Fungal Rhinosinusitis
Summary
Fungal rhinosinusitis comprises a variety of clinically distinct diseases with substantial regional variability in their prevalences and pathophysiologies. Presentations may vary from asymptomatic fungal colonization to acute fulminant invasive disease. Noninvasive fungal rhinosinusitis consists of several particularly severe and recalcitrant variants of chronic rhinosinusitis (CRS), which require aggressive medical and surgical management. This chapter discusses the underlying pathobiology and classification of fungal rhinosinusitis, as well as the diagnosis and management according to the current best evidence. Medical management is tailored to the specific disease process and may include the use of corticosteroids, antifungals, antibiotics, saline irrigations, and immunotherapy. Tailored surgical management and useful adjunctive techniques, such as the canine fossa trephine and the frontal drill-out procedure, are also discussed.
Introduction
Fungal rhinosinusitis comprises a variety of clinically different diseases, ranging from fatal acute infection to long-standing, almost symptomless fungal colonization. The exposure to airborne fungi varies considerably worldwide, and the pathogenesis and physiopathology of CRS, particularly chronic fungal rhinosinusitis, are subjected to substantial geographic and regional variability. In addition, socioeconomic factors seem to play a role in the incidence of fungal rhinosinusitis. Consequently, scientists may observe distinct clinical courses of fungal rhinosinusitis.
Our current level of understanding of the pathophysiology prevents us from stating with certainty what the essential trigger for the development of fungal sinonasal inflammation is. This may be the fungal hyphae themselves, their breakdown products, or other antigens contained within eosinophilic mucus. Alternatively, it may be products of the mucosal immune response to these fungal elements, such as the accumulation of eosinophils and their toxic metabolites.
Moreover, the pathogenesis of rhinosinusitis is highly complex, and experimental work becomes more and more sophisticated. Thus, possible confounders are difficult to control. These factors may in part explain the inconsistency of our current knowledge on fungal sinus disease. In some common sinus conditions, particularly CRS with tissue eosinophilia or eosinophilic mucus, it remains controversial if fungal elements are relevant pathogenic factors, disease modulators, or innocent bystanders.1
Fungus Biology
Classification of Fungi
Fungi belong to the biological domain of eukaryotes and form a separate taxonomic kingdom ( Fig. 21.1 ). Unlike bacteria, they have a nucleus; in contrast to animal cells, they have a cell wall; and in contrast to plants, they have no chlorophyll and are therefore dependent on organic nutrients (heterotrophic). Fungi possess chitinous cell walls containing β-glucans, plasma membranes containing ergosterol, 80S ribosomal RNA (rRNA), and microtubules composed of tubulin. Clinically, unicellular yeast, dermatophytes, and dimorphic fungi are distinguished from molds, which can form multicellular hyphae. The latter are the most relevant group in rhinosinusitis and may be further divided into pigmented (dematiaceous) and nonpigmented (hyaline) molds. Zygomycetes, including Mucor and Rhizopus, are important causes of opportunistic invasive fungal rhinosinusitis.
Over 70,000 different mold species have been recognized. Their usual habitat is the soil. Here, during the vegetative phase, they form filamentous structures (hyphae), which grow to a loose clew (mycelium). From the mycelium, a fruiting head (conidiophore) develops, bearing variable amounts of conidia (asexual spores). Following release from the fruiting head, during the propagation phase, spores are airborne due to their low diameter of ~2 to 5 µm ( Fig. 21.2 ) and constitute a relevant fraction of the bioaerosol.
Rhinosinusitis-related Fungi and Fungal Allergy
Fungal rhinosinusitis is most frequently caused by molds. Frequent sinusitis-related mold genera include Alternaria, Aspergillus, Cladosporium, Fusarium, and Penicillium. However, depending on geographic distribution, other fungi, such as Bipolaris, may be common. The conidia of Alternaria and Fusarium are larger (35-µm diameter) than the conidia of most other species (2.5–10 µm). Aspergillus fumigatus conidia have a particularly small diameter (2–5 µm) and are a frequent cause of bronchopulmonary aspergillosis. Occasionally, other fungi may cause rhino-sinusitis, such as Mucor, Rhinosporidium, and Cryptococci. These opportunistic invasive fungal infections usually occur in immunocompromised hosts and frequently take a serious course. Histoplasma, Blastomyces, Paracoccidia, and Coccidia are pathogenic fungi occurring in some regions of the world and may cause infections in immunocompetent hosts.
