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\begin{document}

\title{How to manage the aspergillus skull base osteomyelitis when it is only a
probable diagnosis?}



\author[1]{Xihong Cao}%
\author[2]{Yating Wang}%
\author[3]{Qingyu Zhang}%
\author[2]{Lijuan Chen}%
\author[2]{Zhengwen Zhu}%
\author[4]{Huang Jie}%
\affil[1]{Science City Hospital of Sichuan Province, Mianyang}%
\affil[2]{BenQ Medical Center,The Affiliated BenQ Hospital of Nanjing Medical University, Nanjing, Jiangsu Province}%
\affil[3]{BenQ Medical Center,The affiliated BenQ Hospital of Nanjing Medical University,Nanjing ,Jiangsu Province}%
\affil[4]{The Affiliated BenQ Hospital of Nanjing Medical University}%


\vspace{-1em}



  
  \date{May 25, 2024}


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\selectlanguage{english}
\begin{abstract}
Purpose:Aspergillus basicranial infection is a rare disease, often
associated with delayed or unproven diagnosis, the management of which
is unclear. Methods:We report a probable case of otogenic skull base
aspergillus osteomyelitis,review invasive basicranial
osteomyelitis,manage and follow up the patient by galactomannan(GM) test
and magnetic resonance imaging(MRI) during the treatment of
voriconazole. Results:%
\end{abstract}%



\sloppy


How to manage the aspergillus skull base osteomyelitis

when it is only a probable diagnosis?

\textbf{Introduction}

Fungal skull base osteomyelitis(SBO) is a rare and life-threatening
opportunistic infection that predominantly occurs in immunocompromised
hosts.However, the diagnosis and therapeutic management are poorly
defined. We report a probable case of Aspergillus basicranial infection
in a senile diabetic patient. The purpose is to illustrate the
importance of fungal serology examination in the diagnosis and
therapeutic management.

\textbf{Case report}

An 84-year-old diabetic patient was admitted on January 19, 2021.
presenting with right peripheral nerve palsy, intolerable otalgia,
hearing loss, dysphagia, hoarseness, and bucking. Three months prior to
admission, fungal clumps were found in his right external auditory canal
and were treated with triamcinolone acetonide and econazole nitrate
cream. Subsequently, he was diagnosed with otitis media and underwent
multiple courses of antibiotic and steroid therapy.

Magnetic resonance imaging (MRI) and computed tomography (CT) revealed
temporal bone osteomyelitis (Fig. 1). The patient underwent a
mastoidectomy and experienced relief from otoalgia. Histological
examination of intratemporal tissue showed hyperplastic fibrous tissue
with partial hyalinization and calcification; no fungi were detected
following methenamine silver staining (Fig. 2). High-throughput
sequencing did not yield any reliable positive results. The
1-3-\selectlanguage{greek}β-\selectlanguage{english}D-glucan (BDG) assay and Galactomannan test (GM test) results were
55.45 pg/ml and 1.85.Concurrently,the patient developed a fever with a
productive cough,Baumanii and Candida were isolated from a sputum
analysis. Antibiotic treatment, combined with voriconazole, was
administered and discontinued after 10 days.

All the symptoms improved, but the patient began experiencing pain in
the occiput and left otalgia over the following four months, eventually
developing left hearing loss. An enhanced MRI showed skull base
osteomyelitis (SBO), small abscesses in the prevertebral space, and
enhanced thickened dura (Fig. 3). The values of the BDG assay and GM
test increased to 70.7 pg/ml and 4.5, respectively. The patient was
diagnosed with basicranial Aspergillus infection and treated with
voriconazole. Blood drug concentration and GM test were monitored
monthly. The GM test value gradually declined to below 0.5 in 6 months,
with clinical and radiological remission and no change in liver and
renal function. The patient attempted to change or stop voriconazole,
but had to resume the medication due to an increased GM test value. To
date, the patient has remained in clinical remission for over 22 months
(Fig. 4).

\textbf{Discussion}

Galactomannan is a polysaccharide component of Aspergillus cell
walls,and it is released during tissue invasion by Aspergillus hyphae.
Beta-D-glucan (BDG) is present in the cell walls of almost all
pathogenic fungi, such as Candida, Aspergillus, and several other genera
(except Mucorales and Cryptococcus). These two serologic biomarkers have
been introduced for the diagnosis of invasive aspergillosis (IA) over
the last four decades.

