Fungal rhinosinusitis

INTRODUCTION — Fungal rhinosinusitis encompasses a wide variety of fungal infections that range from merely irritating to rapidly fatal. Fungal colonization of the upper and lower airways is a common condition, since fungal spores are constantly inhaled into the sinuses and lungs. However, colonization is distinct from infection, and most colonized patients do not become ill with fungal infections. "Fungal rhinosinusitis" is the most appropriate term to describe fungal infection of the paranasal sinuses since concomitant involvement of the nasal cavity is seen in most cases [1].

Fungal colonization as well as the pathophysiology, clinical manifestation, diagnosis, and treatment of invasive fungal rhinosinusitis will be discussed here. An additional disorder, which involves a hypersensitivity response to colonizing fungi, is called allergic fungal rhinosinusitis and is reviewed separately. (See "Allergic fungal rhinosinusitis".)

FUNGAL COLONIZATION — Patients with anatomic abnormalities of the paranasal sinuses that impair drainage, such as nasal polyps or chronic inflammatory states, are vulnerable to fungal colonization in these areas. Areas of mucosal injury may cause pooling of mucus and subsequent colonization by fungus. However, these abnormalities are generally of no clinical importance. Aspergillus species are the most common colonizers of the sinuses, but many other species are also reported [2]. Generally, in chronic rhinosinusitis, the microbiome does not include fungi, but fungi are present in a small subset of patients, particularly those with polyps and/or recent use of antibacterial agents [3].

In patients with radiographic abnormalities and risk factors for invasive disease, colonization is distinguished from invasive disease by endoscopic examination with biopsy. (See 'Diagnosis' below.)

Fungus balls — Fungal hyphae can become intertwined in dense collections and form fungus balls if there is obstruction of the paranasal sinuses [2,4]. Patients usually present with symptoms of chronic rhinosinusitis and involvement of only one sinus cavity. Computed tomography is very accurate in diagnosing this process and often shows a metal-dense spot within the fungus ball. This finding was reported in 72 percent of cases in one series of 160 patients [2,5]. There may be mild sclerosis of the surrounding bone [2,4]. Directed endoscopic surgery to correct the obstruction and to extract the fungus ball is highly effective [2,6-8]. Recurrence after surgical removal is uncommon [2]. Antifungal agents do not offer clear benefit [2]; however, glucocorticoids are commonly used during the perioperative period to reduce inflammation.

ALLERGIC FUNGAL RHINOSINUSITIS — Allergic fungal rhinosinusitis, which involves a hypersensitivity response to colonizing fungi, is reviewed separately. (See "Allergic fungal rhinosinusitis".)

INVASIVE FUNGAL SINUSITIS — The marked rise in the number of immunocompromised patients has led to an increase in unusual manifestations of aggressive fungal infections. Invasive fungal rhinosinusitis is one such form of infection that appears to be increasing in frequency. Although invasive fungal rhinosinusitis can occasionally be seen in apparently immunocompetent patients, the vast majority of cases involve patients with some form of immunosuppression.

Invasive fungal rhinosinusitis can be broadly classified as either acute or chronic [1]. Acute invasive fungal rhinosinusitis tends to occur in patients with profound immunosuppression, has a time course of days to a few weeks, and involves hyphal invasion of blood vessels with resulting tissue infarction [1]. In patients who are less immunocompromised, chronic invasive fungal rhinosinusitis occurs. This is a slowly destructive process with a typical time course of greater than 12 weeks; histopathology shows tissue destruction with a sparse inflammatory reaction [1].

The most common underlying diseases in patients with all forms of invasive fungal rhinosinusitis are [4,9]:

●Hematologic malignancies

●Hematopoietic cell transplantation [10]

●Chemotherapy-induced neutropenia

●Solid organ transplantation

●Advanced HIV infection [11,12]

●Diabetes mellitus

●Glucocorticoids (systemic or intranasal)

Infection in immunocompromised patients may be attributable to invasion by fungi that have chronically colonized the sinuses or to inhalation of fungal spores. Many patients with invasive fungal rhinosinusitis have a history of chronic rhinosinusitis, and some have anatomic abnormalities of their sinuses or antibacterial exposure that predispose to fungal colonization. However, infection may occur in immunocompromised hosts with previously normal sinuses.

