Emerging Mold Infections: Hyalohyphomycosis

Filamentous fungi (molds) can be divided into 2 broad morphologically distinct groups: those that produce aseptate hyphae and those that produce aseptate (or rarely septated) hyphae. Identification of aseptate hyphae in tissue is virtually pathognomonic of zygomycosis (mucormycosis)-disease caused by fungi of the class Zygomycetes (order Mucorales). The discovery of septate hyphae in tissue is less diagnostic; septate hyphae may be caused by fungi that typically grow as yeasts (eg, Candida and Trichosporon) or a vast number of species of molds. The septate molds are often divided into those with darkly pigmented hyphae (phaeohyphomycetes) and those with pale or colorless (hyaline) hyphae (hyalohyphomycetes).

In common usage, hyalohyphomycosis describes infection caused by filamentous fungi that produce hyaline hyphae in tissue (Table). Although infection due to Aspergillus fits this description, aspergillosis is typically not included in this classification. The past few decades have seen significant changes in the epidemiology of fungal disease. Although aspergillosis continues to be the predominant invasive mold infection of immunocompromised patients, the other hyalohyphomycetes have become increasingly reported causes of disease. There are probably several reasons for this phenomenon, including increasingly potent immunosuppressive and chemotherapeutic drugs and the widespread use of broad-spectrum antibiotics and prosthetic implants.¹

Table

Here we discuss the agents of hyalohyphomycosis, with a focus on 2 increasingly important genera, Fusarium and Scedosporium.

FUSARIUM INFECTIONS (FUSARIOSIS)

Fusarium is a genus of filamentous saprophytic fungi found in soil and detritus. While typically considered phytopathogens, Fusarium species are also associated with human localized infections, sinopulmonary infections, and toxin ingestions. Over the past 3 decades, Fusarium has increasingly been associated with disseminated disease in immunosuppressed patients. Fusarium solani is the species most commonly associated with human disease, but Fusarium oxysporum, Fusarium moniliforme, and Fusarium proliferatum have also been implicated.²

Localized Fusarium infection results from either direct inoculation or contamination of a wound, and cutaneous and musculoskeletal infections have been described. Examples of direct inoculation with consequent infection include onychomycosis, osteomyelitis, and septic arthritis. Contamination of existing wounds by conidia can also lead to fusariosis. Wounds at increased risk include those associated with trauma, burns, and ischemic necrosis.³

Fusarium species have also been implicated in infections of the eye, including endophthalmitis and keratitis. An outbreak of Fusarium keratitis, which occurred in Singapore and in the United States during the period of June 2005 through May 2006, was traced to a particular contact lens solution, leading to its removal from the market. An epidemiological investigation suggested a strong association between keratitis cases and improper use by the consumer of the contact lens solution (ie, reuse of the solution or use after the expiration date).^4,5

Although Aspergillus and Candida species are important causes of morbidity and mortality in immunocom-promised patients, other fungi, including Fusarium species, are gaining recognition as opportunistic pathogens in these patients. Disseminated Fusarium infections typically occur in patients with acute leukemia and prolonged neutropenia. However, conditions such as AIDS and severe burns are also risk factors.¹ The portal of entry in most patients is unknown, but inhalation, ingestion, and entry through nonintact skin have been suggested.⁶

Disseminated fusariosis should be considered in any immunocompromised patient with fever and skin lesionsrefractory to antibiotics. Skin lesions are present in most patients with disseminated fusariosis and typically appear as erythematous or gray macules or nodules with central ulceration or eschar formation.³ Definitive diagnosis is made by blood cultures and skin biopsy. The genus is one of the few mold pathogens that is commonly isolated from routine blood cultures-recovered in up to 50% of patients with disseminated disease.⁷ In vitro, Fusarium species are easily cultivated and identified by their characteristic banana-shaped macroconidia (Figure 1). As with most hyalohyphomycetes, Fusarium species produce angioinvasive, septate, acutely branching hyphae in tissue.

Figure 1 - This culture is positive for Fusarium species. Note thetypical banana-shaped macroconidia, microconidia, and septatehyphae. (Courtesy of Duane Hospenthal, MD.)

The overall prognosis for patients with disseminated fusariosis is poor. In a study of leukemia patients with disseminated infection, survival rates at 30 and 90 days were 50% and 21%, respectively.⁸ Factors that were predictors of death included disseminated disease, hematopoietic stem cell transplantation, neutropenia, and lung involvement.

