Emerging infections caused by non-Aspergillus filamentous fungi

Accepted Manuscript Emerging infections caused by non-Aspergillus filamentous fungi Abby P. Douglas, Sharon C-A. Chen, Dr Monica A. Slavin PII:

S1198-743X(16)00027-6

DOI:

10.1016/j.cmi.2016.01.011

Reference:

CMI 504

To appear in:

Clinical Microbiology and Infection

Received Date: 2 December 2015 Revised Date:

2 January 2016

Accepted Date: 9 January 2016

Please cite this article as: Douglas AP, Chen SC-A, Slavin MA, Emerging infections caused by non-Aspergillus filamentous fungi, Clinical Microbiology and Infection (2016), doi: 10.1016/ j.cmi.2016.01.011. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

ACCEPTED MANUSCRIPT

Emerging infections caused by non-Aspergillus filamentous fungi Authors: Abby P. Douglas1, Sharon C-A. Chen2, Monica A. Slavin1,3, 4, 5 1Victorian

Infectious Diseases Service, Royal Melbourne Hospital, Melbourne, Victoria,

Australia 2Centre

3Department

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for Infectious Diseases and Microbiology Laboratory Services, ICPMR – Pathology West, Westmead Hospital, University of Sydney, New South Wales, Australia of Infectious Diseases, Peter MacCallum Cancer Centre, Melbourne, Victoria,

Australia

5University

of Melbourne, Melbourne, Victoria, Australia

Correspondence to: Dr Monica Slavin Department of Infectious Diseases

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Peter Doherty Institute for Infection and Immunity, Melbourne, Victoria, Australia

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4The

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Peter MacCallum Cancer Centre St. Andrew’s Place

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East Melbourne, Australia, 3002 Phone: +61 396561707

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Fax: +61 396561185

E. mail: [email protected]

Conflicts of Interest

The authors declare no conflicts of interest.

Running title Emerging infections caused by non-Aspergillus filamentous fungi

ACCEPTED MANUSCRIPT Abstract There are three broad groups of non-Aspergillus moulds: the mucormycetes, the hyalohyphomycetes and melanized fungi. Infections with these pathogens are increasingly reported, particularly in the context of increasing use of immunosuppressing agents and

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improved diagnostics. The epidemiology of non-Aspergillus mould infections varies with geography, climate and level of immunosuppression. Skin and soft tissue infections are the predominant presentation in the immunocompetent host and pulmonary and other invasive

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infections in the immunocompromised host. The more common non-Aspergillus moulds include Rhizopus, Mucor, Fusarium and Scedosporium species, however other emerging

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pathogens are Rasamsonia and Verruconis species which are discussed in this article. Outbreaks of non-Aspergillus mould infections have been increasingly reported, with contaminated medical supplies and natural disasters as common sources. Currently culture and other conventional diagnostic methods are the cornerstone of diagnosis. Molecular

increasingly used.

filamentous

fungus,

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Keywords:

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methods to directly detect and identify mould pathogens in tissue and body fluids are

non-Aspergillus

moulds,

epidemiology,

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phaeohyphomycetes, mucormycetes, hyalohyphomycetes, melanized fungi

ACCEPTED MANUSCRIPT Introduction

Non-Aspergillus filamentous fungal (or mould) infections are increasingly reported. Factors that may contribute to the emergence of these infections include increasing use of

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immunosuppressing agents, selection for these moulds in the setting of current antifungal prophylaxis, better recognition of these infections due to improvements in mould identification, increasing construction work and natural disasters [1-4]. The epidemiology of

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non-Aspergillus mould infections may be changing and better understanding of this and the appreciation of geographical or regional differences is important to inform guidelines for

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management of such infections.

This article aims to provide an overview of invasive fungal disease (IFD) due to nonAspergillus moulds with particular focus on the epidemiology and diagnosis of infections due

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to previously uncommon, and emerging moulds of clinical interest. Emerging pathogens from the three broad groups of non-Aspergillus moulds are discussed: Apophysomyces spp., Sakasenea spp. and Syncephalastrum racemosum from the mucormycetes Scedosporium

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aurantiacum, Rasamsonia spp., Paecilomyces spp., Acremonium spp. and Schizophyllum spp

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from the hyalohyphomycete group and Verruconis gallopava of the melanized fungi group.

Mucormycetes

Mucormycetes include the order Entomophthorales, which are discussed in another article of this special edition, and the Mucorales, which we will focus on in this section. As a group, the Mucorales are the most common cause of non-Aspergillus mould infection in humans [5,6] and

ACCEPTED MANUSCRIPT are reported to have increased in incidence over time in some countries such as France and Switzerland [4,7]. However, their incidence in other regions is uncertain.

The epidemiology of mucormycosis varies with geographic region [5, 7-10]. Rhizopus species

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are consistently the most commonly identified mucormycete in human infection [5,11]. The second most common cause of human infection varies between studies [11] however predominant groups are Mucor and Rhizomucor, and Lichtheimia (formerly known as Absidia

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and Mycocladus), the last of which is more frequent in European studies [12,13].

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Infection follows inhalation, ingestion or percutaneous inoculation of spores [14].

Risk

factors for infection are similar for all types of Mucorales and include haematologic malignancy with or without haematopoietic stem cell transplantation (HSCT), prolonged neutropenia or corticosteroid use, poorly controlled type 2 diabetes mellitus (DM) and

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trauma [9, 12, 15]. In developed countries, the predominant risk factor is haematologic malignancy, with pulmonary infection the key manifestation. In developing countries such as

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India, rhino-orbital-cerebral mucormycosis (ROCM) in uncontrolled DM predominates [10,15]. Soft tissue infection is the third most common manifestation and can be seen in both

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immunocompromised and immunocompetent individuals [15]. In immunocompromised hosts, there is a tendency for angioinvasion with subsequent dissemination [16], although recovery from blood culture is rare. Mucorales infections are generally associated with high morbidity and mortality [11], with the possible exception of skin and soft tissue infections in immunocompetent individuals.

Apophysomyces and Saksenaea species

ACCEPTED MANUSCRIPT Apophysomyces species are emerging pathogens, with A. elegans by far the predominant species causing infection, mostly in the context of trauma with necrosis of soft tissue and muscle [10]. These soft tissue infections can be rapidly progressive in both the immunocompetent and immunocompromised with significant mortality rates despite

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amphotericin B treatment and debridement. The majority of cases are reported from warm climates in the USA and India. A. elegans is the second most common agent of mucormycosis in India [10]. Of case reports of A. elegans soft tissue infections in the literature, the majority

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are in immunocompetent hosts (74%). Survival in immunocompetent patients was similar to that in immunocompromised patients, with a significant mortality in both groups (24%

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mortality vs 30%). The second most common presentation is ROCM [17], with rare reports of renal mucormycosis, usually in the context of dissemination [18].

Notably, outbreaks of infection have followed natural disasters, well illustrated by the cluster

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of A. trapeziformis soft tissue infections following a tornado in Joplin, USA (see outbreaks section). Infection caused by more uncommon Apophysomyces include 8 case reports of A.

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variabilis infections, all of necrotising soft tissue infection [19,20], and 1 case of a novel

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species, A. mexicanus with soft tissue infection following traumatic inoculation [21].

Saksenaea vasiformis is a complex of species that includes S. oblongispora and S. erythrospora [22]. S. vasiformis infections are emergent worldwide [5, 13, 22-24], with cases predominantly occurring in tropical and subtropical climates [25]. As for Apophysomyces spp., most infections follow trauma and other mechanisms of percutaneous introduction such as tattoos, intramuscular injections and vascular catheters [25-27]. In a recent study of cases of invasive mucormycosis across Australian hospitals, 5.4% of Mucorales infections were due to Saksenaea spp. and 50% of these were in immunocompetent hosts following trauma [28]. In a

ACCEPTED MANUSCRIPT review of reported Saksenaea infections, over 80% of cases of infection affected immunocompetent individuals [29]. Most infections involve the skin and soft tissue [29] with rare reports of ROCM in patients with diabetes [30]. Pulmonary, renal and disseminated

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infections occur in both immunocompetent and immunosuppressed patients [31-34].

Syncephalastrum spp.

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Reports of Syncephalastrum racemosum infection remain rare with skin and soft tissue, ROCM and pulmonary manifestations described from diverse geographic locations (Table 1). The

Hyalohyphomycetes

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immunocompromised hosts.

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majority of cases appear to follow traumatic inoculation but have also occurred in

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The hyalohyphomycetes, or hyaline moulds, are filamentous fungi characterised by a lack of pigmentation, with branching septate hyphae that can be difficult to distinguish from

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Aspergillus microscopically. They include the relatively more common genera of Fusarium and Scedosporium, as well as many previously rare but now emerging fungi such as Paecilomyces, Acremonium, Schizophyllum and Rasamsonia. These organisms are ubiquitous in the environment, found in soil, plant material and water; some are associated with infections in particular host groups or clinical settings eg. Rasamsonia in cystic fibrosis patients [43] (see below).

Fusarium spp.

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In US and South American populations, Fusarium is the second most common non-Aspergillus mould causing human infection [44,45], however studies from Australia have found

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Scedosporium to be more common than Fusarium [5].

More than 50 species of Fusarium have been identified, however only a few cause human infection [46]. Members of the F. solani species complex are the most common pathogenic

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species, causing ~50% of infections, followed by those of the F. oxysporum species complex (~20%) and F. verticillioidis and F. moniliforme (~10% each) [46]. The principal portal of

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entry is considered to be the airways, followed by the skin at site of tissue breakdown or onychomycosis. Patients at high risk of fusariosis are those with profound and prolonged neutropenia and/or T cell immunodeficiency [5, 47, 48].

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Among immunocompetent hosts, keratitis and onychomycosis are the most common infections [46]. In immunocompromised patients, the most common presentations include

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pneumonia, sinusitis and fungaemia with or without cutaneous lesions (50-58% of cases) [46, 47, 49], with very high mortality in the setting of fungaemia (94% at 12 weeks)[48]. There

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have been outbreaks of fusarial keratitis in contact lens wearers (see outbreaks) and peritonitis in patients receiving peritoneal dialysis [50].