Invasion of tissues adjacent to the sinuses occurs after the fungi establish local infection. The aggressiveness of tissue invasion may vary depending upon the underlying immune status of the host. Profoundly immunocompromised patients and those with poorly controlled diabetes can experience rapidly progressive disease over the course of a few hours, whereas the disease may be more indolent in patients with well-controlled diabetes or normal immune function. The spread of infection out of the sinuses is usually due to direct extension, but fungemia with metastatic spread can also occur.

The fungi most often implicated in causing invasive rhinosinusitis are species of Aspergillus, Fusarium, the Mucorales, and dematiaceous (brown-black) molds, but the clinical presentation depends upon the causative pathogen [4,9-12]:

●Acute, fulminant infections are usually due to Aspergillus species, Fusarium species, and the Mucorales. (See "Epidemiology and clinical manifestations of invasive aspergillosis" and "Mycology, pathogenesis, and epidemiology of Fusarium infection" and "Mucormycosis (zygomycosis)".)

●Indolent, chronic rhinosinusitis is most commonly caused by dematiaceous molds, such as Bipolaris, Curvularia, and Alternaria spp, as well as by Aspergillus spp and other hyaline molds, such as Scedosporium apiospermum complex. (See "Epidemiology, clinical manifestations, and diagnosis of Scedosporium and Lomentospora infections".)

Candida species have been rarely reported to cause invasive rhinosinusitis in immunocompromised hosts, including in a patient with AIDS [13] and in a hematopoietic cell transplantation recipient [10], but generally do not cause rhinosinusitis despite their ability to colonize the sinuses.

Acute fungal sinusitis — Patients with acute fungal rhinosinusitis usually present acutely with fever, facial pain, and nasal congestion and can have changes in vision or mentation. Facial numbness and diplopia can occur in the setting of cranial nerve involvement. Patients can already have extension of the infection outside the sinuses at the time of presentation.

Computed tomography (CT) and magnetic resonance imaging (MRI) show sinus involvement and may reveal bony erosions or extension of the infection to the globe, brain, cavernous sinus, or carotid artery (image 1) [14,15]. CT has higher sensitivity than MRI for detecting bony erosions, whereas MRI has higher sensitivity for soft tissue abnormalities, such as brain or eye involvement [16]. The majority of patients with acute fungal rhinosinusitis have multiple sinuses involved, with the maxillary and ethmoid sinuses being the most common. However, none of the findings on imaging are sufficiently specific to allow for a diagnosis of fungal versus bacterial infection [17].

A high degree of suspicion must be maintained in the immunocompromised patient with sinus complaints, especially facial pain. The nares and oral cavity should be carefully examined for necrotic areas; early nasal endoscopic evaluation by an otolaryngologist is essential [18]. Necrosis results from vascular invasion by the fungi and can appear as palatal or gingival eschars or as sloughing of the nasal septum with perforation. Sensation is frequently lost in the malar areas, and visual loss can occur with involvement of the orbit or optic nerve. Orbital involvement can also result in proptosis and fixation of the globe.

Chronic fungal sinusitis — Patients with the chronic, indolent form of invasive fungal rhinosinusitis usually present with symptoms of chronic rhinosinusitis and few, if any, systemic complaints. These patients are often older and only mildly immunocompromised. Diabetes mellitus and low-dose glucocorticoids are risk factors that are often noted. Aspergillus spp and brown-black molds, and not the Mucorales, are more likely to cause this form of sinusitis. Chronic fungal rhinosinusitis has also been described in a patient who used intranasal cocaine, presumably because the resulting chronic irritation of the nasal passages allowed for fungal invasion [19].

Patients often endure the symptoms of chronic rhinosinusitis for months before the development of a complication, such as visual changes from orbital invasion or neurologic complaints due to brain involvement. The physical examination may reveal tenderness over the maxillary sinuses and erythema overlying the malar areas. Proptosis and fixation of the globe are seen with orbital involvement.