In addition to their role in rhinosinusitis, molds may cause immunoglobulin E (IgE)–mediated allergic rhinitis. The most common allergen sources of fungal allergic rhinitis are Alternaria, Aspergillus, Cladosporium, Fusarium, and Penicillium. The incidence of mold allergic rhinitis is correlated with fungal spore concentrations in ambient and indoor air. Approximately 10% of people in the United States have a positive allergy test to fungi, and ~5% are supposed to have some allergic symptoms.
Environmental Burden and Human Exposure
Airborne fungal spores are ubiquitous and more or less continuously taken up by inhalation. Exposure to airborne spores shows considerable variability worldwide and depends on environmental conditions, including temperature, humidity, and season of the year. Indoor mold exposure is generally equal or slightly lower but closely correlates with outdoor mold concentrations. Various methods to count airborne spores are available. With Burkhardt traps, the number of fungal spores per cubic meter can be assessed. Andersen samplers provide the number of viable fungal elements, measured in colony-forming units per cubic meter ( Fig. 21.3 ). Information on individual exposure can be obtained with personal samplers. In the United States, particularly high viable spore counts were registered in the Southeast by Shelton and coworkers,2 a region where fungal rhinosinusitis is frequently reported. In Central Europe, an average of ~100 viable mold spores per hour are inspired and ~400 in the Southwest United States. Not only spores but also fungal fragments of hyphae are airborne and inhalable. Fungal fragments are frequently <5 µm and nonviable. The concentrations of airborne hyphal fragments may be significantly higher than that of spores. Hyphal fragments may easily pass the nasal airways and reach the bronchial and alveolar region.
Note
The exposure to airborne fungi and physiopathology of CRS are subject to substantial regional variability; even in the same geographic location, it is likely that several distinct presentations, severities, and clinical courses will be observed for fungal rhinosinusitis.
Fungus-related Sinus Disease
Classification of Fungal Rhinosinusitis
Fungal rhinosinusitis is frequently categorized as acute invasive, granulomatous invasive, chronic invasive, fungal colonization, fungus ball, and eosinophilic fungal rhino-sinusitis (EFRS), including allergic fungal rhinosinusitis ( Fig. 21.4 ).3
Acute invasive fungal rhinosinusitis almost exclusively occurs in immunocompromised hosts and is characterized by hyphal invasion of surrounding tissues, vascular invasion, and tissue necrosis. Today, mortality ranges between 20 and 50%.
Note
Acute invasive fungal rhinosinusitis has a mortality rate of 20 to 50%; a high index of suspicion must be maintained whenever symptoms of rhinosinusitis are present in immunocompromised hosts.
In granulomatous invasive fungal rhinosinusitis, noncaseating granulomas around sparse hyphae are found. Granulomatous invasive fungal rhinosinusitis occurs mainly in India and Pakistan. A 15% mortality rate has been reported.
Chronic (i.e., > 4 wk) invasive fungal rhinosinusitis is a nongranulomatous, slowly destructive process with abundant hyphae on histopathologic examination. Chronic invasive fungal rhinosinusitis is commonly seen in patients with less severe immune dysfunction and mainly occurs in the context of acquired immunodeficiency syndrome (AIDS), diabetes mellitus, and corticosteroid treatment. A 40% mortality rate has been reported.
Fungal colonization is usually found in patients with impaired mucociliary transport, particularly on nasal crusts. Symptoms are mainly related to formation of nasal crusts.
A fungus ball is a noninvasive, dense conglomeration of fungus hyphae mostly found in the maxillary sinus accompanied by a weak noneosinophilic mucosal inflammatory response.
EFRS is a noninvasive chronic eosinophilic sinus inflammation frequently associated with nasal polyps. A characteristic of eosinophilic fungal rhinosinusitis is the presence of highly viscid sinus secretions with eosinophil decay products, termed eosinophilic mucus by Bent and Kuhn.4 Although frequently used, the term eosinophilic mucin is a misnomer.
