Medical Mycology Case Reports 11 (2016) 1–4
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Medical Mycology Case Reports
journal homepage: www.elsevier.com/locate/mmcr
Difficult diagnosis of invasive fungal infection predominantly involving
the lower gastrointestinal tract in acute lymphoblastic leukaemia
Gulhadiye Avcu a, Deniz Yilmaz Karapinar b,n, Pinar Yazici c, Muhterem Duyu c,
Suleyha Hilmioglu Polat d, Berna Atabay e, Basak Doganavsargil f, Bulent Karapinar c
a
Department of Pediatric Infectious Diseases, Ege University, Faculty of Medicine, Izmir 35040, Turkey
Department of Pediatric Hematology, Ege University, Faculty of Medicine, Izmir 35040, Turkey
c
Department of Pediatric Intensive Care, Ege University, Faculty of Medicine, Izmir 35040, Turkey
d
Department of Medical Microbiology, Ege University, Faculty of Medicine, Izmir 35040, Turkey
e
Department of Pediatrics, Tepecik Training and Research Hospital, Izmir 35110, Turkey
f
Department of Medical Pathology, Ege University, Faculty of Medicine, Izmir 35040, Turkey
b
art ic l e i nf o
a b s t r a c t
Article history:
Received 4 November 2015
Received in revised form
29 January 2016
Accepted 29 January 2016
Available online 30 January 2016
Invasive fungal infections are most commonly seen in immunocompromised patients and usually affect
the respiratory system. Gastrointestinal system involvement of mucormycosis and invasive aspergillosis
is rarely reported in childhood. Here we describe a 5 year old boy with acute lymphoblastic leukaemia
who developed invasive fungal infection particularly affecting the lower gastrointestinal system to
emphasise the difficulties in diagnosis and management of invasive fungal infections in immunocompromised patients.
& 2016 The Authors. International Society for Human and Animal Mycology. Published by Elsevier B.V.
This is an open access article under the CC BY-NC-ND license
(http://creativecommons.org/licenses/by-nc-nd/4.0/).
Keywords:
Invasive aspergillosis
Aspergillus flavus
Gastrointestinal bleeding
Mucor
Leukaemia
Child
1. Introduction
Invasive aspergillosis (IA) is a life-threatening opportunistic
infection that usually affects immunocompromised patients [1].
Immunsuppressive therapies, high-dose corticosteroids, severe
and prolonged neutropenia are the factors that facilitate the infection. Majority of the cases are caused by Aspergillus fumigatus,
followed by Aspergillus flavus, Aspergillus niger, and Aspergillus
terreus [2]. IA most commonly involves the respiratory tract, lung
or sinus but the central nervous system, cardiovascular system,
and other tissues may be infected as a result of hematogenous
spread [3]. Gastrointestinal (GI) aspergillosis, which is associated
with high mortality, is a rarely seen form of extra-pulmonary aspergillosis and is most often described in the setting of disseminated disease [3]. GI involvement is rarely seen in mucormycosis, and most reported cases are associated with malignant haematological diseases [4].
Here, we describe a child with acute lymphoblastic leukaemia
(ALL) who developed probable invasive aspergillosis and
n
Corresponding author.
E-mail address: dyilmazk@yahoo.com (D.Y. Karapinar).
diagnosed with GI mucormycosis by histopathologic examination
simultaneously. He survived with aggressive antifungal therapy
and surgery.
2. Case
A 5-year-old boy was diagnosed with CALLA ( þ), pre-B cell ALL
in July 2013. He was put on Standard risk arm of ALL BFM 2000
Protocol at day 30. The patient was referred to our intensive care
unit because of clinical deterioration and severe lower gastrointestinal system bleeding. At the admission day, at day 0, the
patient's general condition was poor, with tachycardia and respiratory distress present. His body temperature was 38.5 °C, and
jaundice, abdominal distension and mucositis were also observed.
