Hyalohyphomycosis (Acremonium, Fusarium, Paecilomyces, Scedosporium and Others)
Authors:Elias N. Kiwan, M.D., Elias J. Anaissie, M.D.
During the past decade, the opportunistic moulds have become a clinical challenge in the management of immunocompromised patients (9,12,21,66). While aspergillosis remains the most common mould infection in this patient population (12), new opportunistic pathogens have been increasingly reported as a cause of life-threatening infections worldwide. Hyalohyphomycosis is among the most frequently reported infection (5).
MICROBIOLOGY
Hyalohyphomycosis is a term that describes a fungal infection caused by moulds whose basic tissue form is in the nature of hyaline, light colored, hyphal elements that are branched or unbranched, occasionally toruloid, and without pigment in their wall (1). The number of organisms causing hyalohyphomycosis is increasing and includes various species of Fusarium, Penicillium, Scedosporium, Acremonium, Paecilomyces, Scopulariopsis, Basidiomycota, Schizophyllum, Beauvaria, Trichoderma, Chaetoconidium, Chrysosporium, Microascus, and others (23,63).
EPIDEMIOLOGY
Agents of hyalohyphomycosis are commonly found in soil, polluted waters, and decaying organic materials worldwide and are important plant pathogens. Penicillium marneffei is restricted to Southeast Asia (23,26). Two likely routes of human infection have been identified: respiratory (4,18,61) and integumentary (16,49). Serious localized infections are extremely rare in otherwise healthy individuals and result from direct inoculation of organisms into human tissue such as skin, bone, or joint. Both localized and disseminated infections are more common in immunocompromised patients, including those with cancer, human immunodeficiency infection, and those undergoing organ or bone marrow transplantation (9,21,66) (Table 1).
CLINICAL MANIFESTATIONS
Fusarium Species
These organisms may cause localized infections of the nails and cornea in the normal host. Localized deep Fusarium infections are rare, but can occur in non-immunosuppressed individuals following direct inoculation of fusaria into various body sites following trauma or instrumentation. Localized infections include endophthalmitis, cellulitis, osteomyelitis, arthritis, and peritonitis among patients undergoing peritoneal dialysis (9,31,49,51).
Disseminated infections occur most commonly in patients with hematological malignancies and occasionally in patients with extensive burns (16). The most frequently implicated species include F. solani, F. oxysporum, F. moniliforme and less commonly, F. proliferatum, F. chlamydosporum, and F. anthophilum (15,16,32,39). Disseminated infection can involve almost any organ and usually presents as a persistent fever in a profoundly neutropenic cancer patient with multiple cutaneous lesions, although occasionally sinusitis and/or rhinocerebral infection, pneumonia, endophthalmitis or pyomyositis may be the presenting manifestation (8,16,51).
Three types of cutaneous lesions may develop in the setting of disseminated fusariosis: (1) multiple erythematous, subcutaneous nodules; (2) painful erythematous macules and papules with progressive central necrosis (ecthyma gangrenosum-like lesions); and (3) target lesions consisting of ecthyma gangrenosum-like lesions surrounded by a thin rim of erythema. Extensive cellulitis of the face or the extremities with or without fasciitis may also occur (16,51) (Table 1).
Scedosporium Species
These pathogens are associated with a wide spectrum of infections caused by two species: 1) Pseudallescharia boydii (perfect state) or Scedosporium apiospermum(imperfect state) and 2) Scedosporium prolificans (S. inflatum) (41,73). Penicillium boydii can cause eumycotic mycetoma and a variety of other infections in the normal host, including infections of the cornea, soft tissue and bone. Deep-seated infections, such as sinusitis, endophthalmitis, and pneumonia, occur more frequently in the immunocompromised host; these infections appear to be more severe and have a tendency for dissemination and central nervous system involvement (29,41,44,50,65) (Table 1).
Paecilomyces Species
Paecilomyces lilacinus and Variotii are implicated as etiological agents of keratitis, endophthalmitis, skin infection, and peritonitis in dialysis patients. An outbreak of infection with P. lilacinus in a bone marrow transplant unit has resulted in serious infections and death (52).
Acremonium Species
Members of the genus Acremonium (Cephalosporium) have long been recognized as etiological agents of nail and corneal infection, mycetoma, osteomyelitis, peritonitis in dialysis patients, meningitis following spinal tap, cerebritis in intravenous drug users, and endocarditis in patients with prosthetic valve. Invasive Acremonium infections (disseminated infection, peritonitis, cerebritis, pneumonia) have been reported in patients with serious underlying medical conditions (50).
