Disseminated fungal infections in neutropenic patients carry an extremely poor prognosis with reports of a 1 year survival in the region of 20%.1 The median survival for stem cell transplant recipients with Fusarium infection in this study was 25 days. Recovery from myelosuppression seems to be crucial for survival from this infection with few, if any, reports of recovery without adequate neutrophil counts.
The presenting features of Fusarium species infections range from persistent refractory fever to localised symptoms such as pneumonia, sinusitis, and painful skin lesions. The dermatological manifestations include onychomycosis, a localised cellulitis at the site of injection, or diffuse skin nodules or vesicles in disseminated disease.2 The pulmonary radiological features include nonspecific infiltrates, nodular, and cavitating lesions.
Prophylaxis with fluconazole has reduced the incidence of haematogenous candidiasis, but has not halted the increase in the incidence of opportunistic moulds such as Fusarium species. Itraconazole prophylaxis is increasingly being used in transplant patients but, although it has activity against a number of moulds, it has variable absorption in these patients and breakthrough infections may occur in association with low levels.
Potential treatments for Fusarium infection include conventional and lipid formulations of amphotericin B, itraconazole, GCSF, granulocyte transfusion, and debridement surgery. However, voriconazole is increasingly being used to treat infections unresponsive to the more conventional antifungals and is reported in the literature to be effective both in vitro and in vivo against these resistant moulds.3, 4, 5, 6
Case report
We report the case of a 19-year-old female diagnosed with severe aplastic anaemia (SAA) 14 months prior to receiving a sibling allogeneic peripheral blood stem cell transplant (PBSCT). She received supportive therapy for a year and presented to our unit with a white blood cell count 1.29 
109/l, neutrophils 0.13 109/l, supported platelets 30 109/l, and supported Hb 10.4 g/dl. At 2 weeks prior to admission she was treated for a clinically diagnosed pneumonia with meropenem for 11 days.
At 3 days into the admission she again developed fever and was treated with meropenem, teicoplanin and, 6 days later, liposomal amphotericin B (AmBisome®, Gilead Sciences Ltd, Abington, UK) at a dose of 3 mg/kg. After 16 days, she continued to have a low-grade fever with a normal chest X-ray and high-resolution CT chest (HRCT), and was switched from the above regimen to Ceftriaxone (2 g o.d.) and Metronidazole (500 mg t.d.s) only.
At 2 days after the antimicrobial regimen change, she began her conditioning with MabCampath® (alemtuzimab) 100 mg in five divided doses and cyclophosphamide 2000 mg/kg in four divided doses. She received graft-versus-host disease prophylaxis with cyclosporine 1 mg/kg b.d. from the day prior to PBSC infusion (non-T-cell depleted) and a short course of methotrexate with folinic acid. She also received allopurinol, aciclovir, ciprofloxacin, cotrimoxazole, colistin and oral itraconazole solution prophylaxis (400 mg/day) along with amphotericin B mouthwash and defibrotide 10 mg/kg b.d. for prophylaxis against veno-occlusive disease.
During the conditioning she remained pyrexial and became increasingly short of breath. A repeat HRCT was performed at day -2, which showed dense consolidation in both lower lobes consistent with a probable fungal infection. She was consequently restarted on liposomal amphotericin B, 3 mg/kg, changed back to meropenem and teicoplanin and commenced on G-CSF injections. On day +3, she underwent a bronchoscopy and alveolar lavage from which was cultured Enterococcus faecium, sensitive to teicoplanin, and a 'light growth' of Candida species. Other fungal studies were negative.
On day +10, she complained of a painful fifth digit on her right foot. An area of sloughed skin was found between her fourth and fifth toes and swabs were taken. The following day, the pain had worsened and the foot had become erythematous and swollen with some tracking on the dorsum of the foot extending to the shin. On the basis of the clinical appearance of the lesion voriconazole 200 mg i.v. b.d. was started immediately and AmBisome® discontinued. At this time, she was still profoundly neutropenic with a neutrophil count of 0.04 109/l. On day +13 F. dimerum was isolated from swabs taken from the intertrigo on the right foot and an interdigital swab from the left foot.
By the third day of voriconazole treatment, the foot had begun to improve with reduced erythema and swelling. Her neutrophil count had risen to 0.11 109/l. Her clinical state continued to improve and on day +19, with a neutrophil count of 9.0 109/l she was switched to oral voriconazole (200 mg b.d.) for a further 2 weeks. A repeat HRCT showed clear lung fields and G-CSF was stopped. She was discharged after complete resolution of the foot and chest infections, on day +26. At 1 year post transplant, she remains well and free of infection (Figures 1a, b and 2).
