Secondary Logo

Updates in management of acute invasive fungal rhinosinusitis

Craig, John R.

Current Opinion in Otolaryngology & Head and Neck Surgery: February 2019 - Volume 27 - Issue 1 - p 29–36
doi: 10.1097/MOO.0000000000000507
NOSE AND PARANASAL SINUSES: Edited by Samuel S. Becker and Nithin D. Adappa

Purpose of review Acute invasive fungal rhinosinusitis (AIFRS) is a rare and often fatal disease, that remains incompletely understood. Case series and literature reviews constitute most of the literature on AIFRS, and act as the standards by which we treat these extremely complex patients. This review discusses management of AIFRS, with focuses on optimal diagnostic and therapeutic strategies.

Recent findings Mortality rates remain high, around 50% overall, though some recent studies have shown higher survival rates with early diagnosis and complete surgical resection. Some recent publications on AIFRS have focused on the utility of frozen section analysis both to diagnose and potentially guide the completeness of endoscopic surgical debridement. It was also recently shown that complete endoscopic resection of disease leads to higher survival than when disease was incompletely resected. Additionally, a new antifungal agent was recently approved by the FDA, which has a more favorable pharmacologic and side effect profile, though more studies are necessary to determine its utility.

Summary Early diagnosis requires identification of sinusitis symptoms in immunocompromised patients, followed by intranasal biopsy and frozen section analysis. Early surgical debridement and antifungal therapy then remain the cornerstones of AIFRS management.

Video abstract See Video, Supplemental Digital Content 1,

Department of Otolaryngology–Head and Neck Surgery, Henry Ford Health System, Grand Blvd, Detroit, Michigan, USA

Correspondence to John R. Craig, MD, Department of Otolaryngology–Head and Neck Surgery, Henry Ford Health System, 2799 W. Grand Blvd, Detroit, MI 48202, USA. Tel: +1 313 971 9320; fax: +1 313 916 7263; e-mail:

Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's Website (

Back to Top | Article Outline


Fungi are ubiquitous in nature, being inhaled into the nasal cavity with every breath. Fungal spores are deposited into the sinonasal mucus lining, and form part of the normal sinonasal microbiome [1]. In immunocompetent patients, spores are destroyed either by tissue macrophages, or through immunologic cascades that recruit neutrophils for fungal spore removal [2,3]. Although phagocytic cells form the primary defense against fungi, helper and cytotoxic T cells also play a role [3–5]. In immunocompromised patients, spores can germinate into hyphae, invade the mucosa, and possibly neurovascular structures [6,7]. If fungi enter the intravascular space, they can spread and cause both local and distant tissue ischemia, necrosis or hemorrhage.

Acute invasive fungal rhinosinusitis (AIFRS) is defined by presence of fungal hyphae within the sinonasal mucosa, submucosa, vasculature or bone, in the setting of 1 month or less of sinusitis symptoms [8,9]. The most common fungi causing AIFRS include Mucor and Rhizopus spp. from the Zygomycetes class/Mucorales order, and Aspergillus spp. Rarer fungi include Alternaria spp., Candida spp., and Fusarium spp. [2]. Both Aspergillus spp. and Mucor spp. can be angioinvasive, and whereas Mucor spp. has been suggested to be more aggressive with more frequent neurovascular and orbital invasion [10,11], multiple studies have shown that fungus type does not predict survival [12,13▪▪,14▪].

Overall, diabetes (50%) and hematologic malignancy (40%) account for 90% of the immunosuppression causing AIFRS, as was reported in a review of over 800 patients by Turner et al. [13▪▪]. Aspergillus spp. and Mucor spp. can both be found in neutropenic patients and those who take chronic systemic steroids, whereas Mucor spp. has a propensity for diabetic and iron-overloaded patients [2,3]. The mechanisms behind immunosuppression and AIFRS risk remain incompletely understood, but absolute and functional neutropenia are major underlying causes of most AIFRS-associated immunocompromised states. However, patients with HIV/AIDS, iron overload, protein-energy malnutrition, or transplant patients on azole prophylaxis are also at risk for AIFRS, so neutropenia is not the only immunologic risk factor [2,15,16].

