REVIEW

CURRENT
OPINION Updates in management of acute invasive
fungal rhinosinusitis
John R. Craig

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
Downloaded from http://journals.lww.com/co-otolaryngology by BhDMf5ePHKbH4TTImqenVAJP5BDjqW51NEeRHXBI4xxfJ+mpla05wyozwWS/WYS629v0iQQt/nI= on 01/15/2019

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, http://links.lww.com/COOH/A38.
Keywords
aspergillosis, diabetes, invasive fungal sinusitis, mucormycosis, neutropenia

INTRODUCTION symptoms [8,9]. The most common fungi causing

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 immuno-
logic cascades that recruit neutrophils for fungal
spore removal [2,3]. Although phagocytic cells form
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 inva-
sion [10,11], multiple studies have shown that fun-
&& &

the primary defense against fungi, helper and cyto-
toxic T cells also play a role [3–5]. In immunocom-
promised patients, spores can germinate into
hyphae, invade the mucosa, and possibly neuro-
vascular structures [6,7]. If fungi enter the intravas-
cular 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
gus type does not predict survival [12,13 ,14 ].
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: JCraig1@hfhs.org.
Curr Opin Otolaryngol Head Neck Surg 2019, 27:29–36
DOI:10.1097/MOO.0000000000000507

1068-9508 Copyright ß 2018 Wolters Kluwer Health, Inc. All rights reserved. www.co-otolaryngology.com

Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.

Nose and paranasal sinuses
KEY POINTS
 Early diagnosis is essential, which requires identifying
the cardinal symptoms of sinusitis in the following
immunocompromised states: poorly controlled diabetes,
absolute neutropenia (hematologic malignancy, drug-
induced neutropenia), HIV/AIDS, chronic steroid use,
and iron overload. Nasal endoscopy as well as
computed tomography (CT) is warranted in these
patients. Magnetic resonance imaging (MRI) improves
diagnostic accuracy and assesses extent of spread.
 Edema alone can be indicative of early AIFRS; patients
would not always have pale or dusky mucosa with
crusting and ulceration.
 There should be a low threshold to perform intranasal
biopsy with frozen section analysis, based on areas of
concern on nasal endoscopy, CT, and MRI; if no overt
abnormalities are seen but clinical suspicion remains
high, consider middle turbinate biopsy. If biopsy is
negative, but suspicion remains high, the patient should
be taken to the operating room.
 Management requires a multidisciplinary approach,
with the most significant positive predictors of survival
being surgical debridement and antifungal therapy.
 For nasal and sinus disease with orbital and/or
intracranial extension, endoscopic sinus surgery with or
without extended endoscopic sinus approaches are
often sufficient for initial surgical management. Risk
versus benefit of disfiguring or morbid operations, such
as rhinectomy, maxillectomy and orbital exenteration
should be considered on a case-by-case basis, but often
do not improve survival.
Overall, diabetes (50%) and hematologic malig-
nancy (40%) account for 90% of the immunosup-
pression 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 neutrope-
nic 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 immunocompro-
mised states. However, patients with HIV/AIDS, iron
overload, protein-energy malnutrition, or trans-
plant patients on azole prophylaxis are also at risk
for AIFRS, so neutropenia is not the only immuno-
logic risk factor [2,15,16].
SURVIVAL AND PROGNOSTIC FACTORS
Single-institution and multicenter case series
have reported mortality rates from 20 to 80%
30 www.co-otolaryngology.com
Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.
&&
[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 diagno-
&&
sis [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 pub-
lished reports of negative prognostic factors and
overall survival, making it difficult to draw conclu-
sions.
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 ].
DIAGNOSIS
Early diagnosis is the key to managing AIFRS suc-
cessfully. However, diagnosing AIFRS can be chal-
lenging 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 pres-
ent 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 sig-
nifying neurovascular, orbital or intracranial inva-
sion: 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 com-
plete blood count with differential to assess the
absolute neutrophil count (ANC) should be
checked. Patients with an ANC less than 500/ml
&&
are at risk for AIFRS [19 ,24]. No absolute plasma
glucose value has been clearly associated with AIFRS,
Volume 27  Number 1  February 2019
 Updates in management of AIFRS Craig

but ketoacidosis is not required [33]. If glucose and
ANC are normal, physicians should determine
whether patients are HIV-positive, on chronic ste-
roids, or at risk for iron overload. Immunocompro-
mised patients with sinonasal symptoms warrant
sinus computed tomography (CT) and nasal endo-
scopy.
As AIFRS patients are often initially seen by
nonotolaryngologists, sinus CT scans are often
obtained next. No imaging findings are 100% sensi-
tive 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]. Peri-
antral 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 immunocompro-
mised patient with sinonasal symptoms, or inflam-
mation 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 max-
illary and ethmoid sinuses are the most common
sinuses involved, but are not usually accessible for
biopsy in awake patients [12]. The middle turbinate

FIGURE 1. Computed tomography images of right-sided acute invasive fungal rhinosinusitis. (a) Coronal CT bone-window,
showing right-sided maxillary and ethmoid sinus mucosal thickening and partial opacification but no bone erosion around the
maxillary sinus, orbit, or skull base. (b) Axial CT soft-tissue window, showing right pterygopalatine and infratemporal fossae
fat pad obliteration (white arrow). CT, computed tomography.

