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Volume: 12 Issue: 4 August 2014

FULL TEXT

CASE REPORT
Fatal Fusarium solani Infection After Stem Cell Transplant for Aplastic Anemia

Fusarium is a saprophytic and opportunistic pathogen that can cause local tissue infection and life-threatening systemic infection. Systemic infection is rare and is observed primarily in immunocompromised patients. The early diagnosis is difficult, and the optimal treatment is unclear. However, the mortality is high.

A 21-year-old man with aplastic anemia was treated with an allogeneic stem cell transplant. He developed fatal Fusarium solani infection. Fusarium species may be overlooked pathogenic fungi in immunocompromised patients, especially bone marrow transplant recipients.


Key words : Allogeneic, Complications, Fungus, Treatment, Voriconazole

Introduction

Fusarium is a saprophytic and opportunistic pathogen that can cause local tissue infection such as keratitis, arthritis, onychomycosis, or severe life-threatening systemic infection. Systemic infection is observed primarily in immunocompromised patients. Fusarium spores invade a host by inhalation or settling into areas of skin breakdown or foreign bodies. The clinical manifestations are diverse and complex. The diagnosis is difficult and established from the association of clinical features, blood culture, and morphologic identification. The optimal treatment strategy for patients with severe Fusarium infection is unclear. The outcome of aggressive fusariosis is very much affected by the host immune status.1 Prevention of Fusarium infection is the cornerstone of treatment. We treated a patient who had aplastic anemia who developed a fatal Fusarium solani infection after an allogeneic stem cell transplant.

Case Report

A 21-year-old man with no significant medical history presented to our hospital; his disease was diagnosed as severe aplastic anemia. He had no sibling donors and was matched to his mother by human leukocyte antigen type (5/6). He developed fever on the third hospital day and was treated with meropenem (3 days). His temperature did not recover to normal until he was given antifungal therapy with amphotericin B and itraconazole for 5 days and subsequent itraconazole alone for maintenance antifungal therapy. Pretreatment of the patient included a combination of fludarabine (30 mg/m2/d from days 1-5), anti-thymocyte globulin (25 mg/kg/d from days 3-5), and cyclophosphamide (50 mg/kg/d from days 2-5). Donor stem cells were infused on day 0 (mononuclear cell count, 6.05 ×109/kg; CD34-positive cell count, 3.63 ×106/kg). Methotrexate (19 mg/d) and cyclo-sporine (45 mg/d) in short courses were used to prevent graft-versus-host disease and granulocyte colony-stimulating factor was used to promote engraftment.

Ten days after transplant, he returned with persistent fever. Although meropenem and teicoplanin were used together, the temperature was not effectively controlled. On day 12, he presented with scrotal pain and rash with crusting and exudation. The scrotal skin secretion increased gradually and he developed multiple crusted areas with decrustation. The skin lesions invaded the glans. His balanus became red, swollen, and accompanied with secretions. Syphilis and human immunodeficiency virus antibodies were negative. He was treated with ganciclovir (5 mg/kg, twice daily) for presumed virus infection, but fever persisted. On day 15, amphotericin B was used but the infection persisted.

On day 20, the white blood cell count showed engraftment, and the short tandem repeat-polymerase chain reaction (PCR) test confirmed that the donor was successfully engrafted (Figure 1). On day 24, he presented with left eye blurred vision. His vision declined and he had no light perception. Ultrasonography of the eyes showed a left eye vitreous opacity (Figure 2 anterior ischemic optic neuropathy, and the right eye was normal (Figure 3). On day 37, he developed scattered bilateral lower limb small purple skin nodules and muscle soreness. On day 38, he developed headaches, irritability, nausea, and vomiting. Computed tomography scan of the brain showed low density in the brainstem and right ventricular anterior horn (Figure 4). The chest computed tomography scan showed no abnormalities.

