Chronic Aspergillus sinusitis

Chronic invasive and granulomatous Aspergillus rhinosinusitis

Chronic rhinosinusitis (CRS) accounts for >90% of all cases of rhinosinusitis, and the correct diagnosis of each category of CRS is important for optimum therapy and predicting the course (Chakrabarti 2009). Fungal organisms are the aetiology agent of CRS in 6-12% of the patients, Aspergillus spp. being the leading cause (Hope, 2005; Laury, 2010).


Classification and epidemiology

The most recent and widely classification categorized rhinosinusitis as invasive and non-invasive is based on the histopathological findings of the invaded tissue (Deshazo, 1997; Das, 2009). The non-invasive category of fungal sinusitis is defined by the absence of hyphae within the mucosal and other tissues of the paranasal sinuses and includes fungal colonization, fungal ball and allergic fungal rhinosinusitis (Soler, 2012). Invasive fungal rhinosinusitis is defined by the presence of fungal hyphae within the mucosa, submucosa, bone or blood vessels of the paranasal sinuses. It is further subdivided into acute invasive (fulminant) and chronic invasive categories, the latter including chronic granulomatous and chronic invasive fungal sinusitis with a time of course of >12 weeks (Chakrabarti, 2004). These last two entities are the subject of this article. Some authors have defined “mixed fungal sinusitis” as a combination of invasive and non-invasive disease and propose it as a different entity with completely different outcome and implications for therapy (Busaba, 2002; Rupa, 2013).

Chronic invasive fungal sinusitis is most commonly seen in western populations (Busaba, 2002) and Japan (Nakaya, 2009), whereas granulomatous invasive fungal rhinosinusitis is most commonly observed in Africa (Sudan), Southeast Asia (India, Pakistan, Saudi Arabia) (Alrajhi, 2001; Chopra, 2006; Krishnan 2014), Korea (Hoon Kim, 2012) and in some south-western states of United States (Stringer, 2000; Currens, 2002).


Underlying conditions

Chronic invasive fungal rhinosinusitis often occurs in the context of subtle immunosuppression as seen in diabetes, corticosteroid use and human immunodeficiency virus infection. However, cases have been reported in individuals without obvious immune defects (Alrhaji, 2001). Aspergillus fumigatus is the most common agent isolated.

Chronic granulomatous invasive fungal rhinosinusitis is also known as primary paranasal granuloma and indolent fungal sinusitis; it develops in immunocompetent patients or well-controlled diabetics, almost exclusively in association with Aspergillus flavus infection (Hope, 2005; Challa, 2010).


Clinical presentations and imaging

A fungal aetiology should be suspected in patients with refractory or recurrent sinusitis. Diagnosis is often delayed, particularly in immunocompetent patients (Alrajhi, 2001). Fungal invasion into surrounding tissues occurs slowly over time and specific symptoms will reflect which anatomical area is affected. Both chronic invasive and granulomatous Aspergillus rhinosinusitis are characterised by a mass within one or more paranasal sinuses with evidence of invasion of contiguous structures such as the base of the skull, orbit and brain. The disease is usually persistent and recurrent.

Chronic invasive fungal rhinosinusitis usually commences in deeper sinuses such as the posterior ethmoid and sphenoid sinuses and has a gradual onset followed by a progressive course. Patients often endure symptoms of chronic rhinosinusitis such as sinus pain, nasal discharge, headache (Jhuo, 2011), low-grade fever and intermittent epistaxis. Invasion of the maxillary floor leads to palatal erosions. Tenderness overlying a maxillary sinus with accompanying skin erythema is often observed on physical exam (Gorovoy, 2012). When the infection expands out of the ethmoid sinuses medially into the orbit, the orbital apex syndrome has been a common clinical presentation with proptosis ~ third, four and sixth cranial neuropathy and diminished vision. Occasionally, invasion of adjacent structures such as the orbit, cavernous sinus, and anterior cranial fossa may lead to epidural abscess, parenchymal cerebritis or abscess, meningitis, cavernous sinus thrombosis, osteomyelitis, mycotic aneurism, stroke and haematogenous dissemination (DeShazo, 2009). Intranasal examination reveals nasal congestion and polypoid mucosa; soft tissue masses may be identified (Stringer, 2000).