* Mucins are a family of high molecular weight, heavily glycosylated proteins (glycoconjugates) found in several body fluids, including breast milk. The protein core is encoded by a group of approximately 20 genes, termed MUC genes.
EFRS may be further divided into allergic fungal rhinosinusitis (AFRS) with a positive diagnostic test for IgE-mediated allergy to the fungal elements detected within the sinus. It is considered as an IgE-mediated mucosal hypersensitivity directed against fungal antigens deposited on sinus mucosa. If type I allergy tests to molds are negative, but eosinophilic mucus with fungal elements is found, the term nonallergic EFRS is appropriate. Eosinophilic mucus may also occur in the absence of fungal elements and is categorized as nonfungal EFRS ( Table 21.1 ).There are several problems with this classification. The main problem is that a surgical procedure is required to confirm the presence of a fungus ball, eosinophilic mucus, or fungal invasion of sinus mucosa. Thus, allocation of patients in no-surgical clinical drug trials based on this classification is difficult. Moreover, the definition eosinophilic mucus is not very stringent. If present in a typical form, it is easily recognized clinically, but frequently secretions within the sinuses are less tenacious. Charcot-Leyden crystals are described as a typical but not obligatory histopathologic finding. Importantly, eosinophilic mucus may occur with and without fungal elements, resulting in an overlap between fungal and nonfungal disease. Finally, fungal elements can be detected in the CRS without eosinophilic mucus, a condition not considered in this classification.
Diagnosis
Relevant investigations in patients with suspected fungal sinusitis include medical history (previous surgery, immune suppression, aspirin intolerance, bronchial asthma, and previous dental treatment), clinical examination (involvement of the orbit, nasal polyps at endoscopy, dental state, and tissue necrosis), microbiological examinations for fungus detection, histopathologic investigations to detect eosinophilic mucus or fungal elements within the mucus, radiologic examinations, and allergy tests. If invasive fungal sinusitis is suspected, additional immunologic tests are indicated.
Fungus Detection
To diagnose fungal rhinosinusitis, fungal elements from the nose or paranasal sinuses must be detected. However, detection of fungal elements does not prove a fungal etiology of disease because fungi are frequently innocent bystanders and are found in a considerable proportion of the healthy population.5,6 Moreover, fungus positivity is subjected to considerable variability ( Table 21.2 ) in patients with CRS and healthy individuals.6 If mucociliary transport is impaired for any reason, including CRS, the chance to detect fungal organisms increases because inhaled spores are less effectively removed from the nose.
Accuracy of fungus detection depends on various factors, including collection site, collection method, and mode of fungus detection (culture, polymerase chain reaction [PCR], and histology). Nasal swabs, nasal lavages, sinus secretions obtained during surgery, and sinus mucosa differ in fungus detection rates.7 Nasal lavage is a valuable noninvasive sampling method.1 To avoid sample contamination with airborne fungal spores, immediate processing under laminar flow is recommended. In specimens obtained during surgery, it seems important that sinus mucosa and mucus are sent for pathologic and microbiological examination. In 1994, the Mayo Clinic reported that 51 out of 789 (6.5%) histopathologic sinus specimens were consistent with a diagnosis of eosinophilic mucus sinusitis, and in 31 specimens (4%), both eosinophilic mucus and fungi were detected. Twenty specimens (2.5%) with eosinophilic mucus without fungi were categorized as AFRS-like syndrome.6 Five years later, fungal sinusitis was detected in almost 100% of the Mayo patients with CRS. Ponikau and coauthors reported that the correct diagnosis of fungal disease essentially depends on preservation and thorough investigation of eosinophilic mucus, which the authors reported in 96% of their patients.6 The authors further reported that eosinophilic mucus should be treated with mucolytic agents to release entrapped fungi from the mucus and allow contact with the growth medium. No comparative study of fungus detection rates in specimens treated or not with mucolytics such as dithiothreitol (DTT) was found. DTT liquefaction of thick bronchial sputum did result in slightly higher bacterial detection rates in one study but not in another. DTT liquefaction sounds reasonable for tenacious eosinophilic mucus, but its significance for nasal lavages remains unclear.
