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\begin{document}

\title{Management of acute invasive fungal rhinosinusitis with
orbit-cranio-facial involved------ our experience with 8 cases}



\author[1]{Yang Yang}%
\author[1]{Li-Fang Shen}%
\author[1]{Feng Wang}%
\author[1]{Haihong Chen}%
\affil[1]{Zhejiang University School of Medicine First Affiliated Hospital}%


\vspace{-1em}



  
  \date{May 26, 2024}


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\selectlanguage{english}
\begin{abstract}
Key points: ? Diagnosis of AIFRS should be alert in the
immunocompromised patient presenting with new-onset, rapidly progressive
sinusitis with facial-cranio-orbital spread. ? Extended debridement
should be considered on a case-by-case basis. ? Antifungal agent
contributed greatly to the outcome of AIFRS. ? Prognosis mostly up to
the balance of underlying disease and fungal invasion, more emphasizes
should be focused on comprehensive treatment. ? AIFRS with
facial-cranio-orbital involved often had a disastrous end.%
\end{abstract}%



\sloppy


\textbf{Management of acute invasive fungal rhinosinusitis}

\textbf{with orbit-cranio-facial involved------ our experience with 8
cases}

\textbf{Key points:}

\begin{itemize}
\tightlist
\item
  Diagnosis of AIFRS should be alert in the immunocompromised patient
  presenting with new-onset, rapidly progressive sinusitis with
  facial-cranio-orbital spread.
\item
  Extended debridement should be considered on a case-by-case basis.
\item
  Antifungal agent~contributed greatly to the outcome of AIFRS.
\item
  Prognosis mostly up to the balance of underlying disease and fungal
  invasion, more emphasizes should be focused on comprehensive
  treatment.
\item
  AIFRS with facial-cranio-orbital involved often had a disastrous end.
\end{itemize}

\textbf{1 Introduction}

Acute invasive fungal rhinosinusitis (AIFRS) are rare events which
generally occurs in immunocompromised patients, management of such
disease means great challenge to ENT doctor because of its dangerous
outbreak and poor general condition, with mortality up to
50-80\%{[}1,2{]}.

The concept of invasive fungal infection refers to the invading of
fungal hyphae to epithelial tissue, bone, with potential neural and
vascular invasion. It generally classified into chronic invasive fungal
rhinosinusitis (CIFRS) and acute invasive fungal rhinosinusitis (AIFRS).
CIFRS is an indolent infection with a slow destructive process while
AIFRS is defined by a time course of less than 4 weeks' duration, with
predominant vascular invasion and fast spread which need an urgent
management.

In this paper, by analyzing the clinical features, management and
follow-up of 8 AIFRS patients with orbit-cranio-facial invasion, we
aimed to share clinicians with our experience on how to manage such a
disease and discuss the main factors which predict the survival
outcomes.

\textbf{2 Materials and methods}

\textbf{2.1 Study design and patients.}

This is a retrospective analysis, including 8 cases of ''acute invasive
fungal sinusitis with cranio-facial-orbit involved'' who admitted to our
hospital from Feb.2016 to Oct.2022. There were 4 males and 4 females,
with an average age of 59.8\selectlanguage{ngerman}±13.1 years. The lesions originated from
nasosinus, with a rapid spread to orbit, skull base, face and/or palate.
A definitive diagnosis based on histopathological examination (6 cases),
or microbiological detection (1 case), or gross sign of mucor growth (1
case).

\textbf{2.2 Clinical data of the participants}

All Patients' data including age/sex, main symptoms, underlying
diseases, sites of infection, causative fungus, CT/MR findings,
individualized therapeutic schedule, following-up and the prognosis were
listed in table1-3, Fig1-2, supplementary Fig1-4. Tissue sample for
histopathological examination were collected during operation, swab
sample for microbiological detection was taken from nose's or eye's
secretions. Lesion scopes were mostly based on CT/MR findings.
retrospective analyzed the treatment and prognosis of these cases, we
shared our experience on management of AIFRS patients with
cranio-facial-orbit involved.

\textbf{2.3 Ethical consideration}

This study was approved by ethical committee of our hospital that
exempted it from requiring individual patient consent. All procedures
performed in studies were in line with declaration for ethical
consideration.

