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)
|Acremonium infections||AmBd 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|
|Dermatophytosis||Effective agents include Itra (PO), Vori (PO), Keto (top), miconazole (top), clotrimazole (top), terb, AmBd, & Fluc (least efficacy)|
| • Localized tinea infections||Topical azoles (econazole) or terb|
| • Extensive nail head tinea infections or cutaneous||Terb 500 mg/d|
|Itra 200–400 mg/d|
|Alternative: Griseofulvin 500 mg/d (top)|
| Paracoccidioidomycosis||AmBd 0.5–1.0 mg/kg/d; LFAB|
|Itra 200–400 mg/d|
|Keto 200–400 mg/d|
| • Mucosal/skin and invasive disease||Itra 400 mg/d|
| • Disseminated and life-threatening infection||AmBd 0.7–1.0 mg/kg/d; LFAB|
|Penicilliosis||AmBd 0.5–1.0 mg/kg/d; LFAB|
|Itra 200–400 mg/d|
|Vori activity comparable to Itra|
|Sporotrichosis||AmBd 0.5–1.0 mg/kg/d; LFAB|
|Terb 250 mg/d (investigational)|
| • Lymphocutaneous disease||Itra 200–400 mg|
| • Bone, pulmonary, CHS||AmBd 0.5 mg/kg/d; LFAB, then Itra 400 mg/d|
| •F solani|
| •F oxysporon||Vori and Posa (F. oxysporon more susceptible to extended-spectrum triazoles; F. solani, resistance of has been reported with ESTs)|
| •F moniliforme||F.solani generally sensitive in-vitro to polyenes. LFAB 5 – 15 mg/kg/d; AmBd|
| •F proliferatum||1.0–1.5 mg/kg/d Limited information on Combination Vori and LFAB >3 mg/kg/d (± G-CSF); Combination LFAB and Terb|
|Fusariosis||Includes 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 infection||G-CSF/GM-CSF for neutropenia; high dose of Fluc + AmBd|
| • Catheter-related infections||Remove intravascular catheter|
|Paecilomyces infections||AmBd 1.0–1.5 mg/kg/d|
| •P. lilacinus||LFAB 5 mg/kg/d starting dose|
| •P. variotii||Extended 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 infections||Lesional 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 infections||Itra 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 infections||Itra 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 infections||Itra 200–600 mg/d|
|AmBd 1.0–1.5 mg/kg/d + 5FC 100 mg/kg/d|
| Dactylaria infections||Itra 200–600 mg/d|
|AmBd 1.0–1.5 mg/kg/d + 5FC 100 mg/kg/d|
| Exophiala jeanselmei & some Rhinocladiella spp. are dematiaceous moulds||Activity 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) infections||Itra 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. apiosspermum||Surgical 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.|
| • Keratitis||Topical antifungal agents (± Vori)|
|Endophthalmitis: intravitreal and systemic AmBd and Fluc or Vori; surgical evisceration may be required for eradication.|
| • Skin and soft tissue||Surgical 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|
| • Brain||Mortality 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 infections||For 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 brumpti||Debridement of infected tissue and removal of involved foreign bodies required to reduce the risk of dissemination.|
| •Sc. brevicaulis||Posa+Terb (68% of strains)|
•T. longibrachiatum (most common)
|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
| •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.asahii||Fluc; Fluc 800 mg + AmBd 0.8–1.0 mg/kg/d|
| •T. asteroids||Vori (in-vitro Vori >> Fluc, Itra); Posa; Ravu|
| •T. inkin||Azole + GM-CSF (disseminated disease)|
| •T. cutaneum|
| •T. ovoides|
| •Malassezia fungemia||Remove catheter; Fluc 400–800 mg/d|
| • Cutaneous Malassezia||AmBd 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 rubra||AmBd 0.5–1.0 mg/kg/d ± 5-FC 100 mg/kg/d|
| •Hansenula anomaia||Fluc (400–800 mg/d); EST with responses.|
| •Saccharomyces cerevisiae|
| • Rhinocerebral/skin/GI|
• 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 – limited||Excision; 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).