Scedosporium spp.

Scedosporium prolificans, recently proposed to adopt the generic name Lomentospora prolificans, and members of the S. apiospermum species complex (which now include fungi previously described as Pseudallescheria boydii) are the most common pathogens in this

ACCEPTED MANUSCRIPT genus [51-53]. Amongst the S. apiospermum species complex, in addition to the more common S. apiospermum and S. boydii, S. aurantiacum, and S. dehoogii have recently been described as human pathogens [51, 54, 55]. Because there are species-specific differences in virulence and

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antifungal susceptibility, identification of the causative agent to species level is essential.

In an Australian study of non-Aspergillus mould infection epidemiology, Scedosporium fungi comprised the largest proportion after the mucormycetes [5]. Risk factors for infection

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include chronic obstructive or suppurative lung disease, haematologic malignancy, solid organ transplantation (SOT) or HSCT, corticosteroid use, neutropenia and DM [5, 51-53]

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however a substantial proportion of infections affect hosts without apparent immune deficiency (22-50%) [51, 56]. In immunocompetent patients, infection is seen particularly following trauma or inhalation associated with near drowning [5, 53, 57].

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In immunocompromised hosts, clinical presentation of L. prolificans and S. apiospermum complex are similar to other invasive mould infections with the exception of positive blood

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cultures for L. prolificans occurring in up to 50% of neutropenic patients [56]. 50% of transplant recipients have disseminated disease at presentation with involvement of skin and

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CNS [58] presenting with fever (90%), focal CNS symptoms (40%), appearance of rash (30%) and fungaemia (72%) [56,59]. There is a very high mortality rate for disseminated scedosporiosis with additional predictors of poor prognosis being lack of neutrophil recovery and CNS infection [52].

Acremonium spp.

ACCEPTED MANUSCRIPT This genus includes approximately 150 species, with only a few implicated as human pathogens [60]. A. kiliense and A. falciforme are the most common pathogens with

A.

roseogriseum, A. strictum, A. patronii and A. recifei also described as opportunistic pathogens [60]. These emerging pathogens mainly affect immunocompromised patients following HSCT,

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SOT or haematologic malignancy [6, 61].

In a recent review, two thirds of cases were localised infections, and one third were

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disseminated infections in immunocompromised hosts [60]. Classically following a penetrating skin injury, localised infections tend to appear as either subcutaneous nodules

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with discharging sinuses or less commonly as mycetomas. [62]. Onychomycosis, otomycosis, endophthalmitis and complications in burn patients have been described [63] and allergic fungal rhinosinusitis is well recognised [64]. Pneumonia, arthritis, osteomyelitis, endocarditis, meningitis, peritonitis and sepsis with fungaemia in immunocompromised patients have been

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reported [65,66]. In addition, there are occasional reports of fungaemia in otherwise normal hosts with prosthetic material such as subclavian catheters, mitral valve replacements and

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pacemakers. [67-69]. There was a notable outbreak of catheter related A. kiliense fungaemia

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among HSCT patients [70](see outbreak section).

Paecilomyces spp.

The genus Paecilomyces includes two main pathogenic species: Paecilomyces variotii and Paecilomyces lilacinus. P. liliacinus has recently been reclassified as Purpureocillium lilacinus. [71]. The portal of entry of infection is often a break in the skin or an intravenous catheter [72].

ACCEPTED MANUSCRIPT The most common clinical manifestations are oculomycosis and cutaneous and subcutaneous infections [73], however there are increasing reports of clinically significant and serious infections affecting any body site [6]. Risk factors for invasive infection include not only leukaemia, SOT and HSCT [74,75] but also HIV/AIDS, DM and liver cirrhosis [73,76]. In these

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patients, manifestations include pneumonia, sinusitis, osteomyelitis, disseminated infection and fungaemia [73], with fungaemia and sinusitis being the most commonly reported. There have been uncommon reports of peritonitis in the context of CAPD [77] and liver

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transplantation [78], and an outbreak of P. lilacinus skin infection with some cases of dissemination in HSCT patients due to contaminated skin lotion [72]. A mortality rate of

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14.3% for P. lilacinus was observed in a recent review of the literature [73], which is generally lower than for other hyalohyphomycete infections.

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Trichoderma spp.

Trichoderma spp. were previously thought to be non-pathogenic, however Trichoderma

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longibrachiatum and T. citrinoviride have emerged as opportunistic pathogens in immunocompromised patients [79]. Likely sources of infection are non-sterile water sources

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and aerosols [80].

Fatal disseminated T. longibrachiatum infections have been described in patients with haematologic malignancies and both SOT and HSCT [79,81,82]. The most common sites of isolation in human clinical specimens are the respiratory tract (40%), deep tissue (30%) and superficial tissues (26%) [83]. Deep pulmonary infection [84], invasive sinusitis [85] and peritonitis in CAPD patients have been reported [86]. There have been rare cases of endocarditis [5,87], brain abscess [88] and a case of fatal mediastinitis in a patient with

ACCEPTED MANUSCRIPT congenital heart disease on CAPD [89].

Rasamsonia spp.

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Previously known as Geosmithia spp., this genus has recently been renamed Rasamsonia [90]. These organisms may have been previously underreported as they were frequently misidentified as Penicillium or Paecilomyces species [90].

Rasamsonia argillacea species

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complex is truly an emerging pathogen with increasing descriptions of pulmonary infection in those with chronic granulomatous disease and as a colonizing organism in patients with cystic

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fibrosis [43, 91]. The most common portal of entry is the respiratory tract and pulmonary infection can rapidly extend across tissue planes from lungs to adjacent ribs. Bone and CNS involvement can occur following dissemination from the lung [90].

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In at risk groups as described above, dialogue with the diagnostic laboratory is critical as

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Schizophyllum spp.

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specific incubation conditions are required to recover this organism (see later).

The basidiomycete Schizophyllum commune was first reported as a human pathogen causing onychomycosis in 1950 by Kligman [92]. Up until recently, S. commune was thought to be a rare cause of human disease. However, there have been increasing reports of infection, with 118 cases being reported to date (table 2). 41% of cases were of sinusitis, commonly allergic rhinosinusitis, 29% of cases were allergic bronchopulmonary mycosis (ABPM), and overall 94% of cases involved the upper or lower respiratory tract. Extrapulmonary cases reported include a single case each of onychomycosis, meningitis and palatal ulceration, 2 cases of

ACCEPTED MANUSCRIPT brain abscess and 2 of ocular infection. The majority of reports originate from Japan, India, Iran, United States and Austria, which may reflect increased awareness and reporting in these locations [93]. Whilst the 2 brain abscess cases were in mildly immunocompromised individuals (a diabetic and one taking corticosteroids), the majority of infections, especially

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empyema was described in an otherwise healthy patient [105].

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sinusitis and ABPM, are described in immunocompetent patients. Interestingly, a fatal case of

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Melanized fungi

The melanized fungi, so named as they produce melanin resulting in dark pigmentation of their colonies, are also known as phaeohyphomycetes or dematiaceous fungi. Ubiquitous in the environment, there are over 100 species of fungi [109]. Melanized fungal infections

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generally result from inhalation or percutaneous inoculation of fungal spores through trauma. They tend to produce superficial infection in immunocompetent patients, but can readily

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disseminate and have the potential to cause deep infections in the immunocompromised [110,111]. There are increasing reports of clinical infection (figure 1), with some of the more

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common aetiological genera including Alternaria, Bipolaris, Cladophialophora and Exophiala [112]. Common presentations and risk groups are summarised in table 3. There is also an observed predisposition of melanized fungi, in particular Cladophialophora bantiana, to cause CNS infection in immunocompetent patients [122].

Verruconis gallopava Previously known as Ochroconis gallopava or Dactylaria gallopava, Verruconis gallopava has been encountered worldwide, however there has been a prominence of reports from

ACCEPTED MANUSCRIPT Southeastern USA [123]. Environmental sources of Verruconis spp. include soil, decaying vegetable material [124, 125], cave rocks [126], thermal soils and hot springs [127], coal waste piles and broiler house litters [128,129].

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This fungus has emerged as an important pathogen, particularly in SOT recipients [5,130-132] and those with haematological malignancy undergoing chemotherapy [123, 133] (table 4). Infections present in pulmonary and extra-pulmonary sites including brain, spleen and skin

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Outbreaks of non-Aspergillus moulds

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[131-133,156]. Infection may be disseminated in immunocompromised hosts [5, 109].

There have been several notable outbreaks of non-Aspergillus moulds reported in the literature (table 5) with an increasing number of these reports over time, particularly in 2014.

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Common precipitating factors include natural disasters and contamination of medical supplies. One outbreak which resulted in a particularly high level of morbidity and mortality

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occurred in the USA in 2012. In this outbreak, methylprednisolone acetate for injection was inadvertently contaminated with various fungi, in particular the pathogen Exserohilum

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rostratum resulting in 728 cases of infection and 61 deaths [158]. 229 cases of meningitis, 310 of spinal/paraspinal infection, 148 of meningitis with spinal/paraspinal infection, 32 peripheral joint infections and 40 strokes occurred. Such outbreaks highlight the tendency for non-Aspergillus moulds to cause infection in otherwise healthy individuals if the normal innate barriers of protection (eg skin) are breached. The increasing number of reported outbreaks may be related to increased awareness and surveillance but Vijaykumar et al. identify gaps in current practice around testing for reducing melanized mould contamination in pharmaceutical manufacturing [169].

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Advances in Laboratory Diagnostics

Since clinical manifestations of non-Aspergillus mould infections are often non-specific, timely,

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accurate detection of the causative agent is essential to inform the choice of antifungal therapy. Currently culture, and other conventional, diagnostic methods are still the

tissue and body fluids are increasingly used [170].

