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\begin{document}

\title{Changing trends in the survival of immunosuppressed children with
invasive fungal rhinosinusitis: a retrospective observational cohort
study}



\author[1]{Amit RItter}%
\author[2]{Shlomit Barzilai-Birenboim}%
\author[1]{Olga Gordon Rapana}%
\author[2]{Salvador Fischer}%
\author[2]{Itzhak Levy}%
\author[1]{Ethan Soudry}%
\author[2]{Dror Gilony}%
\affil[1]{Rabin Medical Center}%
\affil[2]{Schneider Children's Medical Center of Israel}%


\vspace{-1em}



  
  \date{May 16, 2024}


\begingroup
\let\center\flushleft
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\selectlanguage{english}
\begin{abstract}
Objectives: Acute invasive fungal rhinosinusitis has been associated
with high mortality rates. We aimed to explore the contribution of novel
detection and treatment methods on the outcome of immunosuppressed
children with acute invasive fungal rhinosinusitis. Design:
Retrospective observational cohort study. Setting: A tertiary children's
hospital. Participants: The records of all children with a hematologic
or oncologic disease who developed AIFR between 2005-2020 were reviewed.
Results: Thirty-four patients were included. Aspergillosis and
mucormycosis were diagnosed in 20 patients (59\%) and 12 patients
(35\%), respectively. Panfungal polymerase chain reaction (PCR) was
associated with a change of treatment in 36\% of patients. Aggressive
surgical approach was adopted and 71\% of the patients underwent
multiple surgical procedures. Overall, 26\% of patients died of disease,
however no disease-specific death occurred since 2012. Diagnosis using
panfungal PCR (p=.04) and treatment with novel antifungal medications
(p=.017) were significantly associated with disease-specific survival.
Conclusions: Enhanced fungal detection using panfungal PCR and treatment
with novel antifungal agents, combined with rapid diagnosis and
treatment, aggressive surgical approach and better control over the
underlying oncological disease, may significantly improve the outcome of
immunosuppressed children with acute invasive fungal rhinosinusitis.%
\end{abstract}%



\sloppy


\textbf{Changing trends in the survival of immunosuppressed children
with invasive fungal rhinosinusitis: a retrospective observational
cohort study}

\textbf{ABSTRACT}

\textbf{Objectives:} Acute invasive fungal rhinosinusitis has been
associated with high mortality rates. We aimed to explore the
contribution of novel detection and treatment methods on the outcome of
immunosuppressed children with acute invasive fungal rhinosinusitis.

\textbf{Design:} Retrospective observational cohort study.

\textbf{Setting:} A tertiary children's hospital.

\textbf{Participants:} The records of all children with a hematologic or
oncologic disease who developed AIFR between 2005-2020 were reviewed.

\textbf{Results:} Thirty-four patients were included. Aspergillosis and
mucormycosis were diagnosed in 20 patients (59\%) and 12 patients
(35\%), respectively. Panfungal polymerase chain reaction (PCR) was
associated with a change of treatment in 36\% of patients. A more
aggressive surgical approach as well as treatment with liposomal
amphotericin B and novel antifungals were adopted in recent years.
Overall, 26\% of patients died of disease, however no disease-specific
death occurred since 2012. Diagnosis using panfungal PCR (\emph{p=.04} )
and treatment with novel antifungal medications (\emph{p=.017} ) were
significantly associated with disease-specific survival.

\textbf{Conclusions:} Enhanced fungal detection using panfungal PCR and
treatment with novel antifungal agents, combined with rapid diagnosis
and treatment, aggressive surgical approach and better control over the
underlying oncological disease, may significantly improve the outcome of
immunosuppressed children with acute invasive fungal rhinosinusitis.

\textbf{Key words:} Infectious/inflammatory, Pediatric sinus/nose,
Pediatric rhinology.

