lipid formulations of amphotericin B in lieu of the older and more harmful deoxycholate preparation.
Lipid-based formulations of amphotericin B have improved safety profiles, less renal toxicity, and are effective in treating AIFR (18,27). Though randomized clinical trials of invasive fungal infections in the treatment of AIFR comparing lipid-based formulations with the deoxycholate preparation are not available, evidence derived from treatment of other disseminated and invasive fungal infections favors equal if not greater efficacy and reduced complications in patients receiving the lipid formulation (7). Recently, small case series specifically addressing paranasal sinus disease demonstrate significantly greater survival rates in patients receiving lipid amphotericin B than in those managed with ABD (28,29). The ability to deliver higher total doses (5 to 7.5 mg/kg/day) with reduced toxicity highlights the issue of higher drug cost as the lone remaining obstacle to more widespread utilization of lipid-based formulations of amphotericin B (7,28).
The introduction of extended spectrum azoles, voriconazole, and posaconazole, has expanded the available options both for antifungal therapy of acute disease as
well as prophylaxis of recurrent invasive fungal infections in immunocompromised populations. Voriconazole produces survival advantages with fewer side effects than amphotericin B in the treatment of systemic invasive aspergillosis (30), while posaconazole demonstrates both survival benefits and reduced drug costs over standard therapy with amphotericin B in the management of the same invasive fungal condition (31). Posaconazole is active against the mucoracea while voriconazole is not. Posaconazole has been shown to be a cost-effective medication in the prevention of invasive fungal disease in neutropenic patients (25). The efficacy of posaconazole and voriconazole in treating Aspergillus AIFR has been reported. Baumann reported the successful use of voriconazole following sphenoidotomy in four cases of AIFR resulting from Aspergillus, while Chirch reported a successful case of combination therapy with caspofungin and voriconazole for Aspergillus AIFR in the absence of surgery (32,33). The reduced side effects of these agents may prompt their use both in treatment and prophylaxis within the medically compromised patient population at risk for AIFR. At the present time, however, clinicians should institute voriconazole therapy without hesitancy when either Pseudoallescheria boydii or Aspergillosis is identified. P. boydii
well as prophylaxis of recurrent invasive fungal infections in immunocompromised populations. Voriconazole produces survival advantages with fewer side effects than amphotericin B in the treatment of systemic invasive aspergillosis (30), while posaconazole demonstrates both survival benefits and reduced drug costs over standard therapy with amphotericin B in the management of the same invasive fungal condition (31). Posaconazole is active against the mucoracea while voriconazole is not. Posaconazole has been shown to be a cost-effective medication in the prevention of invasive fungal disease in neutropenic patients (25). The efficacy of posaconazole and voriconazole in treating Aspergillus AIFR has been reported. Baumann reported the successful use of voriconazole following sphenoidotomy in four cases of AIFR resulting from Aspergillus, while Chirch reported a successful case of combination therapy with caspofungin and voriconazole for Aspergillus AIFR in the absence of surgery (32,33). The reduced side effects of these agents may prompt their use both in treatment and prophylaxis within the medically compromised patient population at risk for AIFR. At the present time, however, clinicians should institute voriconazole therapy without hesitancy when either Pseudoallescheria boydii or Aspergillosis is identified. P. boydii
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