Emerging & Rare Fungal Infections in Solid Organ Transplant Recipients

Authors

  • B. M. Kubak,

    Corresponding author
    1. Division of Infectious Diseases, David Geffen School of Medicine at UCLA. Ronald Reagan UCLA Medical Center, Los Angeles, CA
      * Corresponding author: Bernard M. Kubak, bkubak@mednet.ucla.edu
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  • S. S. Huprikar,

    1. Division of Infectious Diseases, Mount Sinai School of Medicine, Mount Sinai Medical Center, New York, NY
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  • the AST Infectious Diseases Community of Practice

    1. Division of Infectious Diseases, David Geffen School of Medicine at UCLA. Ronald Reagan UCLA Medical Center, Los Angeles, CA
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* Corresponding author: Bernard M. Kubak, bkubak@mednet.ucla.edu

Introduction

Newly emerging and rare fungal agents are increasingly reported as genuine pathogens in posttransplant fungal infections. The description ‘emerging’ has been coined for these fungal agents as they have not been traditionally implicated, recognized, or recovered as the etiological agents of fungal infections in immunocompromised patients. An increased understanding of the importance of these emerging and rare fungal pathogens has developed from infections reported in patients with hematological malignancies undergoing chemotherapeutic regimens and conditioning for bone marrow transplantation (1–6). The ‘rare’ fungal agents have been increasingly reported in susceptible patients with unique risk factors including solid organ transplantation (7–11). The detection and isolation of these fungi correlates with the pathophysiology and clinical symptoms thereby confirming their causative role in disease.

Although in many cases, the exposure source is unknown; immunocompetent and immunocompromised patients will come into contact with these emerging and rare potential pathogens as a result of environmental contact with soil and vegetation/plant material, contaminated and polluted water, sewage, wood, certain foods and decaying fruit. Several species are widely disseminated in air and presumably acquired by inhalation of fungal structures such as spores, conidia or actual hyphal elements. Specific modes of acquisition such as traumatic exposure or contamination of wounds or intravascular access sites are generally accepted. Many of these moulds and yeasts were originally considered nonpathogenic contaminants from clinical specimens (e.g. surveillance cultures of respiratory, sinus, skin, or wound sources) and might have been initially dismissed as the etiologic agent (s) of infection. Most patients infected with emerging and rare fungal agents have unique risk factors such as neutropenia, poorly controlled diabetes mellitus, malnutrition, renal failure, inherent disorders of immunity and anatomy, and receipt of chemotherapy or other immunosuppressive medications (1,3,6,12). One established example of these rare fungal agents infecting patients with disordered immunity and anatomy occurs in end-stage lung disease due to cystic fibrosis or advanced pulmonary fibrosis and bronchiectasis (5). The underlying pulmonary architectural distortion and mucosal defects predispose these patients to colonization and infection with Scedosporium, Zygomycetes, and dematiaceous moulds. Such ‘colonization’ may result in posttransplant infection in a subgroup of lung transplant recipients (13,14).

Disease presentations include pulmonary, dermatological, and central nervous system involvement as well as widely disseminated disease involving other less reported sites. The disease potential of the emerging moulds may depend on several specific and yet unrecognized fungal virulence factors. Reported factors include melanin (especially with the dematiaceous fungi), proteases, phospholipases, catalases, calcineurin, and lipid signaling molecules (15). The milieu of post transplant immunosuppression, the intensity of rejection therapy, and graft dysfunction facilitate the acquisition of fungal spores and moulds leading to disease. Exposure to selective antifungal agents, specifically azole prophylaxis or therapy, may contribute to this shift in incidence of infection with the emerging fungi. Voriconazole usage has been associated with zygomycosis in hematopoietic stem-cell transplant (HSCT) recipients in some medical centers (16–18).

Multicenter controlled trials of risk factors, diagnostic approaches, and prophylaxis and treatment strategies for emerging fungal infections in organ transplant recipients are limited. Many of the clinical practices are evolving from small case series, anecdotal experiences, and joint center reviews.

The following diseases will be discussed in this section: zygomycosis, hyalohyphomycosis, scedosporiosis (pseudoallescheriosis), phaeohyphomycosis, chromoblastomycosis, mycetoma, emerging yeast infections, and dermatophytosis. Specific agents and associated diseases are listed in Table 1.

Table 1.  Emerging fungal pathogens listed by more common reported sites of infection and clinical syndromes.
Sepsis/FungemiaPulmonaryGenitourinaryCentral Nervous SystemOcular (& Ear)Skin/SubcuatenousIntra-abdominal
  1. Y = Yeast, otherwise Mould form.

  2. Fusarium spp.: F. solani, F. oxysporum, F. moniliforme

  3. Paecilomyces spp.: P. variotii, P. lilacinus

  4. Trichoderma spp.: T. longibrachiatum, T. viride, T. harzianum

  5. Scedosporium spp: Pseudallescheria boydii (sexual state), Scedosporium apiospermum (asexual state)

  6. Scopulariopsis spp.: S. brumptii, S. brevicaulis

  7. Malassezia spp.: M. furfur; M. pachydermatis

  8. Zygomycoses: Rhizopus oryzae, Rhizopus microsporus; Mucor spp.; Cunninghamella bertholletiae; Absidia corymbifera; Apophysomyces elegans

  9. Phaeohyphomycoses:

  10. Alternaria: A. alternaria. A. tenuissima

  11. Bipolaris: B. hawaiiensis, B. spicifera

  12. Cladophialophora bantiana: also known as Xylohyha bantiana and Cladosporium trichoides

  13. Curvularia: C. lunata, C. geniculata, others

  14. Dactylaria: D. gallopava, D. constrictaExophiala: E. jeanselmei var jeanselmei, E. jeanselmei var lecanii-corni, E. spinifera, E. monliae, E. castellanii

  15. Pialophora: P. repens, P. richardsiae, P. verrucosa (chromoblastomycosis)

  16. Ramichloridium mackenziei

  17. Scedosporium: S. prolificans, formerly S. inflatum

Acremonium
Fusarium spp.
Hasemula (Y)
Malassezia
spp. (Y)
Paecilomyces
Trichoderma
spp.
Trichosporon (Y)
Rhodotorula (Y)
Fusarium spp.
Malassezia spp. (Y)
Paecilomyces
Pencillium marneffei
Scedosporium spp.
Scopulariopsis spp.
Trichoderma spp.
Trichosporon beigelii (Y)
Zycomycoses (Rhizopus, Mucor, Apophysomyces, Cunninghamella)
Phaeohyphomycoses
Bipolaris spp.
Curvularia spp.
Cladophialophora
bantiana
Dactylaria gallopava/constricta
Scedosporium
prolificans
Malassezia spp. (Y)
Trichosporon (Y)
Zycomycoses (Rhizopus, Absidia)
Fusarium spp.
Paecilomyces
Scedosporium spp.
Trichosporon beigelii (Y)
Trichoderma spp.
Zycomycoses (Rhizopus, Mucor, Cunninghamella, Apophysomyces, Absidia)
Phaeohyphomycoses
Bipolaris spp.
Wangiella dermatitidis
Cladophialophora
bantiani
Ramichloridium
mackenziei
Dactylaria gallopava
Onchroconis gallopavum


Rhinocerebral
Fusarium spp.
Paecilomyces
Scedosporium spp.
Trichoderma spp.
Zycomycoses (Rhizopus, Mucor)
Phaeohyphomycoses
Alternaria alternata
Bipolaris
spp.
Curvularia spp.
Exserohilum rostratum
Exophiala spp.
Dactylaria gallopava
Ramichloridium
mackenziei
(ear)
Fusarium spp.
Scedosporium spp.
Trichosporon (Y)
Zygomycoses (Rhizopus, Mucor, Cunninghamella, Apophysomyces)
Phaeohyphomycoses
Alternaria alternata
Curvularia
spp.
Exserohilum rostratum
Exophiala spp.
Phialophora spp.
Wangiella dermati-tidis

Keratitis

Fusarium spp.
Scedosporium spp.

