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\begin{document}

\title{FUNGAL OSTEOMYELITIS OF FRONTAL BONE FOLLOWING COVID ASSOCIATED
MUCORMYCOSIS}



\author[1]{Rupa Mehta}%
\author[1]{Karthik Rao}%
\author[1]{Nitin Nagarkar}%
\author[1]{Anil  Sharma}%
\author[1]{Ambesh Singh}%
\author[1]{Badal Kumar}%
\author[1]{Karthik P}%
\affil[1]{All India Institute of Medical Sciences - Raipur}%


\vspace{-1em}



  
  \date{May 16, 2024}


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\selectlanguage{english}
\begin{abstract}
Introduction - The second wave of COVID 19 lead to resurgence of
opportunistic infections due to injudicious use of steroids. Sinonasal
Mucormycosis was declared as an epidemic during the pandemic. The
mucormycosis was managed effectively by surgical debridement along with
systemic amphotericin B. Now, following the initial treatment of
mucormycosis there is a resurgence, in the form of fungal osteomyelitis
of the frontal bone. Methods -- the prospective study included the cases
from ten patients with fungal osteomyelitis of frontal bone due to
mucormycosis, all the patients underwent surgical debridement of
sequestrum and involucrum with systemic antifungals. Results - The
average duration of the recurrence was 22 days following the initial
treatment Range (10 days to 33 days). Extracranial bossing following
outer frontal cortex erosion in 30\% of cases, bicortical erosion in
30\%, bifrontal involvement (20\%), dural involvement (30\%), brain
parenchymal involvement and prefrontal cortex (20\%) case. All cases
underwent debridement of entire sequestrous bone and involucrum till
normal bone was identified. The mean duration of admission was 4 weeks
(3 to 6 weeks). All treated patients are currently alive without
disease, confirmed by CECT. Conclusion - The successful treatment of
fungal osteomyelitis due to mucormycosis requires four pronged approach
(1) early detection (2) multidisciplinary management of comorbidities
(3) surgical debridement of necrotic bone and (4) adequate systemic
antifungal therapy. Long term outcomes of fungal osteomyelitis of
frontal bone are yet to be established%
\end{abstract}%



\sloppy


\section*{Introduction}

{\label{introduction}}

In the early 2021 started with mutation of SARS CoV2 and emergence of
B.1.617.1 or Delta variant leading to a deadly resurgence of the
disease. This highly virulent strain led to increased mortality due to
its high infectivity and virulence\textsuperscript{1}. Outbreak of new
opportunistic infection mucormycosis was seen among the post covid
patients. These secondary fungal infections or coinfections are critical
challenges increasing the patient's morbidity and mortality. India has
reported the highest number of mucormycosis cases in the world,
especially following the second wave of the pandemic\textsuperscript{2}.
Mucormycosis was declared as an epidemic by the Government of
India\textsuperscript{3} due to surge in the cases. The mucormycosis was
managed effectively by surgical debridement along with systemic
amphotericin B through the multidisciplinary teams in hospitals across
India\textsuperscript{4}. Now, following the initial treatment of
mucormycosis there is a resurgence, in the form of fungal osteomyelitis
of the frontal bone. This form of presentation has not been previous
recognized, with only a very few case reports describing it. The
resurgence of this disease is attributed to the incomplete clearance,
inadequate amphotericin dosing, comorbidities, immune status and
previous disease extent\textsuperscript{4,5}.

Here in this article, we describe the presentation, clinical features,
radiological, intraoperative findings, and post operative outcomes
following the management of frontal osteomyelitis of fungal origin.

\section*{Subjects and methods}

{\label{subjects-and-methods}}

This is a prospective, single-centre, interventional study at ``Blinded
for review''. This cross-sectional study has included the patients
presenting with recurrence in the frontal bone following the initial
treatment of covid associated mucormycosis by surgical debridement and
systemic amphotericin B . ten patients admitted and treated at our
centre from 1st July 2021 to 30\textsuperscript{th} September 2021 were
included in the data analysis. A detailed proforma to record the
demographic data, clinical presentation, investigations, points in
pathogenesis, and pathogenesis of the management in each patient. The
data analysis was performed using IBM SPSS Statistics for Windows,
Version 25.0. Armonk, NY: IBM Corp. The Institutional Research Cell
approval was obtained for the study under reference
OW/RC/AIIMS-RPR/2021/571. STROBE guidelines has been utilized for data
reporting.