\textbf{KEY POINTS}

\begin{itemize}
\tightlist
\item
  The survival of immunosuppressed children with acute invasive fungal
  rhinosinusitis (AIFR) has improved dramatically over the past decade.
\item
  No patient has died of AIFR since 2012.
\item
  Utilization of PCR for fungal detection was associated with
  significantly improved fungal detection rate.
\item
  Panfungal PCR along with treatment with novel antifungal medications
  were associated with improved survival.
\item
  Low threshold for investigation, rapid and aggressive surgical
  treatment, and better control over the underlying oncological disease
  are also crucial for improved AIFR-specific survival.
\end{itemize}



\textbf{INTRODUCTION}

The expanding use of bone marrow transplantation (BMT) and intensive
chemotherapy in the treatment of children with hematologic and oncologic
disease has placed them at an increased risk for opportunistic
infections such as acute invasive fungal rhinosinusitis (AIFR), a life
threatening infection\textsuperscript{1,2}.

The diagnosis of AIFR is challenging owing to the often-nonspecific
presenting symptoms\textsuperscript{3}. The disease has a rapidly
progressive course, and timely diagnosis and detection of the fungal
pathogens is crucial for successful management and clinical outcome of
patients\textsuperscript{4}. Direct microscopy and histopathology are
the gold standard for diagnosis\textsuperscript{5}. Cultures are used to
identify the culprit agents and their antimicrobial susceptibility.
Since the late 1990s more rapid and sensitive detection methods, such as
in-situ hybridization and polymerase chain reaction (PCR), have been
applied. Nevertheless, the detection spectrum of real-time PCR has been
mostly restricted to a variety of \emph{Candida} or
\emph{Aspergillus}species\textsuperscript{6}.

In recent years, new panfungal PCR assays have been developed in order
to detect a wider range of fungal pathogens\textsuperscript{7,8}. The
use of panfungal PCR assay in addition to histopathology and cultures
seems to contribute to higher detection rates in cases of
AIFR\textsuperscript{4}. Additionally, the introduction of novel
antifungal drugs such as posaconazole and isavuconazole may improve
patients survival rates\textsuperscript{9,10}. Finally, timely surgical
debridement, a cornerstone of the management of AIFR, has been shown to
be an independent prognostic factor in the survival of
patients\textsuperscript{11,12}. Improved endoscopic surgical skills
using advanced instrumentation, high-definition cameras and
intraoperative stereotactic navigation may lead to better survival
outcomes in the management of children with AIFR\textsuperscript{13}.

\emph{Objective}

The aim of the present study was to investigate whether novel rapid
detection methods, advanced antifungal agents, and application of prompt
and aggressive surgical interventions are associated with improved
outcome of immunosuppressed children with AIFR.

\textbf{MATERIALS AND METHODS}

\emph{Study Design and Subjects}

The study protocol was approved by the Institutional Review Board. The
electronic medical records of a tertiary children's hospital were
reviewed for all children (age \textless{}18 years) who underwent
endoscopic sinus surgery (ESS) between 2005-2020. Only children with
pathology proven AIFR were included.

\emph{Diagnostic Methods}

Direct microscopy and histopathology demonstrating invasive fungal
pathogens in the sinonasal mucosa served as the gold standard for
diagnosis of AIFR. Cultures were used for identification of the fungal
pathogen. Panfungal PCR, which was first introduced to our institution
in 2011, was used for rapid detection of the fungal species in addition
to the standard detection methods.

All patients underwent computed tomography (CT) scans of the head and
sinuses, while magnetic resonance imaging (MRI) was used in cases where
intracranial complications were suspected.

\emph{Endoscopic Sinus Surgery}

Necrotic tissues were endoscopically debrided until macroscopically
healthy bleeding margins were reached. Patients were taken back to the
operating room for further debridement whenever suspicion for continued
infection remained. Of note, a more aggressive surgical approach was
adopted in the latter years of the study, including endoscopic resection
of the anterior skull base, clivus, pterygopalatine fossa and
infratemporal fossa whenever these sites were involved.