Box 1

Box 1

Back to Top | Article Outline


Single-institution and multicenter case series have reported mortality rates from 20 to 80% [12,17,18,19▪▪,20–24], with most series reporting mortality rates greater than 50%. A recent meta-analysis of 210 AIFRS cases showed a 60% overall survival, which has not changed significantly over the last 20 years [14▪]. Multiple series have reported negative prognostic factors, such as delayed diagnosis [25], orbital [26,27] and intracranial [12,13▪▪,27] involvement, diabetes [26,28], neutropenia [24], advanced age [13▪▪,29,30] and Mucor species [10,11,22]. There are discrepancies between published reports of negative prognostic factors and overall survival, making it difficult to draw conclusions.

Turner et al. published the largest systematic review of 52 studies and 807 patients, 398 of whom were used for prognostic factor analysis. They reported an overall survival rate of about 50%, with the following factors predicting worsened survival: advanced age, aplastic anemia (20%), renal/hepatic failure (24%), intracranial and cavernous sinus extension (25%), and neutropenia (29%). They reported improved survival in patients who were diabetic (50%), received liposomal amphotericin B (60%) or underwent open (54%) or endoscopic sinus surgery (ESS) (64%) [13▪▪].

Back to Top | Article Outline


Early diagnosis is the key to managing AIFRS successfully. However, diagnosing AIFRS can be challenging because of its rarity and nonspecific clinical presentation. It is helpful to learn about AIFRS in the context of the temporal course of the diagnostic workup and treatment. First, patients usually present with nonspecific sinonasal complaints that have been ongoing for 1 month or less [8]. There is no pathognomonic symptom for AIFRS, but facial pain, facial edema, nasal obstruction and fever have been reported most commonly, occurring in 50–65% of patients [2,13▪▪,19▪▪]. Particularly worrisome signs and symptoms, though less frequent, are those signifying neurovascular, orbital or intracranial invasion: facial numbness, palatal/facial necrosis, vision changes, proptosis and severe headaches.

When patients present with ongoing sinonasal complaints, physicians must consider whether they are immunocompromised. It is case reportable how rare AIFRS is in immunocompetent patients [31,32]. As diabetes and absolute neutropenia are the main risk factors for AIFRS, a basal metabolic panel to assess for hyperglycemia/ketoacidosis, and complete blood count with differential to assess the absolute neutrophil count (ANC) should be checked. Patients with an ANC less than 500/μl are at risk for AIFRS [19▪▪,24]. No absolute plasma glucose value has been clearly associated with AIFRS, but ketoacidosis is not required [33]. If glucose and ANC are normal, physicians should determine whether patients are HIV-positive, on chronic steroids, or at risk for iron overload. Immunocompromised patients with sinonasal symptoms warrant sinus computed tomography (CT) and nasal endoscopy.

As AIFRS patients are often initially seen by nonotolaryngologists, sinus CT scans are often obtained next. No imaging findings are 100% sensitive or specific for AIFRS. Multiple studies have shown the most common CT finding in 80–100% of AIFRS cases to be intranasal or sinus mucosal thickening [19▪▪,24,34], more commonly unilateral [24,34]. Absence of sinus inflammation on CT has high sensitivity and NPV [35]. More aggressive CT findings of osseous erosion and orbit/brain/skin invasion are highly specific for AIFRS [35], but are less common until late in the disease [24,34]. Periantral fat infiltration anterior or posterior to the maxillary sinus is one of the most specific findings for AIFRS (Fig. 1) [35,36]. Groppo et al. [37] analyzed CT and contrast-enhanced MRI findings in 17 AIFRS patients, and found that MRI was more sensitive than CT for diagnosing AIFRS. MRI is superior to CT for distinguishing mucus versus edema, and in assessing invasion beyond the sinuses (periantral fat, orbit, brain). Another benefit of contrast-enhanced MRI is to assess for loss of mucosal enhancement, which can be a sign of ischemia. Groppo et al. [37] found that loss of mucosal enhancement had 64–87% sensitivity and 40–83% specificity.