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cornerstone of diagnosis. Molecular methods to directly detect/identify mould pathogens in

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Visualization of fungal structures allows assessment of their morphology but specificity is low for distinguishing non-Aspergillus hyaline moulds from Aspergillus and even between these and the Mucorales [171]. Immunohistochemical techniques such as in situ hybridization with a specific fluorescent antibody that binds to fungal elements in affected tissue may also aid

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diagnosis but their use has not been clinically validated. In one study, Fusarium was distinguished from Aspergillus elements in tissue sections with 100% positive predictive

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value (PPV) [172].

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Nucleic acid amplification techniques that employ either panfungal PCR assays (combined with DNA sequencing) or fungal species-specific assays may also be used to identify pathogens directly in tissue, blood, serum or sputum [170]. These methods yielded good sensitivity and specificity in small case series [173-175] but methods are not standardised. The application of molecular techniques for the direct detection of Mucorales DNA in fresh and PE tissue specimens is more recent - conventional and real-time PCR 18 and 28S rRNAtargeted assays have been reported with good sensitivity [176-179].

ACCEPTED MANUSCRIPT Species identification may be difficult using phenotypic methods as non-Aspergillus moulds may sporulate poorly eg. Apophysomyces and other genera within the Mucorales, and genera including

Fusarium

and

Scedosporium,

species

complexes.

[170,180,181]..

Fungal

identification by molecular methods is largely reliant on DNA sequencing and comparative

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sequence analysis is now the gold standard for identification of filamentous fungi. The internal transcribed spacer (ITS) loci, and the 28S subunit of the rRNA gene are the most widely used targets for species identification of moulds [170]. The ITS regions are especially and

major

gene

repositories

such

as

the

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discriminatory

GenBank

database

(www.ncbi.nlm.nih.gov) contain large numbers of sequences from this locus enabling ready

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comparison of sequences. However, alternate gene targets including the elongation factor 1-a (EF1-a), RPB2 (encodes the second largest RNA polymerase subunit gene), calmodulin and ßtubulin genes are also used, particularly for identification of Scedosporium [53] and Fusarium [182,183]. ITS sequencing is also insufficient to resolve species identity amongst many

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Mucorales; either the D1-D2 regions of the 28S rRNA gene is sequenced and if unsuccessful, cloning of PCR products to identify species is required [184]. Of note, current public gene

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20% [185].

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repositories are not censored and errors in archived fungal sequences are estimated at 14-

Currently there are no rapid biomarker tests specific to non-Aspergillus mould infections. The presence of Aspergillus galactomannan (GM), a cell wall polysaccharide specific for Aspergillus spp., in serum and BAL fluid may hence assist in differentiating aspergillosis from other hyaline moulds. However, false positive results occur and results should be interpreted in conjunction with clinical and radiological findings [186]. 1,3-β-D glucan (BG), a cell wall constituent of many fungi, may also be detectable in the serum of patients with nonAspergillus mould infection with the exception of mucormycosis [187]. However outside of the

ACCEPTED MANUSCRIPT outbreak of fungal meningitis in US in 2012 where it was applied to CSF with good sensitivity and specificity for infection, there is little experience in using this test to diagnose nonAspergillus mould infections [188].

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Conclusion

Non-Aspergillus mould infections are emerging both in immunocompromised and immunocompetent patients, presenting in many and varying ways. Notably, outbreaks of

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infections with these moulds are increasingly reported, often healthcare-associated or in the aftermath of trauma sustained in natural disasters. There are no specific non-culture based

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tests available and diagnosis relies upon visualisation of hyphae in tissue and further identification by either culture or molecular testing. However, public gene repositories contain errors in to 20% of archived fungal sequences. Agendas for future research include developing better surveillance and diagnostic tests to help with earlier recognition of

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infection and potential sources of infection as well as improving archived sequence accuracy.

ACCEPTED MANUSCRIPT Tables and figures

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Figure 1: Numbers of publications per phaeohyphomycete species per 5 year period.

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Table 1: Syncephalastrum racemosum case reports by year of report: clinical features and outcome Year Case/presentation Setting Management Outcome 2015 Severe pneumonia Non-Hodgkin Amphotericin B, Cure Rodriguezlymhoma caspofungin, surgical Gutierrez[35] resection 2015 Onychomycosis Type 2 DM Surgical Cure Baby [36] debridement Topical nystatin 2014 Subcutaneous Type 2 DM Surgical Cure Mangaraj [37] infection debridement Amphotericin B 2013 Rhino-orbitalType 2 DM Amphotericin B Death Mathuram [38] cerebral infection 2010 Mycetoma dorsum Immunocompetent Lost to follow-up Unknown Amatya [39] of foot patient from Nepal, following trauma 2006 Onychomycosis Immunocompetent Surgical Cure Pavlovic [40] patient following debridement trauma Nystatin ointment 2005 Abdominal wound Immunocompetent Surgical Cure Schlebusch[41] infection patient following debridement trauma Amphotericin B 1980 Cutaneous infection Type 1 DM Unknown Death Kamalam [42] with arteritis (unrelated)

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DM- diabetes mellitus

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Table 2: Schizophyllum commune infection case reports stratified by country and presenting syndrome. Adopted from Chowdhary et al [93], with updates from recent literature. Mycoses (No. of cases) Country (No. of cases) References Sinusitis (44) Austria (16) [93, 94] India (6) [93, 95-97] [93, 98-100] Japan (5) [93] USA (4) Colombia (3) [93] France (3) [93] [93] Serbia (2) U.K. (1) [93] Australia (1) [93] New Zealand (1) [93] [101] Iran (1) South Korea (1) [102] Allergic broncho-pulmonary Japan (21) [93, 103] mycosis (34) India (13) [93, 104] Bronchial mucoid Japan (5) [93] impaction/fungus ball (10) India (4) [93, 97] North America (1) [93] Schizophyllum asthma (2) Japan (2) [93] Fungal pneumonia (4) India (4) [97] Pulmonary infiltrates with Japan (2) [93] eosinophilia/eosinophilic pneumonia (2) Empyema (1) Hong Kong (1) [105] Other pulmonary mycoses (14) Iran (7) [93] [93] Japan (4) Taiwan (1) [93] Italy (1) [93] Serbia (1) [93] Extrapulmonary mycoses (7)* USA (2) [93] Brazil (1) [93] Colombia (1) [93] Austria (1) [106] South Korea (1) [107] India (1) [108] * Includes one case each of onychomycosis, meningitis, ulceration of palate, and 2 cases each of sinoorbital infection and brain abscess.

ACCEPTED MANUSCRIPT Table 3: Well-described phaeohyphomycete infection syndromes Alternaria spp [113-115]

Bipolaris spp [116, 117]

Presentations

Cutaneous and soft tissue infection Oculomycosis Rhinosinusitis Cerebral infection (rare) Solid organ transplant Cushing’s syndrome HSCT

Sinusitis Endophthalmitis Necrotizing pneumonia Brain abscess Immunocompromised patients

Can occur in immunocompetent patients

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Risk groups/factors

Cladophialophora bantiana [118, 119] Cerebral infection

Exophiala dermatidis [120, 121] Lymphadenitis Cutaneous and soft tissue infection Cerebral infection

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Pathogen

Immunocompomised Immunocompetent of Asian decent (cerebral infection)

ACCEPTED MANUSCRIPT Age/ sex 57M

Country

Risk factor

Australia

HM, DM, COPD

53M

Australia

HM, HSCT

2015 Kumaran [134]

55M

India

Gardner

2015 Cardeau-Desangles [135] 2014 Schieffelin [111] 2012 Brokolaki [136] 2012 Qureshi [137]

55M

France

Heart Tx

U/K

USA

69M

2012 Meriden [138] 2009 Mayer [139] 2008 Shoham [130]

Therapy Amph B, Posa

Outcome Died

Vori

Died

Terb, Itra

Died

Died

Solid organ Tx

U/K

U/K

Germany

Double-lung Tx

Skin

Vori

Surv

53M

USA

Renal Tx

Spine, lung

Amph B, Vori

Died

54M 66M 57F 55M 60F 57M

USA USA USA USA USA USA

Double-lung Tx Single-lung Tx Single-lung Tx Single-lung Tx Heart Tx Double-lung Tx

Lungs Lung Lung U/K Lung Lung

Surv Surv Surv Surv Surv Died

58F 67M

USA USA

Single-lung Tx Liver Tx

Lung Brain

69M 53M

USA USA

Brain Spine, lung

34M

USA

Liver Tx Kidney transplant CGD

71M

USA

Kidney Tx

Lung

Amph B, Vori Vori Vori Itra Itraconazole RUL resection, itra, amph B Amph B, itra Amph B, intrathecal amph B, itra Amph B, itra Drainage of abscess, amph B, vori Pneumonectomy, vori, posa Amph B, vori

64F

USA

Kidney Tx

Lung

Surv

Kidney Tx Liver Tx Immunocomp

Lung Lung Lung

Wedge resection, amph B, flucon, vori Itra Lobectomy, vori Vori

Surv Surv Surv

60M 50M 79F

USA USA USA

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Vori

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2007 Hollingsworth [140] 2006 Boggild [141] 2005 Fukushima [133]

Site of involvement Brain, lung Sinus, liver, small intestine Hyperkeratotic plaques over shin Subcutaenous, Lung, brain, peritoneum Skin X 3

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2015 Slavin [5]

EP

Year/Reference

RI PT

Table 4: Verruconis gallopava case reports in literature: clinical features and outcome

Lung

Surv Died Surv Surv Surv Died

28M

Canada

Advanced HIV

Lung, hip, brain

Vori, caspofungin

Died

66F

Japan

CLL

Amph B, flucy, itra

Died

2004 Bravo [142] 2003 Wang [143]

72M

USA

Immunocomp

Lung, lymph nodes, skin, brain Lung

Itra

Surv

13M

Hong Kong

Kidney Tx

Lung abscess, brain, spleen

Died

2002 Zhao [144] 2001 Mazur [145]

68M

China

Pemphigus

Lung abscess

Aspiration lung abscess, amph B, itra Amph B, itra

32F

USA

Lung Tx

Shoulder abscess, lung, brain

Surgical drainage, amph B, flucy, itra

Surv Surv

ACCEPTED MANUSCRIPT USA

Kidney Tx

58F

USA

Lung Tx

38M

USA

Immunocomp

69M

England

CLL

Lung infiltrate, brain, thyroid Lung abscess, skin Chronic lung abscesses Endophthalmitis

