medical management of aspergillus flavus endocarditis

Pediatric Hematology and Oncology, 17:425± 427, 2000Copyright C° 2000 Taylor & Francis0888-0018/00 $12.00 + .00

Brief Report

MEDICAL MANAGEMENT OF ASPERGILLUS FLAVUS ENDOCARDITIS

Kanchana Rao, MRCP, and Vaskar Saha, FRCPCH h Department of PaediatricHaematology and Oncology, Royal London Hospital, London, United Kingdom

h An 11-year-old boy underwent a matched unrelated bone marrow transplant for refractory acutemyeloid leukemia. He developed invasive aspergillus pneumonia and endocarditis post-transplant.The fungal endocarditis was successfully eradicated with liposomal amphotericin at the dose of10 mg/kg/day. Surgical intervention was not required and no serious side effects of liposomalamphotericin were observed at this dose.

Keywords. Aspergillus ¯ avus, bone marrow transplant, endocarditis, liposomal amphotericin

Even with the use of ® ltered laminar ¯ ow rooms, about 5% of bone mar-row transplant (BMT) recipients develop invasive aspergillosis [1]. The mor-tality rate due to invasive aspergillosis in these children approaches 90% [2]and a combined approach of surgery with antifungal therapy is consideredto be the best treatment option [3]. However, surgery may not be feasiblein a sick child. Published information about alternative approaches in sucha condition is minimal. We describe a child with fungal endocarditis, postBMT treated successfully using a high dose of liposomal amphotericin.

CASE REPORT

An 11-year-old boy with refractory acute myeloid leukemia (AML)(FABM2) failed to achieve remission on the Medical Research CouncilAML-12 induction protocol [4] and subsequently also on the FLAG protocol[5]. Remission was ® nally achieved with CLASP (cytarabine and L-aspara-ginase) chemotherapy and sustained with 3 pulses of high-dose cytarabine-based chemotherapy (MIDAC, MACE, and CLASP) [4]. A matched unre-lated T-cell-depleted bone marrow transplant was performed in remission.Oral itraconazole and acyclovir were given as antifungal and antiviral pro-phylaxis, respectively, pre- and post-transplant. Total body irradiation, cy-clophosphamide, and Campath-H were used for conditioning. Methotrexateand cyclosporin were used as prophylaxis for graft versus host disease.

Received 12 July 1999; accepted 7 October 1999.Address correspondence to Vaskar Saha, Department of Paediatric Haematology and Oncology,

Royal London Hospital, London E1 1BB, UK. E-mail: v.saha@mds.qmw.ac.uk

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426 K. Rao and V. Saha

On day 7 post-transplant, the boy became pyrexial and developed a smallnecrotic lesion on the tip of his nose. Ceftriaxone and gentamicin werecommenced along with granulocyte colony stimulating factor (G-CSF). Thelesion progressively increased in size and required debridement on day 13.Liposomal amphotericin at the dose of 5 mg/kg/day was started the sameday. Histological examination of the debrided tissue showed fungal hyphaeand Aspergillus ¯ avus was subsequently isolated on tissue culture. Althoughthe child improved clinically, fever persisted. An echocardiogram (ECHO)on day 27 showed vegetations on the right ventricular wall and near themitral and tricuspid valve lea¯ ets. The vegetations were sized as between9 £ 8 mm and 12 £ 10 mm. The next day the boy developed respiratoryfailure and required ventilation. A chest X-ray (CXR) showed generalizedopaci® cation, and a high-resolution computerized tomography (CT) scanof the chest showed bilateral hazy in® ltrates and nodularity suggestive of in-vasive pulmonary aspergillosis. A bronchoalveolar lavage performed at thesame time failed to isolate any pathogenic organisms. The dose of liposo-mal amphotericin was then increased to 10 mg/kg day ¡ 1. The boy’s clinicalcondition improved steadily and he was extubated 6 days after increasing thedose of liposomal amphotericin. He required no further respiratory support,including oxygen. An ECHO performed on day 42 (2 weeks later) and onday 60 showed normally functioning cardiac valves with no evidence of vege-tations. Repeat CXR and CT scan of the chest also showed marked resolutionof the parenchymal disease.