Nasal endoscopy is the next component of the workup and is indicated in any immunocompromised patient with sinonasal symptoms, or inflammation on sinus CT [34,38]. Extrapolating from CT/MRI studies showing nasal mucosal thickening to be a very common early finding in AIFRS [19▪▪,34], surgeons should assess the entire nasal cavity for mucosal edema. Some case series have also reported intranasal edema to be an early endoscopic finding in AIFRS (Fig. 2a), which may become violaceous (Fig. 2b) before turning pale or black from ischemia or necrosis (Fig. 3a)[2,22]. Endoscopic findings consistent with necrosis include discoloration, eschars/crusting and ulceration (Fig. 3b).





Intranasal biopsy is the next consideration. Most AIFRS involves the middle turbinate, nasal septum or nasal floor mucosa, so attention should be paid to these areas for possible biopsy. The maxillary and ethmoid sinuses are the most common sinuses involved, but are not usually accessible for biopsy in awake patients [12]. The middle turbinate has been shown to be the most common site of fungal involvement in AIFRS (40–90% of cases), with pallor or necrosis being the most common tissue appearance [17,19▪▪,20,24]. Middle turbinate biopsy has 75–86% sensitivity and 100% specificity for diagnosing AIFRS [19▪▪,39]. Payne et al. used the following criteria for biopsying the middle turbinate in 41 AIFRS patients: ANC less than 500/μl, mucosal abnormalities on nasal endoscopy and CT showing sinonasal inflammation. They reported an AIFRS-specific mortality rate of 24%, which they attributed to their low threshold to biopsy the middle turbinate early in the disease, even if no mucosal abnormality [19▪▪]. Although the middle turbinate is commonly involved in AIFRS, if other subsites appear abnormal, they too should be biopsied. Once the biopsy is obtained, it should be taken immediately to the pathologist for frozen section analysis. Frozen section has been shown to have 85% sensitivity, 70% negative predictive value (NPV) and 100% specificity and positive predictive value (PPN) [40▪,41▪,42]. On histopathology, Zygomycetes demonstrate irregular, aseptate broad-branching hyphae, whereas Aspergillus spp. have septate acute-branching hyphae (Fig. 4a and b).



Back to Top | Article Outline


Multidisciplinary management centers on early surgical debridement, antifungal therapy and reversal of the underlying immunodeficiency. Multiple studies have shown that ESS is an independent positive prognostic factor for survival [13▪▪,23,24,30,43▪▪]. Potential reasons for improved survival from surgery include earlier tissue diagnosis, improved antifungal delivery after necrotic tissue removal, decreased fungal burden and improved postoperative sinonasal monitoring. Intraoperatively, most series suggest debriding necrotic sinonasal tissue until bleeding is seen, with repeat surgical debridements as needed. Removal of suspicious sinonasal mucosa generally requires ESS directed at sinuses involved. If turbinates are suspected, they too should be removed. Any necrotic bone should be removed if it can be done safely. Invaded bone may appear discolored or just significantly thinner and weaker compared with healthy bone. Also important to consider is that to remove all the diseased sinus mucosa may require extended endoscopic approaches. For maxillary disease, this could require endoscopic medial maxillectomy [44], endoscopic Denker's approach [45] or Caldwell-Luc antrostomy [46]. For pterygopalatine or infratemporal fossae disease, a transmaxillary approach may be required [47]. For frontal disease, an endoscopic Draf III may be necessary [48].

Intraoperative frozen section has been employed to guide surgical debridement. Although frozen section has 100% PPV for AIFRS, the NPV is 70%, so a negative result does not guarantee a clear margin. Therefore, surgical completion is left largely to the judgment of the surgeon based on preoperative imaging, and intraoperative tissue appearance along with frozen section margins. Roxbury et al. retrospectively reviewed 54 AIFRS patients to assess the effect of complete surgical resection on survival to hospital discharge. Complete resection was defined by either negative frozen section margins or absence of disease seen on postoperative endoscopy. Overall short-term survival was 69.2%. Complete surgical resection resulted in 95.5% survival, as opposed to 42.9% for incomplete resection, and 28.6% if no surgery (P = 0.001) [43▪▪].