Endopthalmitis Uveitis
Acremonium
Fusarium spp.
Paecilomyces
Rhodotorula (Y)
Scedosporium spp.
Scopulariopsis
Trichosporon (Y)
Zycomycoses
Fusarium spp.
Malassezia spp. (Y)
Penicillium marneffei Scedosporium spp.
Paecilomyces
Trichoderma spp.
Zygomycoses (Rhizopus, Mucor)
Phaeohyphomycoses
Alternaria alternata
Bipolaris spp.
Curvularia spp.
Exserohilum
rostratum
Exophiala spp.
Wangiella
dermatitidis
Phialophora spp.
Scedosporium
prolificans
Cladophialophora
bantiana
Dactylaria gallopava
Fusarium spp.
Paecilomyces
Penicillium marneffei
Phaeohyphomycoses
Trichoderma spp.
Trichosporon
beigelii
(Y)
Zycomycoses
MusculoskeletalAngio-invasive/Thrombosis/InfarctionDisseminated disease    
Fusarium spp.
Scedosporium spp.
Trichoderma spp.
Penicillium marneffei
Zygomycoses
Phaeohyphomycoses
Alternaria alternata
Curvularia spp.
Scedosporium
prolificans
Dactylaria gallopava/constricta
Fusarium
Scedosporium
Zygomycoses (Rhizopus,
Mucor)
Phaeohyphomycoses
Fusarium spp.
Malassezia spp. (Y)
Penicillium marneffei
Scedosporium spp.
Trichosporon (Y)
Trichoderma spp.
Zycomycoses (Rhizopus Mucor)
Phaeohyphomycoses
Alternaria alternata
Bipolaris spp.
Curvularia
spp.
Phialophora spp.
Scedosporium
prolificans
Cladophialophora
bantiana
    

Zygomycosis is a collective term generally referring to infections caused by members of the Zygomycetes class, Mucorales order, including Absidia, Apophysomyces, Cunninghamella, Mucor, Rhizopus, and Rhizomucor. These moulds appear in tissue as broad hyphal structures that are ribbon-like, right angle or irregularly branched, and sparsely septated (19–21).

Hyalohyphomycosis is the general term for infections due to fungi with hyaline (i.e. non-pigmented or lightly pigmented), septate, branched, or sometimes mycelial attributes. They can be subcutaneous, organ or tissue specific (with abscess formation) or widely disseminated. Agents include Acremonium, Arthrographis kalrae, Chyrsosporium, Fusarium, Paecilomyces, Penicillium marneffi, Scopulariopsis, and Trichoderma, among others (19–21). Scedosporium spp. (Pseudallescheria) retains a unique place in the hierarchy of emerging fungal infections as it ranks closely behind Candida and Aspergillus infections in organ transplant recipients. Scedosporium apiospermum is the asexual form (anamorph) of Pseudallescheria boydii. Both are filamentous moulds causing hyalohyphomycosis. Historically the sexual form Pseudallescheria boydii has been reported under the heading pseudoallescheriosis (also monosporiosis) with the spectrum of diseases involving cases of mycetoma, localized skin infections from traumatic inoculation, pneumonia, and disseminated disease. The organism is a ubiquitous saprophyte isolated from soil, polluted water, compost material and manure, and decaying vegetation. The organism is often recovered in respiratory specimens from patients with cystic fibrosis and severe bronchiectasis (5,14). Scedosporium prolificans has no known sexual form and is typically classified as phaeohyphomycosis. The phaeohyphomycoses are a heterogeneous group of infections caused by dematiaceous fungi (Table 1). The dematiaceous fungi are characterized by the presence of pale brown-black pigment in the cell walls of their vegetative cells, conidial elements, or both (19–21). The pigment is usually melanin, specifically dihydroxynapthalene melanin. Mycotic infections caused by dematiaceous fungi include phaeohyphomycosis, chromoblastomycosis, mycetoma, and sprorotrichosis (discussed elsewhere). Dematiaceous fungi appear in tissue in any combination of hyphal, pseudohyphal, or yeast-like forms, lacking the cellular forms called muriform cells (sclerotic bodies). While many dematiaceous moulds are darkly pigmented in tissue, pathogens such as Alternaria, Bipolaris, and Curvularia have scanty melanin formation in infected tissues. Consequently, they have a hyaline appearance mimicking the agents causing hyalohyphomycosis, yet they are dematiaceous in culture and retain this association.

Phaeohyphomycoses are classified as follows: 1) superficial, involving infection of the skin and hair; 2) cutaneous and corneal, involving keratinized tissues with greater invasion and tissue destruction; 3) subcutaneous, involving deeper implantation of the fungi resulting in cyst and/or abscess formation; 4) systemic, with the initial portal of entry usually via the lung resulting in sino-pulmonary infection and subsequent dissemination to extrapulmonary sites including the central nervous system, liver, spleen, pancreas and other sites (19–21). The primary pulmonary infection may not have been clincally recognized. Important pathogens in this group include Bipolaris, Exophiala, Exserohilum, Cladosporium, and Curvularia (see Table 1).

Chromoblastomycosis refers to chronic cutaneous and subcutaneous lesions, resulting from traumatic implantation of one of several closely related dematiaceous fungi. The causative organisms are soil saprobes, commonly tropical or subtropical in origin but reported from every continent (19,20). The disease hallmark is the presence of muriform cells, embedded in the granulomatous and suppurative tissue reaction (22). This appearance may be confused with squamous cell carcinoma. In the histopathology literature, muriform cells have been referred to as sclerotic cells, copper pennies, or as fumagoid, chromo or Medlar bodies. Texts may still retain these older descriptions. The identification of these appearances in infected tissues with a specialist in pathological mycology is essential for their exact diagnosis. Members include Cladosporium, Fonsecaea, and Phialophora (see Table 1).

Mycetoma is a chronic inflammatory process characterized by swelling and tumefacation of an affected body part with associated destruction of adjacent subcutaneous tissue, muscle, and bone (19–21). Sinus tract formation draining onto the skin is a component of this infection; usually the causative organism in visible aggregates is contained in the sinus material. Common agents include Pseudallescheria boydii, Madurella mycetomatis, Acremonium spp., and Exophiala spp. among other very rare agents. These agents are most commonly seen in tropical areas, but may be detected in parts of the southern United States.

Trichosporonosis is caused by the geophilic yeast and the occasional human commensal Trichosporon beigelii (19–21). Trichosporon species belong to the Cryptococcacaeae family and are ubiquitous yeasts found in soil and water. The clinical spectrum of trichosporonosis may range from the harmless hair disease white piedra to serious systemic infections. Trichosporon species are characterized by hyphae with rectangular arthrospores, true hyphae, pseudohyphae, and budding yeast. Malessezia species also belong to the Cryptococcacaeae family and appear as budding yeast cells in pityriasis veriscolor or as both budding yeast cells and hyphae in its pathogenic form, tinea versicolor. Rhodotorula are round to oval-shaped, multilateral budding yeasts that are normal inhabitants of moist skin. Rhodotorula share many similar morphologic and physiologic characteristics with Cryptococcus but are less pathogenic.

Dermatophytes are classified according to macroconidial characteristics as well as their natural habitats. Anthropophilic species exclusively parasitize humans, zoophilic prefer lower animals, and geophilic species are soil-dwelling saprophytes. All three groups are capable of producing human disease (19–21).

Colonization with Filamentous Fungi and Infection

Colonization with yeasts and moulds occurs frequently in transplant candidates with end-stage organ disease and in recipients after transplantation (5). Transplant candidates may harbor fungal organisms as a consequence of receiving broad-spectrum antibiotics or immunosuppression. Chronic corticosteroid usage for end-stage lung disease commonly predisposes patients to filamentous mould colonization before transplant (14). In transplant candidates with end-stage bronchiectasis, pulmonary fibrosis, or cystic fibrosis, fungal organisms can be isolated with frequency due to underlying parenchymal disease, dysfunctional clearance mechanisms, and altered immunological responses with and without signs of invasive disease (23). Invasive pulmonary or sinus disease with mycelial fungi or yeasts is considered a contraindication for transplantation until such processes are ameliorated or resolved. Scedosporium and Zygomycetes have contributed to morbidity and mortality in these patients. Pretransplant mortality in cystic fibrosis patients with invasive Scedosporium has been reported. The presence of preoperative respiratory fungi such as Fusarium, Scedosporium, or dematiaceous moulds may result in invasive disease after intensive immunosuppression and transplant. Evidence demonstrating a direct correlation to posttransplant fungal infection has varied among transplant centers (24–28). Distinguishing fungal colonization from active infection prior to and after transplantation should be an essential component of the pre- and posttransplant evaluation (9,29).

Donor/Recipient Derived

Donor-derived fungal infections have been observed with emerging fungal pathogens. Transmission of Monosporium (Scedosporium) from a cadaveric kidney was reported resulting in 50% mortality and 100% graft loss (30). The possibilities exist for donor transmission of Zygomycetes or other filamentous moulds with unrecognized fungal acquisition of unusual fungi from nosocomial sources prior to death. Donors exposed to contaminated water such as near-drownings may have acquired unusual moulds in the lungs facilitating dissemination to other organs. Organ procurement agencies should exercise due diligence in reporting all fungal isolates from a donor to the recipient center, especially pending fungal cultures prior to harvesting. Due to the slow laboratory growth of some emerging fungal pathogens, preliminary fungal cultures may have been reported as ‘negative-preliminary’ in a donor evaluation.