Laboratory test results showed a white blood count of 48/mm3, an
absolute neutrophil count of 6/mm3, haemoglobin of 6.9 g/dL, a
thrombocyte count of 35,000/mm3and C-reactive protein of
11.7 mg/dL (N:0–0.5 mg/dL). The prothrombin time and activated
partial thromboplastin time were prolonged, with a high international normalised ratio. The patient's biochemical values revealed a total bilirubin of 7.3 mg/dL, with direct bilirubin
http://dx.doi.org/10.1016/j.mmcr.2016.01.005
2211-7539/& 2016 The Authors. International Society for Human and Animal Mycology. Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND
license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
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G. Avcu et al. / Medical Mycology Case Reports 11 (2016) 1–4
Fig. 1. CT scan showed colonic mural thickening in the splenic flexure, infarct
formation in the kidney and spleen which were suggestive of IA on the 8th day.
dominance, hypokalaemia and hypocalcaemia. He was intubated
and required sedation, mechanical ventilation and haemodynamic
support. Erythrocytes, platelet suspension and fresh frozen plasma
were administered for continuing upper and lower GI bleeding.
Broad-spectrum antibiotics (piperacillin–tazobactam, amikacin
and vancomycin) were started initially. At day þ 4, the antibiotics
were changed to teicoplanin and meropenem because of the ongoing fever, and caspofungin was added after yeast (Candida krusei) growth in a blood culture at day þ6. Abdominal ultrasonography revealed nothing of note, except hepatomegaly and
minimal abdominal plastering fluid. At day þ 8, the patient was
still febrile but he was no longer neutropenic. Gancyclovir treatment was started following a positive result of a polymerase chain
reaction (PCR) analysis for cytomegalovirus, and voriconazole was
added following the detection of mould in a nasopharyngeal swab.
At this time, a thoraco-abdominal computed tomography (CT) scan
showed colonic mural thickening in the splenic flexure and infarct
formation in the kidney and spleen that were suggestive of IA.
Nodular lesions compatible with IA were detected in the lung
(Fig. 1). Serum galactomannan antigen was positive (44.73), and
fungal cultures of sputum, tracheal aspirate were positive for A.
flavus. At day þ 14, he was afebrile, and teicoplanin and meropenem were stopped. As no further bleeding had occurred over
the previous 48 h, he was taken to the haematology department.
Despite an initial improvement (reduced GI symptoms and haemorrhage) with the voriconazole treatment, the patient developed
massive abdominal distension at day þ16. A new abdominal CT
revealed progression of the fungal lesions and peripheral invasion,
with a covered perforation in the splenic flexure and a new hypodense lesion in the liver that resembled an aspergilloma (Fig. 2).
The patient underwent an immediate bowel resection and splenectomy. After the surgery, he was taken to the paediatric intensive care department. Metronidazole was added to the treatment, caspofungin was stopped, and intravenous liposomal amphotericin B (AmB) (5 mg/kg/day) was started. The patient showed
a clinical improvement after the surgery, with resolution of the
abdominal distension and rectal bleeding. However, at day þ20,
he was febrile again, and teicoplanin was added due to the growth
of coagulase-negative staphylococci in a blood culture. At day
þ22, he was reintubated because of increased respiratory distress,
Fig. 2. CT scan showed progression in fungallesions, peripheral invasion, a covered
perforation in the splenic flexure and a new hypodense lesion in the liver suspecting an aspergilloma on the 16th day.
Fig. 3. CT scan revealed lesions compatible with IA.
and a repeat CT scan showed no change in the lesions, which were
compatible with aspergillus. At this point, inhaled AmB (25 mg
twice weekly) was added (Fig. 3.). At day þ 29, a histopathological
analysis of resected specimens of the bowel and spleen showed
ulceration, with intense inflammation, and non-septate, thick,
variable in diameter fungal hyphae, which were compatible with
mucormycosis (Fig. 4). Culture or PCR for pathogenic fungi from
resected material could not be performed. The dose of liposomal
AmB was increased to 10 mg/kg/day, posaconazole was started,
and voriconazole was stopped. At day þ 34, bone marrow aspiration was performed and resulted in haematological remission. At
day þ37, a tracheostomy was performed due to prolonged ventilator dependence. His lower GI symptoms did not show persistence with this therapy. A galactomannan test positivity showed
G. Avcu et al. / Medical Mycology Case Reports 11 (2016) 1–4
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Fig. 4. Histopathological examination showed the non-septate, thick, variable in diameter fungal hyphae,which were compatible with mucormycosis. (A; jejunum,
Hematoxylin and eosin, 20. B; spleen, d-PAS, 20.).