CT and MRI scan may show involvement of a single paranasal sinus with a mass lesion and thickening of the mucosa [14,15]. Bony erosions may be noted with invasive disease and are most likely to be seen by CT.

Diagnosis — The diagnosis of invasive fungal rhinosinusitis is dependent upon histopathologic demonstration of fungal invasion by biopsy of involved areas [20,21].

Imaging modalities, such as CT and MRI scanning, are suggestive but are not sufficiently sensitive or specific to confirm a diagnosis. Nevertheless, imaging is helpful for defining the extent of disease (image 1) [17]. We generally perform a CT scan as the initial imaging study as it can often be obtained quickly and is more sensitive than MRI for detecting bony erosions [16]. Clinicians should have a low threshold for performing an MRI in patients with abnormalities on CT because the MRI will enhance detection of intracranial, intraorbital, and cavernous sinus involvement.

Evaluation of patients with suspected fungal rhinosinusitis should include early nasal endoscopy with biopsies of affected tissues [18]. Ample tissue biopsies should be obtained from the eschar but, more importantly, from the viable areas abutting the necrotic tissue in an effort to detect vascular invasion and the morphology of the fungus as well as to have optimal specimens for culture. Biopsy specimens should be evaluated intraoperatively to assure sufficient diagnostic tissue is available. If biopsies are done under anesthesia, then debridement of necrotic tissues is usually undertaken in the same setting. Pathology from surgical intervention can guide initial treatment until culture results return. Cultures of the biopsy specimen are usually positive but at times the fragile Mucorales may not grow in culture. Isolation of the infecting fungus is important to guide therapy. It is important to distinguish the agents of mucormycosis from Aspergillus and dematiaceous molds because antifungal therapies are different.

Treatment — Invasive rhinosinusitis remains a very difficult infection to cure because most affected patients are immunocompromised. Overall survival can be poor, and long-term survivors may have significant sinonasal complications, especially when there is intracranial involvement and cranial neuropathies at presentation [22]. Therefore, the diagnosis should be considered early in susceptible patients because prompt targeted treatment is essential for cure.

Initial medical therapy — Signs and symptoms of acute invasive rhinosinusitis in the appropriate host should warrant pre-emptive antifungal therapy with a lipid formulation of intravenous (IV) amphotericin B or, if mucormycosis is ruled out by histopathology showing septate hyphae, voriconazole. Isavuconazole is an alternative agent that can be used for invasive aspergillosis if voriconazole cannot be used. Isavuconazole can also be used for step-down therapy of invasive fungal sinusitis due to mucormycosis [23]. Of the lipid formulations of amphotericin B (AmBisome and amphotericin B lipid complex), the most reported experience has been with AmBisome.

Another important factor in treatment is the restoration of immune function by withdrawal of immunosuppressive medications, control of metabolic perturbations, and control of the underlying illness. The value of adjunctive hyperbaric oxygen [24] or iron chelation therapy [25] remains uncertain.

A lipid formulation of amphotericin B (5 mg/kg per day) has been used as initial therapy of invasive fungal rhinosinusitis, particularly if mucormycosis is likely. We prefer use of one of the lipid formulations of amphotericin B rather than amphotericin B deoxycholate in order to reduce nephrotoxicity. If associated central nervous system (CNS) infection is suspected, we prefer liposomal amphotericin B as the CNS penetration of this formulation was better than that of amphotericin B lipid complex in a rabbit model of Candida meningoencephalitis [26].

Important points to consider include the following:

●Infection due to S. apiospermum complex – Scedosporium species are generally resistant to amphotericin B and should be treated with voriconazole. (See "Treatment of Scedosporium and Lomentospora infections".)

●Infection due to Aspergillus species – The regimen of choice for treatment of invasive infection due to Aspergillus species is voriconazole. Isavuconazole is an alternative if voriconazole cannot be used. An echinocandin (caspofungin, micafungin, or anidulafungin) could be added for patients with severe disease. For patients who are intolerant of voriconazole due to severe reactions, we would choose either a lipid formulation of amphotericin B (eg, AmBisome or Abelcet) or isavuconazole. The decision of which agent to choose depends on organ dysfunction, toxicities, and tolerability. Detailed recommendations are presented separately. (See "Treatment and prevention of invasive aspergillosis".)

