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Chronic invasive Aspergillus sinusitis

Chronic invasive and granulomatous Aspergillus rhinosinusitis

There are 3 discrete clinical entities subsumed under the term chronic Aspergillus rhinosinusitis, namely ‘chronic invasive Aspergillus rhinosinusitis’, fungus ball of the sinus’ (also termed sinus aspergilloma) and ‘chronic granulomatous Aspergillus rhinosinusitis’ or ‘paranasal Aspergillus granuloma’. These entities are defined partly clinically, radiologically and pathologically (Hope, 2005). Fungus ball of the sinus is described elsewhere on this website (link).

Epidemiology

The frequencies of chronic invasive and granulomatous Aspergillus rhinosinusitis are not known. They are common in the Middle East (Milosev, 1969; Yagi, 1999; Dawlatly, 1988; Alrajhi, 2001) and India (Ramani, 1994; Surya Prakash Rao, 1984), but both exceptionally rare in N. America and Western Europe. Both are more commonly caused by A. flavus (approximately 90% of cases) than other species (Hedayati, 2007), although A. fumigatus is implicated a sizeable minority of hronic invasive cases, as are other much less common species. Chronic granulomatous disease usually presents between the ages of 25 and 38 years (Dawlatly, 1988; Yagi 1999).

Underlying conditions

Most patients with chronic invasive Aspergillus rhinosinusitis have no discernible immunocompromising factors (Washburn et al, 1988; Khoo & Denning, 1995), although a substantial minority are diabetics (Oates et al, 1987; Rom et al, 1982; Laranaga et al, 1989; drink alcohol to excess (Stevens, 1978; Zinnerman 1972), or have AIDS (Khoo & Denning, 1994; Meyer et al, 1994; Mylonakis et al, 1997). The immunological assessment of those with a predisposing factor has included assessment of phagocyte function (superoxide generation, chemotaxis and reduction of nitroblue tetrazolium), Aspergillus conidia; killing activity of peripheral blood mononuclear cells, lymphocyte subpopulation and NK cell activity, immunoglobulins and complement activity (Washburn et al, 1988). No defect was identified. Certain animals, especially long-nosed dogs also develop chronic invasive Aspergillus rhinosinusitis. Chronic Aspergillus granulomatous rhinosinusitis only occurs in non-immunocompromised patients and has not been studied as to underlying risk factors.

Clinical presentation and imaging

Chronic invasive rhinosinusitis is a slowly destructive process that most commonly affects the ethmoid and sphenoid sinuses but may involve any paranasal sinus. A common presentation includes chronic nasal discharge and blockage, loss of smell and persistent headache. It cannot be distinguished clinically from other fungal causes of chronic sinusitis. Also frequent are headaches, loss or impairment of smell and the features of chronic sinusitis (nasal stuffiness, etc). Fever is almost universally absent. Perhaps most commonly the presentation features local involvement of critical structures. Most commonly visual symptoms including diplopia, unilateral blindness, pain in the eye and proptosis are encountered. The orbital apex syndrome is characteristic (blindness and proptosis) but facial swelling, cavernous sinus thrombosis or carotid artery occlusion (Clancy & Nguyen, 1998), pituitary fossa or skull base invasion is described (Swift & Denning, 1998).

Chronic granulomatous Aspergillus sinusitis usually presents with unilateral proptosis (Milosev, 1969) caused by a painless, hard, irregular, relatively avascular mass which mimics malignancy. Distortion of the facial architecture by swelling of the medial canthus region or maxilla is frequently seen. Ethmoidal involvement with or without maxillary involvement is typical but occasionally only the maxillary or frontal sinus is involved (Yagi, 1999; Alrajhi, 2001). The sphenoid sinus is rarely involved. Symptoms are present for a mean of 16 months before diagnosis. There is frequent local involvement of local structures with intracranial involvement is seen in at least 50% of cases at the time of diagnosis (Alrajhi, 2001). Bone erosion is a common finding.

Imaging of the cranial sinuses shows opacification of one of more sinuses, local boney destruction and invasion of local structures. 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. Chronic granulomatous disease may mimic malignancy. Some patients with a fungal ball of a sinus or patients with eosinophilic fungal rhinosinusitis have expansion of the boney margin of a sinus, with either boney sclerosis or thinning, but this should not be confused with localised invasion. Some patients develop retro-orbital chronic invasive aspergillosis, which probably originated from the paranasal sinuses, but no sinus disease is visible on imaging.