Figure 1.
(a) F. dimerum cellulitis – proven F. dimerum soft-tissue infection of the foot. (b). F. dimerum culture – culture plate of F. dimerum at 7 days.
Full figure and legend (421K)
Discussion
In this report, we describe the first documented successful treatment of a proven7 F. dimerum cellulitic foot infection with voriconazole, without the need for surgical debridement, despite the infection developing while the patient was on liposomal amphotericin B (3 mg/kg). This illustrates the potential vital role for early voriconazole treatment in suspected mycoses, reducing the morbidity and mortality usually related to these infections.8 The reduced nephrotoxicity of voriconazole as compared to liposomal amphotericin B is a further reason to consider its use early in patients already on a cocktail of toxic medications.
It is unclear in the case of our patient whether the chest sepsis and fungal foot infection were related. By the time our patient developed the foot infection, she had had a prolonged period of neutropenia (<0.5 109/l), due both to the SAA and the transplant procedure. During this time, she had had a fever refractory to broad-spectrum antibiotics and liposomal amphotericin B, shortness of breath and an HRCT suggestive of fungal infection. This is a common clinical scenario for the presentation of pulmonary Fusarium infection.9 Within a few days of commencing voriconazole treatment, the infection at both sites began to resolve. This coincided with the recovery of the patient's neutrophil count, which is known to be associated with the resolution of many episodes of fungal infection.
Although the appearance of the cellulitic foot lesion is more in keeping with a primary skin infection than a metastatic one,9, 10 the two infections may have been linked. It is possible that colonisation or low-grade infection of the patient's skin with F. dimerum may have allowed invasion of the mould at either site. This raises the question of whether it would be both clinically beneficial and cost effective to screen all patients with intertrigo or changes suggestive of onychomycosis, for skin and nail infection by moulds prior to undergoing haematopoietic stem cell transplantation.2 This would allow the identification and sensitivities of any cultured fungi to be explored prior to any potential invasive disease and a decision about eradication to be made.
We consider that this case demonstrates a potential role for the early use of voriconazole in Fusarium infections and raises the question of screening for fungal skin infection/colonisation prior to stem cell transplantation procedures.
References
- Marr KA, Carter RA, Crippa F et al. Epidemiology and outcome of mould infections in hematopoietic stem cell transplant recipients. Clin Infect Dis 2002; 34: 909–917. | Article | PubMed | ISI |
- Gupta AK, Baran R, Summerbell RC. Fusarium infections of the skin. Curr Opin Infect Dis 2000; 13: 121–128. | PubMed | ISI |
- Jeu L, Piacento FJ, Lyakhovetskiy AG, Fung HB. Voriconazole. Clin Ther 2003; 25: 1321–1381. | Article | PubMed | ISI | ChemPort |
- Paphitou NI, Ostrosky-Zeichner L, Paetznick VL et al. In vitro activities of investigational triazoles against Fusarium species: effects of inoculum size and incubation time on broth microdilution susceptibility test results. Antimicrob Agents Chemother 2002; 46: 3298–3300. | Article | PubMed | ISI |
- Ghannoum MA, Kuhn DM. Voriconazole – better chances for patients with invasive mycoses. Eur J Med Res 2002; 7: 242–256. | PubMed | ISI | ChemPort |
- Johnson LB, Kauffman CA. Voriconazole: a new triazole antifungal agent. Clin Infect Dis 2003; 36: 630–637. | Article | PubMed | ISI | ChemPort |
- Ascioglu S, Rex JH, de Pauw B et al. Invasive Fungal Infections Cooperative Group of the European Organization for Research and Treatment of Cancer; Mycoses Study Group of the National Institute of Allergy and Infectious Diseases. Defining opportunistic invasive fungal infections in immunocompromised patients with cancer and hematopoietic stem cell transplants: an international consensus. Clin Infect Dis 2002; 34: 7–14. | Article | PubMed | ISI | ChemPort |
- Baden LR, Katz JT, Fishman JA et al. Salvage therapy with voriconazole for invasive fungal infections in patients failing or intolerant to standard antifungal therapy. Transplantation 2003; 76: 1632–1637. | Article | PubMed | ISI | ChemPort |
- 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: 999–1008. | PubMed | ISI |
- Bodey GP, Boktour M, Mays S et al. Skin lesions associated with Fusarium infection. J Am Acad Dermatol 2002; 47: 659–666. | Article | PubMed | ISI |
Acknowledgements
We are grateful the haematology ward nurses, medical illustration and radiology department at Royal Free Hospital.
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