1068-9508 Copyright ß 2018 Wolters Kluwer Health, Inc. All rights reserved. www.co-otolaryngology.com 31

Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.

Nose and paranasal sinuses

FIGURE 2. (a) Intraoperative endoscopic view showing edema in the left maxillary and anterior ethmoid sinuses (white
asterisks) in a patient with early acute invasive fungal rhinosinusitis. Aspergillus elements had invaded and were identified
within this edematous mucosa. (b) Intraoperative endoscopic view showing violaceous edematous mucosa (white arrows)
along the left lateral wall of the inferior meatus after the invaded inferior turbinate was resected. There was dense mucosal
invasion by Mucor hyphae, but no vascular invasion, so note that there was no pale or black appearance, and the tissue was
bleeding. MS, maxillary sinus.

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/ml, mucosal

FIGURE 3. (a) Intraoperative endoscopic view of a necrotic right middle turbinate with both pale and dusky portions (white
arrow). This had been previously biopsied with the patient awake, and showed dense Mucor hyphal mucosal and vascular
invasion. (b) Intraoperative endoscopic view of focal ulceration and eschar formation over the left anterior septum (white
asterisk), with Alternaria spp. having invaded into the septal mucosa.

32 www.co-otolaryngology.com Volume 27  Number 1  February 2019

Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.

 Updates in management of AIFRS Craig

FIGURE 4. Histopathology of Mucor and Aspergillus mucosal and vascular invasion. (a) Angioinvasion by irregular aseptate,
broad-branching hyphae noted within the wall of an artery (black circles), on haemotoxylin and eosin staining. Fungal hyphae
had invaded through the artery’s adventitia and had migrated to the internal elastic lamina (IEL), but had not invaded into the
intravascular space. (b) Histopathology of Aspergillus mucosal invasion on Grocott–Gomori methenamine silver staining. Note
the characteristic septate, acute branching hyphae (white arrows).

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 turbi-
nate early in the disease, even if no mucosal abnor-
&&
mality [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 immedi-
ately to the pathologist for frozen section analysis.
Frozen section has been shown to have 85% sensi-
tivity, 70% negative predictive value (NPV) and
100% specificity and positive predictive value
& &
(PPN) [40 ,41 ,42]. On histopathology, Zygomy-
cetes demonstrate irregular, aseptate broad-branch-
ing hyphae, whereas Aspergillus spp. have septate
acute-branching hyphae (Fig. 4a and b).
MANAGEMENT
Multidisciplinary management centers on early sur-
gical 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 fun-
gal 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 dis-
ease, this could require endoscopic medial maxillec-
tomy [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 preopera-
tive 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

1068-9508 Copyright ß 2018 Wolters Kluwer Health, Inc. All rights reserved. www.co-otolaryngology.com 33

Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.

Nose and paranasal sinuses
endoscopy. Overall short-term survival was 69.2%.
Complete surgical resection resulted in 95.5% sur-
vival, as opposed to 42.9% for incomplete resection,
and 28.6% if no surgery (P ¼ 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 mucormy-
cosis, and reported no survival benefit from orbital
exenteration except in patients with fever over
101.5 8F. 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 ‘immedi-
ate’ 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 anti-
fungal therapy. ESS could then be performed within
24 h, rather than emergently. This question requires
further study.
34 www.co-otolaryngology.com
Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.
MEDICAL MANAGEMENT
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, vor-
iconazole requires long-term therapeutic monitor-
ing, 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 recom-
mended. 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, pos-
aconazole 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 intrave-
nous formulation is water-soluble, less nephrotoxic
than amphotericin and less hepatotoxic than vor-
iconazole. 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 set-
ting of diabetes, it is intuitive that hyperglycemia
reversal will be beneficial, but no studies have con-
ducted a quantitative analysis of plasma glucose
levels and AIFRS clinical outcomes. Indirect evi-
dence 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 neutro-
penia, Kennedy et al. reviewed 26 bone marrow
Volume 27  Number 1  February 2019

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 cor-
rected, and survival in the neutropenia-controlled
group was significantly higher than the uncon-
trolled group (80 vs. 40%) [63]. Lastly, granulocyte
colony-stimulating factor has been recommended
in mucormycosis patients with hematologic malig-
nancy 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 adjunc-
tive 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 lipo-
somal amphotericin alone [67].
CONCLUSION
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.
Acknowledgements
I would like to thank Natalie Craig, graphic designer,
for her assistance formatting the figures in this article.
Financial support and sponsorship
None.
Conflicts of interest
There are no conflicts of interest.
REFERENCES AND RECOMMENDED
READING
Papers of particular interest, published within the annual period of review, have
been highlighted as:
& of special interest
&& of outstanding interest
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.
1068-9508 Copyright ß 2018 Wolters Kluwer Health, Inc. All rights reserved.
Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.
Updates in management of AIFRS Craig
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(þ) 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 voricona-
zole 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: considera-
tion 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 experi-
ence 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-Asper-
gillus 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.
www.co-otolaryngology.com 35
Nose and paranasal sinuses
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 rhino-
sinusitis. 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 endo-
scopic 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.
36 www.co-otolaryngology.com
Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.
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 rhinocer-
ebral 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 isavuco-
nazole 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; Eur-
opean Confederation of Medical Mycology. ESCMID and ECMM joint clinical
guidelines for the diagnosis and management of mucormycosis. Clin Micro-
biol 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.
Volume 27  Number 1  February 2019