\emph{Systemic Antifungal Therapy}

Prior to the diagnosis of AIFR, all patients were stratified into
categories of risk to develop invasive fungal disease according to
accepted guidelines\textsuperscript{14}. High-risk criteria included
acute myelogenous leukemia (AML), high-risk acute lymphoblastic leukemia
(ALL), relapsing leukemia, and post-BMT. High-risk patients received
prophylactic antifungal therapy with itraconazole or fluconazole, as
part of the institutional policy. In addition, all other children with
hematologic malignancies were prophylactically treated with nystatin or
clotrimazole.

Empirical systemic antifungal therapy was administered as soon as AIFR
was suspected. Indications for empirical antifungal treatment included
persistence of fever and neutropenia despite broad spectrum antibiotic
therapy, signs of locally advanced rhinosinusitis, nasal biopsy positive
for calcofluor-white stain or evidence of invasive fungus in frozen
section. Therapy was adjusted after definitive diagnosis and
identification of the pathogen, in accordance with accepted
guidelines\textsuperscript{15}.

\emph{Data Collection}

The following data were collected from patients' files: demographics,
type of the underlying disease, remission status, laboratory results,
clinical and imaging characteristics, microbiology and pathology,
medical treatment, surgical data, complications, and outcomes.

The follow-up period was defined as the time from diagnosis to data
collection for the study or patient death. Death was considered due to
AIFR when a patient with persistent signs of disease died from systemic
fungal infection, sepsis and/or intracranial complications.

\emph{Statistical Analysis}

All statistical analyses were performed with SPSS v.23.0 (IBM Corp.,
Armonk, NY, USA). Associations between nominal variables were examined
using \selectlanguage{greek}χ\selectlanguage{english}\textsuperscript{2} test and Fisher's exact test. Associations
between continuous and quantitative variables were examined using
Mann-Whitney U-Test. Potential confounding variables were assessed by
Cox proportional hazards regression model. A two-sided p-value of
\textless{}.05 was considered statistically significant for all
analyses.

\textbf{RESULTS}

\emph{Demographic and Clinical Characteristics}

The study included 34 pediatric patients with a median age of 10 years
(range, 3-17 years), and a female to male ratio of 1:1. The demographic
and clinical characteristics of the study cohort are shown
in\textbf{Table 1.} ALL and AML accounted for the majority of all
underlying diseases (56\% and 24\%, respectively). Twenty-two patients
(65\%) met high-risk criteria for fungal infection and were given
prophylactic itraconazole or fluconazole prior to the diagnosis of AIFR.

Most of the patients developed AIFR during disease remission (23
patients, 68\%). In patients post-BMT AIFR was first diagnosed within a
median of 112 days post transplantation (range, 6-1203 days). Ten
patients (29\%) developed AIFR within 6 months of BMT. Thirty-one
patients (91\%) were severely neutropenic (absolute neutrophil count
\textless{}500/mm\textsuperscript{3}) at the time of diagnosis of acute
infection; the mean duration of neutropenia was 17 \selectlanguage{ngerman}± 14 days (median, 13
days; range, 1-68 days). Fever was the most common presenting symptom of
AIFR, in 29 children (85\%), followed by facial swelling in eleven
(32\%). Orbital complications included proptosis (n=4, 12\%),
periorbital edema (n=3, 9\%) and oculomotor nerve palsy (n=3, 9\%).

\emph{Imaging Findings}

Sinus opacification was apparent on preoperative CT in 25 patients
(74\%), with the maxillary (65\%) and ethmoid sinuses (53\%) primarily
involved. Eight patients (24\%) had radiological signs of extrasinus
involvement. These included bony erosion of the maxillary sinus walls,
hard palate, and orbital walls in five patients (15\%), and involvement
of the infratemporal fossa and medial pterygoid muscle in two cases
(6\%). Periorbital or orbital involvement was apparent on CT in 5
patients (15\%). Nine children (26\%) also underwent MRI to assess for
neural invasion or infratemporal or intracranial extension. In two of
these cases MRI revealed skull base involvement with dural enhancement,
and in one case an extension to the pterygopalatine and infratemporal
fossa with thickening and enhancement of the maxillary nerve.