\textbf{Results}

\textbf{3.1 Typical clinic features aided to a rapid diagnosis}

All 8 patients had severe immunocompromised disease, i.e. poorly
controlled diabetes, malignant hematological diseases, cancer (advanced
stage) undergoing chemotherapy afflicted with granulocytopenia, renal
insufficiency. The primary and main symptoms were severe headache,
progressive eye disorder, facial pain. Because of severe underlying
disease, 7/8 patients firstly admitted to corresponding department,
after multi-disciplinary treatment (MDT) consultation, they were
transferred to ENT department (table 1). Radiological features: computed
tomography (CT) and magnetic resonance imaging (MRI) were used
preoperatively to determine the extent of fungal invasion, all patients
showed extra-sinus dissemination: orbit and orbital apex(5/8), cavernous
sinus(2/8), face(3/8), palate(2/8). 6/8 patients had unilateral
involvement and 2 patients with bilateral involvement. CT often showed
heterogeneous opacity with or without bone erosion. MR usually showed a
relative hypointense signal in T2W1 compared with bacterial
inflammation, and an uneven enhancement in enhanced T1-weighted image.
The main radiological findings with CT/MRI and endoscopic findings were
summarized in Fig1-2 and supplementary Fig1-4 respectively. Based on an
immunosuppressive history, rapid spread of orbit-cranial-face invasion,
and radiological features, all cases were suspicion as AFIRS at first
glance. Among them, 6 cases were pathologically confirmed after
operation, 1 case was microbiological confirmed as Rhizopus and the
other one evidenced by gross sign of mucor growth.

\textbf{3.2 Detailed therapeutic strategies were made case by case.}

In principle, surgical debridement and antifungal agents remained the
two cornerstones of AIFRS treatment, and what's more, it should be
performed as soon as possible when diagnosis preliminary made. However,
because of severe underlying disease for these patients, detailed
therapeutic schedule were made case by case. In this group of 8 cases, 6
patients underwent endoscopic debridement with endoscopic surgery (ESS),
most under general anesthesia except one, removal of necrotic tissue as
much as possible according to CT/MR. However, for some region, such as
orbital apex, cavernous sinus, it was difficult to be completely
debrided, detailed information was listed in table3. The other two (6\#
and 8\#) were contraindication to an operation because of poor general
condition under chemotherapy and a rapid disastrous spread. All patients
were given sensitive antifungal drugs when AIFRS diagnosis made.
voriconazole 200mg Q12h for Aspergillus, amphotericin B or amphotericin
B liposome and/or posaconazole for mucor was the first choice. Dose and
duration were scheduled case by case (detailed in table2). All patients
were given broad-spectrum antibiotics and symptomatic supportive
treatment during hospitalization.

\textbf{Follow up and recovery}

Those patients were followed up for 10 days to 58 months, except 2\# and
7\# cured, 4\# still under control with oral Posaconazole intake, the
remaining 5 patients died. Duration from the patient's diagnosis to
death ranged from 10d to 50m (10d, 1m, 2m, 2.5m and 50m respectively),
mainly died of multiple organ failure (MOF) and uncontrolled infection
(detailed in table2).

\textbf{4 Discussion}

\textbf{For patients with typical clinical features,diagnosis of AIFRS
should be alert}

AIFRS is characterized by a rapid spread to adjacent orbits, cavernous
sinus, face, which need an urgent management, early diagnosis is very
important. To immunocompromised patients with severe underlying
diseases, such as AIDS, poorly controlled diabetic, haematological
malignancies undergoing chemotherapy or transplantation, if they were
afflicted by headache, eye pain, impaired vision, nasal obstruction, and
the symptom worsening rapidly, we should be highly alert the diagnosis
of AIFRS. Though lack specificity, some features of CT and MR Imaging
may help us to make such a diagnosis. For example, CT findings showed
unevenly increased density of soft tissues within involved nasal cavity
and sinus, spreading to adjacent area with bone erosion. On MRI image,
the lesion may show equal or low signal on T1WI, while relative high on
T2WI, but compared with acute suppurative inflammation, the signal of
T2WI in AIFRS still showed lower. Infection usually invaded to adjacent
area with unclear boundaries, predominant orbit and cavernous sinus.
Usually the lesion may uneven enhanced after enhancement. However, it's
worth mentioning that if MR enhancement is not obvious, it means tissue
infarction with a necrotizing pathological reaction, and the prognosis
may even worse {[}3{]}. For highly suspected patients, smear or
fluorescent staining of secretions from eyes or nasal should be taken as
soon as possible to obtain a quick microbial evidence. In line with
literature, in most cases, intraoperative frozen section could offer us
a rapid diagnosis {[}4,5{]}.

\textbf{Surgicaldebridement: the more, the better?}

Principally, surgical debridement should be carried out as soon as
possible and as much as possible. However, because of generally poor
condition for such a group, operation should be considered on a
case-by-case basis. For example, case 6 and case 8, after assessment,
they were contraindicated for surgery because of poor general condition.
The extents of debridement were mainly based on CT/MR, however, it was
not always an intellectual~decision to force a complete debridement. For
example, management on the area of orbital apex and cavernous sinus were
extremely difficult. Risk and benefit should be carefully balanced.
Anti-fungal treatment seemed equal important. For example, case2, we
only performed a complete debridement of sphenoid sinus while left the
orbital apex and the cavernous sinus in place. Voriconazole was taken
orally for 4 months after the operation and the patient was cured during
58 months follow-up. The same result displayed in case7. While for
case3, though we gave the patient a thoroughly debridement including
enucleation of orbital contents. However, due to the patient's advanced
age (74 years old), poor diabetes mellitus, severe granulocytopenia and
Mucor invasion, he still died of multiple infections 1m after operation.
According to literature, survival rate seemed not improved by an
aggressive debridement such as orbital contents enucleation,
maxillectomy {[}1,6{]}. The outcomes of our group supported such a
conclusion.