In addition to the sampling method, the sensitivity and specificity of the diagnostic tests used for fungus detection are relevant.7 Fungus culture is the basic microbiological technique. Sabouraud dextrose agar and broth with antibacterials such as gentamicin and chloramphenicol to prevent bacterial overgrowth are common culture media. Plates are incubated for 30 days at 30°C and 37°C. Multiple culture media for the diagnosis of fungal sinusitis yielded higher detection rates than a single culture method. Only viable organisms grow in culture. Theoretically, one single viable spore is detected with cultures, whereas the detection of sensitive PCR assays lies in the range of 100 fungal genomic DNA representing ~10 spores.7 PCR also detects nonviable fungus fragments; this is the probable cause for the higher detection rate observed with PCR. Moreover, PCR is much faster than culture. Because nonviable fungal fragments are frequently antigenic and occur in higher concentrations than viable fungal spores,3 PCR results are clinically relevant.
Fungus elements can also be detected by histopathology. Conventional hematoxylin/eosin stains are rather insensitive. Grocott-Gomori methenamine silver staining depends on the reduction of silver by aldehyde groups produced after oxidation of fungal cell wall components with chromic acid. It is the reference method for histochemical fungus detection. Calcofluor-white is a nonspecific fluorochrome that binds to cellulose and chitin in cell walls and improves microscopic fungus detection. High sensitivity is reported with Fungalase-F (Anomeric Inc., Baton Rouge, LA), a fluorescein-labeled chitinase stain. Autofluorescence is a common problem with all fluorescein-labeled staining techniques. Currently, the combination of culture, PCR, and methenamine silver stain appears to provide the best sensitivity and specificity for fungus detection.
Eosinophilic Mucus Detection
During sinus surgery, particularly thick, gumlike yellow or gray material may be found within the sinus ( Fig. 21.5 ). On histopathologic examination, lamellated aggregates of dense inflammatory cells, mostly eosinophils and some neutrophils, in a background of tenacious-appearing basophil or eosinophil mucus and Charcot-Leyden crystals are seen. The term eosinophilic mucus seems more appropriate than allergic mucus because it frequently occurs in patients without allergy. Clinically, eosinophilic mucus is most often associated with nasal polyps.9 The reported incidence of eosinophilic mucus found during sinus surgery ranges between 5 and 96%.8,10–14 Eosinophilic mucus may or may not contain fungal elements.1,9 Fungal elements within eosinophilic mucus are reported in 40 to 100% of specimens. Pant et al analyzed 188 patients with eosinophilic mucus and found fungi in 55% of mucus specimens ( Table 21.3 ).9 Although clinically easily identified when found in copious amounts, the borderline between eosinophilic mucus and sinus secretions with viable or decaying eosinophils is difficult to define. Moreover, patients with eosinophilic mucus may or may not have IgE-mediated allergy to fungi. It remains unclear if the presence of eosinophilic mucus is a marker of a pathologically distinct form of CRS or if it merely indicates a severe form of eosinophilic CRS, irrespective of fungi or type I hypersensitivity.
Radiographic Imaging of Fungal Rhinosinusitis
Different subtypes of fungal rhinosinusitis demonstrate some specific radiologic features but cannot be distinguished by imaging alone. The radiologic reference methods for sinus disease are computed tomography (CT) scans in three planes without intravenous (IV) contrast. In native CT scans, unilaterality, inhomogeneity of opacification, bony erosion, and sinus expansion may suggest fungal disease and may cause further radiologic investigations. Despite characteristic radiographic features, the diagnosis of fungal sinusitis solely based on radiographic imaging is not reliable.