A check nasal endoscopy was done to look for other focus of infection in
the sinonasal cavity. A complimentary cross sectional radiological
imaging was performed to look for the disease extent and to determine
the intracranial spread. The patients were planned for appropriate open
surgical debridement based on the disease extent. An intraoperative
fungal KOH smear was performed to determine the mucormycosis. After the
ablative surgery, a definitive permanent plastic reconstruction
procedure was deferred due to the possibility of disease recurrence and
contaminated surgical field. The patients were restarted on Liposomal
Amphotericin B, irrespective of the previous cumulative dosing.
High-risk patients were started on a prophylactic dose of low molecular
weight heparin from the 1\textsuperscript{st} postoperative day to
reduce the incidence of thromboembolism\textsuperscript{6,7}. The
patients were started on isotonic saline nasal douching to clear the
slough and debris upon nasal pack removal. Early recovery after surgery
(ERAS) guidelines were strictly followed. All patients received
pulmonary conditioning exercises, incentive spirometry, and chest
physiotherapy. The patients were considered for discharge if they were
clinically stable with reasonable control of comorbidities, completed
their target dosage of amphotericin B and had no radiological evidence
of disease.

\section*{Results}

{\label{results}}

A total of ten patients were admitted for recurrent frontal
osteomyelitis following initial treatment of covid associated sinonasal
mucormycosis. A total of eight patients (80\%) were diagnosed with
recurrent Mucormycosis by KOH mount of pus from the frontal bone
osteomyelitis sent intraoperatively (Fungal elements/broad aseptate
hyphae). Nine patients were male (90\%) and one female (10\%). All the
patients (100\%) had previously diagnosed sinonasal mucormycosis and
previous history of COVID 19 infection. 3 patients (30\%) had previously
undergone orbital exenteration for CAM.

The average duration of the recurrence was 22 days following the initial
treatment Range (10 days to 33 days). The patients presented with
frontal headache (100\%), frontal bulge (60\%), discharging sinus near
the medial canthus (10\%) (Figure -1), and fever (40\%). The diagnostic
nasal endoscopy commonly revealed mucosalization of the nasal cavity
with mild polypoidal changes in the opened sinuses, there was evidence
of pus discharge from the frontal ostium in 30\% cases and 40\% cases
had frontal outflow tract obstruction. Retrospective radiographic review
of these patients showed partial to complete opacification frontal sinus
in 30\% of cases during the initial disease presentation. 30\% of
patients had undergone debridement of frontal sinus during the initial
surgery for CAM.

CECT scan was done to look at the bony status and a complimentary MRI
scan was done to look for the soft tissue extent (intraorbital, orbital
apex and intracranial extension) and as problem solving tool. The cross
sectional imaging revealed extracranial bossing following outer frontal
cortex erosion in 30\% of cases (Figure -2), bicortical erosion in 30\%,
bifrontal involvement (20\%), Dural involvement (30\%), brain
parenchymal involvement and prefrontal cortex (20\%) case (Table -1).

Open surgical debridement was preferred due to recurrent nature of the
disease and for adequate disease clearance. Bifrontal craniotomy with
complete debridement of the frontal bone and pericranial flap was done
in 7 patients (70\%), ipsilateral supraorbital craniotomy was done for 2
patients (20\%), intraoperative CSF leak was seen in 2 patients (20\%)
and was repaired by primary closure with onlay pericranial flap.
reconstruction with free flaps and alloplastic materials were not done
due to the possibility of seeding in the graft and foreign body
reaction. Frank pus was seen in all the patients after exteriorizing the
frontal sinus. Bony sequestrum and involucrum was seen along the frontal
bone in all the cases (Figure -3). Debridement entailed removal of
entire sequestrous bone and a part of involucrum till normal bone was
identified.

None of the patients had post operative CSF leak. A closed suction drain
was placed in the cavity, removed if drain was less than 25ml. Nasal
tamponade packing was removed on postoperatively following 48h.