\emph{Surgical Data}

The median time from onset of fever (29 patients, 85\%) to first
surgical intervention was 4 days (range, 1-10 days). The average number
of ESS per-patient was 3.2 (range, 1-11 surgeries per-patient).
Twenty-four children (71\%) required multiple procedures to control the
disease. The nasal structures that were most involved in AIFR included
the middle turbinates (n=16, 47\%), nasal septum (n=13, 38\%) and
inferior turbinates (n=10, 29\%). Eleven patients (33\%) were diagnosed
with extrasinus involvement, including the palate (n=5, 15\%), the orbit
(n=4, 12\%) and the skull base (n=3, 9\%). Involvement of the
pterygopalatine fossa, nasopharynx or clivus was documented in 4 cases
(12\%). Major surgical complications included one case of significant
intraoperative bleeding which was successfully treated surgically, along
with blood transfusions, anterior and posterior packing and 24-hour
observation in the intensive care unit.

\emph{Fungal Detection Methods}

Overall, in 17 children (50\%) multiple fungal species were detected. In
twelve cases (35\%) identification of fungal pathogens relied solely on
histopathology and fungal cultures. Panfungal PCR, which was first
introduced in our institution in 2011, was utilized in the remaining 22
patients (65\%). PCR detected fungal pathogens in four patients with
negative cultures, and additional fungal species in four patients with
positive cultures (18\% of patients tested by PCR). Overall, the use of
panfungal PCR resulted in a change in antifungal therapy in 8 patients
(36\% of patients tested by PCR).

The most common fungus identified was \emph{Aspergillus} in 20 patients
(59\%). Fifteen fungal pathogens of the order Mucorales were detected in
12 patients (35\%), including \emph{Mucor} (n=6), \emph{Rhizopus} (n=7)
and \emph{Absidia} (n=2). Other pathogens included
\emph{Alternaria}(n=6), \emph{Exserohilum} (n=6), \emph{Curvularia}
(n=3),\emph{Fusarium} (n=3) and \emph{Candida} (n=2).

\emph{Systemic Antifungal Therapy}

Amphotericin B (AmB) (n=8, 24\%) was the empirical antifungal treatment
of choice until 2010, when it was replaced mainly by liposomal
amphotericin B (ambisome) (n=13, 38\%). Novel antifungals, posaconazole
and isavuconazole, have been employed as additional treatment options in
our institution since 2008 and 2017, respectively. Antifungal treatment
was adjusted following the identification of infectious agent\emph{.}

\emph{Disease Outcomes}

Patients were followed with an average duration of 30.5 ± 44.5 months
(median, 12 months; range, 9 days to 167.5 months). Thirteen patients
(38\%) died by the end of follow-up. Systemic fungal infection, sepsis,
and intracranial complications of AIFR were the causes of death in 9
patients (26\%); other complications of the underlying disease,
including non-remission and secondary infections, accounted for the
remaining four deaths (12\%).

The mean survival time of patients who died of AIFR was 98 ± 144 days
(median, 36 days; range, 14-462 days). In a univariate analysis,
diagnosis using panfungal PCR (\emph{p=.04} ) and treatment with novel
antifungal agents (\emph{p=.017} ) were associated with increased rates
of AIFR-specific survival. Remission status was associated with overall
survival (\emph{p=.008} ). However, a regression analysis using the
Cox-proportional hazard model to control for confounding effects did not
identify any significant variable associated with survival
(\textbf{Table 2} ).