Fusarium infections are difficult to treat. Members of the genus are generally resistant to most antifungal agents, including fluconazole, itraconazole, 5-fluorocystosine, and the echinocandins.⁹ Amphotericin B and voriconazole are the most commonly used agents; posaconazole has also been used with some success.¹⁰

Surgical debulking of infected tissue may be required, and it is recommended that any potentially colonized intravenous ports or prosthetic devices be removed. Resolution of neutropenia is usually essential for survival of neutropenic patients with disseminated Fusarium infection; while of unproven benefit, granulocyte colony-stimulating factor is often used in these patients.¹¹

SCEDOSPORIUM INFECTIONS (SCEDOSPORIOSIS)

Agenus of saprophytic fungi, Scedosporium is present in soil, detritus, dung, and stagnant water (Figure 2). The 2 clinically important species are Scedosporium apiospermum (which is an asexual anamorph of Pseudallescheria boydii) and Scedosporium prolificans (formerly Scedosporium inflatum).

Figure 2 - Aculture from a patient with onychomycosis shows conidiaand conidiophores of Scedosporium apiospermum. The bundledfascicles of conidiophores are referred to as the Graphium state and areonly rarely observed. (Courtesy of Nancy Pavlik and Captain GeraldVan Horn, Walter Reed Army Medical Center mycology laboratory.)

Both S apiospermum and S prolificans can cause disease in immunocompromised and immunocompetent patients. As with infections caused by other filamentous fungi, the nature and severity of Scedosporium infections are dictated by the patient's immune status. Immunocompetent patients tend to have localized infections, which usually result from either direct inoculation or inhalation, whereas immunocompromised patients more frequently have deeply invasive or disseminated disease.

Inoculation with Scedosporium species typically occurs with penetrating trauma. However, infections associated with surgery, corticosteroid injections, and intravenous drug use also have been described. Localized disease usually involves bone and joints, the eye, skin, and soft tissue. Mycetoma is the most common infection caused by Scedosporium species in immunocompetent patients; S apiospermum is the most common cause of eumycotic mycetoma in North America.^11,12

Compromised immunity, particularly that associated with neutropenia or transplantation, predisposes persons to more severe disease, including pneumonia, sinusitis, prostatitis, endocarditis, and brain abscesses.^13,14 Severe Scedosporium infections have also been described after near-drowning episodes.¹⁵ The clinical presentations are nonspecific and resemble infections caused by other genera of filamentous fungi, such as Aspergillus. As with aspergillosis, bronchopulmonary scedosporiosis runs the gamut from colonization in the setting of existing disease (eg, bronchiectasis or cavitary lesions) to invasive infections. ¹⁶ Pulmonary disease typically manifests with lowgrade fever, night sweats, weight loss, malaise, nonproductive cough, and chest pain.

Common radiographic findings in patients with Scedosporium pneumonia include nodules, lobar infiltrates, wedge-shaped infarcts, and cavitary lesions.¹⁷ Disseminated Scedosporium infection occurs almost exclusively in the context of immunocompromised status, may occur hematogenously or contiguously, and is associated with high mortality.¹⁸ Although S apiospermum pneumonia is sometimes associated with disseminated disease, S prolificans is the most common cause of disseminated infection in hematopoietic stem cell and solid organ transplant recipients. In one series, researchers found that 69% of hematopoietic stem cell transplant recipients and 53% of solid organ transplant recipients with S prolificans infections had disseminated disease.¹⁹

Because S apiospermum and S prolificans are ubiquitous, a positive culture result from a nonsterile site, such as sputum or skin, may represent colonization, and histological evidence of invasion is a requisite for diagnosing infection. However, a positive culture result from a biopsy specimen or from material aspirated from an abscess should be considered significant. Histopathology of the fungi reveals thin, septate, acutely branching, hyaline hyphae, which usually cannot be differentiated from those of Aspergillus and Fusarium genera.

