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\begin{document}

\title{Fatal invasive gastric mucormycosis: 2 case reports}



\author[1]{amal khsiba}%
\author[1]{manel moalla}%
\author[2]{Salwa Nechi}%
\author[2]{Amina Bani}%
\author[3]{aicha elloumi}%
\author[3]{sana jemal}%
\author[2]{Mohamed Msaddak Azzouz}%
\affil[1]{Mohamed Taher Maamouri Hospital}%
\affil[2]{Mohamed Tahar Maamouri Hospital}%
\affil[3]{La Rabta Hospital}%


\vspace{-1em}



  
  \date{May 18, 2024}


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\selectlanguage{english}
\begin{abstract}
Mucormycosis affects most commonly immunocompromised patients. We report
two cases: a 61-year old female with diabetes whose the upper
gastrointestinal endoscopy showed a budding greyish process which
corresponded with an invasive mycormucosis in histology and a 59-year
old man who presented with worsening of general state. No patients
survived.%
\end{abstract}%



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\textbf{Introduction~:}

Mucormycosis is an uncommon fungal infection that occures usually in
immunocompromised patients such as patients with diabetes, renal
dysfunction, cancer or under immunosupressive therapy. It often affects
sinuses , lungs or skin and less commonly the gastrointestinal tract~;
the stomach being on the top of the list. It is associated with poor
prognosis and high rates of mortality.

\textbf{Cases presentation~:}

\emph{Case one:}

A 61-year old Tunisian female patient with type 2 diabetes mellitus,
hypertension, dyslipidemia and family history of peptic ulcer presented
to our gastoenterology department with a 7-day history of vomiting
preceded by a 4-month history of dry cough for which she took inhaled
corticosteroids. On physical examination, she had no fever. Her body
mass index (BMI) was 29.8 kg/m\textsuperscript{2}. Her blood pressure
was 120/70 mmHg. Her abdominal exam was normal. Initial laboratory
studies showed renal dysfunction with creatinine 163 \selectlanguage{greek}µ\selectlanguage{english}mol/L and
clearance 60 ml/min, Hemoglobin 11.5 g/dL, white blood cell count (WBC)
11100 cells/\selectlanguage{greek}µ\selectlanguage{english}L, C-reactive protein (CRP) 132 g/L and blood sugar 20
mmol/L (table1).

Upper gastrointestinal endoscopy revealed budding and infiltrating
greyish process resting on an ulcerated fundic mucosa (figure 1).

Anatomopathological exam concluded to an invasive mucormycosis by
demonstrating zygomycosis hyphae without any malignant signs (figure 2).

These findings were confirmed by parasitological examination (figure 3).

A brain-face-chest-abdomen and pelvis computed tomography (CT) scan
without contrast was practiced to search other sites of mucormycosis
(figure 4). It revealed a fundic mucosal thickening without any other
infection site confirmed by an ENT exam.

Since the liposomal form of amphotericin B which is less nephrotoxic was
not available in our country, therapy based on conventional amphotericin
B was started on the fifth day of diagnosis at progressive dose 5mg/day
on day one until 25 mg/day (0.4 mg/kg/d) on day 5. The evolution was
marked by an aggravation of renal dysfunction: creatinine 208 \selectlanguage{greek}µ\selectlanguage{english}mol/L and
clearance 25 ml/min.Thus we stopped the antifungal therapy but though
creatinine levels were still high. In day 19, she was programed for a
total gastrectomy but presented a respiratory distress due to pulmonary
embolism. The patient underwent total gastrectomy two months after
diagnosis. The examination of the stomach showed 2 digging ulcers in the
fundus (figure 5).The patient died 10 days after surgery.

\emph{Case two:}

A 59 year old man originally from Cango living in Tunisia without any
medical history presented to the hospital with gastric pain and vomiting
and a fast worsening of the general state. At admission, he had fever
with a temperature at 39\selectlanguage{ngerman}°C. His blood pressure was low : 80/45 mmHg and
his pulse was 110 BPM. Abdominal exam showed epigastric tenderness and a
moderate ascites.Laboratory findings revealed severe normocytic anemia
with 7.1 g/dL hemoglobin, elevated white blood cell count (WBC) 24 900
cells/\selectlanguage{greek}µ\selectlanguage{english}L (93\% neutrophils) and thrombopenia at
72~000/mm\textsuperscript{3}.He had high C-reactive protein (CRP) 231
g/L with a positive procalcitonin test (2.53 ng/ml). We concluded to a
septic shock and the patient had broad-spectrum antibiotherapy and
vascular filling with vasoactive drugs.

Upper gastrointestinal endoscopy revealed a very fragile mucosa and a
gastric ulcer with bleeding stigmata (figure 6). Abdominal ultrasound
was normal besides moderate ascites.

Anatomopathological exam showed typical broad zygomycetes hyphae (figure
7).