No patients had neurological deficits following the surgery, 2 patients
had local wound collection which needed exploration and evacuation under
anaesthesia (Clavein Dindo Grade 3b). All the patients received
prophylactic broad spectrum antibiotic coverage and antifungal treatment
with Amphotericin B. Amphotericin B was continued till radiological
disease clearance. The mean duration of admission was 4 weeks (3 to 6
weeks). All treated patients are currently alive without disease,
confirmed by CECT.

\section*{Discussion}

{\label{discussion}}

Only a handful of case reports have described about the frontal sinus
osteomyelitis following mucormycosis\textsuperscript{8--11}.
Mucormycosis usually affects the nose and paranasal sinuses; the disease
can spread via direct extension or by hematogenous spread. Hossieni and
colleagues\textsuperscript{12} initially have described about the routes
of spread of mucormycosis. We hypothesize the following pathway for the
spread of mucormycosis into the frontal sinus --

\begin{enumerate}
\tightlist
\item
  Via the ethmoidal air cells by direct extension, leading to frontal
  outflow tract obstruction.
\item
  By erosion of frontal sinus floor from superior part of the orbit.
\item
  Perineural spread along the supraorbital or supratrochlear nerves.
\item
  Along the anterior ethmoidal arteries.
\item
  Direct spread to the brain through the roof of the ethmoid and
  cribriform plate to skull base/frontal bone to Basi frontal lobe.
\item
  Disease tracking along the Orbital apex.
\end{enumerate}

In acute osteomyelitis, the patient is toxic with tender swelling over
the bone involved, called Pott's puffy tumour. The Pott's puffy tumour
was initially described as complication of acute bacterial frontal
sinusitis. The successful management of frontal bone osteomyelitis
entails removal of the entire sequestrum and debriding the involucrum
till the normal bony architecture is reached. Frontal sinus obliteration
with the fat, muscle and alloplastic materials have been tried with
varying success. In the setting of mucormycosis, it is utmost important
to clear all the disease till the fresh bleeding is observed. The main
crux of frontal sinus cranialization or obliteration in the mucormycosis
setting is to ensure complete elimination of disease and dead space,
formation of a protective barrier for the intracranial spread and with
the ability to reassess clincoradiologically for disease recurrence. The
use of alloplastic materials is usually not recommended in the settings
of severe infection\textsuperscript{13}.

The disease is more susceptible to complete endoscopic surgical
resection along with bony debridement if detected
early\textsuperscript{14}. Because antifungal medication alone will not
suffice, all grossly diseased tissue must be excised. Debridement should
be repeated until a healthy tissue margin is found, and it should be
done at regular intervals, if necessary. Sinus surgery, wide resection
of necrotic soft tissue and bone, and exenteration of the orbit, if
necessary, are examples of more comprehensive surgical
treatments\textsuperscript{15,16}. According to the available
literature, patients with intracranial extension~are less likely to
react to radical surgery, and their prognosis is
poor\textsuperscript{17}. However, if surgery is done early on, the
chances of survival increase significantly\textsuperscript{14}. It is
well established that the management of comorbid conditions is crucial
in the successful management of mucormycosis. It is also the single most
crucial factor determining the overall prognosis of the
patient\textsuperscript{18}.

As per the AMBILOAD trial\textsuperscript{19}, higher dose preparations
of amphotericin B does not improve the overall outcome compared to the
conventional dosing. Before amphotericin B dosage, factors such as
existing diabetic and hypertension-induced nephropathy must be kept in
mind. There is no strict consensus on the duration and the target dosage
of amphotericin B therapy\textsuperscript{20}, especially in the
recurrent setting. Based on our institutional expert multidisciplinary
team recommendations, we have titrated the target dose based on the
extent of the disease, comorbidities, and response to therapy.

The overall better outcomes in this study can be attributed to the early
detection, prompt surgical debridement, prolonged amphotericin B and
strict management of comorbidities, In a recent systematic review, 80\%
mortality was seen with CNS involvement\textsuperscript{21}; Among the
patients who have survived the CNS, debridement has the minimal or early
invasion of the dura and brain.

Long term outcomes of fungal osteomyelitis of frontal bone are not well
established.

\section*{Conclusion}

{\label{conclusion}}

The successful treatment of fungal osteomyelitis due to mucormycosis
requires four pronged approach (1) early detection (2) multidisciplinary
management of comorbidities (3) surgical debridement of necrotic bone
and (4) adequate systemic antifungal therapy. Long term outcomes of
fungal osteomyelitis of frontal bone are yet to be established, hence
close follow up at regular intervals and disease surveillance is
paramount importance.