Fig. 5. Changes in laboratory parameters with the treatment of different antifungal agents.
increment. Repeated thoracal tomography revealed an increase in
the number and size of the nodules in the lung. Thus, voriconazole
was added to liposomal AmB and posaconazole. The patient had
fever intermittently between the þ40 and þ54th days of hospitalisation, but blood cultures remained sterile. At the end of a 62day follow-up, he was afebrile, no further gastrointestinal bleeding
episodes were seen, a galactomannan test was negative, and the
liposomal AmB dose was reduced to 5 mg/kg/day (Fig. 5). The
patient was referred to the centre that he had been followed up for
his haematological malignancy with triple anti-fungal therapy.
Posaconazole was ceased 15 days after the patient became afebrile.
3. Discussion
The frequency of IFI has increased over the last years because of
the more intensive cytotoxic agents. With the widespread use of
azole prophylaxis candidiasis became less frequent while IA and
mucormycetes increased in patients with haematologic diseases
[5].
IA most commonly affects the lower respiratory system and
nasal sinuses. Other extrapulmonary locations of the infection
include the central nervous system, eyes, skin, kidneys, heart,
bones, joints and GI tract [6]. Aspergillosis is a highly lethal infection in the GI tract, which is the second most common site of IA.
It usually occurs via dissemination from a primary pulmonary
infection, and its frequency is estimated to be about 17% [7]. Primary GI aspergillosis, causing focal invasion as a primary site of
inoculation is rarely reported. Symptoms are often nonspecific.
Patients with GI aspergillosis can present as neutropenic enterocolitis (typhlitis), appendicitis, ileus, colonic ulcers, abdominal
pain or GI bleeding [7].
Mucormycosis is a systemic opportunistic, fatal infection in
immunocompromised patients which most commonly affects the
paranasal sinuses (39%) and lungs (24%), more likely skin (19%),
brain (9%) and GI tract (7%) [8]. Due to the invasion of mesenteric
arteries and intravascular thrombosis, tissue ischaemia leading to
infarction and perforation of the intestine in both GI aspergillosis
and mucormycosis can occur.
Early diagnosis of IFI in GI tract is difficult in neutropenic patients. The diagnosis is delayed because the organism can seldom
be isolated from blood or tissue culture. It is difficult to discriminate between IA and mucormycosis on the basis of a radiological examination alone. Therefore, histological confirmation is
often essential [9]. However, for an accurate diagnosis, clinicians
are unable to provide appropriate conditions at all times and
cannot get sufficient material for examination. There are no specific radiological findings that suggest GI aspergillosis or mucor.
Abdominal CT scans may show diffuse thickening of the intestinal
wall or diffuse bowel distention. Ulcerative or necrotic lesions are
commonly detected with endoscopy or surgery [10].
The choice of antifungal agent must be based on the clinical
characteristics of the IFI and the local epidemiology with considering the increase in the incidence of mucormycetes [9]. Voriconazole is the primary therapy for IA while high doses of liposomal AmB are recommended for GI mucormycosis. Adjuvant
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G. Avcu et al. / Medical Mycology Case Reports 11 (2016) 1–4
surgery is essential in the management of Mucor and recommended in case of intestinal aspergillosis to avoid perforation
or obstruction [9].
In our case, the patient’s main symptoms were abdominal
distension and rectal bleeding. The strongly positive galactomannan test (44.73), together with the growth of A. flavus in
sputum and tracheal aspirate, and the radiological findings,
especially the lung involvement, pointed to IA. Urgent surgical
intervention played a key role in controlling the disease. However,
it was surprising that the histological findings were consistent
with mucormycosis because Mucor was not detected in the previous microbiological examinations. This raises questions about
the actual diagnosis: Was it only IA, co-infection or breakthrough
infection under voriconazole therapy? Tissue culture could help to
provide a definitive diagnosis.
In conclusion, early diagnosis of IFI is difficult but essential to
reduce mortality. Clinicians must be aware of the unexpected involvements and also the possibility of coinfection and breakthrough infection. Survival of these patients will improve with
early surgical intervention in addition to aggressive antifungal
treatments.
Conflict of interest
There are none.
Acknowledgement
There are none.
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