Microbial culture of scrotal skin secretions suggested growth of Fusarium species (Figure 5), and 2 blood cultures also showed growth of Fusarium species. The internal transcribed spacers of Fusarium recombinant DNA were amplified in a PCR system (Figure 6). The results of blood cultures and PCR suggested that the Fusarium species isolated from blood and skin secretions were Fusarium solani. Antifungal therapy with amphotericin B and voriconazole was not continued because of severe renal dysfunction (serum creatinine, 323 μmol/L; urea nitrogen, 31.4 mmol/L); amphotericin B was discontinued and voriconazole was used alone. Although symptomatic treatment was given concurrently, the disease continued to deteriorate, and the patient died of multiple organ failure on day 56 after transplant.

Discussion

There are no large, prospective reports about Fusarium infection in immunocompromised patients. Since the first report of a case of Fusarium solani infection in 1973,2 Fusarium infection has become the neglected fungal infection among patients who have hematologic malignant diseases. There are > 50 Fusarium species that have been identified, but only a few species cause human infection including Fusarium solani most frequently (50%), Fusarium oxysporum (20%), Fusarium moniliforme (10%), and Fusarium verticillioides (10%).1 However, Fusarium infection is rare. The present patient had severe immuno-deficiency after transplant. In our opinion, the immunodeficiency and delay of white blood cell engraftment contributed to aggressive fusariosis.

Fusarium species can produce mycotoxins and invade vessels. In humans, Fusarium species can cause many diseases including superficial or locally invasive allergic disease or disseminated infection. Disseminated infection is observed primarily in immunocompromised patients and usually is manifested by persistent refractory fever, resistance to antifungal drugs, and other manifestations including sinusitis, infection of the nasal region and brain, cellulitis at broken skin, dermal pain, endophthalmitis, pneumonia, myositis, and infections of the central nervous system.1,3-5 The most frequently involved organ is skin (70%-90%), followed in frequency by the lungs and nasal sinuses.6 Fungal endophthalmitis is a destructive intraocular infection that has a poor visual prognosis, especially when Fusarium is the genus involved.7 The clinical features of Fusarium endophthalmitis may include fever and progressive reduction of visual acuity to complete blindness. Separate brain lesions caused by Fusarium species are rare. Cerebral fungal abscess caused by Fusarium oxysporum was reported in a patient who had acute promyelocytic leukemia.8 The mortality of cerebral fungal infection is almost 100% when it is treated with typical antifungal agents such as amphotericin B. Combining second-generation triazoles such as voriconazole with neurosurgery may increase overall survival.

The clinical manifestations of the present patient were complex and atypical. The infection presented with local lesions and aggressive involvement, progressed rapidly, and caused multiple organ involvement including disseminated skin lesions, endophthalmitis, and central nervous system infection.

The diagnosis of fusariosis primarily depends on the clinical manifestations, pathogen morphology identification, and molecular biology detection. The typical morphology of Fusarium species includes banana-shaped macroconidia.9 Histopathologic examination reveals hyaline acute-branching septate hyphae similar to those found in aspergillosis. Unlike disseminated Aspergillus infection, disseminated fusariosis can be diagnosed by blood culture in > 40% patients.1,3 Nevertheless, the species identification of Fusarium is difficult. In addition to morphologic identification, diagnostic approaches include serologic detection, electrophoretic karyotype analysis, PCR sequencing, and other methods.

The treatment of fusariosis is difficult. The therapy of localized fusariosis is important to prevent progression to disseminated fusariosis and includes surgical excision and systemic antifungal therapy.6,10 However, the prompt treatment of disseminated fusariosis is unclear.3 Fusarium species are resistant to most antifungal drugs. Different species of Fusarium have different sensitivity to antifungal drugs. Fusarium solani may be more susceptible to amphotericin B but less susceptible to voriconazole than Fusarium oxysporum.11 Voriconazole may be a good choice, particularly when using amphotericin B or its liposome drug is ineffective.12 No randomized prospective studies evaluating combination therapy for disseminated fusariosis are available. However, there are isolated case reports of successful treatment of disseminated fusariosis that show that combination therapy is more effective than monotherapy.1,3,9,13 In addition to antifungal treatment, the adjuvant treatment of fusariosis includes surgical debulking of infected tissue, removal of venous catheters, cleaning air and water, and granulocyte colony-stimulating factor or granulocyte-macrophage colony-stimulating factor transfusions.3 Transfusion of granulocyte colony-stimulating factor and granulocytes frequently are used in patient who have poor prognosis from fusariosis such as persistently neutropenic patients.