Flucon, Amph B, itra

Died

Aspiration, amph B, itra Right upper lobectomy, itra Fluco, intravitreal amph B, itra Amph B, itra

Surv

58M

Australia

Heart Tx

Lung abscess

59M

USA

Liver Tx

Lung, brain

63M

USA

Liver Tx

68M

USA

Liver Tx

Lung, brain abscess Lung, brain

46M

USA

Heart Tx

Brain abscess

30M

USA

Heart Tx

Lung abscess

Aspiration, amph B

Surv

60M

USA

Lymphoma

Brain abscess

Died

62M

USA

CLL

Amph B, flucy, flucon None

U/K

U/K

AML

Flucy

Died

RI PT

32M

Lungs, liver, kidney, brain Subcutaneous infection

Surv Died Surv

Amph B

Died

Amph B, craniotomy

Died

Amph B, flucy, itra

Surv

None

Died

SC

M AN U

2001 Malani [132] 2000 Burns [146] 2000 Odell [147] 2000 Bowyer [148] 1998 Jenney [131] 1996 Rossman [149] 1995 Kralovic [150] 1994 Vukmir [151] 1993 Prevost-Smith [152] 1992 Mancini [153] 1991 Sides [123] 1990 Terreni [154] 1986 Fukushiro [155]

Died

AC C

EP

TE D

Amph B- amphotericin B, flucy- flucytosine, itra- itraconazole, flucon- fluconazole, vori- voriconazole, terb- terbinafine, posaposaconazole, HM- haematologic malignancy, Tx- transplant, CGD- chronic granulomatous disease, immunocompimmunocompetent, CLL- chronic lymphocytic leukemia, CML- chronic myelogenous leukemia, U/K- unknown, surv- survived

ACCEPTED MANUSCRIPT Table 5: Non-Aspergillus mould outbreaks reported from 2005-2015 Publication

Location

Vector/ context Long-term intravenous catheters in HSCT patients (single hospital) Trauma from tornado

No. of cases/type

Outcomes

Predom Rx

Acremonium kiliense

Ioakimidou 2013 [70]

Greece

3 fungaemias, likely line infection

0 deaths

Vori Line removal

Apophysomyces trapeziformis Bipolaris hawaiiensis

Neblett Fanfair 2012 [2] Small 2014 [157]

Joplin, Missouri, USA USA

13 soft tissue infections

5 deaths

Contaminated triamcinolone intravitreal injections Contaminated methylprednis olone injections

14 cases of endophthalmitis

8 with decreased VA

Amph B (7) Echino (3) Azoles (4) Unknown

Exserohilum rostratum

Smith 2013 [158]

USA

749 infections: - 229 meningitis - 310 spinal or paraspinal inf’n - 148 meningitis plus spinal inf’n - 32 peripheral joint inf’n 20 cases of endophthalmitis

61 deaths

Vori +/- Amph B

Fusarium oxysporum

Buchta 2014 [159]

Czech Republic

Cataract surgery, likely contaminated filling material

19 with very poor VA 2 enucleate d 55/164 Corneal transplant ation (US cohort) 4 deaths

Vori

Fusarium spp

Chang 2006 [160]

USA Hong Kong Singapore

Contaminated contact lens solution

164 cases of keratitis in USA > 250 worldwide

Fusarium verticillioides

Georgiadou 2014 [161]

Larissa, Greece

Hospital reconstruction works

Mucormycoses

Davies 2015 [162]

7 bloodstream infections in immunocompeten t patients 4 cases of rhinoorbital-cerebral mucormycosis >200 cases of gastroenteritis 6 cases of peritonitis

Unknown

Unknown

Unknown

Unknown

3 cases reported: 2 alive 1 death

Amph B

5 deaths

Unknown

5 deaths

Variable Posa Amph B Caspo Amph B

Record flooding Contaminated yogurt Earthquake 2010, peritoneal dialysate bag storage Contaminated hospital linen Contaminated allopurinol tablets and packaged food Contaminated air ducts

Lee 2014 [163] Torres 2014 [164]

USA

Rhizopus delemar Rhizopus microsporus

Duffy 2014 [165] Cheng 2009 [166]

Louisiana, USA Hong Kong

Rhizomucor spp

ElMahallawy 2015 [167]

Egypt

Chile

SC

M AN U

TE D

EP

AC C

Colorado, USA

Mucor circinelloides Paecilomyces variotii

RI PT

Pathogen

5 pediatric patients 12 patients with haem malignancyinvasive intestinal rhizopus 5 pediatric acute leukemic patients

3 deaths

Unknown

Unknown

ACCEPTED MANUSCRIPT Scedosporium Rhizopus Exserohilum Bipolaris Fusarium

Pokala 2014 [168]

Dallas, Pediatric medical centre

Hospital construction

31 pediatric cancer patients

9 deaths

Unknown

RI PT

Vori- voriconazole, amph B- amphotericin B, posa- posaconazole, caspo- caspofungin, echino- echinocandins, inf’n- infection

References

SC

[1] Georgiadou SP, Velegraki A, Arabatzis M, Neonakis I, Chatzipanagiotou S, Dalekos GN et al. Cluster of Fusarium verticillioides bloodstream infections among immunocompetent patients in an internal medicine department after construction works in Larissa, Central Greece. J Hosp Infect. 2014;86:267-271.

M AN U

[2] Neblett Fanfair R, Benedict K, Bos J, Bennett SD, Lo YC, Adenbanjo T. Necrotizing cutaneous mucormycosis after a tornado in Joplin, Missouri, in 2011. N Engl J Med 2012;367:2214-2225 [3] Lau A, Chen S, Sorrell T, Carter D, Malik R, Martin P et al. Development and clinical application of a panfungal PCR assay to detect and identify fungal DNA in tissue specimens. J Clin Microbiol 2007;45:380-385

TE D

[4] Ambrosioni J, Bouchuiguir-Wafa K, Garbino J. Emerging invasive zygomycosis in a tertiary care centre: epidemiology and associated risk factors. Int J Infect Dis 2010;14 (suppl 3):e100e103

EP

[5] Slavin M, van Hal S, Sorrell TC, Lee A, Marriot DJ, Daveson K et al. Invasive infections due to filamentous fungi other than Aspergillus: epidemiology and determinants of mortality. Clin Microbiol Infect 2015; 21: 490.e1-490.e10 [6] Pfaller MA, Diekena DJ. Epidemiology of invasive mycoses in North America. Crit Rev Nicrobiol 2010;36:1-53

AC C

[7] Bitar D, Lortholary O, Le Strat Y, Nicolau J, Coignard B, Tattevin P et al. Population-based analysis of invasive fungal infections, France, 2001-2010. Emerg Infect Dis. 2014;20:11491155 [8] Spellberg BJ, Edwards J Jr, Ibrahim A. Novel perspectives on mucormycosis: pathophysiology, presentation and management. Clin Microbiol Rev 2005; 18: 556-569. [9] Petrikkos G, Skiada A, Lortholary O, Roilides E, Walsh TJ, Kontoyiannis DP. Epidemiology and clinical manifestations of mucormycosis. Clin Infect Dis 2012; 54 (Suppl 1): S8-15 [10] Chakrabarti A, Singh R. Mucormycosis in India: unique features. Mycoses 2014;57(suppl 3): 85-90.

ACCEPTED MANUSCRIPT [11] Petrikkos G, Skiada A, Drogari-Apiranthitou M. Epidemiology of mucromycosis in Europe. Clin Microbiol Infect 2014; 20 (Suppl. 6):67-73 [12] Skiada A, Pagano L, Groll A, Zimmerli S, Dupont B, Lagrou K et al. Zygomycosis in Europe: analysis of 230 cases accrued by the registray of the European Confederation of Medical Mycology (ECMM) Working Group on Zygomycosis between 2005 and 2007. Clin Microbiol Infect 2011; 17:1859-1867

RI PT

[13] Lanternier F, Dannaoui E, Morizot G, Elie C, Garcia-Hermoso D, Huerre M et al. A global analysis of mucormycosis in France: the RetroZygo Study (2005-2007). Clin Infect Dis. 2012; 54 (suppl I): S35-S43

SC

[14] Spellberg BJ, Filler SG, Edwards JE, Jr. Current treatment strategies for disseminated candidiasis. Clin Infect Dis. 2006; 42: 244-251

M AN U

[15] Roden MM, Zaoutis TE, Buchanan WL, Knudsen TA, Sarkisova TA, Schaufele RL et al. Epidemiology and outcome of zygomycosis: a review of 929 reported cases. Clin Infect Dis 2005; 41: 634-653 [16] Greenberg RN, Scott LJ, Vaughn HH, Ribes JA. Zygomycosis (mucormycosis): emerging clinical importance and new treatments. Curr Opin Infect Dis 2004; 17: 517-525 [17] Suryanarayan RS, Panda NK, Pragache G, Chakrabarti A, Saravan K. Sinoorbital mucormycosis due to Apophysomyces elegans in immunocompetent individuals- an increasing trend. Am J Otolaryngology 2006; 27: 366-369

TE D

[18] Thomas AJ, Shah S, Mathews MS, Chacko N. Apophysomyces elegans- renal mucormycosis in a healthy host: a case report from south India. Indian J Med Microbiol 2008; 26: 269-271

EP

[19] dela Cruz WP, Calvano TP, Griffith ME, White CE, Kim SH, Sutton DA et al. Invasive Apophysomyces variabilis infection in a burn patient. J Clin Microbiol 2012; 50:2814-2817