DISCUSSION

Invasive nasal aspergillosis is an unusual presentation of systemic as-pergillus infection in the immunosuppressed patient. Although isolation ofAspergillus species on nasal screening is thought to be predictive of invasivemultisystem disease, this is not thought to be bene® cial for patients man-aged in ® ltered laminar ¯ ow settings [6]. Our patient developed invasivecutaneous disease even though he was managed in a HEPA-® ltered cubicle.The ® nding of Aspergillus ¯ avus on nasal cultures together with the CT fea-tures of invasive pulmonary aspergillosis and vegetations on the ventricularwall, unusual in bacterial endocarditis, favor a diagnosis of fungal endocardi-tis. In this case itraconazole prophylaxis failed, which may re¯ ect the wideinter- and intraindividual variability of the drug when administered orally toneutropenic patients [7]. In this case, progressive pulmonary disease withendocardial involvement developed while the patient was on standard rec-ommended doses of liposomal amphotericin. Recommendations for man-agement in such cases are varied and usually include surgical resection ofthe vegetations. Since this was not feasible in this boy’s condition, we electedto increase the dose of liposomal amphotericin to 10 mg/kg day ¡ 1. This

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Management of Aspergillus Flavus Endocarditis 427

proved effective, and he quickly became better with marked improvementin the respiratory condition and disappearance of cardiac vegetations.

Toxicity observed at this dose was persistent hypokalemia and a transientincrease in urea and creatinine on day 30. Hypokalemia was successfullymanaged with potassium supplements and amiloride, a potassium-sparingdiuretic. The rise in urea and creatinine levels was less than 2-fold and co-incided with the time when the patient was unwell and in need of intensivetreatment, which could have aggravated the rise in these compounds. Wedid not note any other adverse effects. Serum potassium and creatinine nor-malized with the withdrawal of high-dose liposomal amphotericin.

Because of the attendant renal toxicity of amphotericin and the fact thatdoses cannot be escalated without causing severe adverse effects, it is nowthe standard practice in our unit to use liposomal amphotericin instead ofamphotericin. We have now used this high dose of liposomal amphotericinin other patients with suspected/proven disseminated fungal disease withno signi® cant toxicity. To our knowledge there is only one other previous re-port of nonsurgical treatment of fungal endocarditis [8]. In that case, a childwith neuroblastoma and aspergillus endocarditis was successfully treated withliposomal amphotericin at a dose of 5 mg/kg day ¡ 1. In our case, disease pro-gressed on this dose and the clinical condition improved only when the dosewas increased to 10 mg/kg day ¡ 1. Where surgical debridement of invasiveaspergillosis is not feasible, particularly in the BMT setting, liposomal am-photericin alone at a dose of 10 mg/kg day ¡ 1 can be used effectively withlittle toxicity.

REFERENCES

1. Kibbler CC, Manuel RJ. The epidemiology and prevention of invasive aspergillosis. J Hosp Infect.1998;39:95± 109.

2. Chanock SJ, Walsh TJ. Evolving concepts of prevention and treatment of invasive fungal infectionsin paediatric bone marrow transplant recipients. Bone Marrow Transpl. 1996;18(Suppl 3):S15 ± S20.

3. Denning DW. Treatment of invasive aspergillosis. J Infect. 1994;28:25 ± 33.4. Hann IM, Stevens RF, Goldstone AH, et al. Randomised comparison of DAT versus ADE as induction

chemotherapy in children and younger adults with acute myeloid leukemia. Results of the MedicalResearch Council’s 10th AML trial (MRC AML 10). Adult and childhood leukemia working partiesof the Medical Research Council. Blood. 1997;89:2311± 2318.

5. Anarita C, Barbara G, et al. FLAG: an effective and tolerable protocol for the treatment of poor riskacute myeloid leukemias. Leukemia. 1994;8:1842± 1846.

6. Allen C, Joseph A, Jorge M, Stephen C. Invasive aspergillosis in acute leukemia: correlation with nosecultures and antibiotic use. Ann Int Med. 1979;90:4 ± 9.

7. Cheymol G., Porier JM. Prevention of aspergillosis with itraconazole in neutropenic patients. BullAcad Natl Med. 1999;183:371± 380.

8. Kennedy HF, Michie JR, Richardson MD, Simpson EM, Wilson N. Aspergillus ¯ avus endocarditis in achild with neuroblastoma. J Infect. 1998;36:126± 127.

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