Six days later, the patient developped an hemophagocytic syndrome
confirmed by cytological examination of the bone marrow.~The evolution
was rapidly fatal with continuous decrease in hemoglobin level despite
transfusions and the patient died within 8 days after admission.

\textbf{Discussion:}

Zygomycosis was first described as a cause of human disease in 1885
{[}1{]}.Unlike other fungal opportunist infections which affect patients
with cancer, recipients of organ transplant or with compromised
immunity, mucormycosis can touch patients with diabetes mellitus
{[}1-3{]}, renal insufficiency, alcoholism {[}4-6{]}or even with an
intact immunity system {[}7-9{]}. These underlying conditions not only
predispose to the disease but also worsen the outcome of patients. Our
first patient had diabetes and renal insufficiency as a risk factors of
mucormycosis {[}9{]}.

The mode of transmission of mucormycosis involves inhalation or
ingestion of spores and direct inoculation into damaged mucocutaneous
surfaces {[}8{]}.

The common sites of infection are sinuses(39\%) which constitue the
predilected infection site in diabetic patients, skin (19\%) in
particular in patients with no risk factor and lungs (24\%) in patients
with cancer {[}1,10{]}.

The gastrointestinal tract is less commonlyaffected (7\%) with67\% of
stomach infection and 25\% of intestine infection {[}1,9{]}.Factors
predisposing for gastrointestinal mucormycosis (GIM) include
malnutrition, typhoid fever, uremia and penetrating trauma {[}8,11{]}.

The clinical manifestations of GIM include fever, abdominal pain,
nausea, vomiting, diarrhea, hemorrhage, or gastrointestinal perforation
{[}8,12{]}. Our first patient presented only vomiting and the second
patient presented withfever, abdominal pain and vomiting. The
confirmation of diagnosis is based on anatomopathological examination of
tissue samples showing fungal hyphae {[}8,13{]}.

GIM is usually fatal with 85\% of mortality {[}1,10,14{]},.The mainstay
of therapy in GIM is a combination of surgical debridement and
intravenous antifungal therapy. Early initiation of antifungal therapy
improves survival and can even exempt the patient from surgery in case
of non-invasive form of the disease {[}10{]}.A
delayintreatmentgreaterthan6daysworsens the prognosis and seems to
double the mortality rates {[}8{]}. The cornerstone of drug-therapy is
amphotericin B which constitutes the first line treatment at a daily
dose of 1 to 1.5 mg/kg for a duration of 4-6 weeks {[}4,8,15{]}. The
liposomal form is prefered for its lower risk of nephrotoxicity and the
possibility to administrate higher doses~: 5 to 10 mg/kg/day
{[}1,16,17{]}. Posaconazole and isavuconazole are also effective agents
and can be used as second line therapy. Surgical debridement of necrotic
tissue is often required for invasive mucormycosis {[}17{]}. In our
first patient, liposomal form of amphotericin B was not available in our
country thus we started treatment with conventional amphotericin B at
low doses which was stopped at day 5 because of worsening of renal
dysfunction and we opted for the surgical debridment. As for the second
patient, he did not receive this treatment since he was in a septic
shock.

\textbf{Conclusion~:}

Gastric mucormycosis is a rare entity that affects usually predisposed
patients such as immunocompromised, alcoholic and diabetic patients but
sometimes immunocompetent ones. Its treatment is based on amphotericin B
and surgical debridment of all necrotic tissues. The mortality rates
remain high up to 85\%. However, an early diagnosis and prompt therapy
can improve prognosis.

\textbf{Ethical approval:}

Patient personal data have been respected.

\textbf{Authorship list:}

Manel Moalla:manel.moalla@hotmail.com

Salwa Nechi~:salwanechi@hotmail.com

Amina bani~:Minouchaminabani@gmail.com

Aicha Elloumi~:aicha@elloumi.net

Sana Jemal~:jemelsana.benayed@gmail.com

Mohamed Moussaddek Azouz: mm.azouz@rns.tn

\textbf{Authors' contribution:}

1. Have made substantial contributions to conception and design, or
acquisition of data, or analysis and interpretation of data~: Manel
Moalla, Salwa Nechi, Amina Bani, Aicha Elloumi, Sana Jemal

2. Been involved in drafting the manuscript or revising it critically
for important intellectual content: Amal Khsiba, Manel Moalla

3. Given final approval of the version to be published. Each author
should have participated sufficiently in the work to take public
responsibility for appropriate portions of the content~: Mohamed
Moussaddek Azouz

4. Agreed to be accountable for all aspects of the work in ensuring that
questions related to the accuracy or integrity of any part of the work
are appropriately investigated and resolved~: Amal Khsiba, Manel Moalla,
Mohamed Moussaddek Azouz