Other pathogens known to cause hyalohyphomycosis include: species of Scopulariopsis (34,48,62), Chrysosporium (59,67), Chaetoconidium (43), Coniothyrium species (27,33), and Penicillium marneffei (discussed in a separate chapter) (Table 1).
LABORATORY DIAGNOSIS
Prompt diagnosis of hyalohyphomycosis is hampered by the lack of serological tests and specific radiological findings. The definitive diagnosis requires the isolation of the offending pathogen from clinical specimen (blood, skin, sinuses, lung, others). Culture identification is important because of the histopathologic similarities between the various agents of hyalohyphomycosis (including Aspergillus species), and the variable susceptibility of these fungi to antifungal agents. In addition, these organisms may be confused on histopathological examination with the dematiacious fungi. However, after staining with the Fontana-Masson stain, the pigmented elements of the dematiaceous fungi are seen (pigmentation due to melanin) and the correct diagnosis made (1).
Fusarium is the only opportunistic mould that can easily be recovered from the bloodstream. Blood cultures are positive in 60% of patients with disseminated infection compared with <5% in patients with other opportunistic mould infection including aspergillosis (4).
Immunohistological staining using polyclonal fluorescent antibody reagents may be useful in infections caused by some agents of hyalohyphomycosis (37). Novel molecular methods are currently being evaluated for the specific and early diagnosis of these infections.
PATHOGENESIS
Risk factors for infection are similar to those described with other opportunistic fungi and include significant exposure to pathogens, severe and prolonged immunosuppression, and organ dysfunction. Several virulence factors have been identified: (1) production of mycotoxins that may suppress humoral and cellular immunity and cause tissue breakdown (4,49); (2) adherence to prosthetic material (catheter, contact lenses) (3,26,64); and (3) production of enzymes such as proteases and collagenases (38).
SUSCEPTIBILITY IN VITRO AND IN VIVO
Limited data exist to correlate the clinical outcome of hyalohyphomycosis with in vitro susceptibility testing (42). Because of the significant variations in the methods of in vitrosusceptibility of moulds, a rank of order rather than actual MICs is presented in Table 2.
ANTIMICROBIAL THERAPY
General
The hyalohyphomycosis are difficult to diagnose and often refractory to conventional antifungal therapy, particularly when the host is persistently immunosuppressed. These infections occur in two settings: in normal hosts in whom surgery and antifungal therapy (local or systemic) is frequently curative (35,72); and in immunocompromised hosts where the critical factor for a favorable outcome is recovery from immunosuppression (17).
Various antifungal agents are available that may be effective against some of these infections. Amphotericin B and its lipid formulations have been the mainstay of therapy of invasive fungal infections in severely immunosuppressed patients, although newer triazoles (itraconazole, voriconazole) (68) and caspofungin are now available and may be effective in certain settings (Table 2).Since susceptibility of these pathogens to antifungal agents may be variable and at times difficult to predict, testing the susceptibility of the offending pathogen responsible of a specific infection is recommended.
Duration of therapy is determined by the achievement of a complete eradication of the infection and resolution of immunosuppression (see specifics below under endpoints for monitoring therapy). The optimal doses of potentially active antifungal agents are presented in Table 3.
Specific Infection (Tables 2-4)
Fusarium Species
Most patients with disseminated fusarial infection and persistent profound immunosuppression succumb to their infection despite intensive antifungal therapy. The immune status of the host remains the single most important factor predicting outcome of disseminated infection (7,10,16) (Table 4). By contrast, localized infections, particularly in hosts with normal immunity, respond well to therapy.
Since susceptibility of Fusarium spp to antifungal agents is variable, no agent can be considered the drug of choice, and testing individual strains involved in specific infections is recommended. Serious Fusarium infection may be treated with amphotericin B at a dose of at least 1.0 mg/kg/day or with one of the lipid formulations of amphotericin B at higher doses (3-5 mg/kg/day) (7,30,40) (Table 3). Anecdotal responses have been observed with voriconazole (57) and itraconazole (13,20,28,57). Initial therapy consists of either a lipid amphotericin B product at higher dose or an intravenous formulation of itraconazole or voriconazole (Table 3). Caspofungin is not active in vitro against Fusarium species (14). In vivo studies with this agent are in progress.Given the resistance of fusarial species to antifungal agents, a combination of the above mentioned agents might be considered but it is of unproven value. Topical natamycin is the drug of choice for fusarial keratitis. This agent is, however, not available for systemic administration.