\textbf{Antifungal agent was important to AIFRS patients}

As to our experience, once suspicion of AIFRS was raised according to
clinical manifestation, antifungal treatment should be initiated as soon
as possible, usually Voriconazole for Aspergillus and amphotericin B for
Mucor. In recent years, FDA has approved isavuconazole, which was
effective against Aspergillus and some Mucor, and it was water-soluble,
with less impact on renal function and hepatic function than
amphotericin B {[}7,8{]}.

Antifungal treatment was equal or even more important than surgical
debridement, as we learned inflammation could not be fundamentally
solved by operation. If the patients could not tolerate anti-fungal
treatment, mainly because of hepatic and renal dysfunction, their
prognosis were usually poor, such as case3 and case5, though they
underwent an extensive debridement, still died after 1 and 2.5 months
after diagnosis. On the contrary, for case1,2, 4,7, though only
administered a part debridement, the results were not so bad after
antifungal treatment. There were also reports which showed some survival
AIFRS cases were managed only by medical treatment {[}9{]}.

As for the duration of antifungal treatment, although it was clear that
patients suffered with invasive fungal infection need a long time of
antifungal therapy, however, up to now, there was no consensus on the
optimal duration. We suggested a range of 6-12 months if the patient
could be tolerated with the drug. However, most of them died within
several months. We also have a group of 6 patients with CIFRS (not
provided in the data), who maintained oral antifungal drugs for 6-14m
after operation, and had a good prognosis.

\textbf{Prognosis mostly up t} o \textbf{underlying disease, we should
focus more emphasizes on comprehensive treatment.}

Prognosis of AIFRS is extremely poor. It's mortality rate was high up to
50-80\% {[}1{]}. Now with the rapid development of endoscopic
technology, more thorough debridement was possible, and more effective
antifungal drugs could be available, however, compared with 20 years
ago, the mortality rate did not decreased significantly {[}10{]}. Why?
The end of AIFRS largely depends on the struggle between the body's
immunity and fungal invasion, for those patients with severe
neutropenia, poorly controlled DM, immunosuppressive therapy and
insufficient hepatic and renal function, if they infected with fungi,
especial highly invasive Mucor, a disastrous end was almost inevitable,
such as case 3,5,6,8 in our group, so we should focus more emphasizes on
comprehensive treatment.

\textbf{5 Conclusion}

In a word, clinical suspicion of AIFRS should be alert in the
immunocompromised patient presenting with new-onset, rapidly progressive
sinusitis with facial-cranio-orbital spread. A multidisciplinary
approach consisting of antifungal therapy, surgical debridement,
immunodeficiency reversal, and supportive treatment were essential to
improve the control. We need more focus on comprehensive assessment, an
extended debridement such as maxillectomy and orbital exenteration
should be considered on a case-by-case basis. The outcome of AIFRS with
facial-cranio-orbital involved was usually fatal which mainly defined by
the underlying disease.

\textbf{Acknowledgements}

We thank all staff participated in the treatment of these patients

\textbf{Conflict of interest}

The authors declare no conflicts of interest.

\textbf{References}

{[}1{]} 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(5):1112-1118

{[}2{]} Vengerovich G, Echanique KA, Park KW, et al. Retrospective
analysis of patients with acute invasive fungal rhinosinusitis in a
single tertiary academic medical center: a 10-year experience. Am J
Rhinol Allergy. 2020;34(3):324-330

{[}3{]} Choi YR, Kim J, Min HS, et al. Acute invasive fungal
rhinosinusitis: MR imaging features and their impact on prognosis.
Neuroradiology. 2018; 60(7):715--723.

{[}4{]} Kim DH, Kim SW, Hwang SH. Usefulness of intraoperative frozen
section for diagnosing~acute~invasive~fungal~rhinosinusitis: A
systematic review and meta-analysis. Int Forum Allergy Rhinol.
2021;11(9):1347-1354

{[}5{]} Alkhateb R, Menon PD, Tariq H, et al. Accuracy of Intraoperative
frozen section in detection of acute invasive fungal rhinosinusitis.
Arch Pathol Lab Med. 2021; 145(6):736-743.

{[}6{]} 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(2):109--116.

{[}7{]} 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(10020):760--769.

{[}8{]} Sivasubramanian G, Chandrasekar PH. Efficacy and safety
of~Isavuconazole~for the treatment of invasive Aspergillus infection- an
update of literature. Expert Opin Pharmacother. 2022;23(5):543-549.

{[}9{]} Sideris G, Arvaniti A, Giotakis E, et al. Fourteen cases of
acute invasive fungal rhinosinusitis: is there a place for less
aggressive surgical treatment? Oral Maxillofac. Surg. 2022; doi:
10.1007/s10006-022-01120-8.

{[}10{]} 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(6):1454--1464.

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