Acute Invasive Fungal Sinusitis
The clue to diagnosis is to know that the patient is immune suppressed. Noncontrast CT features of acute invasive fungal sinusitis include often unilateral, sometimes bilateral circumferential mucosal thickening or complete opacification. The ethmoid and sphenoid sinuses are frequently involved. Bone destruction of sinus walls without bony expansion is suspicious of invasive fungal sinusitis. Sinus walls may remain intact with fungal dissemination along perineural and perivascular channels. Magnetic resonance imaging (MRI) ( Fig. 21.6 ) reveals variable T1-and T2-weighted signal intensity of the mucus within the involved sinus, and the inflamed mucosa of the involved sinus demonstrates high T2 signal intensity and contrast enhancement. As the disease progresses, invasion of adjacent structures, including the orbit and anterior cranial fossa, is observed. The periantral fat planes are poorly delineable. Vascular invasion and thrombosis, meningitis, epidural abscess, cerebritis or cerebral abscess, cavernous sinus involvement, mycotic aneurysm, osteomyelitis, intracranial hemorrhage, cerebral infarct, and orbital abscess may be present. CT scans did not help to detect invasive rhinosinusitis in children with febrile neutropenia because abnormal CT findings were found in all patients.
Chronic Invasive Sinusitis
On noncontrast CT, slightly hyperdense more or less homogeneous soft tissue within one or more sinuses is frequently seen. Typically, there is no bony expansion, but bone destruction and infiltration of surrounding tissues mimicking a malignancy. Slight to intermediate hypointensity is seen on T1, and very low signal intensity on T2-weighted images is common.
Fungus Ball
A fungus ball appears as a mass within the lumen and is usually limited to one paranasal sinus and is commonly unilateral ( Fig. 21.7 ). The maxillary sinus is most frequently affected, followed by the sphenoid sinus. Fungus balls typically appear hyperdense on noncontrast CT scans and frequently show calcifications. Sinus walls may be hypersclerotic or expanded and thinned. On T1-weighted MRI, a fungus ball appears hypointense. Calcifications and paramagnetic metals, such as iron, magnesium, and manganese, generate areas of signal void in T2-weighted images.
Eosinophilic Mucus Chronic Rhinosinusitis
Fungal and nonfungal eosinophilic mucus rhinosinusitis cannot be distinguished by CT.9 Usually, several sinuses are involved. Unilaterality is not an indicator of eosinophilic mucus rhinosinusitis. In noncontrast CT, eosinophilic mucus is hyperdense with a characteristic serpiginous appearance. Bony erosion and expansion are common in advanced disease. The sinus content shows no contrast enhancement. On MRI, eosinophilic mucus is usually hyperintense on T1- and hypointense on T2-weighted images due to its high protein and low water content. The inflamed mucosa is hypointense on T1 and hyperintense on T2 and shows gadolinium enhancement.
Allergy Tests
In patients with rhinosinusitis, allergy tests commonly serve to identify atopy
* Atopy is the inherited disposition to develop IgE antibodies to allergens and is frequently identified by positive skin prick tests or by detection of serum-specific IgE antibodies to common allergens. Sensitized individuals who develop symptoms after exposure to allergens mediated by specific IgE antibodies are allergic.
or symptomatic IgE-mediated allergy. The role of IgE-mediated allergy in CRS is difficult to define. In the context of fungal CRS, allergy tests serve to differentiate between allergic and nonallergic eosinophilic mucus and identify patients with a systemically detectable IgE response to fungus allergens present on the surface of sinus mucosa. This is one of the Bent and Kuhn criteria for AFRS.4 Positive tests to nonfungal allergens do not allow the diagnosis of AFRS.Epicutaneous Test for Immunoglobulin E–Mediated Hypersensitivity
Today, skin prick tests with allergen extracts are the reference method. Allergen extracts for the majority of relevant fungal allergens are commercially available. The preparation of allergen extracts from cultured mold is difficult secondary to low protein and high carbohydrate contents and the presence of potent proteolytic enzymes. The composition of the allergen panel used for routine tests should consider which fungi are frequent in the geographic region. For instance, the fungi Bipolaris spicifera (synonyms Curvularia spicifera, Drechslera spicifera, and Helminthosporium spiciferum) and Exserohilum spp. are uncommon human allergens in Central Europe but frequently cultured from sinuses in the United States. Alternaria, Aspergillus, Cladosporium, Fusarium, and Penicillium occur almost worldwide. Cross-reactivity of some mold species has been described.
Serum-specific Immunoglobulin E
Specific IgE measurements in blood serum (ssIgE) are less sensitive than skin prick tests. If skin prick tests are not applicable, specific IgE to fungal allergens in blood serum can be assessed. Alternative in vitro methods include basophil activation tests and cellular allergen stimulation test enzyme-linked immunosorbent assay (CAST-ELISA).