Scedosporium Species
The drugs of choice for infections caused by Pseudallescharia boydii/Scedosporium apiospermum are the newer triazoles itraconazole and voriconazole (55) (Tables 2-4). Localized infections in an immunologically intact host are best treated with a combination of triazole (itraconazole or voriconazole), local injections of amphotericin B (septic arthritis,endophthalmitis) and surgical debridement. Multiple brain abscesses in a patient with acute lymphoblastic leukemia was treated successfully with posaconazole despite progression on itraconazole, amphotericin and ketoconazole (46a).
In the setting of persistent immunosuppression, maximal tolerated dose of a triazole, in combination with an amphotericin product may be considered but has not been properly evaluated.
Scedosporium prolificans/inflatum is typically resistant to all antifungal agents both in vitro and in vivo. Severe and disseminated infections are commonly fatal unless rapid improvement in immune status occurs (2,54). A combination of antifungal agents may be considered but is of unproven value. Surgical debridement of infected tissue appears to be the only means of halting progression of localized infection with this pathogen.
Troke P, Aguirrebengoa K, et al. Treatment of Scedosporiosis and Voriconazole: Clinical Experience with 107 Patients. Antimicrob Agents Chemother 2008;52 (5): 1743-1750.
Beier F, et al. Successful Treatment of Scedosporium apiospermum Soft Tissue Abscess with Caspofungin and Voriconazole in a Severely Immunocompromised Patient with Acute Myeloid Leukemia. Transpl Infect Dis. 2010 Jul 1. [Epub ahead of print]
Acremonium Species
The agents of choice for these infections are amphotericin B (and its lipid formulations) and the newer triazoles, itraconazole and voriconazole (46,71). Surgical resection of localized lesions is considered a part of successful management (69,70) (Tables 2-4).
ADJUNCTIVE THERAPY
Because of the frequent resistance of some agents of hyalohyphomycosis to current antifungal agents, effective therapy requires a coordinated medical and surgical approach (Tables 2-6).
Surgery should always be considered in patients with localized infections but may not be possible in severely thrombocytopenic patients (24).
Enhancing the immune status of the host is critical and relies on tapering or discontinuing immunosuppressive drugs and immunotherapy with colony-stimulating factors (granulocyte or granulocyte-macrophage), gamma-interferon (53) and white blood cell transfusions (16,17,22,45) (Tables 5 and 6).
ENDPOINTS FOR MONITORING THERAPY
Therapy can be monitored by regular evaluation of the various parameters of infection in a specific patient: e.g. deferevescence, resolution of skin lesions and pulmonary infiltrates, etc. In normal hosts, antifungal therapy should be continued until complete resolution of all symptoms and signs of infection. In immunosuppressed patients, therapy should be continued for a few weeks after all of the following has been achieved:
(1) resolution of all clinical and laboratory findings of infection
(2) recovery from immunosuppression (absolute neutrophil counts > 1000/ mL for at least 7 consecutive days and CD4 counts > 400/mL for 2 consecutive months)
(3) resolution of clinically significant graft vs. host disease when present, and
(4) discontinuation of all immunosuppressive agents (4,6,58).
VACCINES
No vaccines are available.
PREVENTION AND INFECTION CONTROL MEASURES VACCINES
Primary Prophylaxis
Because of the high mortality rate in patients with invasive hyalohyphomycosis, and the variable susceptibility of pathogens to antifungal agents, efforts should focus on preventing these infections. Measures to prevent these infections include:
1)Prevention of exposure of high-risk patients to agents of hyalohyphomycosis: Standard air control measures in hospital wards caring for high-risk patients are of paramount importance and prevent entry of contaminated outside air into the hospital. New data suggest that these opportunistic fungi are present in water and water systems worldwide, including in hospitals (8,11). Thus, infection control measures should be put in place at institutions experiencing such infections to prevent exposure of high-risk patients to contaminated tap water (8,11). Patient education to avoid skin breakdown and prevent contact between areas of skin breakdown and tap water (in the hospital and the patient’s residence) is also important.
2)Treatment of colonized/infected tissues in high-risk patients prior to initiation of immunosuppressive therapies: Prior to commencing immunosuppressive therapies, all high-risk patients should be examined for the presence of skin lesions, and tissue breakdown (including that associated with onychomycosis), to rule out the presence of infection or significant colonization that may progress to severe infection during immunosuppression (10,16,45,61,51).