Orbital and intracranial extension of AIFRS have generally been found to be poor prognostic factors. Orbital involvement creates the dilemma of whether or not to perform a disfiguring orbital exenteration. Studies to date have not shown improved survival with orbital exenteration. Turner et al. [13▪▪] showed no survival benefit in 80 patients who underwent orbital exenteration. Roxbury et al. [43▪▪] showed that 15 AIFRS patients with orbital involvement had nearly the same survival as patients with disease limited to the sinuses, and only one of those patients had an exenteration. Hargrove et al. performed a meta-analysis of 224 patients with orbital mucormycosis, and reported no survival benefit from orbital exenteration except in patients with fever over 101.5 °F. The authors highlighted that inconsistent data limited the analysis, and presence or absence of fever should not act as a guide for performing an exenteration [29]. When patients have intracranial extension, neurosurgery consultation is necessary. Studies generally show poor survival [12,13▪▪,49], though some studies show success with craniotomy [50,51]. Benefits versus risks of craniotomy must be weighed on a case-by-case basis.

Another issue receiving minimal attention in the literature is the effect of time to surgery on survival in AIFRS. Multiple series have declared AIFRS a surgical ‘emergency,’ suggesting ‘immediate’ surgery [17,52,53]. However, very little evidence supports this. Yohai et al. reviewed 145 AIFRS cases and assessed the effect of delay of amphotericin and surgery on survival. Delay of medical and surgical treatment more than 6 days was associated with decreased survival, with amphotericin delay having a more profound effect than delay of surgery. No statistical analysis was reported [25]. More recently Vaughan et al. [14▪] analyzed 37 mucormycosis cases, and they found no significant difference in survival between patients having surgery 1–30 days after diagnosis (1–6 days: 61%, 7–12 days: 54%, 13–30 days: 75%). Declaring AIFRS a surgical urgency versus emergency has important implications. If AIFRS is diagnosed during nighttime hours, and ESS is suggested emergently, risks may be incurred, such as surgeon fatigue or logistical errors because of the operating room staff being unfamiliar with endoscopic surgeries. Without clear survival benefit shown for emergent ESS, perhaps in these scenarios, less risk would be incurred by first initiating antifungal therapy. ESS could then be performed within 24 h, rather than emergently. This question requires further study.

Back to Top | Article Outline


Antifungal therapy should be initiated as soon as AIFRS is diagnosed. The review by Yohai et al. [25] showed that survival declined substantially if amphotericin was delayed 6 days after symptom onset. Azole agents have replaced amphotericin as the mainstay for aspergillosis, with voriconazole being the first-line drug choice [54]. However, voriconazole requires long-term therapeutic monitoring, and has various acute and delayed side effects [55▪]. Amphotericin has remained the mainstay for mucormycosis, with multiple studies showing it to be an independent predictor of survival [13▪▪,25,29]. Its use is limited by nephrotoxicity, and therefore when possible, liposomal amphotericin is recommended. Some studies have shown survival benefit with the liposomal formulation [13▪▪,30,56,57], though nephrotoxicity can still occur. In patients who cannot tolerate liposomal amphotericin, posaconazole has been recommended as a second-line agent, as it has activity against Mucor spp. [58,59].

The Food and Drug Administration (FDA) recently approved a new second-generation azole drug, isavuconazole, and it has potential in treating both aspergillosis and mucormycosis. The intravenous formulation is water-soluble, less nephrotoxic than amphotericin and less hepatotoxic than voriconazole. It is also available in an oral formulation, with excellent bioavailability. It has in-vitro activity against Aspergillus spp. and several Mucor spp. [60,61]. A randomized controlled trial showed it to be noninferior to voriconazole with respect to survival in treating aspergillosis, with a lower side-effect profile [55▪]. A smaller single-arm, open-label trial assessed isavuconazole in 37 mucormycosis patients. A matched case–control analysis showed no survival difference between patients receiving isavuconazole and amphotericin [62▪]. The evidence for isavuconazole use is stronger for aspergillosis, but future studies will be important in determining its potential role for mucormycosis.

