Fusarium spp. are emerging as pathogens that can cause life-threatening invasive opportunistic infections, mainly among patients with bone marrow suppression and neutropenia. Currently, Fusarium spp. are considered the second most-common mold as cause of opportunistic infection in these patients, being Aspergillus spp. the first ones (Bodey et al. 2002; Cooke et al. 2009). Fusarium spp. are also the most common cause of fungemia with skin manifestations. (Bodey et al. 2002) reported 76% of 46 patients with hematologic malignancies or solid tumors, considered to have definite Fusarium infections, had skin lesions. (Nucci and Anaissie 2007) also reported 61 hematopoietic stem cell transplant recipients with hematologic malignancies or solid tumors with disseminated Fusarium infection, and metastatic skin lesions was the most frequent clinical presentation, occurring in 46(75%) of patients.
The combination of cutaneous lesion and positive blood cultures, involving or not other sites are the most frequent pattern of disseminated fusariosis. The most common clinical presentation is a persistently febrile patient with prolonged and profound neutropenia who develops disseminated characteristic skin lesions, with a positive blood culture for a filamentous fungi (Nucci and Anaissie 2007). This was the case of our patient.
The most common Fusarium involved in human infections are F.solani, F.oxysporum and F.verticillioides (Gupta et al. 2000; Tezcan et al. 2009). To our knowledge, we describe here the second case of disseminated fusariosis caused by F.napiforme, and the first case with identification confirmed by molecular techniques, including sequencing.
The first invasive case by F.napiforme was described in 1993 (Melcher et al. 1993) in a patient diagnosed with acute myeloid leukemia, under cytoreduction and profound granulocytopenia following high-dose of cytosine arabinoside, mitoxantrone, and VP-16. Since then, no other cases have been described.
The diagnosis of Fusarium in laboratory includes some criteria such a positive direct mycological examination showing typical septated hyphae branching at 45°. However, the identification of Fusarium to the species level is often difficult and requires a specialized laboratory and skilled personnel. In such situations, molecular biology techniques might be helpful for the definitive diagnosis. Furthermore, the early diagnosis of invasive disease might be helpful to guide the correct antifungal therapy, which is crucial for patient recovery (Galimberti et al. 2012; Busemann et al. 2009; Azor et al. 2009). In our study, molecular methods allowed a faster and accurate identification of the causative agent as belonging to F.napiforme group. In addition, the strains F111 and 2008, from blood and air respectively, showed 100% sequencing alignment, suggesting that the the air may have been the source of the infection. Samples 2009 and 2010, isolated from the blood, and skin isolate 1994 were also aligned. Thus, it seems that we had two variants of F.napiforme. Therapy for invasive fusariosis is a challenging problem, mainly because Fusarium shows high MICs to antifungal agents, and therefore, there is no proven effective treatment regimen (Tezcan et al. 2009; Guzman-Cottrill et al. 2004; Rothe et al. 2004). The treatment of choice for invasive fusariosis is amphotericin B. However, it is controversial, since there are reports of Fusarium showing MICs for AMB ranging from 1 to 4 μg/mL. Triazoles, as voriconazole and posaconazole, have also been used successfully (Pereira et al. 2013; Tortorano et al. 2008). Furthermore, different Fusarium can exhibit variable susceptibility patterns.
In the present case, patient was treated with amphotericin B deoxicolate, initiated after laboratory confirmation of Fusarium fungemia. However, the time between the onset of symptoms and the blood culture was fifteen days and the time between the blood culture and the positive result for Fusarium was fifteen days more. The isolate of F.napiforme in the present case was resistant to amphotericin B, with MIC ranging from 2-4 μg/ml. Delay in antifungal therapy plus the resistance profile could have contributed to the patient’s death three days after antifungal drug was initiated.
In conclusion, Fusarium spp. are emerging as a fungi of relevance in medical mycology, since they are associated with low susceptibility profiles to antifungal drugs and high mortality rate, mainly in imunocompromissed patients. These facts highlight the importance for faster and more accurate diagnostic tests, contributing to earlier and precise diagnosis and treatment of this life-threatening infection.
Nucleotide sequence accession numbers
The sequences determined in this study have been submitted in (Sakai et al. 2014) and deposited in NCBI database with the accession numbers KM099396 to KM099400.
Informed consent was obtained from the patient for the publication of this report and any accompanying images.