Geographic and Occupational Exposure

Many of the opportunistic fungi causing infection have worldwide geographic distribution. An assessment of pretransplant residence, travel, or exposure to areas of geographically-restricted mycoses is required. Tropical or subtropical travel or residency prior to or after organ transplant should be noted for possible exposure to agents of chromoblastomycoses, phaeohyphomycoses, and geographically restricted mycoses. Transplant tourism should be investigated in any organ transplant recipient returning from Southeast Asia, the Middle East, China, or India as geographically restricted moulds and yeasts may have been acquired in those areas (31). Potential emerging fungi can include Penicillium marneffi (Southeast Asia), chromoblastomycotic agents (India, Middle East, Africa, China), dematiaceous moulds from all areas mentioned (e.g. Ramichloridium mackenzie from Egypt, Israel, Saudi Arabia), among other agents (19,20).

Transplant recipients with occupational exposure to emerging moulds should be closely monitored. These includes agricultural and greenhouse workers, carpenters, and workers exposed to soil, particulate, decaying vegetation, sewage and manure, compost material, and residential sites of mould habitation such as attics, crawlspaces, and garages. Workers and transplant recipients exposed to natural disaster cleanups (i.e. hurricanes, floods, and tsunamis) may become exposed to unusual moulds and yeast.

Diagnosis

Infection due to emerging moulds and yeasts can be difficult to diagnose. Advances in clinical laboratory mycology have significantly enhanced the isolation and identification of these rare and fastidious moulds and yeasts from suspect clinical specimens (see Table 2). Specialized specimen collection and processing techniques, specific mycological culture media, and select histological staining techniques are mandatory for detection (19). Close communication between the transplant team and the mycology and pathology laboratory is essential for their diagnosis and for determination of antifungal susceptibility.

Table 2.  Laboratory & radiological approaches in the diagnosis of emerging fungal pathogens (2,9,33,34).
AgentMethodDescription & Comments
ZygomycosisSmear and cultureDirect visualization of sparsely septate broad hyphae in tissue significant in appropriate clinical settings. (Note: literature often describes ‘non-septate’ hyphae although sparsely septate hyphae are morphologically apparent). Culture yield may be low; however, identification by culture methods to genus and species level is recommended for prognosis and due to variable response to newer antifungal agents.
RadiologicalChest and pleural CT imaging useful for diagnosis. Characteristics include: consolidation, pleural effusion, and focal cavitation.Cavitation common on CT but air crescent sign less frequently observed.
 Rhinocerebral zygomycosis: MRI with gadolinium or CT with contrast of brain, sinuses, and orbits very useful in determining extent of infection and guiding surgical resection; bony invasion and/or destruction often visualized.
 Neurovascular involvement can help in determining prognosis and visual-loss risks.
Nucleic acid detectionDNA microarray detection of R. microsporus and M.racemosus in blood, BAL, and tissue samples
HyalohyphomycosisCulture & histopathologyHyalohyphomycoses appear as hyaline, colorless or lighly pigmented, septate, branching, filamentous fungi. Tissue specimens may resemble Aspergillus species or other filamentous fungi.
 Fusarium: Blood cultures are positive in many clinical infections. Smears of cutaneous lesions may complement blood cultures in disseminated disease with demonstration of areas of tissue necrosis and hyaline branching septate hyphae.
 Stains: GMS, PAS, calcoflour white.
 Penicillium: P. marneffei are spherical to oval, 2.5 to 5 micrometer in diameter, and resemble those of Histoplasma capsulatum.
RadiologicalChest: non-specific findings that include cavities, consolidation, alveolar or interstitial infiltrates, nodules, airspace and reticular opacities. MRI with gadolinium for detection of brain abscesses – single or multiple lesions or infarction with surrounding edema.
 Scedosporium: Real time PCR based assay allows for quick specific and quantitative detection of S. apiospermum from blood, serum, and lung samples in murine model..
Nucleic acid detectionFusarium: PCR & single-stranded conformational polymorphism assays can enhance early diagnosis from blood, tissue, and BAL specimens and differentiate from other filamentous fungi. Assays are limited to research facilities. DNA microarray detection of F. oxysporum & F. solani in blood, BAL, and tissue samples
PhaeohyphomycosisCulture & histopathologyInfections characterized by septate darkly pigmented (brown-black; melanin-containing) branched/unbranched structures enhanced with Masson-Fontana (MF) staining. Histopathological diagnosis of dematiaceous hyphae by MF in biopsies of cutaneous, pulmonary, brain, bone, & other viscera.
 Scedosprorium: A high rate of postive S. prolificans blood cultures seen in neutropenic patients compared with solid organ transplant patients. Histopathology of Scedosporium is identical to that of aspergillosis and therefore the species are frequently misidentified.
RadiologicalChest: diffuse consolidative changes and nodular opacities. Proclivity for central nervous system infection: MRI with gadolinium for detection of brain abscesses – single or multiple lesions or infarction with surrounding edema.
Nucleic acid detectionScedosporium: Real time PCR based assay allows for quick specific and quantitative detection of S. prolificans from blood, serum, and lung samples in murine model. DNA microarray detection of S. prolificans in blood, BAL, and tissue samples.
TrichosporonosisSmear & culturePositive blood culture. Smear shows hyaline septate fungal hyphae and pseudohyphae. Histopathology resembles Candida
Nucleic acid detectionDNA microarray detection of T. asahii in blood, BAL, and tissue samples
DermatophytosisClinical/smear (culture)/histopathologyCharacteristic features depend on the dermatophyte (Microsporum, Trichophyton, Epidermophyton) and location of infections (spores on hair surface: ectothrix; spores within shaft: endothrix; hyphal elements and arthrospores in the skin visible on KOH mount of skin scraping; nails, nailbed and surrounding skin). Spectrum of clinical disease depends on infection of hair, follicles, skin ranging from erythematous, scaly patches, hair loss/color alteration; glabous skin, cup-shaped crusts with shallow ulcers; edematous, b oggy, nodular lesions (kerion), (Note: transplanted children with dark skin should always be examined for Trichophyton (black dot) Tinea capitis),
DermatophytosisClinical/smear (culture)/histopathologyTrichophyton is able to propagate in the stratum corneum; Appearances include erythema, scaling, fissuring, with folliculitis or perifolliculitis and erythematous popular/papulopustular lesions. Various configurations and polycyclic configurations & bizarre configurations are seen with advancing, sharp, or diffuse borders depending on the agent and site of infection. Direct mycotic invasion of the dorsal nail plate can encompass the entire nail or appear with sharply marginated white spots in various stages of infection (Trichophyton spp.)

These emerging moulds and yeasts lack the ‘classic’ clinical and radiological presentations associated with more familiar fungal pathogens (e.g. Aspergillus, Candida, and Cryptococcus). Clinical signs and symptoms of emerging moulds or yeasts may be incorrectly attributed to these more common fungal pathogens and, too often, can be firmly established or widely disseminated before time-consuming tests for standard fungal, bacterial, and viral pathogens are completed (4,9). The challenge of emerging fungal infections supports an aggressive diagnostic approach. The clinical suspicion for these pathogens should be investigatived by diagnositic imaging studies, biopies, and cultures. Such procedures can include: interventional radiological procedures, ultrasound or computed tomography (CT) scan guided biopsies, open surgical biopsies, video-assisted thoracoscopic sampling and magnetic resonance (MR) imaging to delinate suspicious lesions. The following clinical specimens have all provided useful material to support the diagnosis of infection by emerging moulds and yeasts: empyema material, lung nodules and cavity contents, bronchoaveolar fluid, gastrointestinal lesions, fluid collections (abdominal, thoracic, pancreatic, pericardial), hepatosplenic lesions, skin lesions, musculoskeletal irregularities, hematomas, and sinus contents (32). Histopathologic analysis of biopsy specimens that demonstrate septate hyphae on hematoxylin and eosin (H&E) staining may be indistinguishable from and confused with Aspergillus, Fusarium, Scedosporium and Trichoderma (4). Delayed or incorrect identification may lead to the initiation of incorrect treatment and result in further tissue destruction and/or dissemination by the emerging fungi.

Fungal serological assays and polymerase chain reaction (PCR) detection methods for many of the emerging moulds and yeasts are limited or non-existent, and often restricted to specialized research facilities (33,34). With few exceptions, the available serological assays fall short in clinical utility; molecular assays for fungal antigen detection are also limited with the emerging moulds and yeast.

