Current Fungal Infection Reports (2019) 13:308–319 https://doi.org/10.1007/s12281-019-00364-4 CURRENT MANAGEMENT OF FUNGAL INFECTIONS (S JACOBS, SECTION EDITOR) Updates on the Treatment of Non-Aspergillus Hyaline Mold Infections Saman Nematollahi1 & Shmuel Shoham2 Published online: 26 November 2019 # Springer Science+Business Media, LLC, part of Springer Nature 2019 Abstract Purpose of Review This review summarizes both the recent and relevant studies about the treatment of non-Aspergillus hyaline molds. Recent Findings Given the rarity of these infections, there have been no large randomized clinical trials regarding the most effective antifungal therapy. Summary Although there are more data for the treatment of Fusarium and Scedosporium, there are limited data with case reports that address the other rare hyalohyphomycetes. As we develop improved diagnostic techniques and larger fungal registries, we may be able to determine efficacious treatment modalities. We hope that future research will focus on implementing clinical trials with the new antifungals and ongoing development of novel fungal agents. Keywords Hyaline molds . Hyalohyphomycetes . Emerging fungal infections . Antifungal therapy . Fusarium . Scedosporium Introduction epidemiology of hyalohyphomycoses and then transition to a review of their treatment drawing from the published litera- Treatment of invasive infections due to non-Aspergillus hya- ture and from our own experiences. line molds (hyalohyphomycetes) is challenging. These molds are of particular concern due to their intrinsic resistance to many standard antifungal drugs and their potential for causing Background and Epidemiology devastating disease. The most common infections are due to Fusarium spp. and Scedosporium/Lomentospora,followedby Hyalohyphomycetes, which are normally present in soil, wa- Paecilomyces spp., Acremonium spp., Scopulariopsis spp., ter, and vegetation, are increasingly recognized as causes of Trichoderma spp., and Rasamsonia spp. These filamentous infection. Reasons for this include a growing population of at- fungi have branching septate hyphae that lack pigment and risk patients, broad use of prophylaxis effective against other are often confused with Aspergillus. It can also be difficult organisms (e.g. Aspergillus, Candida, bacteria), and improved to determine whether their presence in clinical specimen is fungal diagnostic techniques [1, 2]. reflective of colonization or invasive disease. Consequently, Data regarding hyalohyphomycoses are available from ep- accurate diagnosis and institution of proper treatment is often idemiology studies in the USA and Australia. The US based delayed. In this article, we will briefly touch on the Transplant-Associated Infection Surveillance Network This article is part of the Topical Collection on Current Management of (TRANSNET) identified 1208 invasive fungal infections in Fungal Infections solid organ transplantations (SOT) and 983 invasive fungal infections in hematopoietic stem cell transplantations * Saman Nematollahi (HSCT) from 2001 to 2006. Of those, 169 (8%) were due to [email protected] non-Aspergillus molds, with Fusarium accounting for 22% and Scedosporium for 16% [3, 4]. By contrast, an Australian 1 Department of Medicine, Division of Infectious Diseases, Johns study of non-Aspergillus mold infections found that 33% were Hopkins University School of Medicine, Baltimore, MD, USA due to Scedosporium spp., 8% Fusarium spp., and 2% 2 Transplant and Oncology Infectious Diseases Program, Johns Paecilomyces spp., indicating that epidemiology may differ Hopkins University School of Medicine, Baltimore, MD, USA by locale [5]. Curr Fungal Infect Rep (2019) 13:308–319 309 Fusarium species are grouped into ten phylogentic species and subtropical climates and Scedosporium with more tem- complexes [6]. Most infections are probably due to F. solani perate climates and certain geographic locales (e.g., species complex [7]. In the TRANSNET data set, F. solani Australia). Major host factors to consider are immunodeficien- accounted for 27% of Fusarium infections, but almost 60% cy states such as hematological malignancy, solid organ trans- were reported as unspecified Fusarium spp. [4]. Clinical man- plant (especially lung), and bone marrow transplant. ifestations in non-immunocompromised patients are most fre- Abnormal pulmonary architecture and mucosal defects can quently keratitis and onychomycosis. In immunocompro- predispose to colonization with fungi such as Fusarium spp., mised patients, infectious sites also include the skin, sinuses, Scedosporium spp., Purpureocillium lilacinum,and lower respiratory tract, and bloodstream [7].Diagnosisistyp- Paecilomyces variotii, which can then progress to infection. ically made by tissue