●Infections due to most dematiaceous fungi (phaeohyphomycosis) are more likely to be chronic and to respond to a triazole, such as voriconazole, posaconazole, itraconazole, or perhaps isavuconazole. For these infections, we favor voriconazole.

The usual dosing of voriconazole is 6 mg/kg IV every 12 hours for two doses, then 4 mg/kg IV every 12 hours. The IV formulation is recommended for at least the initial few days. Oral step-down therapy, using 200 mg twice daily, can be used following an initial response to the IV formulation. We recommend measurement of trough voriconazole levels in order to keep the trough serum concentration above 1 mcg/mL and less than 5.5 mcg/mL. (See "Pharmacology of azoles", section on 'Serum drug concentration monitoring'.)

Isavuconazole is given as loading doses of 200 mg of isavuconazole (equivalent to 372 mg of isavuconazonium sulfate) every 8 hours for six doses (48 hours) via oral (2 capsules) or IV administration, followed by 200 mg once daily orally or IV starting 12 to 24 hours after the last loading dose [27]. Isavuconazole is formulated as the prodrug, isavuconazonium sulfate.

In patients initially receiving polyene therapy (ie, amphotericin B), the duration of intravenous therapy depends upon the underlying immune status of the host, the extent of surgical debridement, and the response to therapy. We recommend continuing intravenous therapy until there is a clear clinical response and reversal of as many of the immunocompromising conditions as possible (eg, recovery from neutropenia, tapering of glucocorticoids, or engraftment in hematopoietic cell transplant recipients). This usually requires weeks of therapy and may require two to three months of therapy in patients with severe immunosuppression and slow clinical responses.

Surgical therapy — Surgical debridement remains the cornerstone of multidisciplinary management of acute invasive fungal rhinosinusitis. Sinus surgery has been shown to be an independent prognostic factor for survival in multiple studies [28-30]. This benefit is generally attributed to decreased fungal burden and removal of avascular necrotic tissue, into which systemic antifungal agents penetrate poorly. As a secondary benefit, wide debridement and sinus marsupialization facilitates postoperative endoscopic monitoring for remaining disease. The goals of primary endoscopic sinonasal surgery are the resection of all involved mucosa and bone up to dura and periorbita. This may be achieved through the application of a variety of expanded endonasal approaches including endoscopic medial maxillectomy [31], septectomy, and frontal sinus drill out [32].

The surgical extirpation may be initially guided by the gross appearance of tissue; resection to healthy, bleeding tissue is required. Any involved underlying bone may be either removed or drilled out. Intraoperative frozen section may be useful in guiding the extent of debridement required. In one report, complete surgical resection (defined as negative intraoperative frozen section margins or postoperative nasal endoscopy without evidence of gross disease) was associated with significantly higher short-term survival [33].

Extension of fungal involvement through the periorbita confers a significant increase in mortality and poses a therapeutic dilemma for the patient and management team [34]. Extending the debridement to include orbital exenteration has not been shown to improve survival in several studies [28,33,35]. It remains unclear whether these findings merely reflect the sequelae of more aggressive underlying disease; however, they do introduce significant uncertainly into the potential benefits of exenteration when weighed against the associated morbidity and disfigurement. Consequently, the decision to proceed with orbital exenteration must be made on a case-by-case basis but should be considered when the underlying disease process has a good prognosis and the orbital disease does not appear to extend into the superior orbital fissure or optic canal.

Transdural and intracranial extension portends a poor prognosis. Some studies have suggested a role for craniotomy [36,37], but the decision to proceed with neurosurgical debridement must be carefully weighed against the chances of survival [22,38].

The optimal timing of surgery for acute invasive fungal rhinosinusitis has been the subject of limited study. The general consensus remains that this diagnosis should be considered a surgical emergency, but the literature is somewhat divided on this topic. Some reports suggest that a surgical delay of more than six days has been associated with decreased survival [39], while others found no difference regardless of whether surgery was performed between days 1 and 30 after the initial diagnosis [40]. While this remains a subject where further study is required, the recommendation for emergent surgery should remain the standard approach.