AC C

[20] Guarro J, Chander J, Alvarez E, Stchigel AM, Robin K, Dalal U et al. Apophysomyces variabilis infections in humans. Emerg Inf Dis 2011; 17: 134-135 [21] Bonifaz A, Stchigel AM, Guarro J, Guevara E, Pintos L, Sanchis M et al. Primary cutaneous mucormycosis produced by the new species Apophysomyces mexicanus. J Clin Microbiol 2014l 52: 4428-4431 [22] Alvarez E, Garcia-Hermoso D, Sutton DA, Cano JF, Stchigel AM, Hoinard D et al. Molecular phylogeny and proposal of two new species of the emerging pathogenic fungus Saksenaea. J Clin Microbiol 2010; 48: 4410-4416 [23] Saksena SB. A new genus of the Mucorales. Mycologic 1953; 45: 426-436

ACCEPTED MANUSCRIPT [24] Chakrabarti A, Kumar P, Padhye AA, Chatha L, Singh SK, Das A et al. Primary cutaneous zygomycosis due to Saksenaea vasiformis and Apophysomyces elegans. Clin Inf Dis 1997; 24: 580-583 [25] Ribes JA, Vanover-Sams CL, Baker DJ. Zygomycetes in human disease. Clin Microbiol Rev 2000; 13: 226- 301

RI PT

[26] Oberle AD, Penn RL. Nosocomial invasive Saksenaea vasiformis infection. Am J Clin Pathol 1983; 80:885-888 [27] Parker C, Kaminski G, Hill D. Zygomycosis in a tattoo, caused by Saksenaea vasiformis. Australia J Dermatol 1986; 27: 107-111

SC

[28] Kennedy KJ, Daveson K, Slavin M, van Hal S, Sorrell TC, Lee A et al. Mucormycosis in Australia: contemporary epidemiology and outcome. Personal communication.

M AN U

[29] Gomes MZR, Lewis RE, Kontoyiannis DP. Mucormycosis caused by Unusual Mucormycetes, Non-Rhizopus, -Mucor and –Lichtheimia species. Clin Microbiol Rev 2011; 24: 411-445 [30] Garcia-Martinez J, Lopez-Medrano F, Alhambra A, del Palacio A. Rhinocerebral zygomycosis caused by Saksenaea vasiformis in a diabetic patient. Mycoses 2008; 51: 549553

TE D

[31] Aarset H, Aasarod K, Bergan U, Angelsen A. Acute renal infarction in a woman with slight asthma. Nephrol Dial Trnaplant 2001; 16: 1711-1712 [32] Peter E, Bakri F, Ball DM, Cheney RT, Segal BH. Invasive pulmonary filamentous fungal infection in a patient receiving inhaled corticosteroid therapy. Clin Infect Dis 2002; 35

EP

[33] Solano T, Atkins B, Tambosis E, Mann S, Gottlieb T. Disseminated mucromycosis due to Saksenaea vasiformis in an immunocompetent adult. Clin Infect Dis 2000; 30: 942-943

AC C

[34] Torell J, Cooper BH, Helgeson NG. Disseminated Saksenaea vasiformis infection. Am J Clin Pathol 1981; 76: 116-121 [35] Rodríguez-Gutiérrez G, Carrillo-Casas EM, Arenas R, García-Méndez JO, Toussaint S, Moreno-Morales ME et al. Mucormycosis in a Non-Hodgkin lymphoma patient caused by Syncephalastrum racemosum: case report and review of literature. Mycopathologia. 2015;180:89-93. [36] Baby S, Ramya TG, Geetha RK. Onychomycosis by Syncephalastrum Racemosum: case report from Keral, India. Dermatol Reports. 2015; 7: 5527 [37] Mangaraj S, Sethy G, Patro MK, Padhi S. A rare case of subcutaneous mucormycosis due to Syncephalastrum racemosum; case report and review of literature. Indian J Med Microbiol. 2014;32:448-51

ACCEPTED MANUSCRIPT [38] Mathuram AJ, Mohanraj P, Mathews MS. Rhino-orbital-cerebral infection by Syncephalastrum racemosum. J Assoc Physicians India 2013; 61:339-40 Amatya R, Khanal B, Rijal A. Syncephalastrum species producing mycetoma-like lesions. Indian J Dermatol Venereol & Leprol. 2010;76:284-6 [ 39] Amatya R, Khanal B, Rijal A. Syncephalastrum species producing mycetoma-like lesions. Indian J Dermatol, Venerol & Leprol. 2010; 76: 284-6

RI PT

[40] Pavlovic MD, Bulajic N. Great toenail onychomycosis caused by Syncephalastrum racemosum. Dermatol Online J 2006; 12:7

SC

[41] Schlebusch S, Looke DF. Intraabdominal zygomycosis caused by Syncephalastrum racemosum infection successfully treated with partial surgical debridement and high-dose amphotericin B lipid complex. J Clinical Microbiol 2005; 43:5825-7 [42] Kamalam A, Thambiah AS. Cutaneous infection by Syncephalastrum. Sabouraudia 1980; 18:19-20

M AN U

[43] Barton RC, Borman AM, Johnson EM, Houbraken J, Hobson RP, Denton M et al. Isolation of the fungus Geosmithia argillacea in sputum of people with cystic fibrosis. J Clin Microbiol 2010;48: 2615–2617

TE D

[44] Kontoyiannis DP, Marr KA, Park BJ, Alexander BD, Anaissie EJ, Walsh TJ. Prospective surveillance for invasive fungal infections in hematopoietic stem cell transplant recipients, 2001-2006: Overview of the transplant-associated infection surveillance network (TRANSNET) database. Clin Inf Dis 2010; 50: 1091-1100 [45] Park BJ, Pappas PG, Wannemuehler KA, Alexander BD, Anaisse EJ, Andes DR et al. Invasive non-Aspergillus mould infections in transplant recipients, United States, 2001-2006. Emerg Infect Dis 2011; 17: 1855-1864

EP

[46] Nucci M, Anaissie E. Fusarium infections in immunocompromised patients. Clin Microbiol Rev 2007;20:695–704

AC C

[47] Boutati EL, 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 [48] Campo M, Lewis RE, Kontoyiannis DP. Invasive fusariosis in patients with hematologic malignancies at a cancer center:1998-2009. J Infect 2010;60:331–337 [49] Dignani MC, Anaissie E. Human Fusariosis. Clin Microbiol Infect 2004; 10 (Suppl 1): 6775 [50] Kerr CM, Perfect JR, Craven PC, Jorgensen JH, Drutz JD, Shelburne HA et al. Fungal peritonitis in patients on continuous ambulatory peritoneal dialysis. Ann Intern Med 1983; 99: 334-336 [51] Heath CH, Slavin MA, Sorrell TC, Handke R, Harun A, Phillips M et al. Population-based

ACCEPTED MANUSCRIPT surveillance for sceodsporiosis in Australia: epidemiology disease manifestations and emergence of Scedosporium aurantiacum infection. Clin Microbiol Infect 2009; 15: 689-693 [52] Cortez KJ, Roilides E, Quiroz-Telles F, Meletiadis J, Antachopoulos C, Knudsen T et al. Infections caused by Scedosporium spp. Clin Microbiol Rev 2008; 21: 157–197.

RI PT

[53] Gilgado F, Cano J, Gene J, Guarro J. Molecular phylogeny of the Pseudallescheria boydii species complex: proposal of two new species. J Clin Microbiol 2005; 43: 4930–4942. [54] Chen S, Aronow ME, Wang C, Shen D, Chan CC. Classical pathology of sympathetic ophthalmia presented in a unique case. Open Ophthalmol J 2014; 8:32-8

SC

[55] Gilgado F, Cano J, Gene J, Sutton DA, Guarro J. Molecular and phenotypic data supporting distinct species statuses for Scedosporium apiospermum and Pseudallescheria boydii and the proposed new species Scedosporium dehoogi. J Clin Microbiol 2008; 46: 766–771.

M AN U

[56] Cooley L, Spelman D, Thursky K, Slavin M. Infection with Scedosporium apiospermum and S. prolificans, Australia. Emerg Infect Dis 2007; 13: 1170–7. [57] Katragkou A, Dotis J, Kotsiou M, Tamiolaki M, Roilides E. Scedosporium apiospermum infection after near-drowning. Mycoses 2007;50:412–421

TE D

[58] Husain S, Munoz P, Forrest G, Alexander BD, Somani J, Brennan K et al. Infections due to Scedosporium apiospermum and Scedosporium prolificans in transplant recipients: clinical characteristics and impact of antifungal agent therapy on outcome. Clin Infect Dis 2005;40:89–99

EP

[59] Rodriguez-Tudela JL, Berenguer J, Guarro J, Kantarcioglu AS, Horre R, de Hoog GS et al. Epidemiology and outcome of Scedosporium prolificans infection, a review of 162 cases. Med Mycol 2009; 47: 359–70. [60] Das S, Saha R, Ahmad Dar S, Ramachandran VG. Acremonium species: A review of the etiological agents of emerging hyalohyphomycosis. Mycopathologia 2010; 170: 361-375

AC C

[61] Naggie S, Perfect JR. Molds: hyalohyphomycosis, phaeohyphomycosis, and zygomycosis. Clin Chest Med 2009; 30:337–353 [62] Fincher RME, Fisher JF, Lovell RD, Newman CL, Espinellngroff A, Shadomy HJ. Infection due to fungus Acremonium(Cephalosporium).Medicine (Baltimore). 1991;70:398–409. [63] Sandner K, Schonborn C. Schimmelpilzinfektion der Haut bei ausge- dehnter Verbrennung. Dtsch Gesundheitsw 1973;28:125–8. [64] Mulwafu WK, Lubbe DE, Garb M. Allergic fungal sinusitis secondary to Acremonium species causing unilateral visual loss. East Central Afr J Surg. 2006;11:62–4 [65] Haide C, Padhye AA, Haley LD, Rinaldi MG, Kay D. Acremonium falciforme as a cause of mycetoma. Sabourodia 1976;14:319–26.