The concentration of serum GM in vivo is determined not only by the rate
of production and secretion by the growing fungus but also by the rate
of uptake in the bloodstream, as well as the rate of elimination from
the circulation. A meta-analysis from Mayo Clinic in 2018 shows that
serum GM had a moderate mean sensitivity of 0.71 and high specificity of
0.89. Increasing the cut-off index increased specificity and decreased
sensitivity. A serum GM cut-off of 1.0 seems to provide optimal
sensitivity of 0.79 and specificity of 0.88\textsuperscript{{[}1{]}}. In
another study, the sensitivity, in particular, was very heterogeneous at
the cut-off values of 0.5, 1.0, and 1.5 optical density index.
Currently, due to the large number of false positives, a higher cut-off
of 1.0 is proposed\textsuperscript{{[}2{]}}. Even so, the GM test is
difficult to be considered a gold standard of IA diagnosis.The major
sources of circulating BDG are invasive fungal disease, iatrogenic
contamination, intestinal translocation, intestinal contents: mycobiome
and BDG translocation, hepatic function, bacterial infections, and
manufacturing-associated contamination. A meta-analysis showed that the
BDG assay in ICU patients at risk for IC or candidemia had a mean
sensitivity of 0.81 and mean specificity of
0.60\textsuperscript{{[}1{]}}. The negative predictive value of BDG is
very high,and it could not identify Aspergillus infection.So the BDG
test is clearly less close to being a diagnostic gold standard of
invasive fungal disease than the GM testThe limitation of BDG-based
tests lies in their inability to identify pathogenic microbial species.

Overall, serologic examination is not considered sufficient for a proven
diagnosis. Microscopic examination, culture, and PCR sequencing are also
required, according to the recent EORTC/MSG
guidelines\textsuperscript{{[}3{]}}. Invasive fungal diseases do not
have specific symptoms, signs, or imaging findings. Some studies have
evaluated the early diagnostic value of serum GM tests combined with
computed tomography for invasive pulmonary aspergillosis. The diagnostic
and follow-up performance of the two biomarkers were further improved by
using them as a combination of tests (parallel analysis improves
sensitivity and negative predictive value) or continuous monitoring
(serial analysis improves specificity and positive predictive value). In
this report, pain appeared earliest and persisted in the progression of
the disease; imaging studies provided localization but were not
diagnostic. At the early stage of the disease, the BDG assay and GM test
showed a slight increase, but the presence of Candida in the sputum
examination made us consider them as false positives. Fortunately, we
persisted in monitoring the serological changes dynamically and made the
decision to treat with voriconazole. Serological tests were sensitive
and varied with the severity of the illness and remained valuable for
observation even after the disappearance of symptoms and imaging
changes.

It is known that treating Aspergillus infections in the central nervous
system requires longer periods of drug therapy\textsuperscript{{[}4{]}}.
When the patient stopped taking the medication, the GM test values began
to rise, raising concerns about a possible resurgence of aspergillosis.
The current guidelines do not exhaustively describe these rare clinical
cases, and the optimum duration of antifungal treatment and follow-up
remains uncertain.

Only about half of all invasive fungal infections are diagnosed
pre-death,the value of the GM test is not sensitive and specific enough
to be considered a diagnostic gold standard, according to many
sources.However, when used it in combination with BDG, CT, and MR
imaging and observed dynamically,it demonstrates significant value
during the course of Aspergillus infections and therapeutic management.



\textbf{Abbreviation}

SBO:Skull base osteomyelitis

MRI:Magnetic resonance imaging

CT:Computed tomography

BDG:1-3-\selectlanguage{greek}β-\selectlanguage{english}D-glucan assay (\selectlanguage{greek}β-\selectlanguage{english}D-glucan assay )

GM test:Galactomannan test

IA:Invasive aspergillosis

\textbf{Fig.1}

\textbf{A} : Computed tomography(CT) showed right mastoiditis with
extensive bony erosions of the temporal bone,osteomyelitis and
involvement of the nasopharynx,petrous apex,inferior temporal
fossa,Eustachian tube.