Pathogens

Zygomycosis

Zygomycetes that are reported to cause disease in solid organ transplants include Rhizopus arrhizus, Rhizopus rhizopodiformis, Rhizopus oryzae, Rhizopus microsporus; Mucor spp.; Cunninghamella bertholletiae; Absidia corymbifera; Apophysomyces elegans; Conidiobolus coronatus. Similar to Aspergillus, the agents of zygomycosis are angioinvasive pathogens resulting in hemorrhagic necrosis, vascular thrombosis, and tissue infarction. Described in all solid organ transplant recipients, zygomycosis was generally considered to be a rare complication in this patient population (35) but is now considered an emerging fungal infection. In a recent review of 2410 renal transplant recipients between 1998 and 2008, zygomycosis was the most common fungal infection occurring in 11/21 patients with invasive fungal infections (36–38) Portals of entry for zygomycosis include sinuses, lungs, gastrointestinal tract, and skin. The most frequent sites of infection were rhino-sinusitis and orbits and pulmonary involvement across all solid organ transplants (pulmonary > rhino-sinusitis and orbits > cutaneous > rhinocerebral > disseminated > gastrointestinal > renal) (7,8,35,39,40). In some cases the only manifestation of disease may be dermatologic (41). Most reviews on zygomycoses in organ transplant recipients support a multidisciplinary approach to management that includes surgical debridement (s), correction of underlying metabolic abnormalities, early use of antifungal therapy, and reduction of immunosuppression. In one review, the overall mortality rate of the cohort was 50% (100% with disseminated disease, 41.5% with localized disease, and 93.3% with rhinocerebral disease) (7). Risk factors include renal failure, enhanced immunosuppression, and possibly exposure to antifungals not active against zygomycetes Mortality associated with zygomycosis may be in part due to delays in diagnosis and initiation of appropriate therapy.

In a review of 116 solid organ transplant recipients with zygomycosis (renal 73; heart 16; lung 4; heart/lung 2; liver 19; kidney/pancreas 2), corticosteroid usage was the predominant risk factor (35). Other traditional risk factors included diabetes mellitus (31.8%), hyperglycemia (21.5%), renal failure (13.7%), and acidosis (5.1%). Hyperglycemia and acidosis (3.4%) neutropenia (0.8%), and use of deferoxamine (0.8%) were rare. Immunosuppressive risk factors included steroids as part of a maintenance regimen (98.9%), significant steroid use (78.9%), azathioprine (64.2%), cyclosporine A (51.5%), immunosuppression for rejection 1 month prior to onset of zygomycosis (40%), induction immunosuppression 1 month prior to onset (28.4%), tacrolimus (22.1%), mycophenolate mofetil (11.5%), OKT3 (7.3%), and antithymoglobulin (3.1%). The median time of onset was 60 days although the range was quite broad (1 to 2920 days). Localized disease was significantly more common than disseminated disease, and disseminated disease occurred more frequently after rejection and its treatment. Rhizopus was the most common species accounting for 73% of the cases. Favorable outcomes were described in the patients who received a lipid formulation of amphotericin B (LFAB) combined with aggressive surgical debridement. Immunosuppression was reduced in the majority of patients and was associated with better survival.

Primary cutaneous zygomycosis in organ transplant recipients mostly occurs at the site of medical or surgical interventions. It tends to occur earlier after transplantation and is associated with better outcomes compared to other forms of mucormycosis (41). In lung transplant recipients, mucormycosis of the bronchial anastamosis is a rare complication that requires aggressive bronchoscopic or surgical debridement in combination with systemic antifungal therapy (42). Isolated zygomycosis of the renal allograft has been described (35). Early diagnosis of invasive zygomycosis is imperative along with early antifungal and surgical therapy where amenable (43).

Conidiobolus coronatus causes localized zygomycosis in patients residing in tropical areas. Disseminated C. coronatus infection in a renal transplant recipient has been reported (44). A fatal case of Absidia corymbifera pulmonary infection was reported in the early postoperative period of a lung transplant patient receiving voriconazole prophylaxis (45).

Scedosporium:  Detailed mycological descriptions of Scedosporium can be found in the following website (http://www.scedosporium-ecmm.com). S. apiospermum is the asexual form of Pseudallescheria boydii. S. prolificans is a dematiacious mould and a cause of phaeohyphomycosis, but will also be discussed in this section.

In solid organ transplant recipients, Scedosporium species have been increasingly recognized as significant pathogens with substantial morbidity and mortality (8,14,46–52). Acquisition occurs from contaminated water (e.g. sewage, ponds and polluted streams, retention pools, roadside ditches, farm animal waste contamination, near-drowning events), soil, or unknown sources in many cases. In some series of organ transplant recipients, these fungi accounted for approximately 25% of non-Aspergillus infections. In a review of Scedosporium infections in kidney, kidney-pancreas, heart, heart-lung, liver, lung, and small bowel recipients, 83% of infections were due to Scedosporium apiospermum and 19% due to Scedosporium prolificans (14,46). The disease spectrum included disseminated (46%), pulmonary (43%), cutaneous (31%), and central nervous system (29%). Other reported presentations include sinusitis; soft tissue disease; osteomyelitis and joint infection; fungemia; ocular disease (keratitis, endophthalmitis, orbital granuloma, corneal ulcer); brain abscess; abdominal infection (peritonitis, hepatic and splenic abscess); endocarditis and endovascular infections; foreign body infection; and other forms of localized disease (parotitis, otitis externa, prostatitis, thyroid abscess). Fungemia was reported with Scedosporium in 11% of cases in organ transplant recipients. In contrast to hematopoietic stem cell transplant recipients, neutropenia was not a variable associated with Scedosporium infection in organ transplant recipients.

The median time from transplantation to infection was 4 months for patients with S. apiospermum infection and 2.6 months with S. prolificans (46). The increased elapsed time from transplantation to time of onset of scedosporiosis in organ transplant recipients parallel the time reported for invasive aspergillosis in this group (8,29,46,47). In contrast, onset of infection with S. apiospermum in lung transplant recipients was 14–18 months although pretransplant colonization of S. apiospermum led to infection 4 weeks after lung transplantation in a cystic fibrosis recipient. Husain reported a mortality rate among organ transplant recipients of 54% with S. prolificans and 54.5% with S. apiospermum infections. Disseminated infection, fungemia, and renal failure were variables associated with mortality.

In a review of lung transplant recipients only, Sahi et al. reported invasive pulmonary and sino-pulmonary disease as primary sites of infection with widely disseminated secondary disease including osteoarticular infection, mediastinitis, pleuritis/empyema, brain abscesses, chest wall cellulitis, endophthalmitis, genitourinary infection, and unusual forms including breast implant capsulitis and endobronchial infection (29). A few lung transplant recipients appeared to be colonized pretransplant in sputum and sinuses with one patient progressing to invasive disease. Of note, these included cystic fibrosis recipients. Mortality was 60% in these patients, reflecting disseminated infection.

Pulmonary Scedosporium infection is radiologically indistinguishable from invasive aspergillosis and other moulds (4). Presentations include invasive parenchymal disease, empyema, bronchial colonization, tracheobronchitis, pleuritis, or mycetoma. Radiological patterns of Scedosporium pneumonia vary from nodular, focal consolidative, diffuse or alveolar, cavitary, and unspecified presentations. Furthermore, infection of the central nervous systems and other visceral forms of disease cannot be fully distinguished from the presentations of other moulds.

Voriconazole and surgical debridement, when feasible, have been associated with a better survival with S. apiospermum (see Table 3). An enhanced resistance of S. apiospermum to amphotericin B deoxycholate (AmBd) and LFAB is generally reported. Posaconazole and ravuconazole have favorable in vitro activity against S. apiospermum. Recurrence of S. apiospermum infection following apparently successful treatment and re-transplantation has been reported; and withdrawal of therapy has resulted in clinical relapses (48,52).

Table 3.  Fungal Infection in Organ Transplant Recipients: Treatment Recommendations* (2,5,7,9,12,35,46–48,51,71,100–104)
Organism (alphabetical)Treatment (s)
  1. Abbreviations: AmBd = Amphotericin B deoxycholate; Echinocandins: Casp = caspofungin; Mica = micafungin; Anid = anidulafungin; EST = extended spectrum triazoles: Vori = voriconazole; Posa = posaconazole; Ravu = ravuconazole (out of production); Fluc = fluconazole; Itra = itraconazole; Keto = ketoconazole; 5FC = 5-flucytosine; Terb = Terbinafine; LFAB = Lipid formulation of Amphotericin B (unless specifically indicated, agents include amphotericin B lipid complex (Abelcet), liposomal amphotericin B (Ambisome), amphotericin B colloidal dispersion (ABCD).

  2. *All recommendations are based on specific microbiologic diagnosis. Dosing of respective antifungal agents should be adjusted for renal and hepatic dysfunction. Drug interactions are common notably with calcineurin inhibitors and azoles and EST; consequently, modification of immunosuppression and/or concomitant medications may be required.

