1

Case report

A 53 year-old male with acquired immune deficiency syndrome (AIDS) and poorly controlled diabetes mellitus (DM) presented with a 4-week history of progressive bilateral facial pain and diplopia. On initial examination there was no evidence of palatal or nasal mucosa necrosis, cranial palsies, or facial edema. His initial laboratory studies revealed a decreased white blood cell count (3.08 × 10 ³ cells/μL), markedly decreased CD4 count (26 cells/μL) and markedly elevated HbA1c (12%). A non-contrast CT of his paranasal sinuses revealed bilateral pansinusitis with no evidence of bony erosion (see Fig. 1 ). Endoscopic sinus examination revealed pansinus mucosal thickening and thick, yellow polypoid tissue. The paranasal sinuses were debrided and cultured. No evidence of necrosis or invasive fungal disease was noted endoscopically or on frozen sections. Initially, the concern for acute invasive fungal rhinosinusitis (AIFRS) was low based on clinical, surgical and histopathological examination.

CT sinus without contrast from day 6 revealing pansinusitis without evidence of bony erosion.

On day 11, nasal sinus cultures identified Rhizopus spp . and repeat endoscopic examination revealed extensive necrosis involving the bilateral middle turbinates and the posterior nasal septum extending to floor of the nose. Histopathological examination revealed necrotic bone and mucosa with invasive fungal elements consistent with Mucorales. Necrotic areas were debrided endoscopically and combination antifungal therapy with IV Liposomal Amphotericin B (L-AMB) (10 mg/kg/day) and IV Micafungin was initiated for the treatment of acute invasive Mucorales rhinosinusitis. On days 13–17, his disease progressed to involve the bilateral ethmoid sinuses, bilateral sphenoid sinuses, right frontal sinus, bilateral maxillary sinuses, left medial maxilla and left inferior turbinate necessitating debridement of the involved sinuses, left medial maxillectomy, left inferior turbinectomy, and left sphenopalatine artery ligation.

Clinically, the patient remained stable throughout his admission and his bilateral facial pain and diplopia resolved. On day 25, clinical, surgical, histopathological, and radiographic examination did not reveal evidence of AIFRS. Consequently, he was discharged from the hospital on long-term L-AMB and Micafungin.

On day 65, he presented with recurrent invasive fungal rhinosinusitis. Surgical, radiographic, and histopathological examination demonstrated involvement of the anterior skull base and bilateral pterygopalatine fossae extending to the inferior orbital fissures (see Fig. 2 ). In total, 12 serial endoscopic debridements were required to resect the diseased tissues. Due to the refractory nature of his infection and the development of renal insufficiency (serum potassium 2.2 mmol/L; serum creatinine 2.35 mg/dL) secondary to L-AMB, a newly approved antifungal drug, Isavuconazole (Cresemba), was recommended as an alternative. On day 76, IV Isavuconazole was initiated (loading dose 372 mg every 8 hours for 48 hours; maintenance dose 372 mg daily) for the treatment of L-AMB refractory/intolerant invasive Mucorales rhinosinusitis.

(A) MRI face and sinus with and without contrast from day 71 showing post-surgical nasal exenteration, near complete opacification of the bilateral maxillary sinuses, enhancement of the bilateral pterygopalatine fossas, cribriform plate, and left fovea ethmoidalis. There is no evidence of leptomeningeal involvement or intracranial abscess.

(B) CT sinus without contrast from day 80 re-demonstrating post-surgical nasal exenteration. There is improved aeration of the bilateral maxillary sinuses and evidence of bony erosion of the cribriform plate and hard palate.

At his most recent follow-up (day 94), the patient has significantly improved. Surgical and histopathological examinations revealed trace areas of necrosis involving the bilateral pterygopalatine fossae without evidence of fungal elements (see Fig. 3 ). Clinically, he does not report any significant symptoms or long-term sequelae. Isavuconazole was well tolerated without adverse effects except for elevated liver enzymes (alkaline phosphatase 1021 IU/L, AST 47 IU/L, ALT 48 IU/L). He continues to receive ongoing therapy with IV Isavuconazole and close observation with weekly endoscopic and histopathological examinations.

Endoscopic view of the posterior nasal cavity from day 94 re-demonstrating post-surgical nasal exenteration. Trace necrotic areas were debrided down to healthy mucosa.