The next component of AIFRS management is reversing underlying immunosuppression. Although immunosuppression is the primary source of the disease, much of the evidence supporting immunosuppression reversal is indirect. In the setting of diabetes, it is intuitive that hyperglycemia reversal will be beneficial, but no studies have conducted a quantitative analysis of plasma glucose levels and AIFRS clinical outcomes. Indirect evidence comes from multiple studies showing improved survival for diabetic over neutropenic patients with AIFRS, presumed to be because of the easier reversibility of hyperglycemia compared with neutropenia [13▪▪,24,25,39]. Regarding neutropenia, Kennedy et al. reviewed 26 bone marrow transplant patients with AIFRS who underwent ESS and antifungal therapy. Eventual transplant success and neutrophil recovery was necessary to clear the fungus, though survival was still not guaranteed [27]. Ergun et al. assessed survival outcomes in 11 AIFRS patients, 10 whom had absolute neutropenia. Five of the 10 patients had their neutropenia corrected, and survival in the neutropenia-controlled group was significantly higher than the uncontrolled group (80 vs. 40%) [63]. Lastly, granulocyte colony-stimulating factor has been recommended in mucormycosis patients with hematologic malignancy and ongoing neutropenia, although no clear survival benefit has been shown [64].

Other adjunctive therapies have been reported. Hyperbaric oxygen (HBO) has an antifungal effect in vitro through free oxygen radical formation [65]. Limited evidence exists to support its use in AIFRS, but a review of 28 AIFRS patients by John et al. [66] showed a significant survival benefit with adjunctive HBO use, especially for diabetic patients. Iron chelation requires further study, but one double-blinded randomized controlled trial showed decreased survival in patients receiving desafirox and liposomal amphotericin, compared with liposomal amphotericin alone [67].

Back to Top | Article Outline


AIFRS is a complex and devastating disease, with around a 50% mortality rate. Making the diagnosis early in immunocompromised patients, followed by ESS, antifungal therapy and immunodeficiency reversal are essential to improve survival.

Back to Top | Article Outline


I would like to thank Natalie Craig, graphic designer, for her assistance formatting the figures in this article.

Back to Top | Article Outline

Financial support and sponsorship


Back to Top | Article Outline

Conflicts of interest

There are no conflicts of interest.

Back to Top | Article Outline


Papers of particular interest, published within the annual period of review, have been highlighted as:

  • ▪ of special interest
  • ▪▪ of outstanding interest
Back to Top | Article Outline


1. Lee JT, Frank DN, Ramakrishnan V. Microbiome of the paranasal sinuses: update and literature review. Am J Rhinol Allergy 2016; 30:3–16.
2. Spellberg B, Edwards J Jr, Ibrahim A. Novel perspectives on mucormycosis: pathophysiology, presentation, and management. Clin Microbiol Rev 2005; 18:556–569.
3. Shoham S, Levitz SM. The immune response to fungal infections. Br J Haematol 2005; 129:569–582.
4. McDermott AJ, Klein BS. Helper T-cell responses and pulmonary fungal infections. Immunology 2018; 155:155–163.
5. Kumaresan PR, da Silva TA, Kontoyiannis DP. Methods of controlling invasive fungal infections using CD8(+) T-cells. Front Immunol 2017; 8:1939.
6. Filler SG, Sheppard DC. Fungal invasion of normally nonphagocytic host cells. PLoS Pathog 2006; 2:e129.
7. Frater JL, Hall GS, Procop GW. Histologic features of zygomycosis: emphasis on perineural invasion and fungal morphology. Arch Pathol Lab Med 2001; 125:375–378.
8. Chakrabarti A, Denning DW, Ferguson BJ, et al. Fungal rhinosinusitis: a categorization and definitional schema addressing current controversies. Laryngoscope 2009; 119:1809–1818.
9. deShazo RD, O’Brien M, Chapin K, et al. A new classification and diagnostic criteria for invasive fungal sinusitis. Arch Otolaryngol Head Neck Surg 1997; 123:1181–1188.
10. Ingley AP, Parikh SL, DelGaudio JM. Orbital and cranial nerve presentations and sequelae are hallmarks of invasive fungal sinusitis caused by Mucor in contrast to Aspergillus. Am J Rhinol 2008; 22:155–158.
11. Trief D, Gray ST, Jakobiec FA, et al. Invasive fungal disease of the sinus and orbit: a comparison between mucormycosis and Aspergillus. Br J Ophthalmol 2016; 100:184–188.
12. Monroe MM, McLean M, Sautter N, et al. Invasive fungal rhinosinusitis: a 15-year experience with 29 patients. Laryngoscope 2013; 123:1583–1587.
13▪▪. Turner JH, Soudry E, Nayak JV, et al. Survival outcomes in acute invasive fungal sinusitis: a systematic review and quantitative synthesis of published evidence. Laryngoscope 2013; 123:1112–1118.

