INVASIVE ESOPHAGEAL ASPERGILLOSIS ASSOCIATED WITH ACUTE MYELOGENOUS LEUKEMIA: Successful Therapy with Combination Caspofungin and Liposomal Amphotericin B

Pediatric Hematology and Oncology, 24:63–68, 2007Copyright C© Informa HealthcareISSN: 0888-0018 print / 1521-0669 onlineDOI: 10.1080/08880010601001412

Case Report

INVASIVE ESOPHAGEAL ASPERGILLOSIS ASSOCIATED WITH

ACUTE MYELOGENOUS LEUKEMIA: Successful Therapy with

Combination Caspofungin and Liposomal Amphotericin B

Bulent Alioglu and Zekai Avci � Baskent University Faculty of Medicine,Department of Pediatric Hematology, Ankara, Turkey

Oguz Canan and Figen Ozcay � Baskent University Faculty of Medicine, PediatricGastroenterology and Hepatology Unit, Ankara, Turkey

Beyhan Demirhan � Baskent University Faculty of Medicine, Department of Pathology,Ankara, Turkey

Namik Ozbek � Baskent University Faculty of Medicine, Department of PediatricHematology, Ankara, Turkey

� Aspergillosis is one of the most common invasive fungal infections in patients with leukemia.In this patient group, this form of Aspergillus infection is a life-threatening condition with amortality of 50–100%. The lungs are most often affected, but the esophagus can also be involved.Theauthors report the case of a child with leukemia who developed invasive esophageal aspergillosis. Thecondition was diagnosed by microscopic examination of endoscopic biopsy specimens. The patientwas already receiving empirical liposomal amphotericin B when the diagnosis was made, so a secondantifungal (caspofungin) was added to the regimen. This combination was successful. This case todemonstrates a case of successful treatment of invasive esophageal aspergillosis using combinationtherapy of liposomal amphotericin B and caspofungin.

Keywords acute myelogenous leukemia, Aspergillus, caspofungin, liposomal ampho-tericin B

Infection is the primary cause of morbidity and mortality in patients withhemato-oncologic malignancies. Current chemotherapy protocols have im-proved patient survival, but these intensive regimens often cause extendedperiods of profound neutropenia during which patients are susceptible to

Received 2 May 2006; accepted 1 September 2006.Address correspondence to Bulent Alioglu, Baskent University Department of Pediatrics 6. Cadde,

No: 72/3, 06490, Bahcelievler, Ankara, Turkey. E-mail: [email protected]

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opportunistic infections [1–3]. Candidiasis and aspergillosis are the most fre-quent invasive fungal infections among leukemia patients on chemotherapy.

Invasive aspergillosis is a life-threatening infection, and Aspergillus fumi-gatus accounts for approximately 90% of cases of this illness in patients withleukemia [1–3]. The reported mortality rates in this patient group rangefrom 50 to 100% [1, 2]. The lung is the most common site of invasive As-pergillus infection. Other sites, such as the skin, eyes, brain, thyroid gland,paranasal sinuses, kidneys, bones, spleen, liver, and gastrointestinal system,are involved less frequently [3]. Primary esophageal aspergillosis is very rareduring childhood.

Here we report the case of a young patient with acute myelogenousleukemia (AML) who developed invasive esophageal aspergillosis. The fun-gal infection was diagnosed by microscopic examination of endoscopicbiopsy specimens of the esophagus.

CASE REPORT

A 15-year-old boy was admitted to our hospital with weakness, fever, andweight loss. Two years earlier, he had been diagnosed with French–American–British (FAB) AML-M7. The AML BFM 93 treatment protocol was prescribed,and the patient went into remission. However, he developed a fungal lung in-fection (fungus ball) during the initial phase of this chemotherapy protocol,as has been reported previously [4]. This was successfully treated with 2 weeksof liposomal amphotericin B (LAB) (5 mg/kg/day) followed by 4 weeks ofitraconazole (400 mg/day). Clinical and radiological findings completelyresolved at the end of this therapy. Thirteen months after he completedthe AML BFM 93 protocol, the patient developed bone marrow relapse.He was hospitalized and treated with the IDA-FLAG regimen (idarubicin–fludarabine, cytarabine, and granulocyte colony-stimulating factor) followedby 2 courses of FLAG; however, he did not enter remission. The IDA-FLAGtreatment caused severe neutropenia, pancytopenia, fever, and heartburn.The patient also developed severe pain in his back and epigastrium, accom-panied by nausea, dysphagia, and frequent vomiting. He was unable to drinkfluids.

Physical examination at this stage revealed abdominal distention dueto massive splenomegaly, and epigastric tenderness on deep palpation.The patient was diagnosed with febrile neutropenia, and was treated withcefepime and amikacin. When there was minimal response to these agents,LAB was added as part of empirical treatment on day 7 (1 mg/kg/day).The patient’s back pain did not improve and he continued to exhibitdysphagia and vomiting, so a pediatric gastroenterology consultation wasarranged.

During upper gastrointestinal endoscopy, we observed fragile, edema-tous, ulcerated, circumferential lesions covered with white plaques in the

Invasive Esophageal Aspergillosis Associated with Acute Myelogenous Leukemia 65

FIGURE 1 Upper gastrointestinal endoscopic images of invasive aspergillosis in a patient with AML. Notethe severe circumferential ulceration with white plaques, and the severe narrowing of the esophagus.

lower third of the esophagus (Figure 1). The esophageal lumen was con-stricted to such a degree that the endoscope could not be passed into thestomach. Biopsies were collected from the involved region of the esophagus.The specimens were fixed in formalin and prepared with hematoxylin/eosinand metholamine silver stains because fungal infection was strongly sus-pected. Microscopic examination of the sections revealed fungal hyphaewith characteristic 45-degree acute-angle branching (Figure 2). The patientwas diagnosed with invasive esophageal aspergillosis.

