Case 3

Male patient of 38 years old, with a diagnosis of Acute Myeloid Leukemia with generalized erythematous papules and pustules accompanied by prolonged neutropenia and fever while receiving antibiotics (imipenem, amikacin and piperacillin tazobactam) plus amphotericin B (Figure 5-7). Some weeks before he had a toe infection, which was treated with surgery debridement and oral antibiotics. In the CT scan of sinuses, thorax and abdomen there were some infiltrative images, which were interpreted as septic embolism. Skin biopsy, blood and urine culture and bronchoalveolar lavages were done which confirmed disseminated fusariosis with lung involvement. Voriconazole was added to the treatment without response, finally dying in the intensive care unit of the Austral Hospital.

Figure 5: Generalized erythematous papules on the trunk.

Figure 6: Progression to erythematous papules with a necrotic center.

Figure 7: Necrotic lesion on the fourth toe.

The innate immunity plays a major role in the defense against mold infections [10].

Macrophages and neutrophils damage fusarial hyphae, by gamma interferon, Granulocyte Colony-Stimulating Factor (G-CSF), Granulocyte-Macrophage Colony-Stimulating Factor (GM-CSF) and interleukin-15. The effect of interleukin-15 is mediated by the release of interleukin-8 and by direct stimulation of hyphal damage. Although little is understood about Toll-like receptors and Fusarium, it is believed to be important in invasive fusariosis [11,12].

The superficial form of human infection with Fusarium is seen as keratitis (specially in contact lenses wearers) and onychomycosis. Other non disseminated infections by this agent are sinusitis, septic arthritis, and osteomyelitis, thrombophlebitis or endophthalmitis and pneumonia [13-18].

The most important risk factors for severe fusariosis include prolonged neutropenia and T-cell immunodeficiency, especially in hematopoietic stem cell transplant recipients with severe graftversus- host disease. These last concepts are considered when the neutropenia is prolonged more than 10 days in a row and less than 100/mm³. Other risk factors to consider are skin breakdown close to onychomycosis by Fusarium, prolonged corticoid therapy, diagnosis of aplastic anemia, acute leukemia and allogeneic hematopoietic stem cell transplantation.

The most frequent presentation of disseminated fusariosis is a cutaneous manifestation accompanied by a positive blood culture, with or without lung or sinus involvement. Once recovered the neutropenia, the prognostic of the Fusarium infection improves [4]. The Fusarium infection can develop in any human organ. Fever and skin lesions especially in the face and extremities frequently appeared. These skin lesions can be nodules, erythematous papules and macules, target lesions, which sometimes can have necrotic centers. Cellulitis with or without fasciitis can be diagnosed as well. Lung involvement is associated with higher mortality, even after controlling for immune status.

Fusarium systemic dissemination is considered as having two or more organs involved. It is believed that when a hospitalized patient develops Fusarium infection, the fungus probably have been inside the body before checking in and while in the hospital with the immune system compromised, the fungus develop the systemic infection, as it is considered an opportunistic fungus.

Alert of disseminated fusariosis in the severely immunocompromised patients is brought up when skin lesions in the form of cellulitis or papules appear and a positive blood cultures for mold is received. Blood cultures are frequently positive in fusariosis unlike other severe fungal infection such as aspergillosis due to the fact that Fusarium spp. produces yeast-like structures (adventitious sporulation) that facilitate their dissemination and growth in the blood [19].

The prognosis of disseminated fusariosis is poor and the level of immunosuppression and the extent of the infection determine it. The death rate in persistent neutropenic hosts is close to 100% [4]. The prognosis of fusariosis in the immunocompromised host is directly related to the immune status of the patient, with high death rates in patients with persistent immunodeficiency. Host of HSCT and presence of persistent neutropenia, disseminated disease, and lung involvement predict fatal development [4]. By contrast, patients who had no risk factors as mentioned above or whose only risk factor was high or prolonged corticosteroid therapy have a 67% and 30% survival rates, respectively (P < 0.0001) [4,6].