The overall and disease-specific survival rates increased throughout the
study period. The last patient to die of AIFR was diagnosed in February
2012. Since then, no other patient has died of the disease. Moreover,
since April 2013 only one patient has died of his underlying malignant
disease (\textbf{Figure 1} ). Increased survival was evident
specifically among patients with mucormycosis. Seven of these patients
were diagnosed before 2012 and the remaining five between 2013-2020.
Four patients (33\%) died from complications related to mucormycosis,
all diagnosed before 2012. Of note are two patients with mucormycosis
who survived despite an aggressive disease involving, in one patient,
the orbit, skull base and dura, and in the second the hard palate and
skull base. Both patients received rapid empirical treatment with
ambisome as soon as AIFR was suspected, and underwent multiple
aggressive surgical procedures, including resection of the skull base,
the hard palate and orbit.

\textbf{DISCUSSION}

In this study we analyzed the diagnostic and management patterns of
children with AIFR over the past 15 years and their implications on
outcomes. While still considered an extremely aggressive disease with
dismal prognosis, the results of this study showed a significant
increase in patients' survival in the past decade compared to earlier
years. AIFR had historically been associated with high mortality rates
of 50\%--90\%\textsuperscript{16}. Recently published data indicated
better prognosis with mortality rates of 30-50\% which was attributed
mainly to early detection of AIFR\textsuperscript{17} and aggressive
surgical management\textsuperscript{18}. In the present study, the
overall mortality rate was 38\%, and the disease-specific mortality rate
was 26\%. Nonetheless, no patient has died of AIFR since 2012.

The status of the underlying disease was previously shown to be among
the leading prognostic factors\textsuperscript{4,19}. Hematologic
malignancies, most notably ALL and AML, were reported to be the leading
causes of immunosuppression\textsuperscript{3,4}. The decrease in
overall mortality rate in our study may reflect better control of the
underlying disease, which may have contributed to the change in
AIFR-specific survival. The majority of patients (68\%) developed AIFR
during disease remission, and as expected, had better overall survival
outcomes compared to patients with non-complete remission. These data
highlight the importance of better control of the immunosuppressive
state to improve the prognosis of patients with AIFR.

Early diagnosis and aggressive surgical treatment of AIFR have been
proven to be critical in improving patients'
outcomes\textsuperscript{20}. In the present study a low threshold for
diagnosis led to early investigation and surgical intervention within a
median of 4 days from the onset of fever. In 71\% of our patients,
multiple surgical procedures were performed, and debridement was
repeated until no further disease progression was observed. Moreover,
along with the improvement in technology and experience, a more
aggressive surgical approach was adopted in our institution in the
latter years of the study including pterygopalatine fossa, infratemporal
fossa and skull base debridement as needed, which may have been
associated with the improved survival, observed in recent years.

Novel detection methods and newer systemic antifungal therapies may also
have contributed to improved patient survival. Culture studies had long
been considered the gold standard for identification of the culprit
subspecies in AIFR, but their reported sensitivity was low (30-54\%),
and their diagnostic value was further limited by the slow growth rate
of fungal pathogens, leading to delays in appropriate antifungal
therapy\textsuperscript{20,21}. Since PCR first came into use in our
practice in 2011, it has become a leading detection method, and was used
in \textgreater{}90\% of cases. Although recognized as an augmenting
tool to improve diagnosis of AIFR, PCR was not included in the revised
definitions of invasive fungal disease published in 2008, because the
technique had not yet been clinically validated\textsuperscript{22}.
More recent data, however, have shown that with the advantage of rapid
detection of mixed infection in a single specimen, panfungal PCR is more
sensitive and specific than cultures and direct sequencing in patients
with fungal rhinosinusitis\textsuperscript{8}. In our practice, we found
panfungal PCR to be superior to fungal cultures in the detection of
pathogens and to be associated with a change of treatment in nearly
one-fifth of cases.

