Clinical

• AIFS usually presents with symptoms similar to acute sinusitis such as fever, nasal congestion, purulent nasal discharge, headache and facial pain

• A high degree of suspicion must be maintained in the immunocompromised patient with sinus complaints, particularly facial pain or headache.

• Nasal endoscopy and a detailed head and neck examination are crucial for early detection of this condition.

• The fungi in AIFS are angioinvasive; infarction of infected tissues is a hallmark of invasive disease.

• Pale or necrotic areas with a black eschar due to vascular invasion can appear on the nares, septum, turbinates, oral mucosa, or any other affected area.

• Sensation is frequently lost surrounding the involved areas.

• A biopsy of suspicious tissue should be obtained and brought to pathology for prompt frozen specimen examination.

1. Multiple biopsies of insensate or necrotic areas should be obtained to increase the sensitivity of this examination.

• The most predictive features for AIFS are an absolute neutrophil count below 500/uL and mucosal abnormalities of the septum or turbinates.

• Orbital involvement manifests with periorbital edema, proptosis, and changes in vision.

• The infraorbital nerve is the most frequently involved cranial nerve and presents with numbness over the malar eminence.

• Involvement of the ethmoid or sphenoid sinuses should prompt concern for intracranial spread.

1. MRI demonstrates involvement of the cavernous sinus or intracerebral contents and should be obtained but should not delay excision of the involved tissue.

• Hematogenous spread of AIFS is rare but should be considered if new lesions appear elsewhere during the treatment course.

Radiology

• CT scan of the sinuses should be obtained with contrast in patients suspected of having AIFS; contrast will not be taken up by devascularized or necrotic tissue.

• The areas that should be evaluated on CT scans include:

1. Periantral fat pad thickening

2. Bone dehiscence or thickening

3. Orbital contents

5. Pterygopalatine fossa

6. Nasolacrimal duct

7. Lacrimal sac

– An abnormality associated with one of these variables has a sensitivity of 95%, meanwhile involvement of two variables has a sensitivity and specificity of 100%.

• An MRI with contrast should be obtained if there is concern for intracranial involvement based on the CT findings or clinical examination.

Histopathology

• Diagnosis of AIFS relies primarily upon identification of fungi invasion into tissue by histopathology with culture confirmation.

• Staining for fungus requires the use of calcofluor white and methenamine silver stains.

• Histopathology reveals hyphal invasion of the mucosa, submucosa, and blood vessels with thrombosis and tissue infarction.

• The hyphae of Mucorales are different from those of other fungi and often allow for identification.

1. Mucorales hyphae are broad (5 to 15 microns in diameter) with irregular, 90-degree branching and lack of septations.

2. Ascomycetous molds such as Aspergillus are narrower (2 to 5 microns in diameter) and have regular branching with many septations.

• Serum tests such as the (1->3)-beta-D-glucan assay and the Aspergillus galactomannan assay can detect fungal wall components and can be used to aid in the diagnosis of AIFS.

1. Neither test is positive with mucormycosis as Mucorales does not share these wall components.

• The presence of hyphae invading into tissue provides a presumptive diagnosis that should lead to further clinical evaluation and treatment.

1. The absence of hyphae does not rule out AIFS when the clinical picture is highly suggestive.

– Further evaluation with imaging and possibly surgical exploration may be indicated.

• Cultures of the biopsy specimen are important to distinguish Mucormorales from Aspergillus or other molds as the antifungal therapies may differ.

2. Treatment with liposomal amphotericin should be continued until the cultures are complete.

– Mucormorales is less sensitive to triazoles than other fungi, and should be the presumed infectious organism until culture shows otherwise.

• Prompt intervention plays an important role in the care of patients with AIFS, and has been shown to lead to improved outcomes.

• Treatment of AIFS involves a combination of surgical debridement of involved tissues and antifungal therapy.

Antifungal Therapy

• Immediately after the diagnosis of AIFS is made, antifungal therapy should be started.

• Liposomal amphotericin B is the appropriate first-line agent due to its broad antifungal coverage.

1. Use of the liposomal formation is particularly important for patients with renal insufficiency.

• If tissue culture reveals an organism other than Mucorales, antifungal therapy can be changed to an alternative medication.

• Infections due to Aspergillus are treated with voriconazole with or without an echinocandin (caspofungin, micafungin, or anidulafungin).

• Oral itraconazole, posaconazole, or isavuconazole can all be used for stepdown therapy after the acute stage of AIFS from any organism has passed.

1. This can take up to 3 or 4 weeks or until the patient shows signs of clinical improvement.

• Posaconazole or isavuconazole can also be used as salvage therapy for the patient who does not respond to, or is unable to tolerate, amphotericin B.

Other Medical Management

• Correction of the predisposing cause of the infection such as hyperglycemia, metabolic acidosis, iron overload, neutropenia, or immunosuppressive drugs is a critical part of treatment of AIFS.

• Patients who are neutropenic secondary to a hematologic malignancy or its treatment are also frequently pancytopenic.

1. Transfusions of appropriate blood products may be required prior to surgical debridement.

• Hyperbaric oxygen therapy has been used in the treatment of AIFS, but the benefit of this therapy has not been established.

Surgery

• After the diagnosis of AIFS is made, the patient should be scheduled for prompt surgical debridement of the involved tissue.

• Imaging studies should be formatted appropriately to allow them to be used for image guidance during the debridement.