Table -- 1: Case Description\selectlanguage{english}
\begin{longtable}[]{@{}lllllll@{}}
\toprule
Age & Sex & Comorbidities & Extent of mucormycosis & Duration of onset
following initial CAM Treatment & Extent of present disease &
Intraoperative CSF Leak\tabularnewline
62 & M & DM + HTN & SNP & 29 & Left frontal sinus, erosion of outer
frontal sinus table, dura free, brain free & No\tabularnewline
52 & M & DM + HTN + HYPOTHYROIDISM & SNOC & 10 & Bilateral frontal
sinus, erosion of both frontal sinus tables, dural enhancement,
prefrontal cortex involved & Yes\tabularnewline
30 & M & DM & SNO & 19 & Left frontal sinus, erosion of outer frontal
sinus table, dura free, brain free & No\tabularnewline
43 & M & DM & SNO & 16 & Bilateral frontal sinus, erosion of both
frontal sinus tables, dural enhancement, prefrontal cortex involved &
Yes\tabularnewline
33 & M & DM & SNC & 26 & Left frontal sinus, erosion of inner frontal
sinus table, dura free, brain free & No\tabularnewline
40 & F & DM + HTN & SN & 26 & Left frontal sinus, erosion of outer
frontal sinus table, dura free, brain free & No\tabularnewline
45 & M & DM + HTN & SN & 31 & Left frontal sinus, erosion of outer
frontal sinus table, dura free, brain free & No\tabularnewline
43 & M & DM & SNP & 33 & Left frontal sinus, erosion of inner frontal
sinus table, dura free, brain free & No\tabularnewline
46 & M & DM & SN & 14 & Left frontal sinus, erosion of outer frontal
sinus table, dura free, brain free & No\tabularnewline
39 & M & DM + HTN + HYPOTHYROIDISM & SN & 16 & Left frontal sinus,
erosion of outer frontal sinus table, dura free, brain free &
No\tabularnewline
M -- Male, F -- Female, DM -- Diabetes Mellites, HTN -- Hypertension, SN
-- Sinonasal, SNP -- Sinonasopalatal, SNO -- Sinonasoorbital, SNOC --
Sinonasoorbitocerebral, SNC - Sinonasocerebral & M -- Male, F -- Female,
DM -- Diabetes Mellites, HTN -- Hypertension, SN -- Sinonasal, SNP --
Sinonasopalatal, SNO -- Sinonasoorbital, SNOC -- Sinonasoorbitocerebral,
SNC - Sinonasocerebral & M -- Male, F -- Female, DM -- Diabetes
Mellites, HTN -- Hypertension, SN -- Sinonasal, SNP -- Sinonasopalatal,
SNO -- Sinonasoorbital, SNOC -- Sinonasoorbitocerebral, SNC -
Sinonasocerebral & M -- Male, F -- Female, DM -- Diabetes Mellites, HTN
-- Hypertension, SN -- Sinonasal, SNP -- Sinonasopalatal, SNO --
Sinonasoorbital, SNOC -- Sinonasoorbitocerebral, SNC - Sinonasocerebral
& M -- Male, F -- Female, DM -- Diabetes Mellites, HTN -- Hypertension,
SN -- Sinonasal, SNP -- Sinonasopalatal, SNO -- Sinonasoorbital, SNOC --
Sinonasoorbitocerebral, SNC - Sinonasocerebral & M -- Male, F -- Female,
DM -- Diabetes Mellites, HTN -- Hypertension, SN -- Sinonasal, SNP --
Sinonasopalatal, SNO -- Sinonasoorbital, SNOC -- Sinonasoorbitocerebral,
SNC - Sinonasocerebral & M -- Male, F -- Female, DM -- Diabetes
Mellites, HTN -- Hypertension, SN -- Sinonasal, SNP -- Sinonasopalatal,
SNO -- Sinonasoorbital, SNOC -- Sinonasoorbitocerebral, SNC -
Sinonasocerebral\tabularnewline
\bottomrule
\end{longtable}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image1/image1}

\end{center}
\end{figure}





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