Historically, AmB has been considered the drug of choice for treatment
of invasive fungal infections, and it remains the agent with the
broadest antifungal spectrum\textsuperscript{23}. However, its use has
become limited due to high incidence of adverse effects and substantial
risk of nephrotoxicity which led to adaptations of
therapy\textsuperscript{23,24}. With improved safety profile and greater
efficacy, novel agents such as liposomal AmB, triazoles and
echinocandins have gradually become the drugs of choice for invasive
fungal infections\textsuperscript{10,22,24,25}. In the current study,
since 2011 AmB, which was associated with decreased survival, has been
replaced as the treatment of choice by liposomal AmB, and novel
triazoles and echinocandins. We believe that this may have contributed
to the improved survival in recent years.

The main limitations of this study include its retrospective design and
small cohort size. Nonetheless, the study's duration period enabled us
to view with perspective the trends in management and survival of
children with AIFR.

\textbf{CONCLUSION}

In this study we present encouraging data on improved survival in
immunosuppressed children with AIFR. While still considered one of the
deadliest infectious diseases in this population, we observed that low
threshold for investigation, utilization of PCR for fungal detection,
treatment with novel antifungal agents combined with rapid and
aggressive surgical treatment and better control over the underlying
oncological disease, dramatically reduced AIFR mortality rates. We
suggest that panfungal PCR should have an increasing role in the
detection of fungal pathogens and that novel antifungal drugs should
become an essential part of the treatment regimen.