Severe T-cell immunodeficiency is the major risk factor for fusariosis in the group of patients who had Hematopoietic Stem Cell Transplant (HSCT) [20]. The overall incidence of fusariosis is 6 cases per 1,000 HSCTs. The incidence is lowest (1.5 to 2/1,000) among autologous recipients, intermediate (2.5 to 5/1,000) in matched related and matched unrelated allogeneic recipients, and highest (20/1,000) among recipients of mismatched related donor allogeneic HSCTs [20]. Locally invasive and usually late infections may also develop among solid organ transplant recipients, but these appear to be less common than those among HSCT patients [21] (Table 1).

Table 1: Clinical manifestation and methods of diagnosis for Fusariosis [22-25].

The diagnosis comes from biopsies or cultures with Fusarium isolation. The 1,3-β-D-glucan test is usually positive in invasive fusarial infections but cannot distinguish Fusarium from Candida, Aspergillus or Trichosporon, which are also detected by this method of diagnosis. However, in a high-risk patient with fungal infection is highly suggestive of fusariosis is a positive 1,3-β-D-glucan test and a negative galactomannan test, which would be positive in case of aspergillosis. Additionally, PCR technique can be used for the detection of Fusarium spp. in blood and tissue [22,23].

Diagnostic work up with Fusarium infection

1. Culture and biopsy of skin site or sinus if involvement suspected.

2. Bronchoalveolar lavage and biopsy if pneumonia suspected.

3. Blood culture, 1,3-β-D-glucan test, galactomannan test (positive in aspergillosis).

4. Check for adventitious sporulation in blood and tissue biopsies as it is found in fusariosis and not in aspergillosis.

Microbiologist must be very cautious in diagnosing Fusarium infection, because Fusarium spp. may contaminate laboratory specimens and pseudo-outbreaks of fusariosis may occur giving away a false positive [24]. In tissue, the hyphae are similar to those of Aspergillus spp. with hyaline and septate filaments that typically dichotomize in acute and right angles. However, adventitious sporulation may be present in tissue and is highly suggestive of fusariosis especially in the high-risk population [25].

The European Organization for Research and Treatment of Cancer and the Mycoses Study Group classify invasive fungal disease in three types: proven, probable and possible. Based on this classification it is defined as a proven invasive fungal infection if the fungus is detected in the histological analysis or in a culture of a sample of tissue obtained from a site of the disease or from blood. “Probable” depends on the simultaneous presence of 3 elements: the factors of the host, the clinical manifestations of mycosis and the mycological evidence in the laboratory. If it meets the criteria of a host factor plus the clinical manifestation, but does not meet the mycological lab evidence it is considered “possible”. It should be noted that in the three patients mentioned above, a proven invasive fungal disease was defined, since they met the criteria of the host, the clinical criteria and the demonstration of fungal elements in tissues with positive culture for Fusarium [26].

Treatment of localized infection in these patients result beneficial by surgical debridement, while disseminated infection requires the use of systemic agents and immunotherapy. Localized skin lesions in immunocompromised patients deserve special attention, since the skin may be the source for disseminated infections. Hence, local debridement should be performed and topical natamycin or amphotericin B should be used before starting with immunosuppressive therapies.

Keratitis is usually treated with topical natamycin or else topical and oral voriconazole [27]. Depending on the Fusarium species, the susceptibility to treatments. Usually the treatments of choice are voriconazole and posaconazole or amphotericin B. Data on combination therapy for fusariosis are limited to a few case reports with no solid recommendation: caspofungin plus amphotericin B, amphotericin B plus voriconazole, amphotericin B and terbinafine, and voriconazole plus terbinafine [21,28-30]. Special air filters, such as HEPA filters in hospitals are important to control airborne indoor fungi. This filter consists of a High Efficiency Particulate Air (HEPA)- type filter, filtering virus, bacteria, fungus and molecules up to 1.0μm size particles. Fusarium spores can easily be carried by wind, causing transmission and subsequent infection to humans. Suggesting that the air may be a potential source for fusariosis in an indoor environment such as a hospital [31].