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Discussion

Acute invasive fungal rhinosinusitis (AIFRS) is a rare but frequently fatal infection that usually affects patients with poorly controlled DM and/or immunosuppression. AIFRS is characterized by fungal invasion of the paranasal sinuses and nasal cavity with frequent extension to adjacent structures, including the palate, orbit, and brain. Recognition of evolving AIFRS requires a high index of suspicion because early symptoms may mimic acute sinusitis (e.g. sinus pain, headache, congestion). The disease is heralded by rapid progression with symptoms of facial edema, vision changes, and cranial nerve palsies associated with evidence of pale ischemia, purple black crusting, or frank necrosis. Concurrent surgical, clinical, and radiologic examination may help establish the diagnosis but definitive diagnosis requires histopathological confirmation of invasive fungal elements .

The organisms primarily responsible for AIFRS include species from the genus Aspergillus and the order Mucorales, which includes Mucor spp . and Rhizopus spp . These saprophytic fungi are ubiquitous in the environment, but may become pathogenic in patients with impaired neutrophil activity and/or hyperglycemia. Normally, these fungi are cleared by polymorphonuclear phagocytes and possess an active ketone reductase system allowing them to thrive in acidic, glucose rich environments . Thus, AIFRS primarily affects immunocompromised and/or DM patients, and reversal of these predisposing conditions is essential for disease clearance .

Despite aggressive multimodal therapy, the prognosis of AIFRS remains grim with short-term mortality rates reported to range from 30–83% . Successful treatment depends on a timely diagnosis, aggressive surgical debridement, high dose systemic anti-fungal therapy, and management of predisposing risk factors.

Amphotericin B is the drug of choice for the treatment of invasive mucormycosis . Unfortunately, high doses of conventional Amphotericin B are poorly tolerated and significant nephrotoxicity usually develops if administered for more than a few days. Lipid formulations of Amphotericin B are associated with reduced rates of nephrotoxicity; however, significant rates of nephrotoxicity can develop at high doses . Additionally, Mucorales are highly resistant to most antifungals and may demonstrate resistance to Amphotericin B . Thus, alternative antifungals are essential for patients who cannot tolerate Amphotericin B and for patients with refractory invasive Mucorales rhinosinusitis.

Currently, only two antifungals, Posaconazole and Isavuconazole, are FDA approved to treat invasive mucormycosis . Posaconazole, an oral triazole antifungal agent, appears to have clinically useful activity against Mucorales species, however, it exhibits suboptimal absorption and variable bioavailability . Isavuconazole (Cresemba), a novel azole antifungal, has been shown to be safe and clinically effective against invasive mucormycosis when compared to untreated cases of mucormycosis, which is associated with a mortality rate of 97–100%. In an open label, non-comparative trial of patients with primary mucormycosis, refractory mucormycosis, and intolerant mucormycosis, the all-cause mortality at day 42 was 38% . Furthermore, Isavuconazole offers distinct advantages over Amphotericin B and Posaconazole. It is not known to cause nephrotoxicity, is well tolerated, and possesses excellent absorption and bioavailability . The most common side effects include gastrointestinal complaints, headache and abnormal liver enzymes. In most cases, the adverse hepatic effects are reversible when the drug is discontinued .

Given the rarity of the disease, no randomized control trials exist regarding the treatment of invasive mucormycosis with Isavuconazole. To date, only one case report has described successful Isavuconazole use in a patient with acute invasive Mucorales rhinosinusitis . In that case, Isavuconazole was initiated for a total duration of 506 days due to the development of renal insufficiency secondary to L-AMB and refractory mucormycosis. Isavuconazole was well tolerated except for a transient skin rash associated with prolonged sunlight exposure. 2 years after termination of Isavuconazole, the patient does not exhibit any evidence of invasive fungal disease.

To our knowledge, we report the first case of successful treatment of acute invasive Mucorales rhinosinusitis with Isavuconazole in a patient with AIDS. Initially, our patient presented with signs and symptoms suggestive of sinusitis. However, given his history of AIDS and DM, a high index of suspicion was maintained and early endoscopic debridement in combination with systemic antifungal therapy was initiated for the treatment of acute invasive Mucorales rhinosinusitis. His AIFRS was atypical because it persisted despite multiple endoscopic debridements and combination systemic antifungal therapy. Eventually, he developed a severe recurrence and renal insufficiency secondary to L-AMB. Alternative therapy with IV Isavuconazole was instituted and his renal insufficiency resolved. Overall, the patient improved remarkably and tolerated Isavuconazole with minimal adverse effects. Isavuconazole contributed to the successful treatment of this patient’s refractory invasive Mucorales rhinosinusitis and should be considered as an alternative to Amphotericin B in patients with resistant invasive Mucorales rhinosinusitis or Amphotericin induced renal insufficiency.