ACCEPTED MANUSCRIPT [66] Beaudreuil S, Buchler M, Al Najjar A, Bastides F, Francois M, Duong TH et al. Acute septic arthritis after kidney transplantation due to Acremonium. Nephrol Dial Transplant 2003; 18: 850–851.

RI PT

[67] Kouvousis N, Lazaros G, Christoforatou E, Deftereos S, Petropoulou MD, Lelekis M. Pacemaker pocket infection due to Acremonium species. Pacing Clin Electrophysiol.2002;25:378–9. [68] Guarro J, Del Palacio A, Gene J, Cano J, Gonzalez CG. A case of colonization of a prosthetic mitral valve by Acremonium strictum. Rev Iberoam Micol. 2009;26:146–8.

SC

[69] Purnak T, Beyazit Y, Sahin GO, Shorbagi A, Akova M. A novel fungal pathogen under the spotlight—Acremonium species associated fungaemia in an immunocompetent host. Mycoses 2011; 54:78-80

M AN U

[70] Ioakimidou A, Vyzantiadis TA, Sakellari I, Arabatzis M, Smias C, Douka V et al. An unusual cluster of Acremonium kiliense fungaemias in a haematopoietic cell transplantation unit. Diagn Microbiol Infect Dis 2013; 75: 313-316 [71] Luangsa-Ard J, Houbraken J, van Doorn T, Hong SB, Borman AM, Hywel-Jones NL et al. Purpureocillium, a new genus for the medically important Paecilomyces lilacinus. FEMS Microbiol Lett 2011; 321: 141–149.

TE D

[72] Orth B, Frei R, Itin PH, Rinaldi MG, Speck B, Gratwohl A et al. Outbreak of invasive mycoses caused by Paecilomyces lilacinus from a contaminated skin lotion. Ann Intern Med 1996; 125: 799–806. [73] Pastor FJ, Guarro J. Clinical manifestations, treatment and outcome of Paecilomyces lilacinus infections. Clin Mircrobiol Infect 2006; 12: 948–60.

EP

[74] Castro LG, Salebian A, Sotto MN. Hyalohyphomycosis by Paecilomyces lilacinus in a renal transplant patient and a review of human Paecilomyces species infections. J Med Vet Mycol 1990; 28:15–26.

AC C

[75] Chamilos G, Kontoyiannis DP. Voriconazole–resistant disseminated Paecilomyces variotii infections in a neutropenic patient with leukemia on voriconazole prophylaxis. J Infect 2005; 51: e225–8. [76] Martin CA, Roberts S, Greenberg RN. Voriconazole treatment of disseminated Paecilomyces infection in a patient with acquired immunodeficiency syndrome. Clin Infect Dis 2002; 35: e78–81. [77] Mandarapu SB, Mukku KK, Raju SB, Chandragiri S. Successful catheter reinsertion in a case of Paecilomyces varioti peritonitis in a patient on continuous ambulatory peritoneal dialysis. Indian J Nephrol. 2015;25:177-9 [78] Polat M, Kara SS, Tapısız A, Demirtaş Z, Sarı S, Kalkancı A et al. Successful treatment of Paecilomyces varioti peritonitis in a liver transplant patient.

ACCEPTED MANUSCRIPT Mycopathologia. 2015;179:317-20 [79] Chouaki T, Lavarde V, Lachaud L, Raccurt CP, Hennequin C. Invasive infections due to Trichoderma species: report of 2 cases, findings of in vitro susceptibility testing, and review of the literature. Clin Infect Dis 2002;35:1360–1367

RI PT

[80] Chen SCA, Blyth CC, Sorrell TC, Slavin MA. Pneumonia and lung infections due to emerging and unusual fungal pathogens. Sem Resp Crit Care Med 2011; 32: 703-716 [81] Myoken Y, Sugata T, Fujita Y, Asaoku H, Fujihara M, Mikani Y. Fatal necrotizing stomatitis due to Trichoderma longibracheatum in a neutropenic patient with malignant lymphoma: a case report. Int J Oral Mazillofac Surg 2002; 31: 688–91

SC

[82] Richter S, Cormican MG, Pfaller MA, Lee CK, Gingrich R, Rinaldi MG, Sutton DA. Fatal disseminated Trichoderma longibrachiatum infection in an adult bone marrow transplant patient: species identification and review of the literature. J Clin Microbiol 1999;37:1154–60.

M AN U

[83] Sandoval-Denis M, Sutton DA, Cano-Lira JF, Gené J, Fothergill AW, Wiederhold NP et al. Phylogeny of the clinical relevant species of the emerging fungus Trichoderma and their antifungal susceptibilities. J Clin Microbiol. 2014 ;52:2112-25. [84] De Miguel D, Gómez P, González R, García-Suárez J, Cuadros JA, Bañas MH et al. Nonfatal pulmonary Trichoderma viride infection in an adult patient with acute myeloid leukemia.Report of one case and review of the literature. Diagn. Microbiol.Infect. Dis 2005;53:33–37

TE D

[85] Furukawa H, Kusne S, Sutton DA, Manez R, Carrau R, Nichols L et al. Acute invasive sinusitis due to Trichoderma longibrachiatum in a liver and small bowel transplant recipient. Clin. Infect. Dis. 1998;26:487–489

EP

[86] Bren A. Fungal peritonitis in patients on continuous ambulatory peritoneal dialysis. Eur. J. Clin. Microbiol. Infect. Dis. 1998;17:839–843.

AC C

[87] Rodríguez Peralta LI, Mañas Vera MR, García Delgado MJ, Pérez de la Cruz AJ. Endocarditis caused by Trichoderma longibrachiatum in a patient receiving home parenteral nutrition. Nutr Hosp. 2013 May-Jun;28(3):961-4. [88] Seguin P, Degeilh B, Grulois I, Gacouin A, Maugendre S, Dufour T, Dupont B, Camus C.. Successful treatment of a brain abscess due to Trichoderma longibrachiatum after surgical resection. Eur. J. Clin. Microbiol. Infect. Dis. 1995;14:445–448. [89] Santillan Salas CF, Joshi AY, Dhiman N, Banerjee R, Huskins WC, Wengenack NL, Henry NK. Fatal post-operative Trichoderma longibrachiatum mediastinitis and peritonitis in a paediatric patient with complex congenital cardiac disease on peritoneal dialysis. J Med Microbiol. 2011;60:1869-71 [90] Giraud S, Favennec L, Bougnoux ME, Bouchara JP. Rasamsonia argillacea species complex: taxonomy, pathogenesis and clinical relevance. Future Med 2013;8:967-978

ACCEPTED MANUSCRIPT [91] De Ravin SS, Challipalli M, Anderson V, Shea YR, Marciano B, Hilligoss D et al. Geosmithia argillacea: an emerging cause of invasive mycosis in human chronic granulomatous disease. Clin Infect Dis 2011; 52:e136–e143 [92] Kligman AM. A basidiomycete probably causing onychomycosis. J Invest Dermatol 1950; 14: 67–70.

RI PT

[93] Chowdhary A, Randhawa HS, Gaur SN, Agarwal K, Kathuria S, Roy P et al. Schizophyllum commune as an emerging fungal pathogen: a review and report of two cases. Mycoses 2013; 56:1–10 [94] Buzina W; Braun H; Freudenschuss K; Lackner A; Schimpl K; Stammberger H. The basidiomycete Schizophyllum commune in paranasal sinuses. Mycoses 2003. 46 Suppl 1:23-7

SC

[95] Verma S, Gupta P, Singh D, Kanga A, Mohindroo NK, Jhobta A. Schizophyllum commune causing sinusitis with nasal polyposis in the sub-Himalayan region: first case report and review. Mycopathologia 2014; 177: 103-110

M AN U

[96] Adikary R, Joshi S. Comment on: Schizophyllum commune sinusitis in an immunocompetent host. Indian J Med Microbiol 2012; 30: 249 [97] Singh PK, Kathuria S, Agarwal K, Gaur SN, Meis JF, Chowdhary A. Clinical significance and molecular characterization of nonsporulating molds isolated from the respiratory tracts of bronchopulmonary mycosis patients with special reference to basidiomycetes. J Clin Microbiol 2013; 51: 3331-3337

TE D

[98] Ahmed MK, Ishino T, Takeno S, Hirakawa K. Bilateral allergic fungal rhinosinusitis caused by Schizophyllum commune and Aspergillus niger, A case report. Rhinology 2009; 47: 217221

EP

[99] Toya T, Shinohara A, Tatsuno K, Seo S, Nannya Y, Ichikawa M et al. A case of Schizophyllum commune sinusitis following unrelated cord blood transplantation for acute lymphoblastic leukemia. Int J Hematol 2013; 98: 261-263

AC C

[100] Tsukatani T, Ogawa H, Anzawa K, Kobayashi E, Hasegawa H, Makimura K et al. Schizophyllum commune-induced allergic fungal rhinosinusitis and sinobronchial mycosis. Med Mycol Case Rep 2015; 8: 10-13 [101] Nazeri M, Ardehali MM, Moazeni M, Hashemi SJ, Fallahi AA, Ehteram H et al. A case of fungus ball type pansinusitis caused by Schizophyllum commune. Med Mycol Case Rep 2012; 1: 115-118 [102] Won EJ, Shin JH, Lim SC, Shin MG, Suh SP, Ryang DW. Molecular identification of Schizophyllum commune as a cause of allergic fungal sinusitis. Ann Lab Med 2012; 32: 375379 [103] Ogawa H, Fujimura M, Takeuchi Y, Makimura K, Satoh K. The definitive diagnostic process and successful treatment for ABPM caused by Schizophyllum commune: a report of two cases. Allergol Int 2012; 61: 163-169

ACCEPTED MANUSCRIPT [104] Chowdhary A, Kathuria S, Singh PK, Agarwal K, Gaur SN, Roy P et al. Molecular characterization and in vitro antifungal susceptibility profile of Schizophyllum commune, an emerging basidiomycete in bronchopulmonary mycoses Antimicrob Agents Chemother 2013; 57: 2845-2848

RI PT

[105] Chan JFW, Teng JLL, Li IWS, Wong SCY, Leung SSM, Ho PO et al. Fatal empyema thoracis caused by Schizophyllum commune with cross-reactive cryptococcal antigenemia. J Clin Microbiol 2014; 52: 683-687 [106] Hoenigl M, Aspeck E, Valentin T, Heiling B, Seeber K, Krause R et al. Sinusitis and frontal brain abscess in a diabetic patient caused by the basidiomycete Schizophyllum commune: case report and review of the literature. Mycoses 2013; 56: 389-393

SC

[107] Sa HS, Ko KS, Woo KI, Peck KR, Kim YD. A case of sino-orbital infection caused by the Schizophyllum commune. Diagn Microbiol Infect Dis 2012; 73: 376-377

M AN U

[108] Saha S, Sengupta J, Banerjee D, Khetan A, Mandal SM. Schizophyllum commune: a new organism in eye infection. Mycophathologia 2013; 175: 357-360 [109] Revankar SG, Sutton DA. Melanized fungi in human disease. Clin Microbiol Rev 2010;23:884–928.