In the presence of cellulitis, a bone scan should be obtained to rule out osteomyelitis. Consideration should be given to resection of all infected tissues and the use of topical and systemic antifungal agents (directed at the specific organism recovered). In addition, primary skin lesions following a trauma or insect bite should be considered as potentially infected by an agent of hyalohyphomycosis, hence requiring biopsy, culture, and surgical debridement if such infection is confirmed (16,60).
Secondary Prophylaxis
Because of the risk of relapse of previously infected patients (9,47), secondary prophylaxis should be utilized and relies on the use of the antifungal agent that controlled the infection during the initial episode and/or with the agent that has the best in vitro activity against the offending pathogen. Agents likely to be useful include IV amphotericin B or its lipid formulations, and the newer triazoles itraconazole, and voriconazole (56) (Table 2). Delaying cytotoxic therapy until the original infection has been eradicated and using prophylactic/pre-emptive granulocyte transfusions or cytokines (if delaying therapy is not possible) should be considered in patients with a prior invasive infection (16,25). Granulocyte transfusions may "buy time" until spontaneous marrow recovery occurs (16,19,22).
COMMENTS
Because of the uncommon nature of these infections, solid data regarding their optimal management are lacking. New strategies such as combination antifungal therapy, and antifungal therapy plus immune enhancement are recommended but are not supported by solid evidence. These infections are difficult to manage and are best prevented. Since impairment of the immune system is the most important predisposing and prognostic factor for these infections, future studies should focus on optimizing host immunity in patients at high-risk for these infections.
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Table 1. Hyalohyphomycosis*: Spectrum of Infection of Most Common Pathogens
Pathogen |
Normal host |
Immunosuppressed host |
|---|---|---|
Fusarium spp. |
Keratitis Endophthalmitis Bone/joint infection Skin infection Onychomycosis Mycetoma Peritonitis (CAPD) |
Disseminated Sinusitis Pneumonia Cellulitis Endophthalmitis |
Scedosporium spp. |
Sinusitis Keratitis Endophthalmitis Skin and soft tissue infection Osteomyelitis Brain abscess and meningitis |
Disseminated infection Sinusitis Pneumonia Brain abscess and meningitis |
Scopulariopsis spp. |
Onychomycosis Keratitis Otomycosis Prosthetic valve endocarditis |
Disseminated infection Sinusitis Pneumonia Cellulitis |
Paecilomyces spp. |
Sinusitis Keratitis Onychomycosis Endocarditis Otitis Cellulitis Peritonitis (CAPD) |
Disseminated infection Pneumonia Pyelonephritis Cellulitis Osteomyelitis |
Acremonium spp. |
Keratitis Onychomycosis Osteomyelitis/septic arthritis Meningitis Endophthalmitis |
Disseminated infection Peritonitis Cerebritis Pneumonia Dialysis-access fistula infection |
CAPD: Continuous abdominal peritoneal dialysis
* Penicillium marneffii is discussed in a separate chapter.
Table 2. In Vitro Antifungal Susceptibility of Common Agents of Hyalohyphomycosis and Drug of Choice
Pathogen |
Amphotericin B |
Caspofungin |
Fluconazole |
Voriconazole |
Itraconazole |
Natamycin |
|---|---|---|---|---|---|---|
Fusarium spp |
Variable * |
Resistant |
Resistant |
Variable* |
Variable† |
Susceptible, topical alone† |
S. apiospermium ¨ |
Intermediate |
Susceptible |
Intermediate-Susceptible |
Susceptible |
Susceptible† |
NT |
S. inflatum ¨ |
Resistant |
NT |
Resistant |
Resistant |
Resistant |
NT |
P. lilacinus ª |
Intermediate |
NT |
NT |
Susceptible |
Susceptible† |
NT |
¨Scedosporium ªPaecilomyces
NT: not tested. * Variable: May be species or strain specific. †denotes drug of choice
Topical natamycin application for fusarial keratitis; Natamycin not available as a systemic agent.
Miconazole has activity against S. apiospermum and P. lilacinus, but is associated with significant toxicity. Ketoconazole is moderately active against S. apiospermum and P. lilacinus but has erratic bioavailability. Other triazoles such as Itraconazole and voriconazole are more potent, safer, have oral and intravenous formulations and thus are more appropriate therapeutic agents.
Flucytosine has no activity against Fusarium spp, S. apiospermium and S. inflatum.