\textbf{B} : CT scan showed postoperative surgical cavity 17 days after
mastectomy.



\textbf{Fig.2}

\textbf{A:} Otoscopy images show external auditory canal after treatment
of triamcinolone acetonide and econazole nitrate cream cream.

\textbf{B} : Images of surgical cavity 5 weeks after mastoidectomy
respectively.

\textbf{C} : Histological examination in mastoid mucosa shows
hyperplastic fibrous tissue with partial hyalinization and
calcification.

\textbf{D} : No fungi were found after methenamine silver staining.

\textbf{Fig.3}

\textbf{A} : On admission

\textbf{B} : 5 month after right mastoidectomy,before voriconazole
treatment

\textbf{C} : 11month after right mastoideduractomy,6 month after
voriconazole treatment

\textbf{D} : 17month after right mastoidectomy,12month after
voriconazole treatment

Axial and sagittal post contrast T1-weighted enhanced MR scan around
Eustachian tube scan confifirming SBO extending from the right to the
left along cranial base bone, prevertebral space( red arrow) with little
abscesses ( green arrow),enhancement of the thickened dura(blue
arrow)and parapharyngeal tissue.Meningeal enhancement is a evidence of
convincing intracranial extension.Images shows the diffuse infective
lesions improved by both of mastoidectomy(yellow arrow)and
voriconazole(pink arrow),but the extending lesions cannot be prevented
by surgery.

\textbf{Fig.4}

The upper limits of GM test and BDG assay are 0.5 and 37.5 (pg/ml)
respectively.

The negative result of BDG assay is labelled as 37.5((pg/ml) in Table.

Pain(1: No pain;2:Mild pain,need no painkiller;3: Moderate pain, need
painkiller;4:Severe pain,poor effective of painkiller)

\textbf{O} :Operation

\textbf{V} :Treatment with voriconazole

\textbf{C} :Chose voriconazole from another manufacturer

\textbf{W} :Drug withdrawal of voriconazole

\textbf{R} : Retreatment of voriconazole

\textbf{Declarations}

\textbf{Ethical Considerations} :The patient gave their informed consent
to participate~and~consent to publish~, and the treatment was approved
by the institute's committee on human research.

\textbf{Competinginterests} :The authors declare that they have no
conflicts of interest.

\textbf{Authors'contributions} :The data were collected by Zhenwen Zhu
and Yating Wang.Xihong Cao analysed all the data,and provided the
treatments~with Jie Huang.The pathological analysis was done by Lijuan
Chen.Qingyu Zhang helped in imaging analysis.

\textbf{Funding} : No foundings.

\textbf{Availability of data} :The data cannot be shared openly to
protect patient's privacy.

\par\null

\textbf{Reference}

{[}1{]} von Lilienfeld-Toal M, Wagener J, Einsele H, Cornely OA, Kurzai
O. Invasive Fungal Infection. Dtsch Arztebl Int. 2019 Apr
19;116(16):271-278. doi: 10.3238/arztebl.2019.0271.

{[}2{]} Leeflang MM, Debets-Ossenkopp YJ, Wang J, Visser CE, Scholten
RJ, Hooft L, Bijlmer HA, Reitsma JB, Zhang M, Bossuyt PM,
Vandenbroucke-Grauls CM. Galactomannan detection for invasive
aspergillosis in immunocompromised patients. Cochrane Database Syst Rev.
2015 Dec 30;2015(12):CD007394. doi: 10.1002/14651858.CD007394.pub2.

{[}3{]} Donnelly, J. P. et al. Revision and Update of the Consensus
Definitions of Invasive Fungal Disease From the European Organization
for Research and Treatment of Cancer and the Mycoses Study Group
Education and Research Consortium. Clin Infect Dis 71, 1367-1376,
doi:10.1093/cid/ciz1008 (2020).

{[}4{]} Clemons, K. V., Schwartz, J. A. \& Stevens, D. A. Experimental
central nervous system aspergillosis therapy: efficacy, drug levels and
localization, immunohistopathology, and toxicity. Antimicrob Agents
Chemother 56, 4439-4449, doi:10.1128/AAC.06015-11 (2012).\selectlanguage{english}
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