Granulomatous fungal sinusitis usually runs an even more indolent course and chiefly involves the maxillary and ethmoid sinuses, nose, orbit and cheek. The most common presenting symptom is unilateral proptosis or an enlarging, painless and irregular mass in the cheek, orbit, nose or paranasal sinuses mimicking an orbital tumour (Hoon Kim, 2012; Halderman, 2014). Other symptoms at the time of presentation include severe nasal congestion/obstruction, sinus pain/pressure, headaches and facial numbness. Physical exam findings include unilateral proptosis, swelling of the medial canthus region or maxilla, numbness over the trigeminal V2 distribution, congested mucosa, and polypoid changes to the mucosa on nasal endoscopy. Chronic granulomatous disease may mimic malignancy.

The imaging findings are similar in both entities (Goroboy, 2012). Radiological findings generally include a hyper-attenuating soft-tissue collection on non-contrast computed tomography (CT) within one or more of the paranasal sinuses. Iso- or hypo-intense signals are observed on T1-weighted magnetic resonance images (MRI), and marked hypo-intense signals are observed on T2-weighted MR images (Aribandi, 2007). Mottled lucencies or irregular bone destruction may be seen in the paranasal sinuses. It is known that CT is superior to MRI for evaluating the sinunasal anatomy and identifying surgical landmarks, although MRI should be ordered when orbital or intracranial involvement is suspected. Generally findings are unilateral and present in only 1 to 2 sinuses; the appearance is homogeneous and there is more diseased tissue outside the sinuses than within them. There may also be sclerotic changes in the bony walls of the affected sinuses representing chronic sinus disease. These radiological characteristics help to differentiate fungal rhinosinusitis from paranasal sinus malignancy although sometimes differentiation may not be possible based on imaging findings (Oates, 1987; Stringer, 2000; Reddy, 2010).


Pathology and mycology diagnosis

The most important differences between chronic and granulomatous invasive fungal rhinosinusitis are the histopathological characteristics. Adequate quantities of sinus contents and biopsy specimens of diseased and healthy mucosa and bone adjacent to areas of frank necrosis must be obtained for pathologic analysis.

Chronic invasive fungal rhinosinusitis is characterized by dense accumulation of hyphae infiltrating mucosa, blood vessels, and adjacent tissues as muscles and bones, which often exhibit necrosis and a nonspecific inflammatory infiltrate. Granulomatous invasive fungal rhinosinusitis is characterized by non-caseating granuloma with scanty fungal hyphae (visualised in around 50% of cases (Hope, 2005)) within Langerhans-type giant cells, together with surrounding vasculitis and perivascular fibrosis. Surrounding tissue typically shows a mild amount of inflammation consisting of eosinophils, lymphocytes and plasma cells in a setting of dense fibrosis (Das, 2009; Soler, 2012).

Fungi do not stain well with routine stains; special silver-impregnated fungal stains (Gomori methenamine silver) and fungal cultures are required for accurate diagnosis of the fungal sinusitis and sub-classification (Hoon-Kim, 2012). Cultures of tissue are positive in 30-70% of cases of chronic fungal rhinosinusitis (deShazo, 1997; Chakrabarti, 2009; Challa, 2010). Polymerase chain reaction (PCR) identifies the genus or species of fungus in >70% of chronic rhinosinusitis (Kim 2005). Serological data may be used as indirect evidence to implicate Aspergillus spp. when cultures are negative or not obtained. Species specific precipitating antibodies are present in >90% of cases in chronic invasive disease and correlates well with disease progression, usually to A. flavus (Hedayati, 2010; Chakrabarti, 1992). Similarly, precipitating antibodies to Aspergillus spp. are present in around two-thirds of cases of chronic granulomatous sinusitis, especially a positive IgG to A. flavus (Yagi, 1999; Currens, 2002; Hope, 2005).



