Monday, 02 April 2018 09:02

Fusarium: A Pathogen of the Modern Era

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The genus Fusarium contains a globally distributed group of molds consisting of at least 20 species complexes and an ever-changing number of individual species, many of which are pathogens. Diseases caused by Fusarium spp. have evocative names: “ear rot”, “head scab”, and the particularly alarming “sudden death syndrome”. However, you need not worry about contracting these as their hosts are corn, wheat, and soybean, respectively. Fusarium diseases of plants have been known for over a century and still rank among the “top 10” most important plant pathogens. However, Fusarium is not restricted to plant hosts and it has been observed that the same strain of F. oxysporum can cause disease in both tomatoes and mice.

Fusarium Human Disease

Although humans have presumably been exposed to Fusarium throughout history, the first infection was reported only in 1958 when an agricultural worker contracted keratitis following a blow to the eye by a cow’s tail. Since then, a total of 12 species have been implicated in human disease, with F. solani and F. oxysporum accounting for the majority (≈70%) of cases. Fusarium infection in immunocompetent hosts is rare and typically manifests as keratitis, onychomycosis, or cutaneous infection following a breakdown of the skin barrier.

The course of infection is very different in immunocompromised patients. In this population, skin lesions arise and infection often progresses to disseminated disease. Overall mortality is ≥60% with a meta-analysis showing 100% mortality among patients with persistent neutropenia, regardless of treatment. Fusarium infection is particularly associated with hematologic malignancies, particularly in those who have undergone hematopoietic stem cell transplants (HSCT). Correspondingly, the exponential increase in HSCT since the 1990’s has been mirrored by an increase in Fusarium infection. 

Septate hyphae (A) and/or curved macroconidia (B) can be seen on Gram-stain of positive blood culture broth containing Fusarium. Images courtesy of (A) Thea Brennan-Krohn and (B) Audrey SchuetzFigure 1. Septate hyphae (A) and/or curved macroconidia (B) can be seen on Gram-stain of positive blood culture broth containing Fusarium. Images courtesy of (A) Thea Brennan-Krohn and (B) Audrey Schuetz.

Fusarium Diagnosis and Antimicrobial Susceptibility

Fusarium can be recovered in culture from biopsies of infected tissue and may be seen in histologic sections. However, reproductive structures are often absent or poorly developed in tissue so definitive identification cannot be made at this stage. Fusarium is also one of the few molds that can be recovered from blood cultures. The reason for this is unclear but it has been hypothesized to result from conidial formation allowing for dispersal throughout the media. Approximately 40% of patients with disseminated disease will have a positive blood culture. On Gram stain, septate hyphae (Figure 1A) exhibit variable staining and microconidia or macroconidia (Figure 1B) may also be observed. 

Fusarium sp. Growth on potato dextrose agar. On (A), this Fusarium isolate displays a non-pigmented front. On the reverse (B), a striking pigment is evident, which is especially pronounced after extended incubation. Images courtesy of Thea Brennan-Krohn.Figure 2. Fusarium sp. Growth on potato dextrose agar. On (A), this Fusarium isolate displays a non-pigmented front. On the reverse (B), a striking pigment is evident, which is especially pronounced after extended incubation. Images courtesy of Thea Brennan-Krohn.

Definitive diagnosis is accomplished through culture. Fusarium grows well on potato dextrose agar (Figure 2) where it may display rose, purple, or other pastel colored pigmentation on the front or reverse of the colony, distinguishing it from Aspergillus. Microscopic observation of lactophenol cotton blue stained slides show round or ovoid microconidia and banana shaped fusiform macroconidia (Figure 3). Identification to the species level is more difficult but may be achieved by sequencing of the 28S ribosomal RNA gene. MALDI-TOF has also shown promise for Fusarium identification but commercially available databases must be augmented for optimal performance. Non-culture based techniques including PCR have also been developed for Fusarium detection in patients and the environment. However, the relative infrequency of Fusarium infection combined with high potential for environmental contamination may present impediments to achieving high positive predictive value with non-culture tests in clinical practice.

Lactophenol cotton blue stain of Fusarium sp. showing hyphae and characteristic banana shaped macroconidia. Image courtesy of Audrey Schuetz. Figure 3. Lactophenol cotton blue stain of Fusarium sp. showing hyphae and characteristic banana shaped macroconidia. Image courtesy of Audrey Schuetz.

One of the reasons it is important to identify Fusarium as quickly as possible is that the antifungal susceptibility profile of this organism is notable for extensive intrinsic resistance, in contrast to many other commonly isolated molds. Fusarium is resistant to echinocandins, 5-flucytosine, and most azoles. Voriconazole, posaconazole, and isavuconazole may retain activity in a species-dependent manner, and amphotericin B shows almost universal activity.  However, interpretation of susceptibility results is complicated by the fact that no breakpoints are available for this organism, due to historic infrequency of infection and subsequent lack of outcome data.

Fusarium Treatment

Epidemiological cutoff value (ECV) data combined with existing outcome studies suggest that liposomal amphotericin B, voriconazole, and isavuconazole are options for treatment, either alone or in combination. However, even with antifungal treatment, severity of disease remains linked to a patient’s immune status. As such, treatment of immunosuppressed HSCT patients presents a dilemma. On one hand, restoration of immune function results in a >3-fold increase in overall survival in patients infected with Fusarium. On the other, removal of immunosuppression may result in the patient succumbing to complications from transplant. Current practice guidelines acknowledge the difficulty in treating systemic disease and highlight the importance of early detection and control of localized infection to prevent dissemination. 

Environmental Sources and Infection Control

Given the severity of Fusarium infection in vulnerable populations and its intrinsic antifungal resistance, infection control strategies are of particular importance. However, since Fusarium is found on environmental surfaces, plant material, water, and in the air, it is uniquely challenging to limit its acquisition. Environmental surveys have demonstrated that pathogenic species found in hospitals may be similar to those found infecting patients. However, surveys do not always show this association with disease, implying existence of unknown or under-sampled reservoirs. For example, in Brazil, an outbreak in a children’s cancer hospital was traced to the water source and was controlled only after addition of 0.2 µm filters to all faucets and showerheads. Infection control measures for other molds and fungi, such as those recommended by CDC, are likely effective for Fusarium mitigation but it may be impossible to completely eliminate it given its ubiquity.

Conclusions

Recent advances in cancer treatment have led to a marked increase in Fusarium in immunocompromised individuals. This population is extremely susceptible to infections by bacteria, yeast, and molds, including environmental molds such as Fusarium. Unfortunately, acquisition is difficult to prevent and treatment is complicated by intrinsic antifungal resistance, highlighting the importance of early diagnosis and treatment of localized infection. Until the relatively recent increase in the immunocompromised population, Fusarium infection was rare and understudied as a human pathogen. Now, this organism is poised to increase in frequency, necessitating research into diagnostics, infection control practices, and novel antifungal drugs.

 

The above represent the opinions of the author and does not necessarily reflect the opinions of the American Society for Microbiology.

 

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Last modified on Monday, 02 July 2018 15:14
Kenneth (K.P.) Smith

Kenneth (K.P.) Smith is a postdoctoral fellow in James Kirby’s laboratory at Beth Israel Deaconess Medical Center. His research interest is in development of drugs and diagnostics for multidrug-resistant Gram-negative bacteria.

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