Largest meta-analysis of positive and negative prognostic factors of survival.

14▪. Vaughan C, Bartolo A, Vallabh A, et al. A meta-analysis of survival factors in rhino-orbital-cerebral mucormycosis - has anything changed in the past 20 years? Clin Otolaryngol 2018; 43:1454–1464.

Recent large meta-analysis showing that survival has not changed over last 20 years.

15. Marty FM, Cosimi LA, Baden LR. Breakthrough zygomycosis after voriconazole treatment in recipients of hematopoietic stem-cell transplants. N Engl J Med 2004; 350:950–952.
16. Imhof A, Balajee SA, Fredricks DN, et al. Breakthrough fungal infections in stem cell transplant recipients receiving voriconazole. Clin Infect Dis 2004; 39:743–746.
17. Gillespie MB, O’Malley BW Jr, Francis HW. An approach to fulminant invasive fungal rhinosinusitis in the immunocompromised host. Arch Otolaryngol Head Neck Surg 1998; 124:520–526.
18. Sun HY, Singh N. Mucormycosis: its contemporary face and management strategies. Lancet Infect Dis 2011; 11:301–311.
19▪▪. Payne SJ, Mitzner R, Kunchala S, et al. Acute invasive fungal rhinosinusitis: a 15-year experience with 41 patients. Otolaryngol Head Neck Surg 2016; 154:759–764.

One of the largest single-institution studies showing one of the highest survival rates in literature, suggesting that early diagnosis with middle turbinate biopsy may improve survival, and 90% of patients had hematologic malignancy.

20. Jung SH, Kim SW, Park CS, et al. Rhinocerebral mucormycosis: consideration of prognostic factors and treatment modality. Auris Nasus Larynx 2009; 36:274–279.
21. Petrikkos G, Skiada A, Sambatakou H, et al. Mucormycosis: ten-year experience at a tertiary-care center in Greece. Eur J Clin Microbiol Infect Dis 2003; 22:753–756.
22. Husain S, Alexander BD, Munoz P, et al. Opportunistic mycelial fungal infections in organ transplant recipients: emerging importance of non-Aspergillus mycelial fungi. Clin Infect Dis 2003; 37:221–229.
23. Chen CY, Sheng WH, Cheng A, et al. Invasive fungal sinusitis in patients with hematological malignancy: 15 years experience in a single university hospital in Taiwan. BMC Infect Dis 2011; 11:250.
24. Valera FC, do Lago T, Tamashiro E, et al. Prognosis of acute invasive fungal rhinosinusitis related to underlying disease. Int J Infect Dis 2011; 15:e841–e844.
25. Yohai RA, Bullock JD, Aziz AA, Markert RJ. Survival factors in rhino-orbital-cerebral mucormycosis. Surv Ophthalmol 1994; 39:3–22.
26. Bhansali A, Bhadada S, Sharma A, et al. Presentation and outcome of rhino-orbital-cerebral mucormycosis in patients with diabetes. Postgrad Med J 2004; 80:670–674.
27. Kennedy CA, Adams GL, Neglia JR, Giebink GS. Impact of surgical treatment on paranasal fungal infections in bone marrow transplant patients. Otolaryngol Head Neck Surg 1997; 116:610–616.
28. Parikh SL, Venkatraman G, DelGaudio JM. Invasive fungal sinusitis: a 15-year review from a single institution. Am J Rhinol 2004; 18:75–81.
29. Hargrove RN, Wesley RE, Klippenstein KA, et al. Indications for orbital exenteration in mucormycosis. Ophthalmic Plast Reconstr Surg 2006; 22:286–291.
30. Sun HY, Forrest G, Gupta KL, et al. Rhino-orbital-cerebral zygomycosis in solid organ transplant recipients. Transplantation 2010; 90:85–92.
31. Larsen K, von Buchwald C, Ellefsen B, Francis D. Unexpected expansive paranasal sinus mucormycosis. ORL J Otorhinolaryngol Relat Spec 2003; 65:57–60.
32. Ruoppi P, Dietz A, Nikanne E, et al. Paranasal sinus mucormycosis: a report of two cases. Acta Otolaryngol 2001; 121:948–952.
33. Roden MM, Zaoutis TE, Buchanan WL, et al. Epidemiology and outcome of zygomycosis: a review of 929 reported cases. Clin Infect Dis 2005; 41:634–653.
34. DelGaudio JM, Swain RE Jr, Kingdom TT, et al. Computed tomographic findings in patients with invasive fungal sinusitis. Arch Otolaryngol Head Neck Surg 2003; 129:236–240.
35. Middlebrooks EH, Frost CJ, De Jesus RO, et al. Acute invasive fungal rhinosinusitis: a comprehensive update of CT findings and design of an effective diagnostic imaging model. AJNR Am J Neuroradiol 2015; 36:1529–1535.
36. Silverman CS, Mancuso AA. Periantral soft-tissue infiltration and its relevance to the early detection of invasive fungal sinusitis: CT and MR findings. AJNR Am J Neuroradiol 1998; 19:321–325.
37. Groppo ER, El-Sayed IH, Aiken AH, et al. Computed tomography and magnetic resonance imaging characteristics of acute invasive fungal sinusitis. Arch Otolaryngol Head Neck Surg 2011; 137:1005–1010.
38. DelGaudio JM, Clemson LA. An early detection protocol for invasive fungal sinusitis in neutropenic patients successfully reduces extent of disease at presentation and long term morbidity. Laryngoscope 2009; 119:180–183.
39. Saedi B, Sadeghi M, Seilani P. Endoscopic management of rhinocerebral mucormycosis with topical and intravenous amphotericin B. J Laryngol Otol 2011; 125:807–810.
40▪. Melancon CC, Clinger JD. The use of frozen section in the early diagnosis of acute invasive fungal sinusitis. Otolaryngol Head Neck Surg 2017; 157:314–319.