Acremonium infectionsAmBd 1.0–1.5 mg/kg/d
LFAB 5 mg/kg/d, starting dose
Vori; Terb; Vori+Terb
Removal of infected catheters, tissue, & intravascular thrombi facilitates eradication.
Variable susceptibilities to both AmBd and azoles are reported. Combination medical/surgical therapy is accepted with debridement of infected tissue and combination AmBd (or LFAB) plus azole agent (Vori, Fluc or ketoconazole) can been utilized.
Deep dermatophytic infections
 •Trichophyton spp.Fluc 400–800 mg/d (correct for renal function); ESTs may have utility.
 •Microcporon spp.Itra 200–400 mg/d
 •Epidermophyton spp.Terb 250 – 500 mg/d
DermatophytosisEffective agents include Itra (PO), Vori (PO), Keto (top), miconazole (top), clotrimazole (top), terb, AmBd, & Fluc (least efficacy)
 • Localized tinea infectionsTopical azoles (econazole) or terb
 • Extensive nail head tinea infections or cutaneousTerb 500 mg/d
Itra 200–400 mg/d
Alternative: Griseofulvin 500 mg/d (top)
Dimorphic Moulds
 ParacoccidioidomycosisAmBd 0.5–1.0 mg/kg/d; LFAB
Itra 200–400 mg/d
Keto 200–400 mg/d
 Paracoccidioidomycosis
 • Mucosal/skin and invasive diseaseItra 400 mg/d
 • Disseminated and life-threatening infectionAmBd 0.7–1.0 mg/kg/d; LFAB
PenicilliosisAmBd 0.5–1.0 mg/kg/d; LFAB
Itra 200–400 mg/d
Vori activity comparable to Itra
SporotrichosisAmBd 0.5–1.0 mg/kg/d; LFAB
Terb 250 mg/d (investigational)
 • Lymphocutaneous diseaseItra 200–400 mg
 • Bone, pulmonary, CHSAmBd 0.5 mg/kg/d; LFAB, then Itra 400 mg/d
Fusarium infections
 •F solani
 •F oxysporonVori and Posa (F. oxysporon more susceptible to extended-spectrum triazoles; F. solani, resistance of has been reported with ESTs)
 •F moniliformeF.solani generally sensitive in-vitro to polyenes. LFAB 5 – 15 mg/kg/d; AmBd
 •F proliferatum1.0–1.5 mg/kg/d Limited information on Combination Vori and LFAB >3 mg/kg/d (± G-CSF); Combination LFAB and Terb
FusariosisIncludes surgical resection of localized skin disease (with or without antifungal therapy), removal of infected foreign bodies such as intravascular catheters, correction of neutropenia, and antifungal therapy.
Mortality from disseminated fusariosis in OTRs remains high. Fusarium spp often resistant to AmBd; some improved efficacy with high dose LFAB (amphotericin B lipid complex). Moderate in-vitro susceptibility of Fusarium spp. with Vori, Posa, Ravu, & caspofungin. In-vitro activities of Vori similar to or better than those of Itra and amphotericin B against Fusarium spp.
 • Disseminated infectionG-CSF/GM-CSF for neutropenia; high dose of Fluc + AmBd
 • Catheter-related infectionsRemove intravascular catheter
Paecilomyces infectionsAmBd 1.0–1.5 mg/kg/d
 •P. lilacinusLFAB 5 mg/kg/d starting dose
 •P. variotiiExtended spectrum triazoles (EST) (investigational)
Vori: some activity against P. lilacinus
Posa / Ravu: good in-vitro activity against P. lilacinus
Casp and terb: in vitro activity against P. variotti
Successful treatment of Paecilomyces cellulitis in a renal transplant recipient has been reported with miconazole, but surgical excision is required for possible resolution.
Phaeohyphomycosis (Dematiaceous moulds)
 Alternaria infectionsLesional excision; intralesional miconazole or AmBd; local ketoconazole application (cutaneous disease)
Itra 200–600 mg/d
AmBd 1.0–1.5 mg/kg/d + 5FC 100 mg/kg/d
EST (Vori, Posa, Ravu)
 Bipolaris infectionsItra 200–600 mg/d
AmBd 1.0–1.5 mg/kg/d + 5FC 100 mg/kg/d
Vori with in-vitro activity; ESTs investigational
 Cladophialophora infectionsItra 200–600 mg/d
AmBd 1.0–1.5 mg/kg/d + 5FC 100 mg/kg/d
EST including Vori and Posa
The MIC ranges of Itra, Vori, & AmBd comparable against Cladophialophora bantiana and Exophiala dermatitidis.
 Curvularia infectionsItra 200–600 mg/d
AmBd 1.0–1.5 mg/kg/d + 5FC 100 mg/kg/d
EST
 Dactylaria infectionsItra 200–600 mg/d
AmBd 1.0–1.5 mg/kg/d + 5FC 100 mg/kg/d
ESTs
 Exophiala jeanselmei & some Rhinocladiella spp. are dematiaceous mouldsActivity with amphotericin B, Itra, Vori and Posa
 Ramichloridium obovoideum (mackenziei)Similar to recommendations for Phaehyphomycosis
Surgical resection + EST ± intraventricular AmBd;
EST (Vori, Posa) for CNS disease with limited reports of success
 Wangiella (Exophiala) infectionsItra 200–600 mg/d
AmBd 1.0–1.5 mg/kg/d + 5FC 100 mg/kg/d
Vori 400 mg/d, Posa
Scedosporiosis (Pseudallescheriasis)S. apiospermum responds to EST and surgical debridement.
S. apiosspermumSurgical debridement for amenable cases plus systemic therapy (voriconazole, posaconazole); limited work with combination therapy (plus echinocandin)
S. prolificans (generally resistant to antifungal agents)Drainage of abscesses & resection of any infected foreign body (e.g. an infected AV-fistula) are mandatory in conjunction with antifungal therapy (e.g. Vori; Fluc followed by miconazole); concomitant reduction or elimination of immunosuppression is often necessary.
 • KeratitisTopical antifungal agents (± Vori)
Endophthalmitis: intravitreal and systemic AmBd and Fluc or Vori; surgical evisceration may be required for eradication.
 • Skin and soft tissueSurgical excision of cutaneous and musculoskeletal disease is preferred treatment; repeat excisions required for recurrent disease in conjunction with prolonged antifungal therapy.
Options: Surgical debridement ± Itra 400 mg/d + 5FC 100 mg/kg/d. Madura foot: Itra 400 mg/d
Severe skin infections: vacuum seal technique
 • BrainMortality high despite antifungal treatment. CNS disease requires excision in most cases. Brain abscesses require surgical drainage and an EST (Vori); CNS-infected survivors have been treated with resection and either Vori, AmBd + miconazole, or AmBd, some responses with miconazole ± intraventricular miconazole (for CNS infections) In some cases, limited efficacy with Itra 400 mg/d + 5FC 100 mg/kg/d + LFAB 5 mg/kg/d; an EST (Vori) may provide significant benefit due to enhanced CNS penetration in conjunction with surgical resection. Some considerations of enhanced efficacy Vori plus terbinafine. Intraventicular antifungal agents (AmBd [50 – 500 mcg]± hydrocortisone) via an Omaya reservoir can be utilized in conjunction with systemic antifungal therapy.
Scedosporium infectionsFor Scedosporium apiospermum (Pseudallescheria boydii) Vori (or Posa); resistance to amphotericin B & echinocandins.
 •Scedosporium apiospermum (asexual form)Some reports with response to LFAB >5 mg/kg/d starting dose (Vori in-vitro fungicidal concentration for Scedosporium apiospermum lower than AmBd & Itra.)
Reports of responses: Itra 200–600 mg/d; AmBd 1.0–1.5 mg/kg/d
Posa; Ravu,, display promising in vitro activity
Increased in-vitro antifungal activity against S. apiospermum was observed with combination AmBd and an azole (i.e. Itra or miconazole).
In vitro resistance to AmBd and 5FC; favorable outcomes for limited disease reported with some azoles (Vori &, Keto, miconazole, Itra). Vori and caspofungin demonstrate in-vitro activity against P. boydii and some filamentous fungi. In-vitro activities of Vori similar to or better than those of Itra and AmBd against P. boydii.
 •Scedosporium prolificans (inflatum)S. prolificans resistant to all antifungal agents. Addition of ≥2 agents has been reported:
Vori + Terb synergy, Itra + Terb synergy
Additive or synergistic effect noted with AmBd, ESTs, and colony stimulating factors. Variable results with GM-CSF (prolonged survival in mice
albaconazole (limited experience)
experimental: Ravu + Casp
EST (voriconazole) with terbinafine possibly effective
Scopulariopsis
 •Scopulariopsis brumptiDebridement of infected tissue and removal of involved foreign bodies required to reduce the risk of dissemination.
 •Sc. brevicaulisPosa+Terb (68% of strains)
AmBd+Casp (60%)
Posa+Casp (48%)
Trichoderma infections
T. longibrachiatum (most common)
T. harzianum
T. koningi
T. pseudokoningii
T. viride
General: removal of infection peritoneal dialysis catheters, surgical drainage/removal of localized lesions such as pulmonary mycetomas, sinus collections, abdominal & brain abscesses.
Susceptible or intermediate to high dose AmBd 1.0–1.5 mg/kg/d, Itra, ketoconazole, miconazole, LFAB >5 mg/kg/d starting dose
Resistant to Fluc & 5FC.
Vori & other ESTs display activity against T. longibrachiatum
Yeasts
Trichosporon infection
 •Trichosporon mucoides (formerly beigelii)Almost all isolate from cases of systemic & disseminated infections are T. asahi, T. mucoides, while T. asteroids, T. inkin, T. cutaneum, & T. ovoides are associated with superficial disease.
 •T.asahiiFluc; Fluc 800 mg + AmBd 0.8–1.0 mg/kg/d
 •T. asteroidsVori (in-vitro Vori >> Fluc, Itra); Posa; Ravu
 •T. inkinAzole + GM-CSF (disseminated disease)
 •T. cutaneum
 •T. ovoides
 •Malassezia fungemiaRemove catheter; Fluc 400–800 mg/d
 • Cutaneous MalasseziaAmBd 0.5–1.0 mg/kg/d
Topical agents (clotrimazole, selenium) or oral azoles (Fluc, Itra) effective for treatment of limited cutaneous disease.
Other rare yeast infections
 •Rhodotorula rubraAmBd 0.5–1.0 mg/kg/d ± 5-FC 100 mg/kg/d
 •Hansenula anomaiaFluc (400–800 mg/d); EST with responses.
 •Saccharomyces cerevisiae
Zygomycosis
 • Rhinocerebral/skin/GI
• Pulmonary
• Other forms
Essential cornerstones of management include: surgical resection if amenable, reduction of immunosuppression, control of predisposing metabolic conditions, & correction of neutropenia in conjunction with systemic antifungal therapy – below; mortality remains high.
Surgical debridement (often multiple debridements may be necessary to assure clean margins)
LFAB: starting dose 5 mg/kg/d, may increase if tolerated to 12.5 mg/kg/d, though most data document maximum benefit achieved at 7.5 mg/kg/d.
Resistance or poor activity of most EST against Zygomycetes reported. Posa appears to be active against many of the zygomycetes but variation is seen. Most mycology laboratories do not speciate the Zygomycetes, and in-vitro testing has reported variability in response.
LFAB ≥5 mg/kg/d (extended course). ± posa. Some authors recommend combination therapy then prolonged use of either agent.
Addition of terbinafine with some utility, and for limited skin disease.
AmBd 1.0–1.5 mg/kg/d, dosing from historical responses.
Hyperbaric oxygen therapy as an adjunct aggressive medical / surgical approach, never a 1st line therapy nor a substitute for above.
Adjuvant intrapleural or intracavitary instillation of AmBd has been utilized for local involvement and for inadvertent contamination of noninvaded tissue (lung pleural) with fungus during primary resection
Experimental, limited case reports: adjunctive deferasirox in conjunction with antifungal agents.
Skin disease – limitedExcision; Posa; Terb; Posa + Terb.