\selectlanguage{ngerman}\textbf{Références~:}

{[}1{]} Roden MM, Zaoutis TE, Buchanan WL, Knudsen TA, Sarkisova TA,
Schaufele RL et al. Epidemiology and outcome of zygomycosis: a review of
929 reported cases. Clin Infect Dis. 2005 Sep 1;41(5):634-53. {[}2{]}
Vazquez JA, Sobel JD. Fungal infections in diabetes. Infect Dis Clin
North Am 1995; 9:97--116. {[}3{]} Meyer RD, Armstrong D. Mucormycosis
changing status. CRC Crit Rev Clin Lab Sci 1973; 4:421--51. {[}4{]}
Yu-Huai Ho, Bor-Gang Wu, Yan-Zhong Chen, Lih-Shinn Wang. Gastric
Mucormycosis in an Alcoholic with Review of the Literature. Tzu Chi Med
J 2007;19(3):169--172 {[}5{]} Park YS, Lee JD, Kim TH,Joo YH, Lee JH,
Lee TS, Kim EK. Gastric mucormycosis. Gastrointest Endosc
2002;56:904--5. 11. {[}6{]} Shahapure AG, Patankar RV, Bhatkhande R.
Gastric mucormycosis. Indian J Gastroenterol 2002;21:231--2. {[}7{]}
Abreu BFBB, Márcio Luís Duarte, Lucas Ribeiro dos Santos, Angelo
Sementilli and Felipe Nunes Figueiras. Gastric mucormycosis in an
immunocompetent patient. Rev Soc Bras Med Trop 51(3):401-402, May-June,
2018 {[}8{]} Sehmbey, G., Malik, R., Kosa, D., Srinivasan, I., Chuang,
K. Y., \&Bellapravalu, S. Gastric Ulcer and Perforation due to
Mucormycosis in an Immunocompetent Patient. ACG Case Rep J 2019;6:1--3
{[}9{]} Abdi BatiWotiye., KS, P. \&Ayele, B.A. Invasive intestinal
mucormycosis in a 40- year old immunocompetent patient - a rarely
reported clinical phenomenon: a case report. BMC Gastroenterology (2020)
20:61 {[}10{]}~Adhikari~S, Gautam, A. R., Paudyal, B., Sigdel, K. R.,
\&Basnyat, B. Case Report: Gastric Mucormycosis- a rare but important
differential diagnosis of upper gastrointestinal bleeding in an area of
Helicobacter pylori endemicity. Wellcome~Open~Research~2019~;4:5~
{[}11{]} Lelievre L, Garcia-Hermoso D, Abdoul H, Hivelin M, Chouaki T,
Toubas Det al. Posttraumatic mucormycosis: A nationwide study in France
and review of the literature. Medicine (Baltimore).
2014;93(24):395--404. {[}12{]} Lo OS, Law WL. Ileocolonic mucormycosis
in adult immunocompromised patients: A surgeon's perspective.World J
Gastroenterol.2010;16(9):1165--70. {[}13{]} Song BI. F-18
fluorodeoxyglucose positron emission tomography/computed tomography
image of gastric mucormycosis mimicking advanced gastric cancer: A case
report. World J Clin Cases 2019; 7(10): 1155-1160 {[}14{]} Agha FP, Lee
HH, Boland CR, ,~S F Bradley: Mucormycoma of the colon: early diagnosis
and successful management. AJR Am J Roentgenol. 1985; 145(4): 739--741.
{[}15{]} Greenberg RN, Mullane K, van BurikJA, ~IRaad,~M J Abzug,~G
Ansteadet al. Posaconazole as salvage therapy for zygomycosis.
Antimicrob Agents Chemother. 2006;50:126--33. {[}16{]} Cornely OA,S
Arikan-Akdagli,~E Dannaoui,~A H Groll,~K Lagrou,~A Chakrabarti et al.
ESCMID and ECMM joint clinical guidelines for the diagnosis and
management of mucormycosis 2013. Clin Microbiol Infect.~2014 Apr;20
Suppl 3:5-26 {[}17{]} Malek, A., De la Hoz, A., Arduino, R.,
\&Aisenberg, G. M. Disseminated tuberculosis and gastric mucormycosis
coinfection. IDCases 18 (2019) e00595.

\textbf{Table 1~:} laboratory test results on admission

\textbf{Figure 1:} Upper gastrointestinal endoscopy showingbudding and
infiltrating greyish process

\textbf{Figure 2:} A, B: necrotic and inflammatory material comprising
mycelial filaments suggesting mucormycosis

\textbf{Figure 3.} A: microscopic exam in lactophenol showing large,
irregular and non-septatehyphae

B~:microscopicexam after culture showing the rhizoids and the columella
specific for the species Rhizopus arrhizus.

\textbf{Figure 4} . CT scan of abdomen showing fundic mucosal thickening

\textbf{Figure 5:} resected stomach showing 2 ulcers in the fundus

\textbf{Figure 6:} endoscopy showing fragile mucosa and a gastric ulcer
with bleeding stigmata

\textbf{Figure 7: A:} Typical broad zygomycetes hyphae branching at
right angle (PAS, 400x).

B: Zygomycetes hyphae within the gastric mucosa.

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