TE D

[110] Chowdhary A, Meis JF, Guarro J, de Hoog GS, Kathuria S, Arendrup C et al. ESCMID and ECMM joint clinical guidelines for the diagnosis and management of systemic phaeohyphomycosis: diseases caused by black fungi. Clin Microbiol Inf 2014; 20: 47-75

EP

[111] Schieffelin JS, Garcia-Diaz JB, Loss Jr GE, Beckman EN, Keller RA, Staffield-Coit C, et al. Phaeohyphomycosis fungal infections in solid organ transplant recipients: clinical presentation, pathology, and treatment. Transpl Infect Dis 2014;16:270–8. [112] Revankar SG, Patterson JE, Sutton DA, Pullen R, Rinaldi MG. Disseminated phaeohyphomycosis: Review of an emerging mycosis. Clin Inf Dis 2002; 34: 467-476

AC C

[113] Pastor FJ, Guarro J. Alternaria infections: laboratory diagnosis and relevant clinical features. Clin Microbiol Infect 2008; 14: 734–746 [114] Gilaberte M, Bartralot R, Torres JM, Reus FS, Rodriguez V, Alomar A et al. Cutaneous alternariosis in transplant recipients: clinicopathologic review of 9 cases. J Am Acad Dermatol 2005; 52: 653–659. [115] Morrison VA, Weisdorf DJ. Alternaria: a sinonasal pathogen of immunocompromised hosts. Clin Infect Dis 1993; 16: 265–270 [116] Rosow L, Jiang JX, Deuel T, Lechpammer M, Zamani AA, Milner DA et al. Cerebral phaeohyphomycosis caused by Bipolaris spicifera after heart transplantation. Transpl Infect Dis 2011;13: 419–423.

ACCEPTED MANUSCRIPT [117] Viola GM, Sutton R. Allergic fungal sinusitis complicated by fungal brain mass. Int J Infect Dis 2010; 14(suppl 3): e299–e301 [118] Horre R, De Hoog GS. Primary cerebral infections by melanized fungi: a review. Stud. Mycol. 1999; 43:176–193.

RI PT

[119] Kantarcioglu AS, de Hoog GS. Infection of the central nervous system by melanized fungi: a review of cases presented between 1999 and 2004. Mycoses 2004; 47: 4–13. [120] Chang, X., Li R, Yu J, Bao X, Qin J. Phaeohyphomycosis of the central nervous system caused by Exophiala dermatitidis in a 3-year-old immunocompetent host. J. Child Neurol 2009; 24:342–345.

SC

[121] Hiruma M, Kawada A, Ohata H, Ohnishi Y, Takahashi H, Yamazaki M et al. Systemic phaeohyphomycosis caused by Exophiala dermatitidis. Mycoses 1993; 36:1–7.

M AN U

[122] Filizzola MJ, Martinez F, Rauf SJ. Phaeohyphomycosis of the central nervous system in immunocompetent hosts: report of a case and review of the literature. Int J Infect Dis 2003; 7: 282–286 [123] Sides EH.III, Benson JD, Padhye AA. Phaeohyphomycotic brain abscess due to Ochroconis gallopavum in a patient with malignant lymphoma of a large cell type. J. Med. Vet. Mycol 1991;29:317–322.

TE D

[124] Dwivedi RS. Occurrence of the genus Scolecobasidium Abbott inIndia. Curr. Sci. 1959; 28:374–375. [125] Barron GI, Busch LV.. Studies on the soil hyphomycete Scolecobasidium. Can. J. Bot. 1962;40:77–84.

EP

[126] Nováková A. Microscopic fungi isolated from the Domica Cave system (Slovak Karst National Park, Slovakia). A review. Int. J. Speleol. 2009; 38:71–82

AC C

[127] Tansey MR, Brock TD. Dactylaria gallopava, a cause of avian encephalitis, in hot spring effluents, thermal soils and self-heated coal waste piles. Nature 1973; 242:202–203. [128] Evans HC. Thermophilous fungi of coal spoil tips. I. Taxonomy.Trans. Br. Mycol. Soc 1971; 57:241–254. [129] Waldrip DW, Padhye AA, Ajello L, Ajello M. Isolation of Dactylaria gallopava from broiler-house litter. Avian Dis 1974. 18:445–451 [130] Shoham S, Pic-Aluas L, Taylor J, Cortez K, Rinaldi MG, Shea Y et al. Transplant-associated Ochroconis gallopava infections. Transpl Infect Dis 2008; 10: 442–448. [131] Jenney A, Maslen M, Bergin P, Tang SK, Esmore D, Fuller A. Pulmonary infection due to Ochroconis gallopavum treated successfully after orthotopic heart transplantation. Clin Infect Dis 1998; 26: 236–237

ACCEPTED MANUSCRIPT [132] Malani PN, Bleicher JJ, Kauffman CA, Davenport DS. Disseminated Dactylaria constricta infection in a renal transplant recipient. Transpl Infect Dis 2001; 3: 40–43 [133] Fukushima N, Mannen K, Okamoto S, Shinogi T, Nishimoto K , Sueoka E. Disseminated Ochroconis gallopavum infection in a chronic lymphocytic leukemia: a case report and review of the literature on hematological malignancies. Intern Med 2005; 44: 879–882

RI PT

[134] Kumaran MS, Bhagwan S, Savio J, Rudramurthy SM, Chakrabarti A, Tirumalae R et al. Disseminated cutaneous Ochroconis gallopava infection in an immunocompetent host: an unusual concurrence- a case report and review of cases reported. Int J Dermatol. 2015; 54:32731

SC

[135] Cardeau-Desangles I, Fabre A, Cointault O, Guitard J, Esposito L, Iriart X et al. Disseminated Ochroconis gallopava infection in a heart transplant patient. Transpl Infect Dis 2013; 15:E115-118.

M AN U

[136] Brokalaki EI, Sommerwerck U, von Heinegg EH, Hillen U. Ochroconis gallopavum infection in a lung transplant recipient; report of a case. Transplant Proc 2012; 44:2778-2780 [137] Qureshi ZA, Kwak EJ, Nguyen MH, Silveira FP. Ochroconis gallopava: a dematiaceous mold causing infections in transplant recipients. Clin Transpl 2012;26:e17–23.

TE D

[138] Meriden Z, Marr KA, Lederman HM, Illei PB, Villa K, Riedel S et al. Ochroconis gallopava infection in a patient with chronic granulomatous disease: case report and review of the literature. Medical Mycology 2012; 50:883-889 [139] Mayer N, Bastani B. A case of pulmonary cavitary lesion due to Dactylaria constricta var. gallopava in a renal transplant patient. Nephrology 2009;14:262.

EP

[140] Hollingsworth JW, Shofer S, Zaas A. Successful treatment of Ochroconis gallopavum infection in an immunocompetent host. Infection 2007; 35:367-369

AC C

[141] Boggild AK, Poutanen SM, Mohan S, Ostrowski MA. Disseminated phaehyphomycosis due to Ochroconis gallopavum in the setting of advanced HIV infection. Medical Mycology 2006; 44:777-782 [142] Bravo LO, Ngamy V. Ochroconis gallopavum and Mycobacterium avium intracellulare in an immunocompetent patient. Chest 2004;126:975S [143] Wang TK, Chiu W, Chim S, Chan TM, Wong SS, Ho PL. Dissemianted Ochroconis gallopavum infection in a renal transplant recipient: the first reported case and a review of the literature. Clin Nephrol 2003. 60(6):415-423 [144] Zhao J, Wang Z, Li R, Wang D, Bai Y. Pemphigus patient with pulmonary fungal infection caused by Ochroconis gallopava: the first case report in China. Chung-Hua i Hsueh Tsa Chih [Chinese Medical Journal] 2002; 82:1310-1313 [145] Mazur JE, Judson MA. A case report of a dactylaria fungal infection in a lung transplant

ACCEPTED MANUSCRIPT patient. Chest 2001; 119: 651-653 [146] Burns KE, Ohori NP, Iacono AT. Dactylaria gallopava infection presenting as a pulmonary nodule in a single-lung transplant recipient. J Heart Lung Transplant 2000; 19: 900-902

RI PT

[147] Odell JA, Alvarez S, D. G. Cvitkovich, D. A. Cortese, and B. L. McComb. 2000. Multiple lung abscesses due to Ochroconis gallopavum, a dematiaceous fungus, in a nonimmunocompromised wood pulp worker. Chest 118:1503–1505

[148] Bowyer JD, Johnson EM, Horn EH, Gregson RM. Ochroconis gallapova endopthalmitis in fludarabine treated chronic lymphocytic leukemia. Br J Ophthalmol 2000; 84: 117–121

SC

[149] Rossmann SN, Cernoch PL, Davis JR. Dematiaceous fungi are an increasing cause of human disease. Clin Infect Dis 1996; 22: 73–80

M AN U

[150] Kralovic SM, Rhodes JC. Phaeohyphomycosis caused by Dactylaria (human dactylariosis): report of a case with review of the literature. J Infect 1995; 31:107-113 [151] Vukmir RB, Kusne S, Linden P, Pasculle W, Fothergill AW, Sheaffer J et al. Successful therapy for cerebral phaeohyphomycosis due to Dactylaria gallopava in a liver transplant recipient. Clin Infect Dis 1994; 19: 714-719.