Oral antifungal therapy — After improvement is noted, therapy can be changed to an oral antifungal agent. For patients with mucormycosis, posaconazole delayed-release tablets (300 mg every 12 hours on the first day, then 300 mg per day) or isavuconazole capsules (200 mg once daily) can be used. We do not use the oral suspension of posaconazole since it is not highly bioavailable and requires fatty foods for absorption. When using isavuconazole, loading doses are necessary for the first 48 hours. Loading doses of 200 mg (ie, two capsules) of oral isavuconazole (equivalent to 372 mg of isavuconazonium sulfate) should be given every 8 hours for six doses (48 hours), followed by 200 mg orally once daily starting 12 to 24 hours after the last loading dose. (See "Mucormycosis (zygomycosis)" and "Pharmacology of azoles".)

If itraconazole is to be used for therapy of chronic infections, we recommend using the oral solution and monitoring serum levels to make certain the drug is at a therapeutic level. The liquid formulation of itraconazole overcomes problems caused by poor absorption of the capsule and achieves approximately 30 percent higher concentrations in the serum at the same dose. The solution should be given on an empty stomach to achieve the highest serum concentrations. However, more gastrointestinal upset occurs with the solution formulation, which precludes its use in some patients.

Although voriconazole has excellent absorption, patients receiving this agent should also undergo serum concentration monitoring since there is individual variation in its metabolism. (See "Pharmacology of azoles", section on 'Voriconazole'.)

Suppressive therapy is usually continued for at least three to six months. Some patients who remain immunosuppressed require lifelong therapy. The decision to discontinue therapy should be made on a case-by-case basis; in making this decision, clinicians should consider the clinical and radiographic response to therapy as well as toxicity of the antifungal regimen.

Patients whose rhinosinusitis has resolved but who require further immunosuppressive therapy or who will receive a hematopoietic cell transplant should be placed on an appropriate antifungal agent throughout the period of immunosuppression because of the high risk of relapse of invasive fungal rhinosinusitis.

SUMMARY AND RECOMMENDATIONS

●Fungal rhinosinusitis encompasses a wide variety of fungal infections that range from merely irritating to rapidly fatal. Fungal colonization of the upper and lower airways is a common condition because fungal spores are constantly inhaled into the sinuses and lungs. However, colonization is distinct from disease, and most colonized patients do not become ill with fungal infections. Another manifestation of fungal rhinosinusitis is allergic fungal rhinosinusitis, which involves a hypersensitivity response to colonizing fungi. (See 'Introduction' above and 'Fungal colonization' above and "Allergic fungal rhinosinusitis".)

Epidemiology

●The marked rise in the number of immunocompromised patients has led to an increase in unusual manifestations of aggressive fungal infections. Invasive rhinosinusitis is one such form of infection that appears to be increasing in frequency. (See 'Invasive fungal sinusitis' above.)

●The most common underlying diseases in patients with invasive fungal rhinosinusitis are hematologic malignancies, hematopoietic cell transplantation, chemotherapy-induced neutropenia, solid organ transplantation, advanced HIV infection, diabetes mellitus, and glucocorticoid therapy. (See 'Invasive fungal sinusitis' above.)

●The fungi most often implicated in causing invasive rhinosinusitis are species of Aspergillus, Fusarium, the Mucorales, and dematiaceous (brown-black) molds. (See 'Invasive fungal sinusitis' above.)

Clinical presentation and diagnosis

●Patients with fungal rhinosinusitis may present acutely with fever, facial pain, and nasal congestion and can also have changes in vision and mentation. Facial numbness or diplopia can occur in the setting of cranial nerve involvement. (See 'Acute fungal sinusitis' above.)

●We generally perform a computed tomography (CT) scan as the initial imaging study as it can often be obtained quickly and is more sensitive than magnetic resonance imaging (MRI) for detecting bony erosions. Clinicians should have a low threshold for performing an MRI in patients with abnormalities on CT because the MRI will enhance detection of intracranial, intraorbital, and cavernous sinus involvement. (See 'Diagnosis' above.)