Voriconazole is currently the treatment of choice for Scedosporium (especially S apiospermum) infections, with demonstrated in vitro superiority to amphotericin B. Surgical debridement or excision is generally recommended, especially for bone and soft tissue infections. However, several case reports have described success with voriconazole as lone therapy.^20,21

OTHER HYALOHYPHOMYCETES INFECTIONS

Paecilomyces infections Molds of the genus Paecilomyces are common in the environment, and their isolation from clinical specimens is usually ascribed to contamination. However, certain species, including Paecilomyces lilacinus and Paecilomyces variotii, have emerged as human pathogens, causing disease in both immunocompromised and immunocompetent persons. As with other hyalohyphomycetes, immune suppression predisposes persons to disseminated infection, potentially affecting any organ or system.

Among immunocompetent patients, the spectrum of disease caused by Paecilomyces species includes oculomycosis (typically associated with corneal implantation²²), sinusitis, cutaneous infections, endocarditis (after valve replacement surgery), and peritonitis (among peritoneal dialysis patients23). The susceptibility of Paecilomyces to antifungal drugs appears to vary between species. Voriconazole, posaconazole, and terbinafine each appear to be active against both P lilacinus and P variotii. However, high minimal inhibitory concentrations are noted between P lilacinus and amphotericin B and between P lilacinus and caspofungin.²⁴

Acremonium infections

Three species of the genus Acremonium are emerging as human pathogens: Acremonium falciforme, Acremonium kiliense, and Acremonium recifei. Documented infections include mycetoma, onychomycosis, keratitis, endophthalmitis, endocarditis, meningitis, peritonitis (associated with ambulatory peritoneal dialysis²⁵), osteomyelitis, arthritis (after renal transplantation²⁶), pulmonary infection in a neutropenic leukemic patient,²⁷ and fungemia (after peripheral blood stem cell transplantation²⁸). Acremonium species have shown in vivo susceptibility to azoles and amphotericin B.²⁹

Trichoderma infections

Members of the genus Trichoderma parasitize other hyaline fungi, making them commercially useful. Trichoderma is an emerging opportunistic pathogen. Several species, including Trichoderma longibrachiatum, Trichoderma harzianum, and Trichoderma viride have been implicated in invasive disseminated disease in immunocompromised patients, including those with leukemia, those who have had a transplantation, and those who are receiving continuous ambulatory peritoneal dialysis.³⁰

Limited data are available regarding the susceptibility of Trichoderma species to antifungal drugs. Voriconazole, posaconazole, caspofungin, and anidulafungin exert some activity in vitro. However, the prognosis for those with Trichoderma infection is generally poor regardless of treatment.³¹

Scopulariopsis infections

The genus Scopulariopsis contains both moniliaceous (hyaline) and dematiaceous species, and several species have teleomorphs grouped in the genus Microascus. Scopulariopsis brevicaulis (formerly Penicillium brevicaulum) has historical significance as the causative agent of fatal trimethylarsine oxide poisoning, a compound volatilized when the mold consumes arsenic-containing wallpaper dyes common to the 19th century. More recently, Scopulariopsis species have been implicated in onychomycosis, ³² mycetoma,³³ invasive sinusitis,³⁴ prosthetic valve endocarditis, ³⁵ and disseminated disease in immunocompromised patients.³⁶ Limited data are available regarding the effectiveness of antifungals against Scopulariopsis.³⁷

Penicillium infections

Penicillium species other than Penicillium marneffei rarely cause human infection. P marneffei typically causes disease in the context of AIDS³⁸ or allogeneic bone marrow transplantation.³⁹ Because P marneffei (the only dimorphic species in the genus) does not produce hyphae in tissue, disease caused by this fungus is not typically regarded as hyalohyphomycosis. Non-marneffei Penicillium species, such as Penicillium chrysogenum, have only rarely been reported as a cause of human disease, implicated in pneumonia, prosthetic valve endocarditis, peritonitis in continuous ambulatory peritoneal dialysis patients, endophthalmitis, fungemia, esophagitis, urinary tract infection, and brain abscesses.

Risk factors for infection with these fungi include trauma, surgery, and implanted prosthetic material.⁴⁰ Amphotericin B, itraconazole, and voriconazole have all been used effectively in the treatment of penicilliosis.⁴¹

CONCLUSION

Infections with the hyaline molds are increasingly common and typically occur in immunocompromised patients. Given the widespread use of broad-spectrum antibiotics, potent immunosuppressive drugs, and prosthetic implants, one can reasonably anticipate that the hyalohyphomycetes will become increasingly relevant as opportunistic pathogens.