Reports of infection caused by Scedosporium prolificans in organ transplant recipients are occurring with more frequency. In a general review of S. prolificans, risk factors for scedosporiosis were malignancy (46%), cystic fibrosis (11.7%), and solid organ transplantation (8.6%). Patterns of infection included cutaneous and wound (28.6%), pulmonary (8.5%), disseminated (8.3%), osteoarticular (5.9%), and peritoneal, single case (8). Bilateral endogenous S. prolificans endophthalmitis was reported after pulmonary infection in a bilateral lung transplant recipient; profound vitritis, retinitis, and detached retina with focal infiltrates, necrosis, and invasive mycotic elements were noted (50). S. prolificans is also observed as a colonizer and pathogen in patient with chronic obstructive pulmonary disease, cystic fibrosis, and bronchiectasis. Repeatedly positive cultures in a transplant recipient with a compatible clinical and radiologic presentation warrant close scrutiny. Radiological presentations are non-specific. In osteomyelitis, bone lesions were apparent on radiology and culture and pathology revealed S. prolificans. Blood cultures can be positive and all clinical specimens should include full mycology cultures as a favorable recovery for all infected sites has been reported (e.g. blood, skin and nails, wound, vascular, sinus, ocular-ear, respiratory, cerebrospinal fluid (CSF), brain, endocardium, bone, joint contents, and peritoneum). A common feature in the development of scedosporiosis has been recent augmented immunosuppression for treatments of rejection (i.e. corticosteroids or anti-lymhocyte globulin) with some infections occurring 3–6 months after rejection therapy. Resistance has been reported among all antifungal agents with discouraging responses to a variety of treatment regimens. An additive or synergistic effect was noted with AmBd, an extended-spectrum triazole and colony-stimulating factors (47).

Fusarium: F. solani, F. proliferatum, F. oxysporum, F. moniliforme, and, rarely, F. sacchari have been implicated as causative agents in solid organ recipients (25,53). Fusarium are hyaline, septate moulds that can cause infections resembling disseminated aspergillosis in immunocompromised patients, commonly associated with periods of neutropenia (54). Virulence factors of Fusarium include mycotoxins, adherence factors, proteases, and collagenases. The portal of entry is usually skin, sinopulmonary tree, or unknown in many cases. Clinical presentations have occurred in organ transplant recipients without neutropenia. Clinical manifestations include sinusitis, pulmonary involvement, cutaneous diesease (superficial and deep), bone disease, keratitis, fungemia, peritonitis, endocarditis, and disseminated disease. The histological diagnosis of Fusarium has proven problematic, and is often confused with Aspergillus hyphal elements. Characteristic skin lesions may be a clue to diagnosis. The spectrum of dermatological appearance includes cellulitis, plaques, pustules, target lesions, and necrotic area surrounded by a rim of erythema in a pattern resembling ecthyma gangrenosum. However, presentations in transplant patients may be atypical. Fusarium may occur later in the post transplant period in contrast to fusarial infections in patients with hematological malignancies. Biopsy of skin lesions with fungal-specific stains and inspection by an experienced histomycologistin combination with fungal cultures are strongly recommended. Blood cultures are often positive due to the occurrence of intravascular adventitious sporulation (55). Co-infection with other fungi and bacterial agents can occur.

In organ transplants with limited foci of fusarial disease, surgical resection may be sufficient for cure. However, recurrent disease has been observed despite repeat debridement and prolonged LFAB. Disseminated F. solani disease with tricuspid valve endocarditis and fungemia occurred shortly after double-lung transplantation for cystic fibrosis while on fluconazole prophylaxis (25). Immunosuppression consisted of cyclosporine, azathioprine, and prednisone in this patient and there were no periods of leucopenia or evidence of pretransplant Fusarium colonization. Despite clearance of fungemia with amphotericin B lipid complex, mortality from bacterial superinfection occurred. In a lung transplant recipient, isolated cavitary pulmonary disease was noted which was eradicated with amphotericin B lipid complex (53). In a renal transplant recipient, disseminated cutaneous nodules and necrotic ulcers were observed yielding both F. oxysporum and C. albicans (56). Treatments have included surgical resection of localized skin disease (with or without antifungal therapy), removal of infected foreign bodies such as intravascular catheters, correction of neutropenia, and antifungal therapy. Despite these interventions, mortality from disseminated fusariosis in organ transplant recipients remains high.

Fusarium species are often resistant to AmBd. Limited data suggests an improved efficacy with high dose LFAB. Moderate in-vitro susceptibility of Fusarium spp. has been demonstrated with voriconazole, ravuconazole, caspofungin, and posaconazole (57,58). Reported diffential susceptibility patterns between Fusarium species, specifically F.solani generally sensitive in-vitro to polyenes and F. oxysporon more susceptible to extended-spectrum triazoles such as voriconazole. Limited information on combination therapy (that is, extended spectrum trizole plus polyene antifungal or echinocandin) is available, although combination theraphy maybe considered until final identification and invitro susceptibleity testing is completed. until final identification and invitro susceptibleity testing is completed.

