Aspergillosis

Etiology

• Aspergillosis includes four distinct clinical entities:
• Acute invasive
• Chronic destructive
• Chronic nondestructive
• Allergic
• Pathogens
• Primary pathogen is Aspergillus fumigatus, a ubiquitously inhaled fungal spore.
• Aspergillus flavus is a less common, but more virulent, invasive pathogen.
• It is important for its role in post-harvest colonization of cereal grains and legumes.
• In humans, it affects primarily immunocompromised hosts.
• Aspergillus oryzae is another occasional invasive pathogen (Green, Arch Ophthalmol 1969).
• Primary industrial use: the production of soy sauce, miso, and sake.
• Aspergillus niger: ubiquitous species causing black mold in fruits and vegetables
• Can cause external infections (such as external otitis), but less likely internal disease, such as sinusitis, in humans.
• Extension of primary sinus disease
• Primary orbital aspergillosis is well recognized, but is less common, and must always be considered with unexplained orbital inflammation. An erroneous diagnosis of idiopathic orbital inflammation and inappropriate use of high dose steroids can have disastrous results (Slavin, Arch Ophthalmol 1991).
• Secondary intracranial extension from the orbit can occur, or central nervous system disease can extend into the orbit (Yoon, Ophthal Plast Reconstr Surg 23:400, 2007).
• Inhalation of spores is the most frequent mode of acquiring the organism
• In a series of immunocompromised patients with AIDS chronic inhalation of marijuana smoke was a means of exposure (Johnson, Arch Ophthalmol 1999).
• The acute, invasive type typically affects immunosuppressed, while the chronic and allergic types typically affect immunocompetent patients.

Epidemiology

• In a series of 15 immunocompetent patients with invasive aspergillosis of the orbit (Pushker, Ophthalmology 2011)
• 80% had unilateral involvement.
• The mean age was 35 (range 3 months–60 years).
• 70% were male.
• The epidemiology of immunocompromised patients depends on the clinical setting.

History

• For the acute, invasive type, ask about immunosuppression risk factors:
• Neutropenia
• Glucocorticoids
• Autoimmune disease treatment
• Organ transplant treatment
• AIDS
• For the chronic or allergic types, ask about a history of chronic sinusitis.
• For allergic types, ask about asthma or cystic fibrosis.

Clinical features

• Acute, invasive aspergillosis
• Occurs more commonly in immunocompromised patients but important to recognize in immunocompetent patients
• In a series of eight immuncompetent patients with aspergillosis, isolated to the orbit, restriction of ocular motility was a prominent presenting sign (Aggarwal, Am J Ophthalmol 2016).  
• Invasive aspergillosis primarily affects the nose and paranasal sinuses.
• Orbital involvement worsens the prognosis because it provides a means of intracranial spread.
• It can also affect the lungs, skin, brain, eyes, liver, and kidneys.
• Proptosis, ocular pain, and periorbital inflammation are typical presenting signs of sinus disease with orbital extension (Heier, Ophthalmology 1995).
• Other ophthalmic manifestations include acute retrobulbar optic neuropathy, endophthalmitis, orbital apex syndrome, cavernous sinus syndrome.
• Chronic, destructive aspergillosis
• Slow destruction of sinuses and adjacent structures
• Intraorbital and intracranial extension can occur
• Better prognosis than the acute invasive type
• Chronic, nondestructive, and localized aspergillosis (aspergillomas or fungus balls)
• Occurs in the immunocompetent
• Arises in poorly drained spaces such as the orbit, paranasal sinuses, or brain
• There is a lack of inflammation or bone erosion
• Orbital mass signs/symptoms: pain, proptosis, decreased vision, diplopia, chemosis
• Allergic aspergillosis (allergic fungal sinusitis)
• Occurs in the immunocompetent (Carter, Am J Ophthalmol 1999).
• Originally this entity was described specifically in association with aspergillus and therefore it was termed “allergic aspergillus sinusitis” (Katzenstein, J Allergy Clin Immunol 1983). However, the primary pathogen is now felt to be dematiaceous molds including Curvularia, Alternaria, and Bipolaris, and therefore the term “allergic fungal sinusitis” is currently favored.
• Affects bronchopulmonary system and paranasal sinuses resulting in chronic rhinosinusitis producing nasal polyps and chronic sinusitis
• A history of asthma or atopy is typical.
• The expectoration of brownish mucus plugs is typical and is referred to as allergic mucin because of the abundance of eosinophil, peripheral blood eosinophilia, and hemoptysis.
• Sphenoid sinus involvement can cause optic neuropathy.
• Direct invasion in the orbit can cause proptosis, which is the most common ophthalmic manifestation (Carter, Am J Ophthalmol 1999).
• Diplopia, tearing, and headache are common features.