Recent article reporting on utility of frozen section analysis for diagnosing AIFRS.

41▪. Papagiannopoulos P, Lin DM, Al-Khudari S, et al. Utility of intraoperative frozen sections in surgical decision making for acute invasive fungal rhinosinusitis. Int Forum Allergy Rhinol 2017; 7:502–507.

Recent article reporting on utility of intraoperative frozen section analysis to guide surgical resection in AIFRS.

42. Ghadiali MT, Deckard NA, Farooq U, et al. Frozen-section biopsy analysis for acute invasive fungal rhinosinusitis. Otolaryngol Head Neck Surg 2007; 136:714–719.
43▪▪. Roxbury CR, Smith DF, Higgins TS, et al. Complete surgical resection and short-term survival in acute invasive fungal rhinosinusitis. Am J Rhinol Allergy 2017; 31:109–116.

Recent article analyzing the effect of complete surgical resection on survival in AIFRS not only showing significantly improved survival if complete resection achieved, but also showed no significant survival difference whether disease involved sinuses or extended to orbit.

44. Costa ML, Psaltis AJ, Nayak JV, Hwang PH. Long-term outcomes of endoscopic maxillary mega-antrostomy for refractory chronic maxillary sinusitis. Int Forum Allergy Rhinol 2015; 5:60–65.
45. Lee JT, Suh JD, Carrau RL, et al. Endoscopic Denker's approach for resection of lesions involving the anteroinferior maxillary sinus and infratemporal fossa. Laryngoscope 2017; 127:556–560.
46. DeFreitas J, Lucente FE. The Caldwell-Luc procedure: institutional review of 670 cases: 1975-1985. Laryngoscope 1988; 98:1297–1300.
47. Goyal P, Leung MK, Hwang PH. Endoscopic approach to the infratemporal fossa for treatment of invasive fungal sinusitis. Am J Rhinol Allergy 2009; 23:100–104.
48. Weber R, Draf W, Kratzsch B, et al. Modern concepts of frontal sinus surgery. Laryngoscope 2001; 111:137–146.
49. Lee DH, Yoon TM, Lee JK, et al. Invasive fungal sinusitis of the sphenoid sinus. Clin Exp Otorhinolaryngol 2014; 7:181–187.
50. Munir N, Jones NS. Rhinocerebral mucormycosis with orbital and intracranial extension: a case report and review of optimum management. J Laryngol Otol 2007; 121:192–195.
51. Ma J, Jia R, Li J, et al. Retrospective clinical study of eighty-one cases of intracranial mucormycosis. J Glob Infect Dis 2015; 7:143–150.
52. Abu El-Naaj I, Leiser Y, Wolff A, et al. The surgical management of rhinocerebral mucormycosis. J Craniomaxillofac Surg 2013; 41:291–295.
53. Kasapoglu F, Coskun H, Ozmen OA, et al. Acute invasive fungal rhinosinusitis: evaluation of 26 patients treated with endonasal or open surgical procedures. Otolaryngol Head Neck Surg 2010; 143:614–620.
54. Walsh TJ, Anaissie EJ, Denning DW, et al. Treatment of aspergillosis: clinical practice guidelines of the Infectious Diseases Society of America. Clin Infect Dis 2008; 46:327–360.
55▪. Maertens JA, Raad II, Marr KA, et al. Isavuconazole versus voriconazole for primary treatment of invasive mould disease caused by Aspergillus and other filamentous fungi (SECURE): a phase 3, randomised-controlled, noninferiority trial. Lancet 2016; 387:760–769.