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\textbf{Table 1.} Baseline characteristics of the study population\selectlanguage{english}
\begin{longtable}[]{@{}ll@{}}
\toprule
\begin{minipage}[b]{0.48\columnwidth}\raggedright\strut
Characteristic\strut
\end{minipage} & \begin{minipage}[b]{0.48\columnwidth}\raggedright\strut
All patients (no. of patients = 34)\strut
\end{minipage}\tabularnewline
\midrule
\endhead
\begin{minipage}[t]{0.47\columnwidth}\raggedright\strut
Male gender\strut
\end{minipage} & \begin{minipage}[t]{0.47\columnwidth}\raggedright\strut
17 (50\%)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.47\columnwidth}\raggedright\strut
Median age at study entry, year (range)\strut
\end{minipage} & \begin{minipage}[t]{0.47\columnwidth}\raggedright\strut
10 (3-17\%)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.47\columnwidth}\raggedright\strut
Underlying disease\textsuperscript{*}\strut
\end{minipage} & \begin{minipage}[t]{0.47\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.48\columnwidth}\raggedright\strut
ALL\strut
\end{minipage} & \begin{minipage}[t]{0.48\columnwidth}\raggedright\strut
19 (56\%)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.48\columnwidth}\raggedright\strut
AML\strut
\end{minipage} & \begin{minipage}[t]{0.48\columnwidth}\raggedright\strut
8 (24\%)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.48\columnwidth}\raggedright\strut
Other\textsuperscript{+}\strut
\end{minipage} & \begin{minipage}[t]{0.48\columnwidth}\raggedright\strut
9 (26\%)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.47\columnwidth}\raggedright\strut
Stem-cell transplantation\strut
\end{minipage} & \begin{minipage}[t]{0.47\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.48\columnwidth}\raggedright\strut
Overall\strut
\end{minipage} & \begin{minipage}[t]{0.48\columnwidth}\raggedright\strut
13 (38\%)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.48\columnwidth}\raggedright\strut
Allogeneic\strut
\end{minipage} & \begin{minipage}[t]{0.48\columnwidth}\raggedright\strut
13 (38\%)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.48\columnwidth}\raggedright\strut
Autologous\strut
\end{minipage} & \begin{minipage}[t]{0.48\columnwidth}\raggedright\strut
0\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.48\columnwidth}\raggedright\strut
BMT \textless{}6 months before infection\strut
\end{minipage} & \begin{minipage}[t]{0.48\columnwidth}\raggedright\strut
10 (29\%)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.47\columnwidth}\raggedright\strut
Disease status\strut
\end{minipage} & \begin{minipage}[t]{0.47\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.48\columnwidth}\raggedright\strut
Remission\strut
\end{minipage} & \begin{minipage}[t]{0.48\columnwidth}\raggedright\strut
23 (68\%)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.48\columnwidth}\raggedright\strut
Non-complete remission\strut
\end{minipage} & \begin{minipage}[t]{0.48\columnwidth}\raggedright\strut
11 (32\%)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.48\columnwidth}\raggedright\strut
Severe neutropenia (ANC\textless{}500/mm\textsuperscript{3})\strut
\end{minipage} & \begin{minipage}[t]{0.48\columnwidth}\raggedright\strut
31 (91)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.48\columnwidth}\raggedright\strut
Mean duration of neutropenia, days \selectlanguage{ngerman}± SD\strut
\end{minipage} & \begin{minipage}[t]{0.48\columnwidth}\raggedright\strut
17 \selectlanguage{ngerman}± 14\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.47\columnwidth}\raggedright\strut
Risk classification for fungal infection\selectlanguage{english}\textsuperscript{++}\strut
\end{minipage} & \begin{minipage}[t]{0.47\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.48\columnwidth}\raggedright\strut
Standard risk\strut
\end{minipage} & \begin{minipage}[t]{0.48\columnwidth}\raggedright\strut
12 (35\%)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.48\columnwidth}\raggedright\strut
High risk\strut
\end{minipage} & \begin{minipage}[t]{0.48\columnwidth}\raggedright\strut
22 (65\%)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.48\columnwidth}\raggedright\strut
Post-BMT\strut
\end{minipage} & \begin{minipage}[t]{0.48\columnwidth}\raggedright\strut
13 (38\%)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.48\columnwidth}\raggedright\strut
Relapsing leukemia\strut
\end{minipage} & \begin{minipage}[t]{0.48\columnwidth}\raggedright\strut
11 (32\%)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.48\columnwidth}\raggedright\strut
AML\strut
\end{minipage} & \begin{minipage}[t]{0.48\columnwidth}\raggedright\strut
8 (24\%)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.48\columnwidth}\raggedright\strut
High-risk ALL\strut
\end{minipage} & \begin{minipage}[t]{0.48\columnwidth}\raggedright\strut
6 (18\%)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.47\columnwidth}\raggedright\strut
Surgical treatment\strut
\end{minipage} & \begin{minipage}[t]{0.47\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.48\columnwidth}\raggedright\strut
No. of ESS, mean (range)\strut
\end{minipage} & \begin{minipage}[t]{0.48\columnwidth}\raggedright\strut
3.2 (1-11)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.48\columnwidth}\raggedright\strut
Multiple procedures\strut
\end{minipage} & \begin{minipage}[t]{0.48\columnwidth}\raggedright\strut
24 (71\%)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.48\columnwidth}\raggedright\strut
Extrasinus extension\strut
\end{minipage} & \begin{minipage}[t]{0.48\columnwidth}\raggedright\strut
11 (33\%)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.47\columnwidth}\raggedright\strut
PCR detection\strut
\end{minipage} & \begin{minipage}[t]{0.47\columnwidth}\raggedright\strut
22 (65\%)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.47\columnwidth}\raggedright\strut
Fungal pathogen\strut
\end{minipage} & \begin{minipage}[t]{0.47\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.48\columnwidth}\raggedright\strut
Aspergillus\strut
\end{minipage} & \begin{minipage}[t]{0.48\columnwidth}\raggedright\strut
20 (59\%)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.48\columnwidth}\raggedright\strut
Mucormycosis\strut
\end{minipage} & \begin{minipage}[t]{0.48\columnwidth}\raggedright\strut
12 (35\%)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.48\columnwidth}\raggedright\strut
Other\strut
\end{minipage} & \begin{minipage}[t]{0.48\columnwidth}\raggedright\strut
20 (59\%)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.47\columnwidth}\raggedright\strut
Systemic antifungal therapy\strut
\end{minipage} & \begin{minipage}[t]{0.47\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.48\columnwidth}\raggedright\strut
Amphotericin B\strut
\end{minipage} & \begin{minipage}[t]{0.48\columnwidth}\raggedright\strut
9 (26\%)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.48\columnwidth}\raggedright\strut
Ambisome\strut
\end{minipage} & \begin{minipage}[t]{0.48\columnwidth}\raggedright\strut
13 (38\%)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.48\columnwidth}\raggedright\strut
Voriconazole\strut
\end{minipage} & \begin{minipage}[t]{0.48\columnwidth}\raggedright\strut
11 (32\%)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.47\columnwidth}\raggedright\strut
Mortality\strut
\end{minipage} & \begin{minipage}[t]{0.47\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.48\columnwidth}\raggedright\strut
Overall\strut
\end{minipage} & \begin{minipage}[t]{0.48\columnwidth}\raggedright\strut
13 (38\%)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.48\columnwidth}\raggedright\strut
Dead of infection\strut
\end{minipage} & \begin{minipage}[t]{0.48\columnwidth}\raggedright\strut
9 (26\%)\strut
\end{minipage}\tabularnewline
\bottomrule
\end{longtable}