Testing

• Chest CT, as well as imaging studies of the brain or orbit as appropriate
• Culture of normally sterile site (positive culture isolation of aspergillus in airways does not necessarily indicate disease, as this is ubiquitous).
• Histopathology is characterized by vascular invasion and tissue necrosis:
• Aspergillus species typically have narrow, septated hyphae with acute angle branching.
• Multiple biopsies might sometimes be necessary in rhinosinusitis.

• A serum assay is available for galactomannan, an aspergillus polysaccharide cell wall component released during fungal growth (Choi, Ophthal Plast Reconstr Surg 2008).
• The clinically available studies use enzyme-linked immunosorbent galactomannan assays and polymerase chain reaction, and have moderate sensitivity and specificity.
• They are useful as adjuncts to the clinical evaluation.
• For allergic type: skin test reactivity to aspergillus antigens, peripheral eosinophilia, fungus-specific immunoglobulin E and G, elevated total immunoglobulin E

• For acute, invasive type:
• Therapy for hematologic malignancies
• Hematopoietic cell transplantation
• Solid organ transplantation
• Severe or prolonged neutropenia
• High doses of glucocorticoids
• AIDS
• For allergic type:
• Asthma
• Cystic fibrosis

• Other fungal infections, which can have different treatments
• Mucor: broad, nonseptated hyphae with right-angle branching
• Fusarium: narrow, septated hyphae with acute-angle branching
• Bacterial infection
• Tumor
• Idiopathic orbital pseudotumor

Natural history

• Acute type tends to progress rapidly with poor outcome once disseminated.
• Chronic, destructive type can cause significant morbidity when intraorbital and intracranial extension occur.
• Allergic type’s natural history is not well understood.

Medical and surgical options

• Antifungal agents include intravenous voriconazole and amphotericin B for invasive, acute disease.
• Oral itraconazole is a reasonable therapy for invasive, chronic disease (Massry, Ophthalmology 1996).
• The usual dose is 200 mg, once daily, with meals, in an immuncompetent patient, increased to twice daily in immunocompromised patients.
• The most common side effects are nausea and vomiting, occurring in approximately 10% of patients, and mild elevation of hepatic enzymes in 5% of patients.
• More severe, isolated cases of idiosyncratic hepatitis have been reported with oral itraconazole.
• When possible, immunosuppressive agents should be decreased.
• For rhinosinusitis, surgical debridement is considered important because aspergillus is angioinvasive and causes necrosis by infarction. This creates an environment in which drug penetration is compromised. Excision of aspergillomas and abscesses is mostly necessary to promote tissue healing.
• Six patients treated in Sydney, Australia with conservative debridement and systemic antifungal intravenous medication responded to treatment (Athavale, Ophthal Plast Reconstr Surg 2017). 

Common treatment responses, follow-up strategies

• Acute, invasive type has a poor prognosis.
• Chronic types have a better prognosis.
• Allergic type’s prognosis is not well understood.

• Voriconazole
• Complications: hepatitis, renal failure, increased risk of skin cancer
• Prevention: serum trough concentrations and regular dermatology screenings
• Surgical debridement
• Complications: vision loss, deformity
• Prevention: early empiric treatment and/or serial screening in high-risk situations to prevent aspergillus involvement of the orbit/sinuses

• Patients with invasive disease can die from intracranial spread.
• Intracranial abscess and destruction can cause significant morbidity, including cerebral infarcts.

Previously recommended antibiotics were amphotericin B, flucytosine, or rifampin, but now voriconazole is the antibiotic of choice.

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2. Athavale DD, Jones R, O’Donnell BA, et al. Non-exenteration management of sino-orbital fungal disease. Ophthal Plast Reconstr Surg. 2017; 33:426–429.
3. Carter KD et al. Ophthalmic manifestations of allergic fungal sinusitis. Am J Ophthalmol. 127:189, 1999
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9. Katzenstein AL et al. Allergic Aspergillus sinusitis: a newly recognized form of sinusitis. J Allergy Clin Immunol. 72:89, 1983.
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