or blood cultures with MALDI-TOF and In that regard, predisposing conditions such as skin break- PCR assays increasingly used to assist with identification of down and trauma, and lung diseases with bronchiectasis the organism [7–9]. With regard to fungal biomarkers, (e.g., cystic fibrosis) are important host factors. Given that Fusarium can cross-react with the galactomannan assay and these molds may be resistant to multiple antifungal agents, the beta-d-glucan assay has variable reactivity [10–13]. infections that break through prophylaxis or initial empiric The Scedosporium genus is primarily comprised of the therapy with a mold active agent should raise concern for Scedosporium apiospermum complex (S. apiospermum sensu hyalohyphomycoses. stricto, S. boydii,andPseudallescheria angusta). There are other rare species including S. aurantiacum, S. dehoogii,and Infection vs Colonization? S. minutisporum [14]. S. prolificans is phylogenetically dis- tinct from other Scedosporium spp. and has been renamed The decision to treat is straightforward when culture is obtain- Lomentospora prolificans [15]. The teleomorph (sexual state) ed from a sterile site (e.g., tissue or blood) and when there is of S. apiospermum is known as Pseudallescheria apiosperma histopathologic evidence of invasive infection. More chal- [7]. P. boydii was initially classified as the teleomorph but has lenging are circumstances when organism is retrieved from since been determined to be a different species [14]. non-sterile site specimen such as a sinus aspirate, sputum, Scedosporium/Lomentospora spp. tolerate anaerobic and bronchoalveolar lavage fluid, or urine. Cultures obtained from high saline environments and can be found in sewage, ma- these sites do not necessarily indicate infection. This is partic- nure, and swamps. L. prolificans and S. aurantiacum are pri- ularly true for patients with bronchiectasis such as those with marily found in hot and dry climates and are particularly lo- cystic fibrosis (CF) and non-immunocompromised patients calized to Australia, Spain, and Southern US, whereas with chronic sinusitis. Distinguishing between infection and S. apiospermum species complex is found in temperate cli- colonization requires consideration of host vulnerability, clin- mates and distributed worldwide [16•]. Most infections occur ical signs and symptoms, results of non-culture techniques in immunocompromised patients. Of the 27 Scedosporium (e.g., beta glucan, galactomannan, nucleic acid amplification), infections in the TRANSNET data set, S. apiospermum and radiographic findings. accounted for 70% and L. prolificans for 30% [4]. In immu- nocompetent patients, infection may occur following traumat- When to Pursue Surgical Versus Medical Management ic injury or near drowning in contaminated water. Typical sites Alone? of infection include the sinuses, lower respiratory tract, central nervous system (CNS), and bloodstream [7]. Similar to As a general rule, surgical debridement/drainage of affected Fusarium, Scedosporium is best diagnosed with tissue or areas should be considered in non-pulmonary blood cultures. Molecular assays are increasingly used, but hyalohyphomycoses. This is especially true when there is lo- are still experimental [7, 8]. There may be a role for beta-d- calized skin or soft tissue infection, brain involvement, or glucan and galactomannan index in diagnosing pleural disease. Antifungal therapy should be guided by sus- Scedosporium/Lomentospora, but utility of those assays is ceptibility, with the caveat that Clinical and Laboratory inconsistent [17, 18]. Standards Institute (CLSI) breakpoints have not yet been established for these fungi. Surgical intervention should be strongly considered for L. prolificans given its resistance to Basic Principles of Treatment virtually all available antifungals. For bloodstream infections (e.g., with Fusarium), removal of central venous catheters Hyalohyphomycoses should be considered in patients with may be required [7, 19••, 20•]. There is sometimes a role for compatible exposures, host factors, and clinical features. resection of fungal lung lesions [21], especially if there is no Clues include a history of exposures to soil, dust, vegetation, improvement with medical management alone, but the deci- and water that is suspected or known to be contaminated with sion to operate is often complicated by the high morbidity fungal spores. Fusarium is typically associated with tropical associated with such procedures. 310 Curr Fungal Infect Rep (2019) 13:308–319 Immunomodulation patients with high BMI, severe mucositis, malabsorption, and inability to consume high fat meals. Immunosuppression should be reduced to the extent feasible Voriconazole is available in IV and oral formulations.