Paecilomyces: P. variotii, P. lilacinus, P. marquandii are a rare cause of cutaneous and subcutaneous infection in solid organ transplants including heart, kidney, and liver transplant recipients. Clinical features of skin disease include cellulitis, ulcerations, erythematous and violaceous nodules with central crusting, plaques, draining nodules, and papulopustular lesions (59,60). Other clinical manifestations include sinus disease, wound infections, and osteomyelitis. Devastating oculomycosis (keratitis and endophthalmitis) has also been reported with P. lilacinus. Paecilomyces can produce hyphae in tissue and can be confused with Aspergillus, Fusarium, Penicillium and Pseudallescheria. PCR assays using fungal primers have been successfully employed for accurate and rapid identification of these infections although usage is currently limited; no commercial tests are available. The most common predisposing factors for Paecilomyces cutaneous and subcutaneous infections were solid organ transplantation and corticosteroid therapy. Surgical excision and antifungal therapy have produced variable responses, with frequent relapse reports in solid organ transplant recipients. Miconazole, griseofulvin, AmBd, LFAB, itraconazole, fluconazole, and terbinafine have been used as monotherapy and combination therapy with both complete and partial responses reported. Miconazole and griseofulvin, however, are no longer available in the U.S. and have been associated with toxicity. Voriconazole, posaconazole, and ravuconazole show enhanced invitro and clinical activity.

Trichoderma: Trichoderma species [T. longibrachiatum (most common) T. harzianum, T. koningii, T. pseudokoningii, T. viride] can result in hyalohyphomycosis and can be diagnosed by presence of fine hyaline septate hyphae in tissues. Infection has been reported in renal (peritoneal fluid, brain abscess and lungs), liver (perihepatic hematoma and subcapsular hepatic collection), lung Diagnosis is challenging and requires demonstration of hyphae in tissue sections, positive cultures (rarely reported in blood). (pneumonia and empyema) and small-bowel (invasive sinusitis) transplants (61,62). It is important to note that Trichoderma is often considered a contaminant and is often misdiagnosed as Aspergillus or other hyalohyphomycoses. Molecular diagnostic tools with fungal primers are under investigation. Overall prognosis for these infections has been poor.

Scopulariopsis: Scopulariosis brumptii cutaneous lesions, pericarditis, myocarditis, pneumonia, disseminated disease, and brain abscess have been reported in organ transplant recipients. Angioinvasive disease has been reported in lung transplant patients. Other disease presentations include keratitis, endocarditis, endophthalmitis, meningitis, and fungus ball formation. Clinical similarities between Scopulariopsis and Aspergillus have been noted. Mortality from deep tissue infection remains high in immunocompromised patients despite high-dose AmBd (63,64). Limited in vitro data suggests synergy with posaconazole and terbinafine, AmBd and caspofungin, and posaconazole and caspofungin depending on the strain tested. Other species include S. brevicaulis and S. acremonium.

Acremonium: Acremonium species (A. strictum, A. falciforme) are environment saprophytes found in soil and decaying vegetation. Acremonium is a rare cause of fungemia, acute septic arthritis, subcutaneous abscesses, mycetoma, and pulmonary disease in organ transplant recipients, the majority being renal or heart transplant recipients (64).

Beauveria, Chrysosporium, and Geotrichum are other agents of hyalohyphomycosis reported in isolated cases involving organ transplant recipients. These fungi have been isolated from airway surveillance cultures from lung transplant recipients.

Phaeohyphomycosis:  The clinical spectrum of phaeohyphomycoses includes sinusitis, pulmonary disease, ocular disease (endophthalmitis, keratitis), skin and musculoskeletal disease, central nervous involvement (brain abscess), gastrointestinal involvement, and disseminated disease (30,64–66) (See Table 1). Skin and soft tissue infections can occur on the extremities and mimic bacterial cellulitis. These pathogens can be misdiagnosed as epidermoid, synovial, or trichilemmal cysts. Exophiala spp., Alternaria spp., Phialophora spp., Bipolaris spp., and Exserohilum rostratum are common isolates in this setting. Subcutaneous Exophiala jeanselmei in association with Nocardia asteroides has been reported in transplant recipients (67–69). Multidrug therapy with or without surgical debridement were required for resolution. E. jeanselmei has also been implicated as the cause of chromoblastomycosis in a cardiac transplant patient. Alternaria spp. (A. alternata and A. tenuissima) have been isolated from cutaneous lesions in kidney recipients (64). Cutaneous alternariosis manifests as a superficial epidermal form (fungal hyphae identified in the superficial layers) and dermal type (dermal identification of inflammatory granulomas) (70). Central nervous system disease has been commonly seen with the phaeohyphomycoses; include Cladophialophora bantiana, Onchroconis gallopavum, (Dactylaria gallopava, Dactylaria constricta var. gallopavum), Ramichloridium mackenziei, and Scopulariopsis. Hematogenous dissemination from a pulmonary source or via direct extension from sinus disease are the presumed routes of infection (64).

Chromoblastomycosis:  Chromoblastomycoses are rare deep skin infections caused by emerging moulds that include Aureobasidium pullulans, Exophiala jeanselmei, Cladosporium spp., Fonsecaea spp., Phaeoacremonium parasiticum, Phialophora spp., Rhytidhysteron and Wangiella spp. Chromoblastomycosis usually is seen in organ transplant recipients in tropical and subtropical regions (Brazil, Costa Rica, Mexico in the areas of Oaxaca and Veracruz, Venezuela, Japan, China, and Malaysia). Heart, liver, and renal transplant recipients have been reported with these infections. Cutaneous findings include crusted and/or verrucous lesions or purple nodules (71). These lesions may be confused with Kaposi's sarcoma, squamous cell carcinoma, and draining cystic tumors. Clinically indistinguishable lesions can be seen in other infectious and noninfectious disorders (leishmaniasis, systemic lupus erythematosus, leprosy, cutaneous sarcoidosus, sporotrichosis, cutaneous granuloma, keratocanthoma, lobomycosis, and verrucose tuberculosis).

Emerging Yeasts (Trichosporon, Malassezia, Rhodotorula, and Hansenula)

Trichosporon: Trichosporon species are yeast-like fungi that cause superficial diseases such as white piedra or skin and nail infections in immunocompetent hosts and invasive disease in immunocompromised hosts. While more commonly associated with neutropenia in other immunocompromised hosts, Trichosporon is an emerging pathogen in solid organ transplant recipients. T. asahii and T. mucoides (formerly T. beigelli) are the only pathogens reported in solid organ transplant recipients to date whereas T. asteroides, T. inkin, T. cutaneum, T. ovoides, and T. japonicum have not. Portals of entry include skin (deep), vascular catheters, upper respiratory tract, and gastrointestinal tract. Clinical manifestations included pulmonary disease, fungemia and sepsis, cutaneous lesions (deep), renal and hepatosplenic dysfunction, central nervous system disease and sinus disease, endocarditis, sternal wound infection, mediastinitis, shock, disseminated infection, and chorioretinitis (30,63,72). In renal transplant recipients, isolation of Trichosporon species is usually a benign finding and rarely associated with invasive or deep-seated infections. In one series of 11 renal transplant recipients with T. beigelli funguria (73), urinary tract instrumentation and broad-spectrum antibacterial therapy were risk factors. Of the 7 patients with clinical signs of infection, three patients had symptoms of urinary tract infection and the other four had fever alone. Only two patients had invasive urinary tract infections, one with a bladder fungal ball and the other with a ureteral stent infection. In the former patient, the renal graft was eventually removed but there was no evidence of fungal infection on histopathologic examination. Five patients in this series received no antifungal therapy and did not experience ascending urinary tract or systemic infection. In another prospective series of 475 samples with fungi from 263 liver, kidney, and kidney-pancreas transplant recipients, T. asahii was cultured from 26 clinical samples in 17 kidney recipients, one kidney-pancreas recipient, and one donor (74). Positive cultures were obtained from 22 samples of urine, one fluid from stoma, one wound swab, one tracheal aspirate (from donor), and one ejaculate. Presence of T. asahii represented asymptomatic colonization in all but two cases. In one case, T. asahii was a possible co-pathogen with E. coli in a patient with urosepsis. In another case, it was a possible co-pathogen with E. cloacae in a patient with epididymitis.

Three cases of systemic T. asahii infection have been described in liver transplant recipients (75–77). All three patients had T. asahii isolated from blood and had rapid disease progression and died despite treatment with amphotericin B. Successful treatment of T. mucoides with fluconazole has been reported in a heart/kidney recipient (78). In this case, fever and painful, reddish-purple, pruritic papules were noted six months after kidney transplantation; diagnosis was established by skin biopsy. Prolonged fluconazole therapy was required for resolution. Two cases of fatal invasive Trichosporon infection in renal transplant recipients have also been described (79,80).

Biopsy of clinical specimens may demonstrate a mixture of hyphae, pseudohyphae and budding. Fungal blood cultures may be especially useful. Cross-reactivity with Cryptococcus neoformans capsular polysaccharide exists correlating with a false-positive latex agglutination for Cryptococcus.