The clinical presentation of infections caused by these organisms varies and depends on the patient's underlying immune status. Immunologically intact patients tend to have limited localized disease, usually resulting from direct inoculation. In contrast, immunocompromised patients, such as those with hematological malignancies or who have had a bone marrow or solid organ transplantation, are at risk for deeply invasive or disseminated disease. These infections are difficult to eradicate and are often fatal, making it imperative to be both vigilant and aggressive in the workup of the sick immunocompromised patient.

References:

• Enoch DA, Ludlam HA, Brown NM. Invasive fungal infections: a review of epidemiology and management options. J Med Microbiol. 2006;55(pt 7):809- 818.

• Boutati EI, Anaissie EJ. Fusarium, a significant emerging pathogen in patients with hematologic malignancy: ten years' experience at a cancer center and implications for management. Blood. 1997;90:999-1008.

• Gupta AK, Baran R, Summerbell RC. Fusarium infections of the skin. Curr Opin Infect Dis. 2000;13:121-128.

• Chang DC, Grant GB, O'Donnell K, et al; Fusarium Keratitis Investigation Team. Multistate outbreak of Fusarium keratitis associated with use of a contact lens solution. JAMA. 2006;296:953-963.

• Khor WB, Aung T, Saw SM, et al. An outbreak of Fusarium keratitis associated with contact lens wear in Singapore. JAMA. 2006;295:2867-2873.

• Guarro J, Gené J. Opportunistic fusarial infections in humans. Eur J Clin Microbiol Infect Dis. 1995;14:741-754.

• Ascioglu S, Rex JH, de Pauw B, et al; Invasive Fungal Infections Cooperative Group of the European Organization for Research and Treatment of Cancer; Mycoses Study Group of the National Institute of Allergy and Infectious Diseases. Defining opportunistic invasive fungal infections in immunocompromised patients with cancer and hematopoietic stem cell transplants: an international consensus. Clin Infect Dis. 2002;34:7-14.

• Nucci M, Anaissie EJ, Queiroz-Telles F, et al. Outcome predictors of 84 patients with hematologic malignancies and Fusarium infection. Cancer. 2003; 98:315-319.

• Zaas AK, Alexander BD. Echinocandins: role in antifungal therapy, 2005. Expert Opin Pharmacother. 2005;6:1657-1668.

• Raad II, Hachem RY, Herbrecht R, et al. Posaconazole as salvage treatment for invasive fusariosis in patients with underlying hematologic malignancy and other conditions. Clin Infect Dis. 2006;42:1398-1403.

• Nucci M, Anaissie E. Emerging fungi. Infect Dis Clin North Am. 2006;20:563- 579.

• Tirado-Miranda R, Solera-Santos J, Brasero JC, et al. Septic arthritis due to Scedosporium apiospermum: case report and review. J Infect. 2001;43:210-212.

• O'Bryan TA, Browne FA, Schonder JF. Scedosporium apiospermum (Pseudallescheria boydii) endocarditis. J Infect. 2002;44:189-192.

• Bouza E, Muñoz P. Invasive infections caused by Blastoschizomyces capitatus and Scedosporium spp. Clin Microbiol Infect. 2004;10(suppl 1):76-85.

• Buzina W, Feierl G, Haas D, et al. Lethal brain abscess due to the fungus Scedosporium apiospermum (teleomorph Pseudallescheria boydii) after a neardrowning incident: case report and review of the literature. Med Mycol. 2006; 44:473-477.

• Hospenthal DR. Uncommon fungi. In: Mandell G, Bennett J, Dolin R, eds. Principles and Practice of Infectious Diseases. Philadelphia: Churchill Livingstone; 2005:3068-3079.

• Koga T, Kitajima T, Tanaka R, et al. Chronic pulmonary scedosporiosis simulating aspergillosis. Respirology. 2005;10:682-684.

• Lamaris GA, Chamilos G, Lewis RE, et al. Scedosporium infection in a tertiary care cancer center: a review of 25 cases from 1989-2006. Clin Infect Dis. 2006;43:1580-1584.

• Husain S, Muñoz P, Forrest G, et al. Infections due to Scedosporium apiospermum and Scedosporium prolificans in transplant recipients: clinical characteristics and impact of antifungal agent therapy on outcome. Clin Infect Dis. 2005;40:89-99.