Since he had already been given empirical doses of LAB (1 mg/kg/day)for the previous 18 days, histopathological examination showed invasive in-fection, and this was the second fungal infection during his cancer treatment,we decided to increase the LAB dose to 3 mg/kg/day and add a second an-tifungal drug to the regime. The patient was started on a 6-week course ofcaspofungin administered intravenously at 50 mg/day. Renal, hepatic, orother toxicity from the treatment regimen was not detected. Control uppergastrointestinal endoscopy and biopsy was performed 14 days after the LABand caspofungin combination treatment was completed. This revealed sig-nificant mucosal healing but the severe esophageal stenosis remained. Thepatient underwent gastrostomy and subsequent esophageal balloon dilata-tion. After 9 sessions of balloon dilatation, he was able to swallow fluids and

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FIGURE 2 Cytological specimens showing fungal hyphae with characteristic 45-degree acute-anglebranching, which is characteristic of Aspergillus spp.

eventually solids. However, he died because of multiorgan failure secondaryto leukemic infiltration 8 months after the relapse of AML.

DISCUSSION

Aspergillus infection most often affects the lungs, but can often involve thesinonasal passages and the upper respiratory tract. These fungi can occasion-ally invade deeper tissues and disseminate via the bloodstream to become alife-threatening infection. This is a particular risk in immunocompromisedchildren. Aspergillus fungemia must be considered in any immunosuppressedleukemia patient who develops antibiotic-resistant fever while a central ve-nous catheter is in place. The main risk groups are children with acquiredimmunodeficiency syndrome or leukemia, and patients on immunosuppres-sive therapy [1–3]. Although T-cell function and macrophage activation areintact in patients with acute leukemia, these individuals often experienceextended periods of profound neutropenia due to intensive chemotherapy,and this can lead to opportunistic infections.

Leukemia patients are at risk for infection with Aspergillus or Candidaspecies both in the community and as nosocomial infections. Aspergillus

Invasive Esophageal Aspergillosis Associated with Acute Myelogenous Leukemia 67

species are known to occasionally cause esophagitis, as are other invasivefungal organisms such as Mucor, Histoplasma, and Cryptococcus species. Thesemicroorganisms can be diagnosed by examining sputum, bronchial washes,fine-needle aspirates, and esophageal brushings [5, 6]. Aspergillus esophagi-tis can be diagnosed based on histopathological examination of esophagealtissue specimens obtained during upper gastrointestinal endoscopy. Onereport states that cytological/microbiological examination of esophagealbrushings is a sensitive diagnostic test as well [6]. In cases of Candida orAspergillus infection of the eosophagus and esophageal malignancy, brush-ing can complement endoscopic biopsy in establishing the diagnosis. Tissuespecimens from eosophageal aspergillosis show fungal hyphae with charac-teristic 45-degree acute-angle branching, as we observed in our case [5, 6].It is concluded that direct microscopic examination of a clinical specimenis a crucial first-line procedure in detecting the presence of fungal elementsand is perhaps the most rapid, useful, and cost-effective means of diagnosingfungal infections [7]. However, immunohistologic staining for the exact iden-tification of fungi in clinical specimens has been attempted and monoclonaland polyclonal fluorescent-antibody reagents have been developed for thedifferentiating the genera of Aspergillus, Fusarium, and Scedosporium in situ.In our study, we could not perform immunohistologic staining and cultureof the material failed to give a definitive result. However, we diagnosed thepatient with aspergillosis with endoscopical and histopathological findings.Isolation of Aspergillus spp. from esophageal brushings or biopsy specimensmay indicate a grave prognosis [5]. For children with AML who develop inva-sive aspergillosis, survival depends on early diagnosis and aggressive therapy,together with improvement in hematologic status [5, 6].

Until recently, conventional amphotericin B deoxycholate was consid-ered the drug of choice for primary treatment of aspergillosis, but it wasineffective in approximately 50% of patients with invasive aspergillosis [8,9]. LAB is better tolerated than amphotericin B deoxycholate [8] and is lesstoxic at doses between 7.5 and 15 mg/kg/day [10]. A significant proportionof patients with invasive Aspergillus infection do not respond to treatmentwith conventional or lipid-formulation amphotericin B [8, 9].

Caspofungin is the first echinocandin that has been shown to inhibitthe synthesis of 1.3 β-D-glucan by Aspergillus species [8, 9, 11]. It appears thatmost patients with invasive aspergillosis require combined treatment, such ascaspofungin and LAB, for at least 3 weeks. Research has shown this regimento be effective in 75% of patients with leukemia [12, 13]. Multiple studieshave demonstrated that caspofungin has additive or synergistic effects whenused with amphotericin B or voriconazole [12]. We administered a 6-weekcourse of caspofungin combined with LAB, and this was successful in ourcase. During the first treatment attempt with BFM protocol, the patient hadbeen successfully treated for a fungal lung infection (fungal ball) using LABfollowed by itraconazole.

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In conclusion, clinicians managing patients with acute leukemia who areneutropenic should keep a high index of suspicion for infections such asinvasive aspergillosis, and must administer treatment promptly. This reportemphasizes the importance of gastrointestinal endoscopic examination ofimmunocompromised patients with vague gastrointestinal complaints. Com-bined antifungal treatment modalities could be useful in cases with invasiveesophageal aspergillosis.

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