Serum Total Immunoglobulin E
Serum total IgE may be elevated in type I allergies, but also in several other diseases, including helminthic infections and hyper-IgE syndrome. Patients with negative prick test and/or a negative ssIgE but elevated serum total IgE levels are not classified as atopic. Adult normal serum total IgE values are < 100 IU/mL (< 300 ng/mL) and are lower in children (< 60 IU/mL) and higher in adolescents (< 200 IU/mL). Serum total IgE correlates with severity of allergic asthma and rhinitis. The anti-IgE antibody omalizumab interferes substantially with serum total IgE levels.
In AFRS, following the Bent and Kuhn definition,4 serum total IgE was almost always extensively elevated and correlated with the severity of disease.10,15 Serum total IgE was not elevated in nonatopic, nonfungal CRS patients in five studies. In one study, increased serum total IgE levels were observed in patients with nonfungal and fungal CRS.9 Total serum IgE measurements make sense in geographical regions with high AFRS incidence.
Local Immunoglobulin E Production
Negative skin prick tests, negative ssIgE, and normal serum total IgE do not exclude a pathophysiologic role for IgE within the diseased tissues. Although IgE production has been thought to occur mainly in the germinal centers of lymphoid tissue, it is now clear that local IgE production within the mucosa of the upper and lower airways and gut is a significant IgE source. High local IgE levels may occur in the absence of positive skin prick tests, positive ssIgE, or elevated total serum IgE. Local IgE production within the mucosa of the nose and sinuses occurs in nasal allergy, CRS with polyps with and without atopy, and particularly fungal rhinosinusitis.
Serum-Specific Immunoglobulin G
In AFRS and eosinophilic mucus rhinosinusitis, fungal serum IgG levels were higher than in controls.10 The significance of specific IgG in fungal CRS remains elusive. IgG to common inhalant and food allergens is detectable in almost all individuals, and no established normal values exist. Antigen-specific IgG in the respiratory lining fluid may opsonize inhaled fungal elements and enhance the immune response. In bronchopulmonary aspergillosis, antigen-specific IgG is used as a marker for immune complex-mediated (type III) allergy. Precipitated immune complexes consisting of fungal elements and IgG with surrounding noncaseating granulomas (the pathologic appearance of immune complexes in allergic broncho-pulmonary aspergillosis) have not been demonstrated in AFRS.
Blood Eosinophilia
Blood eosinophilia is common in severe CRS. Eosinophilia is defined as a peripheral blood eosinophil count > 450/µL or > 5% eosinophils in white blood cell (WBC) differential count. Blood eosinophilia may be caused by various disorders, including allergy, infections, autoimmune disorders, myeloproliferative diseases, and parasites. In several studies, peripheral blood eosinophils were correlated with the severity of CRS. Blood eosinophilia is a frequent finding in fungal rhinosinusitis.
Diagnosis of Invasive Fungal Disease in Immunocompromised Hosts
The European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group (EORTC) and the National Institute of Allergy and Infectious Diseases Mycoses Study Group (MSG) defined three levels of probability to the diagnosis of invasive fungal infection that develops in patients with severe immune depression with cancer and in hematopoietic stem cell transplant recipients, namely, “proven,” “probable,” and “possible” invasive fungal infection.11
Note
Definition of severe immune suppression11:
Recent history of neutropenia (< 0.5 × 109 neutrophils/L [< 500 neutrophils/mm3] for more than 10 days) temporally related to the onset of fungal disease
Receipt of an allogeneic stem cell transplant
Prolonged use of corticosteroids (excluding patients with allergic bronchopulmonary aspergillosis) at a mean minimum dose of 0.3 mg/kg daily of prednisone equivalent for more than 3 weeks
Treatment with other recognized T-cell immunosuppressants, such as cyclosporine, tumor necrosis factor-α (TNF-α) blockers, specific monoclonal antibodies (e.g., alemtuzumab), or nucleoside analogues during the past 90 days
Inherited severe immunodeficiency (e.g., chronic granulomatous disease or severe combined immunodeficiency)
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