The outcome of disseminated fusariosis is poor. The overall mortality of Fusarium infection in immuno­compromised patients ranges from 50% to 100%.6 Every effort should be made to prevent these infections and improve the patient’s immune status. It may be necessary to shorten the treatment time and terminate medication in patients who have very poor immunity.

Fusarium species are overlooked pathogenic fungi in immunocompromised patients, especially bone marrow transplant recipients. The clinical course may be difficult because of the complexity of clinical manifestations, difficulty of early diagnosis, unclear optimal treatment, and poor prognosis.


References:

  1. Nucci M, Anaissie E. Fusarium infections in immunocompromised patients. Clin Microbiol Rev. 2007;20(4):695-704.
    CrossRef - PubMed
  2. Cho CT, Vats TS, Lowman JT, Brandsberg JW, Tosh FE. Fusarium solani infection during treatment for acute leukemia. J Pediatr. 1973;83(6):1028-1031.
    CrossRef - PubMed
  3. Dignani MC, Anaissie E. Human fusariosis. Clin Microbiol Infect. 2004;10(suppl 1):67-75.
    CrossRef - PubMed
  4. Nucci M, Anaissie EJ, Queiroz-Telles F, et al. Outcome predictors of 84 patients with hematologic malignancies and Fusarium infection. Cancer. 2003;98(2):315-319.
    CrossRef - PubMed
  5. Rabodonirina M, Piens MA, Monier MF, Guého E, Fière D, Mojon M. Fusarium infections in immunocompromised patients: case reports and literature review. Eur J Clin Microbiol Infect Dis. 1994;13(2):152-161.
    CrossRef - PubMed
  6. Boutati EI, Anaissie EJ. Fusarium, a significant emerging pathogen in patients with hematologic malignancy: ten years’ experience at a cancer center and implications for management. Blood. 1997;90(3):999-1008.
    PubMed
  7. Dursun D, Fernandez V, Miller D, Alfonso EC. Advanced Fusarium keratitis progressing to endophthalmitis. Cornea. 2003;22(4):300-303.
    CrossRef - PubMed
  8. Anten S, Heddema ER, Visser O, Zweegman AS. Cerebral fungal abscess in a patient with acute promyelocytic leukaemia. Br J Haematol. 2008;140(3):253.
    CrossRef - PubMed
  9. Liu K, Howell DN, Perfect JR, Schell WA. Morphologic criteria for the preliminary identification of Fusarium, Paecilomyces, and Acremonium species by histopathology. Am J Clin Pathol. 1998;109(1):45-54.
    PubMed
  10. Heinz T, Perfect J, Schell W, Ritter E, Ruff G, Serafin D. Soft-tissue fungal infections: surgical management of 12 immunocompromised patients. Plast Reconstr Surg. 1996;97(7):1391-1399.
    CrossRef - PubMed
  11. Arikan S, Lozano-Chiu M, Paetznick V, Nangia S, Rex JH. Microdilution susceptibility testing of amphotericin B, itraconazole, and voriconazole against clinical isolates of Aspergillus and Fusarium species. J Clin Microbiol. 1999;37(12):3946-3951.
    PubMed
  12. Vagace JM, Sanz-Rodriguez C, Casado MS, et al. Resolution of disseminated fusariosis in a child with acute leukemia treated with combined antifungal therapy: a case report. BMC Infect Dis. 2007;7:40.
    CrossRef - PubMed
  13. Campo M, Lewis RE, Kontoyiannis DP. Invasive fusariosis in patients with hematologic malignancies at a cancer center:1998-2009. J Infect. 2010;60(5):331-337.
    CrossRef - PubMed


Volume : 12
Issue : 4
Pages : 384 - 387
DOI : 10.6002/ect.2013.0092


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From the Department of Hematology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hu Bei, China
Acknowledgements: The authors have no conflicts of interest to declare, and there was no funding for this study.
Corresponding author: Donghua Zhang, Department of Hematology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hu Bei, China
Phone: +13 36 726 7251
E-mail: zdh62@aliyum.com