Recent randomized controlled trial showing isavuconazoole was as effective as voriconazole for aspergillosis, with lower side effect profile.

56. Kara IO, Tasova Y, Uguz A, et al. Mucormycosis-associated fungal infections in patients with haematologic malignancies. Int J Clin Pract 2009; 63:134–139.
57. Singh N, Aguado JM, Bonatti H, et al. Zygomycosis in solid organ transplant recipients: a prospective, matched case-control study to assess risks for disease and outcome. J Infect Dis 2009; 200:1002–1011.
58. Greenberg RN, Mullane K, van Burik JA, et al. Posaconazole as salvage therapy for zygomycosis. Antimicrob Agents Chemother 2006; 50:126–133.
59. van Burik JA, Hare RS, Solomon HF, et al. Posaconazole is effective as salvage therapy in zygomycosis: a retrospective summary of 91 cases. Clin Infect Dis 2006; 42:e61–e65.
60. Shirley M, Scott LJ. Isavuconazole: a review in invasive aspergillosis and mucormycosis. Drugs 2016; 76:1647–1657.
61. Miceli MH, Kauffman CA. Isavuconazole: a new broad-spectrum triazole antifungal agent. Clin Infect Dis 2015; 61:1558–1565.
62▪. Marty FM, Ostrosky-Zeichner L, Cornely OA, et al. VITAL and FungiScope Mucormycosis Investigators. Isavuconazole treatment for mucormycosis: a single-arm open-label trial and case-control analysis. Lancet Infect Dis 2016; 16:828–837.

Smaller nonrandomized study showing no survival difference between isavuconazole and amphotericin in mucormycosis.

63. Ergun O, Tahir E, Kuscu O, et al. Acute invasive fungal rhinosinusitis: presentation of 19 cases, review of the literature, and a new classification system. J Oral Maxillofac Surg 2017; 75:767.e1–767.e9.
64. Cornely OA, Arikan-Akdagli S, Dannaoui E, et al. European Society of Clinical Microbiology and Infectious Diseases Fungal Infection Study Group; European Confederation of Medical Mycology. ESCMID and ECMM joint clinical guidelines for the diagnosis and management of mucormycosis. Clin Microbiol Infect 2014; 20 (Suppl 3):5–26.
65. Tragiannidis A, Groll AH. Hyperbaric oxygen therapy and other adjunctive treatments for zygomycosis. Clin Microbiol Infect 2009; 15 (Suppl 5):82–86.
66. John BV, Chamilos G, Kontoyiannis DP. Hyperbaric oxygen as an adjunctive treatment for zygomycosis. Clin Microbiol Infect 2005; 11:515–517.
67. Spellberg B, Ibrahim AS, Chin-Hong PV, et al. The Deferasirox-AmBisome Therapy for Mucormycosis (DEFEAT Mucor) study: a randomized, double-blinded, placebo-controlled trial. J Antimicrob Chemother 2012; 67:715–722.

aspergillosis; diabetes; invasive fungal sinusitis; mucormycosis; neutropenia

Supplemental Digital Content

Back to Top | Article Outline
Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.