Aspergillus sphenoid sinusitis requires particular mention because of its frequent devastating complications. The sphenoid sinus lies beneath the pituitary gland and optic nerves and immediately adjacent to both cavernous sinuses and both temporal lobes of the brain. Besides draining much of the venous blood from the brain the cavernous sinus also has within it all the nerves controlling eye movements and sensation to the face and the carotid artery. Thus direct extension of Aspergillus disease from the sphenoid sinus carries the likelihood of major visual disturbance, brain abscess due to Aspergillus or stroke and/or death due to involvement of the carotid artery (Sekhas et al, 1980; Denning et al, 1989). Another intractable complication is osteomyelitis base of the skull (Kountakis et al, 1997; Swift & Denning, 1998). About 10% of all cases of chronic sphenoid sinusitis are due to Aspergillus, the commonest fungal pathogen (Lew et al, 1983), and over 20 cases have been reported, mostly with devastating consequences for the patient. Headache is the most common symptom which can be dull or severe and usually is present for months before other symptoms appear. As other sinuses are not usually involved few symptoms referable to them are described. Treatment is identical to that for other affected sinuses although the surgical approach differs.

Pathology and mycology

In chronic invasive disease the sinus mass is composed of friable, necrotic, or purulent material (Milroy, 1989; Clancy & Nguyen, 1998; Panda, 1998), but in chronic granulomatous disease the mass is firm and difficult to remove surgically (Alrajhi, 2001). In chronic invasive disease fungal hyphae are seen invading contiguous structures whereas in chronic granulomatous disease tissue destruction occurs as a result of expansion of the mass. In chronic invasive disease the histological appearance is that of a sparse low grade mixed cellular infiltrate without prominent eosinophils, fibrosis or granulomas whereas in chronic granulomatous disease, large numbers of loose poorly formed granulomas surrounding giant cells containing fungal hyphae (visualised in around 50% of cases) with many lymphocytes and plasma cells. Both fibrotic and necrotic histological variants of chronic granulomatous disease have been described (Veress, 1973). The vascular appearance, nevertheless, is often abnormal; vessels are characteristically thickened with luminal narrowing due to intimal proliferation with a peri-arterial, cuff-like chronic inflammatory infiltrate progressing to concentric lamellated dense fibrous tissue without demonstrable hyphal elements (Veress, 1973). Hyphae characteristic of Aspergillus are seen in both chronic invasive and granulomatous and are relatively sparse in both conditions. Vascular invasion is not seen in either condition.

The fungal differential diagnosis is wide, as numerous other fungi may cause a similar disease and sphenoid sinusitis is more often caused by bacteria. Cultures of tissue are positive in >50% of cases. Species specific precipitating antibodies are present in >90% of cases in chronic invasive disease (Chakrabarti & Sharma, 2000). Precipitating antibodies to Aspergillus spp. are present in around two-thirds of cases and a positive IgG RAST to A. flavus is also frequently seen in chronic granulomatous disease (Milosev, 1969, Yagi, 1999). Serological data may be used as indirect evidence to implicate Aspergillus spp. when cultures are negative or not obtained.

Treatment

For both chronic invasive and granulomatous Aspergillus sinusitis, surgical debridement followed by prolonged antifungal therapy is required. Surgical debridement is required, along with aeration of the sinuses. Sometimes this can be done endoscopically, but much more commonly it requires significant open surgery. The surgical approach is determined by the CT findings, and extensive involvement of cranial structures, including the brain and may require involvement of neurosurgery and/or plastic surgery. In all cases removal of as much affected bone and mucosa, without infringing on other major structures is the objective.

Amphotericin B is still preferred as primary therapy (Chakrabarti & Sharma, 2000), although the course duration may be significantly shortened nowadays as a switch to oral therapy is required to prevent relapse. Itraconazole has often been used as primary therapy but it is often not successful (Denning et al, 1994, Khoo & Denning, 1995). Sometimes this is because therapeutic serum concentrations are not achieved (e.g. >1mg/l by HPLC or >5mg/1 by bioassay). Use of itraconazole solution may improve exposure in some patients. In those who fail itraconazole, a 3-6 week course of amphotericin B (>0.8mg/kg/d) or lipid-associated amphotericin B (3-5 mg/kg/d) usually secures a remission. Voriconazole and posaconazole are alternative oral treatments.

Chronicity and relapse characterise this disease. A rapid reduction in Aspergillus antibody (precipitin) titre usually follows surgery. Further reduction in titre occurs with successful medical therapy, although this may take months. Follow up should continue for about 5 years. Often it is not clear on presentation whether the patient has saprophytic sinusitis or chronic invasive disease, unless there is clear cut bone destruction on CT scanning. In these cases, histology of bone and mucosa should be diagnostic. In both chronic invasive and granulomatous disease, medical therapy should be started early and continued and scans repeated 4 to 8 weeks after surgery. If there is no improvement or deterioration then more extensive debridement will be necessary, possibly combined with alternative medical therapy.

David W. Denning FRCP FRCPath FIDSA FMedSci
Professor of Medicine and Medical Mycology
Director, National Aspergillosis Centre
Education and Research Centre
University Hospital of South Manchester (Wythenshawe Hospital)
Southmoor Road
Manchester M23 9LT UK

March 2008