Delay in the diagnosis and treatment of chronic fungal sinusitis leads to increased morbidity and mortality (Hoon Kim, 2012). The standard management involves a combination of surgical debridement of necrotic tissues and long-term antifungal treatment, guided by culture results if possible, to prevent relapse. Isolated reports of cases of chronic Aspergillus sinusitis that have responded to surgery without antifungal therapy exist in the literature (Stringer, 2000; Busaba, 2002), although they usually showed high rates of relapse (Alrhaji, 2001). Tight glycaemic control in diabetic patients and discontinuation of corticosteroids is also critical.

Surgical approach is determined by the CT findings. Some authors suggested that angioinvasion might be an independent variable that predicts a worse prognosis in chronic invasive fungal rhinosinusitis. Patients with angioinvasion might benefit from a more aggressive therapeutic approach, such as initial intravenous therapy, wide surgical debridement, more intense assessment of response and alternative therapy if the response is inadequate (Busaba 2002) and consideration of supplementary gamma interferon therapy (Smith, 2014). Scans should be repeated 4 to 8 weeks after surgery.

There is no consensus as to the optimal duration of antifungal treatment for chronic aspergillosis rhinosinusitis, and reports vary widely depending on the severity of the disease and on the institution ~ from 3 months to more than 15 months (Panda, 2008; Nakaya, 2010). Chronicity and relapse characterise this disease. Therapy for those with overt bone disease should be for at least 6 months and possibly for 12 months or longer.

Amphotericin B was the initial antifungal choice for a long time until the azoles became available (Soler, 2012). There are frequent reports of stopping amphotericin B within first days of therapy, because of its toxicity (Siddiqui, 2004; Kim, 2012) and it has shown a high rate of relapse (Rupa, 2014). The advantage of azoles is that they can be given orally as they are often used for long-term therapy in chronic rhinosinusitis. Itraconazole and voriconazole have shown high response rates, in immunocompromised and immunocompetent patients (Gumaa, 1992; Busaba, 2002; Herbrecht, 2002; Sambatakou, 2006; Panda, 2008; Nakaya, 2009; Li, 2010; Nakaya, 2010; Jhuo, 2011; Halderman, 2014; Rupa, 2014). Based on its pharmacokinetics and safety profile, posaconazole (tablets or liquid) is an alternative. A 3-6 week course of amphotericin B (>0.8mg/Kg/d) or lipid-associated amphotericin B (3-5mg/Kg/d) usually secures a remission and should be followed by itraconazole or voriconazole for several months to control the disease and to prevent recurrences (Hoon Kim, 2012). Induction therapy with amphotericin B is generally unecessary unless the patient has already failed therapy with an azole. Amphotericin B is probably less active against A. flavus compared with A. fumigatus (Hedayati, 2007). The usual adult dose of voriconazole is 6mg/kg twice a day on day one followed by 4 mg/kg twice a day for 7 days with the option to decrease to 200 mg orally, twice a day thereafter (Thomas, 2008). The dose of itraconazole should be 200-400mg daily. Serum azole levels should be monitored throughout the treatment.


Outcome and follow up

Patients with granulomatous fungal sinusitis are believed to have a better prognosis than those with invasive fungal rhinosinusitis, although granulomatous invasive fungal rhinosinusitis tends to have a high relapse rate. Overall, morbidity and mortality appears to be lower than acute invasive disease.

Regular follow-up is indicated and should continue for about 5 years. The goal is to identify and treat recurrent disease while localized and before contiguous structures, such as the orbit and brain, are involved. Some authors recommend a CT scan 1 month after surgery and a prolonged course of antifungal chemotherapy, with imaging repeated every 3 or 4 months and endoscopy every 2 to 3 months to evaluate recurrence (Washburn 1988). Use of MR imaging reduces radiation exposure.

Both conditions can lead to bone erosions of the sinus wall and localised invasion; therefore, prompt diagnosis and initiation of appropriate therapy for relapse are essential to avoid a protracted or fatal outcome.

Isabel Rodriguez Goncer, MD

Hospital Universitario de Mostoles

Rio Jucar Street, 28935

Mostoles (Madrid, Spain)

[email protected]


David W. Denning,

Professor of Infectious Disease in Global Health

Director, National Aspergillosis Centre

Education and Research Centre

University Hospital of South Manchester

Southmoor Road

Manchester M23 9LT, UK

[email protected]


December 2015