TE D

[152] Prevost-Smith E, Hutton N, Padhye AA, et al. Fatal phaeohyphomycotic infection due to Dactylaria gallopava and Scedosporium prolificans in a cardiac transplant. In: Proceedings and Abstracts of the Annual 93rd Annual Meeting of the American Society for Microbiology, Atlanta, GA, Washington: ASM Press, 1993: F–35. [153] Mancini MC, McGinnis MR. Dactylaria infection of a human being: pulmonary disease in a heart transplant recipient. J Heart Lung Transplant 1992; 11: 827-830.

EP

[154] Terreni AA, DiSalvo AF, Baker AS Jr, Crymes WB, Morris PR, Dowda H Jr. Disseminated Dactylaria gallopava infection in diabetic patient with chronic lymphocytic leukemia of the Tcell type. Am J Clin Pathol 1990; 94: 105-107

AC C

[155] Fukushiro R, Udagawa S, Kawashima Y, Kawamura Y. Subcutaneous abscesses caused by Ochroconis gallopavum. J Med Vet Mycol 1986; 24: 175-182 [156] Giraldo A, Sutton DA, Samerpitak K, de Hoog GS, Wiederhold NP, Guarro J et al. Occurrence of Ochroconis and Verruconis species in clinical specimens from the United States. J Clin Microbiol 2014; 52: 4189-4201 [157] Small KW, Chan CK, Silva-Garcia R, Walsh TJ. Onset of an outbreak of Bipolaris hawaiiensis fungal endophthalmitis after intravitreal injections of triamcinolone. Ophthalmology 2014; 121; 952-958 [158] Smith RM, Schaefer MK, Kainer MA, Wise M, Finks J, Duwve J et al. Multistate fungal infection outbreak response team. Fungal infections associated with contaminated methylprednisolone injections. N Eng J Med 2013; 369:1598-1609

ACCEPTED MANUSCRIPT [159] Buchta V, Feuermannova A, Vasa M, Baskova L, Kutova R, Kubatova A et al. Outbreak of fungal endophthalmitis due to Fusarium oxysporum following cataract surgery. Mycopathologia 2014; 177:115-121

RI PT

[160] Chang DC, Grant GB, O'Donnell K, Wannemuehler KA, Noble-Wang J, Rao CY et al. Fusarium Keratitis Investigation Team. Multistate outbreak of Fusarium keratitis associated with use of contact lens solution. JAMA 2006; 296:953-963 [161] Georgiadou SP, Velegraki A, Arabatzis M, Neonakis I, Chatzipanagiotou S, Dalekos GN et al. Cluster of Fusarium verticillioides bloodstream infections among immunocompetent patients in an internal medicine department after construction works in Larissa, Central Greece. J Hosp Infect. 2014;86:267-271.

SC

[162] Davies BW, Smith JM, Hink EM, Durairaj VD. Increased incidence of rhino-orbitalcerebral mucormycosis after Colorado flooding. Ophthal Plast Reconstr Surg. 2015 Mar 18 (Epub ahead of print)

M AN U

[163] Lee SC, Billmyre RB, Li A, Carson S, Sykes SM, Huh EY et al. Analysis of food-borne fungal pathogen outbreak: virulence and genome of a Mucor circinelloides isolate from yogurt. MBio. 2014;5:e01390-14 [164] Torres R, Gonzalez M, Sanhueza M, Segovia E, Alvo M, Passalacqua W et al. Outbreak of Paecilomyces variotii peritonitis in peritoneal dialysis patients after the 2010 Chilean earthquake. Perit Dial Int. 2014;34:322-325.

TE D

[165] Duffy J, Harris J, Gade L, Sehulster L, Newhouse E, O'Connell H et al. Mucormycosis outbreak associated with hospital linens. Pediatric Infect Dis J. 2014; 33: 472

EP

[166] Cheng VCC, Chan JFW, Ngan AHY, To KKW, Leung SY, Tsoi HW. Outbreak of intestinal infection due to Rhizopus microspores. J Clin Microbiol. 2009; 47: 2834–2843

AC C

[167] El-Mahallawy HA, Khedr R, Taha H, Shalaby L, Mostafa A. Investigation and management of a rhizomucor outbreak in a Pediatric Cancer Hospital in Egypt. Pediatr Blood Cancer 2015 Jul 23 (Epub ahead of print) [168] Pokala HR, Leonard D, Cox J, Metcalf P, McClay J, Siegel J et al. Association of hospital construction with the development of healthcare associated environmental mold infections (HAEMI) in pediatric patients with leukemia. Pediatr Blood Cancer 2014; 61:276–80. [169] Vijaykumar R, Al-Aboody MS, Sandle T. A review of melanized (black) fungal contamination in pharmaceutical products - incidence, drug recall and control measures. J Appl Microbiol 2015 Jun (Epub ahead of print) [170] Halliday C, Kidd, Chen SCA. Molecular diagnostic methods for invasive fungal disease: the horizon draws nearer? Pathology 2015; 47: 257-269 [171] Sangoi AR, Rogers WM, Longacre TA, Montoya JG, Baron EJ, Banaei N. Challenges and pitfalls of morphologic identification of fungal infections in histologic and cytologic

ACCEPTED MANUSCRIPT specimens: a ten-year retrospective review at a single institution. Am J Clin Pathol 2009; 131: 364-375 [172] Hayden RT, Isotalo PA, Parrett T et al. In situ hybridisation for the differentiation of Aspergillus, Fusarium and Pseudallescheria species in tissue section. Diagnostic Mol Pathol 2003;12:21-26

RI PT

[173] Lau A, Chen S, Sorrell T, Carter D, Malik R, Martin P et al. Development and clinical application of a panfungal PCR assay to detect and identify fungal DNA in tissue specimens. J Clin Microbiol 2007;45:380-385

SC

[174] Harun A, Blyth CC, Gilgado F, Middelton PG, Chen SCA, Meyer W. Development of a mulitplex PCR to detect Scedosporium species in sputa of cystic fibrosis patients. J Clin Microbiol 2011;49:1508-1512

M AN U

[175] Trubiano JA, Dennison AM, Morrissey CO, Chua KY, Halliday CL, Chen SA et al. Clinical utility of panfungal polymerase chain reaction for the diagnosis of invasive fungal disease: a single center experience. Med Mycol. 2015 Nov 2 [Epub ahead of print] [176] Lengerova M, Racil Z, Hrncirova K, et al. Rapid detection and identification of mucormycetes in bronchoalveolar lavage samples from immunocompromised patients with pulmonary infiltrates by use of high-resolution melt analysis. J Clin Microbiol 2014; 52: 2824 – 2828

TE D

[177] Bialek R, Konrad F, Kern J, et al. Based identification and discrimination of agents of mucormycosis and aspergillosis in paraffin wax embedded tissue. J Clin Pathol 2005; 58: 1180–1184.

EP

[178] Cornely OA, Arikan-Akdagli S, Dannaoui E, et al. ESCMID and ECMM joint clinical guidelines for the diagnosis and management of mucormycosis 2013. Clin Microbiol Infect 2014; 20: 5 – 25. [179] Hammond SP, Bialek R,Milner DA,etal. Molecular methods toimprove diagnosis and identification of mucormycosis. J Clin Microbiol 2011; 49: 2151 – 3.

AC C

[180] Balajee SA, Borman AM, Brandt ME, et al. Sequence-based identification of Aspergillus, Fusarium, and Mucorales species in the clinical mycology laboratory: where are we and where should we go from here? J Clin Microbiol 2009;47:877-884 [181] Wang H, Xiao M, Kong FR, et al. Accurate and practical identification of 20 Fusarium species by seven-locus sequence analysis and reverse line blot (RLB) hybridization, and an in vitro antifungal susceptibility study. J Clin Microbiol 2011; 49:1890-1898 [182] O'Donnell K, Sutton DA, Rinaldi MG, et al. Internet-accessible DNA sequence database for identifying Fusaria from human and animal infections. J Clin Microbiol 2010;48:37083718 [183] Hennequin C, Abachin E, Symoens F, et al. Identification of Fusarium species involved in human infections by 28S rRNA gene sequencing. J Clin Microbiol 1999;37:3586-3589

ACCEPTED MANUSCRIPT [184] Walther G, Pawłowska J, Alastruey-Izquierdo A, et al. Barcoding in Mucorales: an inventory of biodiversity. Persoonia 2013; 30: 11 – 47. [185] Nilsson RH, Ryberg M, Kristiansson E, Abarenkov K, Larsson KH, Koljalg U. Taxonomic reliability of DNA sequences in public sequence databases: a fungal perspective. PLoS ONE 2006;1:e59

RI PT

[186] Heng SC, Chen SC, Morrissey CO, Thursky K, Manser RL, De Silva HD et al. Clinical utility of Aspergillus galactomannan and PCR in bronchoalveolar lavage fluid got the diagnosis of invasive pulmonary aspergillosis in patients with haematologic malignancies. Diagn Microbiol Infect Dis 2014; 79: 322-327

SC

[187] Ostrosky-Zeichner L, Alexander B, Kett DH, et al. Multicentre clinical evaluation of the 1,3-B-D-glucan assay as an aid to diagnosis of fungal infections in humans. Clin Infect Dis 2005;41:654-659

AC C

EP

TE D

M AN U

[188] Litvintseva AP, Lindsley MD, Gade L, Smith R, Chiller T, Lyons JL et al. Utility of (1-3)-βD-glucan testing for diagnostics and monitoring response to treatment during the multistate outbreak of fungal meningitis and other infections. Clin Infect Dis 2014; 58: 622-630