1. Normal anatomic landmarks are often altered by the infection.

1. Surgical goals and options should be discussed with the patient.

2. Discussion of possible orbital exenteration if there is orbital involvement should be discussed prior to the procedure.

• In general, debriding or violating the skull base should be avoided as this is difficult to repair in the setting of AIFS.

• Orbital exenteration is typically avoided unless there is obvious ocular dysfunction or frank orbital involvement, and the patient or his or her caregiver has consented to this procedure.

• Serial debridements may be required during the acute phase of the infection.

• Surgery is not curative, but it is believed to serve as a means of decreasing the fungal load to allow for improved response to antifungal therapy.

Chronic Invasive Fungal Sinusitis

Epidemiology

• Chronic invasive fungal sinusitis (CIFS) presents in a similar manner to chronic rhinosinusitis (CRS) with few, if any, systemic complaints.

• Patients with this condition are often older and only mildly immunocompromised.

1. Diabetes mellitus and glucocorticoid use are risk factors for CIFS.

2. This condition has also been reported in intranasal cocaine users.

• Aspergillus and brown molds are the fungi responsible for CIFS.

1. Mucorales is not seen in this condition.

Diagnosis

• Patients with CIFS have typical symptoms of CRS for months before the development of a complication that signifies the severity of this condition.

1. The most common complication is orbital involvement that manifests as visual changes.

– Orbital apex syndrome can be seen with CIFS resulting in proptosis, decreased visual acuity, ophthalmoplegia, and decreased sensation over the forehead area.

2. The brain or cranial nerves can also be involved, causing neurologic sequelae.

1. Soft tissue mass frequently involving one paranasal sinus

2. Bony erosion

• Serum tests such as the (1->3)-beta-D-glucan assay and the Aspergillus galactomannan assay can be used to aid in the diagnosis of CIFS.

• Histopathology also is similar to AIFS, and demonstrates necrosis of the mucosa and blood vessels with low-grade mucosal inflammation.

Management

• Surgical debridement of the involved tissue is the initial treatment of choice for CIFS.

1. Similar to AIFS, a thorough discussion should take place before the surgery regarding the extent of debridement and the potential removal of surrounding structures.

• Antifungal therapy should be initiated immediately after diagnosis.

1. Mucorales is not seen in CIFS, so itraconazole or other triazoles can be alternative antifungual medications used instead of amphotericin B in the acute treatment of CIFS.

• Antifungal therapy should be continued for an extended period of time until the infection has completely resolved.

• The underlying immunocompromising factor should be treated promptly after diagnosis.

1. Patients with diabetes require strict glucose control.

2. Glucocorticoids should be stopped until resolution of the infection.

Granulomatous Fungal Sinusitis

Epidemiology

• Granulomatous fungal sinusitis (GFS) is a rare condition that has been reported almost exclusively in immunocompetent individuals from North Africa.

• It is an invasive fungal sinusitis that is typically associated with Aspergillus flavus.

Diagnosis

• Patients with GFS present with symptoms and a history consistent with CRS.

• This condition often involves the orbit, resulting in proptosis or other compressive symptoms.

• MR shows a mass that is isointense on T1 and hypointense on T2.

• Definitive diagnosis requires the histopathologic findings of granulomas and multinucleated giant cells with pressure necrosis and erosion of the sinonasal mucosa.

Management

• Treatment of this condition is similar to that of chronic invasive fungal sinusitis.

• The primary treatment is surgical debridement of the involved tissue.

1. Surgery is required for diagnosis of GFS.

2. Large openings allow for endoscopic surveillance of this condition in the postoperative setting.

3. Excision of the involved tissue often results in improvement of the proptosis or other ocular findings.

• After surgical removal of the involved tissue, systemic antifungal medications are given until the condition completely resolves.

• Recurrence of GFS is rare.

• The most commonly cultured fungi are Curvularia lunata, Aspergillus fumigatus, and Bipolaris and Drechslera species.

• AFS patients differ from CRS patients in many socioeconomic factors.

1. AFS is found in a higher prevalence in younger patients, African Americans, uninsured patients, and patient from areas with a higher poverty rate.

• The geographic incidence of AFS is mostly confined to the Mississippi River Basin and in the southern United States.

1. There are few reports of AFS outside of the United States.

• The geographic distribution is thought to be secondary to the ambient mold spore concentration in these areas, although there are no studies to support this belief.

Pathogenesis

• It is hypothesized that some external trigger, likely colonizing fungi, activates and upregulates the TH-2 and IL-5 pathways in the setting of a genetic predisposition toward the characteristic eosinophilic response.

• The host becomes sensitized to fungal antigens, and the germinating fungal hyphae serve as antigens for a large allergic response.

• The eosinophilic response causes massive degranulation and release of inflammatory mediators, cytokines, and growth factors that amplify the inflammatory response.

1. This response leads to nasal polyp formation, airway remodeling, and possibly bony demineralization.

• Degranulating eosinophils cause thick, inspissated mucus that fills the sinuses and further damages the sinonasal mucosa.

• Bacterial invasion of the damaged sinonasal mucosa leads to biofilm formation and worsening of the inflammatory process.

Diagnosis

• Patients typically present with symptoms similar to those of CRS with the four cardinal symptoms of (1) rhinorrhea, (2) nasal obstruction, (3) facial pain or pressure, and (4) hyposmia.