Clinical responses have been reported with fluconazole, miconazole, ketoconazole, and posaconazole, as well as combination therapy with AmBd and fluconazole (54,81). Resistance to AmBd and LFAB has been noted with some frequency, resulting in therapeutic failures in immunocompromised patients. Although not yet reported in solid organ transplant recipients, breakthrough infections have been reported in patients with hematologic malignancies receiving echinocandins (82). Colony stimulating factors have been utilized as an adjunctive therapy in non-transplant immunocompromised patients with disseminated disease. Correction of underlying neutropenia and T-cell dysfunction is essential in these patients (54,81).

Malassezia: Malassezia spp.: M. furfur, M. pachydermatis, M. sympodialis; Pityrosporum folliculitis. Malassezia furfur is a lipophilic dimorphic yeast that resides on normal skin and within hair follicles. Clinical presentations in solid organ transplant recipients include pityriasis or tinea versicolor, folliculitis (83), and oncychomycosis (84). Both M. furfur and M. pachydermatis were etiologic agents of folliculitis in a series of heart transplant recipients (83). Eleven heart transplant recipients presented with follicular pruritic, papulopustular, or acneiform skins lesions and were confirmed to have Malassezia folliculitis by KOH preparation and/or culture. Six were successfully treated with a topical preparation of clotrimazole 1% and selenium sulfide lotion. The other five patients failed to respond to topical therapy but were successfully treated with oral fluconazole. A groin abscess due to Malassezia furfur has been described in a liver transplant recipient (85). Disseminated infections, usually in association with vascular catheters and lipid infusions, have not been reported in organ transplant recipients to date. Catheter removal and fluconazole would be the appropriate management of disseminated infections. Pityrosporum folliculitis presents as a clinically superficial skin infection (70). Intravenous lipid infusion and central venous catheters have been historically associated with M. furfur sepsis. Transmission may occur from contact with the hands of a colonized or infected healthcare worker (12).

Rhodotorula: Rhodotorula species are airborne red yeasts that have emerged as pathogens in immunocompromised hosts. Rhodotorula have been described to cause peritonitis in a liver transplant recipient (86) and fungemia in a liver-kidney transplant recipient (87). R. glutinis has also been described infecting a vegetation close to the left atrial appendage of the allograft that was resected at the time of cardiac transplantation (88). The recipient was treated with liposomal amphotericin B for 25 days and was free of infection in the subsequent three years. For R. glutinis and R. mucilaginosa, the lowest MICs were lowest for amphotericin B, flucytosine and posaconazole but higher for fluconazole and the echinocandins (89).

Hansenula: Hansenula anomala has been reported in a case of urinary tract infection in a kidney transplant patient who was receiving immunosuppression therapy (90).

Miscellaneous Fungi (Penicillium, Paracoccidioides, Sporothrix & Dermatophytes)

Penicillium: Penicillium marneffei is a dimorphic fungus endemic in Southeast Asia, southern China, Taiwan, and Hong Kong. More frequently described in AIDS patients, it is an infrequent pathogen in solid organ transplant recipients. Conidial ingestion or inhalation is likely the mode of acquisition (12). Clinical presentations include fever, rigors, weight loss, dry cough, abdominal pain, lymphadenopathy, positive blood or bone marrow cultures, papulonodular skin lesions (some resembling molluscum contagiosum with central umbilication), and osteomyelitis (91). Additional manifestations include keratitis, endophthalmitis, and peritoneal dialysis. Skin lesions may show microabscesses containing lymphocyte and polymorphonuclear leukocytes. PAS stain may show intracellular and extracellular yeast-like cells.

Four cases of penicilliosis have been described in renal transplant recipients (91–94). A Taiwanese man presented 33 months after renal transplantation with fever, weight loss, dry cough, papulonodular skin lesions, and osteomyelitis (91). Cultures of blood and debrided tissue grew Penicillium marneffei. Induction treatment with liposomal amphotericin B (2 mg/kg daily) for 28 days followed by maintenance treatment with itraconazole (400 mg daily) was given with no evidence of relapse after one year. Another patient underwent initial renal transplantation ten years earlier and presented 9 months after a second transplant with fever, chills, rigors, abdominal pain and cough for one week (94). Imaging demonstrated pneumonia and lymphadenopathy. P. marneffei was cultured in blood and bone marrow specimens and the patient recovered with one month of amphotericin B followed by itraconazole. Disseminated disease with duodenal involvement (93) and peritonitis (92) have also been described. Donor transmission has not been described.

Paracoccidioides: Paracoccidioides brasiliensis is a dimorphic fungus endemic to Latin America that rarely causes disease in solid organ transplant recipients. Three reports of paracoccidiomycosis have been described in renal transplant recipients (95–97). Pulmonary involvement was present in all three cases. One patient presented with hyperkeratotic skin lesions and a cavitary lung mass (97) and another patient had relapsed disease after discontinuing antifungal therapy. Routine use of trimethoprim-sulfamethoxazole for primary prophylaxis of Pneumocystis may explain the low incidence of paracoccidiomycosis in organ transplant recipients as it is also effective against Paracoccidioides brasiliensis. Donor transmission has not been described.

Sporothrix: Sporothrix schenckii is a dimorphic fungus found in soil, vegetation, and rotting wood. It has a worldwide distribution and is endemic in temperate and tropical climates. Infection is primarily initiated by trauma to the skin resulting in cutaneous infections marked by suppurative and granulomatous nodules that spread along lymphatic channels. Although it typically does not cause systemic disease, recurrent disseminated infection involving the skin, joints, and central nervous system has been described in a kidney transplant recipient (98). Each recurrence was successfully treated with amphotericin B but the graft failed. Sporothrix cyanescens has been described causing lung lesions in a heart transplant patient (99). After a failure to respond to itraconazole, he was successfully treated with amphotericin B. Newer extended spectrum triazoles have yet to be studied in Sporotrichiosis.

Dermatophytes: Epidermophyton (E. floccosum); Microsporum (M. canis, M. audouinii); Trichophyton (T. mentagrophytes, T. mentagrophytes, T. rubrum, T. tonsurans). Dermatophytic infections usually occur >3–6 months after transplant, but the risk persists indefinitely. Patients often present with dermatophytic infection prior to transplant, especially those with diabetes mellitus, corticosteroid-requiring conditions, and vascular compromise. Misdiagnosis of skin conditions caused by dermatophytes is not uncommon in immunocompromised patients. The emerging fungal pathogens described above may clinically appear as a nonspecific dermatitis or as alterations in skin integrity early in their presentation (e.g. chromoblastomycosis, phaeohyphomycosis; myectoma; scedosporiosis), then develop into a more extensive infection over time. Initial presentations may mimic bacterial cellulitis. In solid organ transplant recipients, dermatophytes can be widespread in distribution, but do not progress to the level of invasion or dissemination as the emerging agents described above. Concurrent diabetes mellitus and renal failure are risk factors for extensive disease. Secondary infections caused by bacterial and other fungal agents are common due to pruritis, irritation, and maceration of the primary dermatophytic infections. Dermatophytes occurring over a joint or tendon may be confused with a pyogenic joint infection. Atypical presentations are common in organ transplant recipients (30,64). Direct inoculation and traumatic abrasion are the usual routes of entry.

Laboratory and Radiological Approaches in the Diagnosis of Fungal Pathogens

A review of appropriate laboratory methods as well as expected radiologic findings for various fungal pathogens is presented in Table 2.

Treatment Recommendations for Specific Fungal Infections

Treatment of fungal infections in organ transplant recipients should be based upon the pathogen recovered as well as the clinical syndrome and sites of involvement associated with the disease in the transplant recipient. Table 3 provides an overview of suggested treatment regimens according to specific pathogens and clinical syndromes. Dosing of respective antifungal agents should be adjusted for renal and hepatic dysfunction. Drug interactions are common notably with calcineurin inhibitors and azoles; modification of immunosuppression and/or concomitant medications may be required. Duration of therapy is based must be individualized between fungal pathogens. This is based on resolution of the respective organ involvement by clinical, readiologic or other means, sensitivity (ies) of the respective agent and pharmcodynamic properties, and individual patient response and their net state of immunosuppression. In some cases, recurrence can be noted with enhanced immunosuppression or removal of the antifungal agent (s). The reader is advised to consult transplant infectious disease specialists for adequacy of therapy, potential ‘indefinite’ therapy or prophylaxis, and future monitoring to ensure the resolution of disease by the respective fungal pathogen.

Disclosure

Huprikar S.: The author has nothing to disclose. Kubak B.: Grant/Research Support, Merck, Inc.; Speaker's Bureau, Pfizer, Schering Plough.

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