●A high degree of suspicion must be maintained in the immunocompromised patient with sinus complaints, especially facial pain. The nares and oral cavity should be carefully examined for necrotic areas. Early nasal endoscopic evaluation by an otolaryngologist is essential. Necrosis results from vascular invasion by the fungi and can appear as palatal or gingival eschars or as sloughing of the nasal septum with perforation. (See 'Acute fungal sinusitis' above.)

●The diagnosis of invasive fungal rhinosinusitis is dependent upon histopathologic demonstration of fungal invasion of tissue by biopsy of involved areas. Evaluation of patients with suspected fungal rhinosinusitis should include early nasal endoscopy with biopsies of affected tissues. Cultures of the biopsy specimen are frequently positive. Isolation of the infecting fungus is necessary to guide therapy. It is important to distinguish the agents of mucormycosis from Aspergillus and dematiaceous molds because antifungal therapies are different. (See 'Diagnosis' above.)

Treatment

●Signs and symptoms of invasive rhinosinusitis in the appropriate host should warrant empiric antifungal therapy with a lipid formulation of intravenous (IV) amphotericin B or, if mucormycosis is ruled out by histopathologic demonstration of septate hyphae, voriconazole. (See 'Initial medical therapy' above.)

●Surgical evaluation should be conducted urgently for both diagnostic biopsy and for debridement. Radical surgical debridement is required in many cases to achieve cure and sometimes requires multiple surgeries. (See 'Initial medical therapy' above.)

●Another important factor in treatment is the restoration of immune function by withdrawal of immunosuppressive medications, control of metabolic perturbations, and control of the underlying illness. (See 'Initial medical therapy' above.)

●We prefer a lipid formulation of amphotericin B dosed at 5 mg/kg IV per day for the initial therapy of invasive fungal rhinosinusitis, particularly if mucormycosis is likely, because the agents of mucormycosis are resistant to voriconazole.

Exceptions to this general recommendation include the following:

•Infection due to Scedosporium apiospermum complex – Scedosporium species are generally resistant to amphotericin B and should be treated with voriconazole. (See "Treatment of Scedosporium and Lomentospora infections".)

•Infection due to Aspergillus species – The regimen of choice for treatment of invasive infection due to Aspergillus species is voriconazole. Isavuconazole is an alternative if voriconazole cannot be used. An echinocandin (caspofungin, micafungin, or anidulafungin) could be added for patients with severe disease. For patients who are intolerant of voriconazole due to severe reactions, we would choose either a lipid formulation of amphotericin B (eg, AmBisome or Abelcet) or isavuconazole. The decision of which agent to choose depends on organ dysfunction, toxicities, and tolerability. Detailed recommendations are presented separately. (See "Treatment and prevention of invasive aspergillosis".)

•Infections due to most dematiaceous fungi (phaeohyphomycosis) are likely to be chronic and to respond to a triazole, such as voriconazole, posaconazole, itraconazole, or perhaps isavuconazole. For these infections, we favor voriconazole.

●The usual dosing of voriconazole is 6 mg/kg IV every 12 hours for two doses, then 4 mg/kg IV every 12 hours. The IV formulation is recommended for at least the initial few days. Oral step-down therapy, using 200 mg twice daily, can be used following an initial response to the IV formulation. It is essential to obtain voriconazole trough serum levels to ensure adequate concentrations and to avoid toxicity. (See 'Initial medical therapy' above.)

●In patients initially receiving a lipid formulation of amphotericin B, the duration of intravenous therapy depends upon the underlying immune status of the host, the extent of surgical debridement, and the response to therapy. We recommend continuing intravenous therapy until there is a clear clinical response and reversal of as many of the immunocompromising conditions as possible (eg, recovery from neutropenia, tapering of glucocorticoids, or engraftment in hematopoietic cell transplant recipients). This usually requires weeks of therapy and may require two to three months of therapy in patients with severe immunosuppression and slow clinical responses. After improvement is noted, suppressive therapy can be given with an oral antifungal agent. The most appropriate oral agent depends upon the causative pathogen. (See 'Initial medical therapy' above and 'Oral antifungal therapy' above.)

●Suppressive therapy is usually continued for at least three to six months. Some patients who remain immunocompromised require lifelong therapy. (See 'Oral antifungal therapy' above.)