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Fellow Hematology & Oncology Department of Internal Medicine Wayne State University 4100 John R, 4th floor Hudson Webber Detroit, Michigan 48201-2020 fax 313/993-0307 vishnubh{at}karmanos.org
Clinical Pharmacy Specialist (Hematology/Oncology) Harper University Hospital/Detroit Medical Center Adjunct Assistant Professor, Pharmacy Practice Eugene Applebaum College of Pharmacy and Allied Health Professions Wayne State University
Clinical Assistant Professor Internal Medicine and Oncology Department of Internal Medicine Wayne State University Barbara Ann Karmanos Cancer Institute
Professor Infectious Diseases and Internal Medicine Director, Infectious Diseases Fellowship Program Wayne State University School of Medicine
Published Online, March 23, 2004. www.theannals.com, DOI 10.1345/aph.1D404
Case Report. A 27-year-old white man with Philadelphia chromosome–positive acute lymphoblastic leukemia underwent a matched unrelated donor peripheral blood stem cell transplantation. The posttransplant course was complicated by acute graft-versus-host disease (GVHD) of the skin and cytomegalovirus antigenemia. Treatment consisted of corticosteroids, cyclosporine, and ganciclovir. After engraftment, the patient developed severe right-sided pleuritic chest pain and exudative pleural effusion. A pleural fluid culture grew Aspergillus terreus; intravenous combination therapy with micafungin plus liposomal amphotericin B (as a part of study protocol) was started.
The patient received micafungin 100 mg from day 25 after transplant to day 29 (day 0 denotes the day of stem-cell infusion). Subsequently, the dose was increased to 200 mg until day 33 after transplantation. Due to decreasing renal function, the study protocol was discontinued and therapy was switched to intravenous voriconazole on day 34 of transplantation. The dose of voriconazole was 6 mg/kg every 12 hours for one day and 4 mg/kg twice daily thereafter. At this time, the peripheral blood leukocyte count (WBC) was 9 x 103/mm3 (Figure 1).
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Within a few days, fever developed with steadily rising WBC count and eosinophilia. On day 45, the WBC count was 78 x 103/mm3, with eosinophils 10.6%. Despite extensive clinical and microbiologic investigations, no source of infection other than invasive aspergillosis was identified. Due to temporal correlation, voriconazole was suspected to be the cause of fever and leukocytosis. The drug was discontinued and, within 2 days, the fever subsided. The patient's WBC count was 10.5 x 103/mm3, with eosinophils 5.7%. Concurrent medications were vancomycin, cefepime, cyclosporine, methylprednisone, and ganciclovir. Colony-stimulating factors were not given.
Antifungal therapy was switched to caspofungin. Unfortunately, acute GVHD (skin and gut) became refractory, and the patient died. According to the Naranjo probability scale, the adverse reaction was probably voriconazole related.2
Discussion. In a large study of voriconazole in the treatment of invasive aspergillosis, transient visual abnormalities, rashes, and elevated liver function test results were the most common adverse events.3 Leukocytosis or eosinophilia have not been previously observed in nearly 1500 voriconazole recipients.4 Furthermore, fever/leukocytosis have not been reported with other triazoles or micafungin. As of this writing, to our knowledge, this is the first case report of such an adverse event.
References
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