Table 3. Dosing Schedule of Antifungal Agents with Activity Against Hyalohyphomycosis [Download PDF]
Agent
Standard daily dose
Maximal daily dose
Polyenes
Amphotericin B
1 mg/kg
1.5 mg/kgÅ
Liposomal Amphotericin B (Ambisome)
3-5 mg/kg
15 mg/Kg
Amphotericin Lipid Complex
3-5 mg/kg
Amphotericin Colloidal Dispersion
3-5 mg/kg
Triazoles
Fluconazole
400 mg
1600 mg
Itraconazle*
400 mg in 2 doses after loading§
800 mg
Voriconazole*
6 mg/kg in 2 doses after loading§
Echinocandins
Caspofungin
70 mg loading then 50 mg
* Use IV formulation in critically ill patients.
§ Loading dose: Itraconazole: 400 mg BID for three days; Voriconazole: 6 mk/kg for two doses.
Å rarely tolerated at this dose
Table 4. Management of Specific Hyalohyphomycosis
Pathogen
Normal host
Immunosuppressed host
Fusarium spp.
Keratitis: topical natamycin 5.0% suspension.
Endophthalmitis: vitrectomy, intravitreal Amphotericin B, and systemic itraconazole or voriconazole. Enucleation in severe cases.
Skin and soft tissue: surgical drainage.
Onychomycosis: avulsion of nail, topical natamycin on open lesions?
Osteomyelitis: surgical debridement, systemic antifungal agents (Amphotericin B or its lipid formulations, itraconazole, voriconazole)
Systemic antifungal agents:
IV Amphotericin B, or its lipid formulations; newer triazoles (itraconazole, voriconazole).
Reversal of immunosuppression.
Surgery if localized infection.
Venous catheter removal in the rare case of catheter related fungemia.
Scedosporium apiospermium
Localized lesion: surgery.
Itraconazole, voriconazole.
Endophthalmitis: vitrectomy, intravitreal Amphotericin B, and systemic itraconazole or voriconazole. Enucleation in extreme cases.
Arthritis: intraarticular injection of Amphotericin B.
Reversal of immunosuppression.
Localized infection: surgery.
Itraconazole, or voriconazole.
Scedosporium inflatum
Localized infection: surgery.
Reversal of immunosuppression.
Localized infection: surgery.
Paecilomyces lilacinus
Skin and soft tissue infection: surgical debridement and drainage.
Endophthalmitis: vitrectomy, intravitreal Amphotericin B, and systemic itraconazole or voriconazole. Enucleation in severe cases.
Reversal of immunosuppression.
Localized infection: surgery.
Itraconazole or voriconazole.
Table 5. Indications for Surgical Removal of Tissue Infected with Hyalohyphomycosis
· Hemoptysis from a single cavitary lung lesion (always perform a computerized chest scan to search for other lesions). · Progressive cavitary lung lesion (always perform a computerized chest scan to search for other lesions). · Infiltration into the pericardium, great vessels, bone or thoracic soft tissue. · Progressive sinusitis. · Osteomyelitis, septic arthritis. · Endophthalmitis. · Resection of infected / colonized tissue prior to commencing immunosuppressive agents to prevent dissemination after cytotoxic therapy. |
Table 6. Reversal of Immunosuppression: Potentially Useful Strategies in Patients with Invasive Hyalohyphomycosis
· Discontinuation / dose reduction of immunosuppressive agents (corticosteroids, other cytotoxic agents) · Recombinant cytokines: -granulocyte-colony stimulating factors (G-CSF) -granulocyte monocyte-colony stimulating factors -gamma interferon. · Stem cell reconstitution with infusion of autologous bone marrow/peripheral stem cells product in the event of progressive infection in patients with severe, uncontrollable, graft versus host disease. · Granulocyte transfusions (stimulated with G-CSF and dexamethasone). |
What's New
Beier F, et al. Successful Treatment of Scedosporium apiospermum Soft Tissue Abscess with Caspofungin and Voriconazole in a Severely Immunocompromised Patient with Acute Myeloid Leukemia. Transpl Infect Dis. 2010 Jul 1. [Epub ahead of print]
Troke P, Aguirrebengoa K, et al. Treatment of Scedosporiosis and Voriconazole: Clinical Experience with 107 Patients. Antimicrob Agents Chemother 2008;52 (5): 1743-1750.
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Revankar SG. Filamentous Fungi Other than Aspergillus and Zygomycetes in Transplant Recipients
Adhikari P, Mietzner T. Cell Mediated Immunity. 2008.
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Hyalohyphomycosis (Acremonium, Fusarium, Paecilomyces, Scedosporium and Others)