• Muñoz P, Marin M, Tornero P, et al. Successful outcome of Scedosporium apiospermum disseminated infection treated with voriconazole in a patient receiving corticosteroid therapy. Clin Infect Dis. 2000;31:1499-1501.

• Porte L, Khatibi S, Hajj LE, et al. Scedosporium apiospermum mycetoma with bone involvement successfully treated with voriconazole. Trans R Soc Trop Med Hyg. 2006;100:891-894.

• Pastor FJ, Guarro J. Clinical manifestations, treatment and outcome of Paecilomyces lilacinus infections. Clin Microbiol Infect. 2006;12:948-960.

• Wright K, Popli S, Gandhi VC, et al. Paecilomyces peritonitis: case report and review of the literature. Clin Nephrol. 2003;59:305-310.

• Espinel-Ingroff A. In vitro fungicidal activities of voriconazole, itraconazole, and amphotericin B against opportunistic moniliaceous and dematiaceous fungi. J Clin Microbiol. 2001;39:954-958.

• Koç AN, Utas C, Oymak O, Sehmen E. Peritonitis due to Acremonium strictum in a patient on continuous ambulatory peritoneal dialysis. Nephron. 1998; 79:357-358.

• Beaudreuil S, Buchler M, Al Najjar A, et al. Acute septic arthritis after kidney transplantation due to Acremonium. Nephrol Dial Transplant. 2003;18:850- 851.

• Herbrecht R, Letscher-Bru V, Fohrer C, et al. Acremonium strictum pulmonary infection in a leukemic patient successfully treated with posaconazole after failure of amphotericin B. Eur J Clin Microbiol Infect Dis. 2002;21:814-817.

• Yamazaki R, Mori T, Aisa Y, et al. Systemic infection due to Acremonium after allogeneic peripheral blood stem cell transplantation. Intern Med. 2006;45: 989-990.

• Mattei D, Mordini N, Lo Nigro C, et al. Successful treatment of Acremonium fungemia with voriconazole. Mycoses. 2003;46:511-514.

• Kredics L, Antal Z, Dóczi I, et al. Clinical importance of the genus Trichoderma. A review. Acta Microbiol Immunol Hung. 2003;50:105-117.

• Kratzer C, Tobudic S, Schmoll M, et al. In vitro activity and synergism of amphotericin B, azoles and cationic antimicrobials against the emerging pathogen Trichoderma spp. J Antimicrob Chemother. 2006;58:1058-1061.

• Gupta AK, Gregurek-Novak T. Efficacy of itraconazole, terbinafine, fluconazole, griseofulvin and ketoconazole in the treatment of Scopulariopsis brevicaulis causing onychomycosis of the toes. Dermatology. 2001;202:235-238.

• Sellier P, Monsuez JJ, Lacroix C, et al. Recurrent subcutaneous infection due to Scopulariopsis brevicaulis in a liver transplant recipient. Clin Infect Dis. 2000; 30:820-823.

• Jabor MA, Greer DL, Amedee RG. Scopulariopsis: an invasive nasal infection. Am J Rhinol. 1998;12:367-371.

• Isidro AM, Amorosa V, Stopyra GA, et al. Fungal prosthetic mitral valve endocarditis caused by Scopulariopsis species: case report and review of the literature. J Thorac Cardiovasc Surg. 2006;131:1181-1183.

• Steinbach WJ, Schell WA, Miller JL, et al. Fatal Scopulariopsis brevicaulis infection in a paediatric stem-cell transplant patient treated with voriconazole and caspofungin and a review of Scopulariopsis infections in immunocompromised patients. J Infect. 2004;48:112-116.

• Ryder NS. Activity of terbinafine against serious fungal pathogens. Mycoses. 1999;42(suppl 2):115-119.

• Cristofaro P, Mileno MD. Penicillium marneffei infection in HIV-infected travelers. AIDS Alert. 2006;21:140-142.

• Woo PC, Lau SK, Lau CC, et al. Penicillium marneffei fungaemia in an allogeneic bone marrow transplant recipient. Bone Marrow Transplant. 2005;35: 831-833.

• Lyratzopoulos G, Ellis M, Nerringer R, Denning DW. Invasive infection due to Penicillium species other than P. marneffei. J Infect. 2002;45:184-195.

• Santos PE, Piontelli E, Shea YR, et al. Penicillium piceum infection: diagnosis and successful treatment in chronic granulomatous disease. Med Mycol. 2006;44:749-753.