Abbreviations: \emph{ALL} , acute lymphoblastic leukemia; \emph{AML} ,
acute myeloid leukemia; \emph{ANC} , absolute neutrophil count;
\emph{BMT} , bone marrow transplantation;\emph{ESS} , endoscopic sinus
surgery; \emph{PCR} , polymerase chain reaction; \emph{SD,} standard
deviation

* Two patients were diagnosed with more than one underlying disease

+ Other diagnoses included aplastic anemia, lymphomas, severe combined
immunodeficiency, hemophagocytic lymphohistiocytosis and Wilm's tumor.

++ Risk to develop invasive fungal disease according to the European
Conference on Infections in Leukemia (reference 14).\selectlanguage{english}
\begin{longtable}[]{@{}lllllll@{}}
\toprule
Covariates & Coefficient & Standard error & P value & HR & 95\% CI &
95\% CI\tabularnewline
\midrule
\endhead
& & & & & Lower & Upper\tabularnewline
Age & .179 & .114 & .116 & 1.197 & .957 & 1.496\tabularnewline
Remission & -.433 & .970 & .655 & .648 & .097 & 4.343\tabularnewline
BMT & -2.652 & 1.418 & .061 & .071 & .004 & 1.135\tabularnewline
Mucormycosis & .554 & .775 & .475 & 1.740 & .381 & 7.939\tabularnewline
Panfungal PCR & -.039 & 1.406 & .978 & .961 & .061 &
15.120\tabularnewline
Amphotericin B & -2.667 & 1.682 & .113 & .069 & .003 &
1.879\tabularnewline
\bottomrule
\end{longtable}

\textbf{Table 2.} Results of multivariate Cox regression model

Abbreviations: \emph{BMT,} bone marrow transplantation; \emph{CI} ,
confidence interval; \emph{HR,} hazard ratio; \emph{PCR} , polymerase
chain reaction.

\textbf{FIGURES LEGEND}

\textbf{Figure 1}

The proportion of patients who died of acute invasive fungal
rhinosinusitis and other complications of the underlying disease
throughout the study period.

\textbf{Hosted file}

\verb`Table 1_ AIFR.DOCX`  available at \url{https://authorea.com/users/733821/articles/711255-changing-trends-in-the-survival-of-immunosuppressed-children-with-invasive-fungal-rhinosinusitis-a-retrospective-observational-cohort-study}

\textbf{Hosted file}

\verb`Table_2_AIFR.docx`  available at \url{https://authorea.com/users/733821/articles/711255-changing-trends-in-the-survival-of-immunosuppressed-children-with-invasive-fungal-rhinosinusitis-a-retrospective-observational-cohort-study}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/Figure-1/Figure-1}

\end{center}
\end{figure}

\selectlanguage{english}
\FloatBarrier
\end{document}

