Pseudallescheria/Scedosporium complex species: From saprobic to pathogenic fungus.

Scedosporiosis is an emerging fungal infection caused by Pseudallescheria/Scedosporium complex species (PSC). This pathogen has been drawn significant interest in recent years due to its worldwide prevalence, the seriousness of its infection, associated with high mortality in both immunocompromised and immunocompetent hosts and its cryptic ecology, distribution and epidemiology across the globe. These species complexes can be found in environments impacted by human. The purpose of this review is to describe the characteristics, mode of transmission, ecology, prevalence, global epidemiology of this fungal group in order to increase the awareness of among clinicians and microbiologists, especially in regions with high endemic, as well as to promote further research on all of its aspects.

Human-impacted areas of France are environmental reservoirs of the Pseudallescheria boydii/Scedosporium apiospermum species complex.

Species of the Pseudallescheria boydii/Scedosporium apiospermum complex (PSC) are emerging fungal pathogens able to chronically colonize the airways of patients with cystic fibrosis (CF). As P. boydii was found more frequently colonizing the lungs of CF patients in France than in other European countries in a previous report, the present study was conducted in order to clarify distribution of PSC species in France and to characterize their natural habitat. The highest densities of PSC isolates were found in human-impacted areas, i.e. agricultural areas, fluids obtained from wastewater treatment plants, playgrounds and industrial areas. PSC was not detected from soil samples collected in forests. Most PSC culture-positive soil samples exhibited a pH range of 6-8. Scedosporium dehoogii, the most abundant species, was detected in all human-impacted area types except vineyards, whereas Scedosporium aurantiacum was mostly found in agricultural areas. Pseudallescheria boydii and S. apiospermum were predominantly isolated from seashores and playgrounds respectively. Pseudallescheria minutispora was found only once from a playground. This study highlights potential sources of contamination of the patients, especially in the CF context.

Comparison of in vitro antifungal activities of efinaconazole and currently available antifungal agents against a variety of pathogenic fungi associated with onychomycosis.

Onychomycosis is a common fungal nail infection in adults that is difficult to treat. The in vitro antifungal activity of efinaconazole, a novel triazole antifungal, was evaluated in recent clinical isolates of Trichophyton rubrum, Trichophyton mentagrophytes, and Candida albicans, common causative onychomycosis pathogens. In a comprehensive survey of 1,493 isolates, efinaconazole MICs against T. rubrum and T. mentagrophytes ranged from ≤ 0.002 to 0.06 µg/ml, with 90% of isolates inhibited (MIC90) at 0.008 and 0.015 µg/ml, respectively. Efinaconazole MICs against 105 C. albicans isolates ranged from ≤ 0.0005 to >0.25 µg/ml, with 50% of isolates inhibited (MIC50) by 0.001 and 0.004 µg/ml at 24 and 48 h, respectively. Efinaconazole potency against these organisms was similar to or greater than those of antifungal drugs currently used in onychomycosis, including amorolfine, ciclopirox, itraconazole, and terbinafine. In 13 T. rubrum toenail isolates from onychomycosis patients who were treated daily with topical efinaconazole for 48 weeks, there were no apparent increases in susceptibility, suggesting low potential for dermatophytes to develop resistance to efinaconazole. The activity of efinaconazole was further evaluated in another 8 dermatophyte, 15 nondermatophyte, and 10 yeast species (a total of 109 isolates from research repositories). Efinaconazole was active against Trichophyton, Microsporum, Epidermophyton, Acremonium, Fusarium, Paecilomyces, Pseudallescheria, Scopulariopsis, Aspergillus, Cryptococcus, Trichosporon, and Candida and compared favorably to other antifungal drugs. In conclusion, efinaconazole is a potent antifungal with a broad spectrum of activity that may have clinical applications in onychomycosis and other mycoses.

Características clínicas y epidemiología de la pseudalescueriasis pulmonar / Clinical characteristics and epidemiology of pulmonary pseudallescheriasis

Antecedentes. Algunos miembros del género Pseudallescheria (anamorfo Scedosporium) están emergiendo como causantes de infecciones humanas graves. Estos hongos pueden alcanzar los pulmones y el árbol bronquial causando una amplia variedad de manifestaciones clínicas, desde colonizaciones de las vías aéreas hasta infecciones pulmonares profundas. Frecuentemente estos hongos pueden diseminarse a otros órganos, mostrando una marcada predilección por el cerebro. En pacientes por otra parte sanos la infección no suele ser invasora, mientras que en el paciente inmunocomprometido se caracteriza por su carácter invasor. Objetivos. Se ha llevado a cabo una revisón de los artículos disponibles sobre infecciones pulmonares por Pseudallescheria/Scedosporium, destacando la distribución geográfica de las mismas, el estado inmunitario de los pacientes, el tipo de infección, las manifestaciones clínicas, el tratamiento y curso clínico de la enfermedad. Resultados y conclusiones. La principal manifestación clínica de los 189 casos de pseudalescheriasis pulmonar revisados fue neumonía (89), seguido por la presencia de bola fúngica (46), y absceso pulmonar (18). En algunos casos de sujetos inmunocompetentes la neumonía fue debida a aspiración con agua contaminada (10/89, 11,2%). Los principales factores de riesgo para las infecciones pulmonares no invasoras fueron la preexistencia de cavidades pulmonares y el tratamiento inmunosupresor para infecciones pulmonares invasoras. La colonización saprofítica de vías aéras se observó principalmente en pacientes con alteraciones de la mucosa, como aquellos con fibrosis quística. La tasa de mortalidad estuvo estrechamente relacionada con el tipo de infección, siendo del 26,8% en las infecciones no invasoras (bola fúngica) y del 57,2% en las invasoras(AU)

Background. Some members of the Pseudallescheria (anamorph Scedosporium) have emerged as an important cause of life-threatening infections in humans. These fungi may reach the lungs and bronchial tree causing a wide range of manifestations, from colonization of airways to deep pulmonary infections. Frequently, they may also disseminate to other organs, with a predilection for the brain. In otherwise healthy patients, the infection is characterized by non-invasive type involvement, while invasive and/or disseminated infections were mostly seen in immunocompromised patients. Aims. We reviewed all the available reports on Pseudallescheria/Scedosporium pulmonary infections, focusing on the geographical distribution, immune status of infected individuals, type of infections, clinical manifestations, treatment and outcome. Results and conclusions. The main clinical manifestations of the 189 cases of pulmonary pseudallescheriasis reviewed were pneumonia (89), followed by fungus ball (26), and chest abscess (18). Some patients had more than one type of invasive pulmonary manifestations. Among patients with pneumonia, several cases of pneumonia associated with near-drowning (10/89, 11.2%) have also been reported in immunocompetent hosts. Major underlying conditions for non-invasive pulmonary infection were preexisting lung cavities and medical immunosuppression for invasive pulmonary infection. Saprobic airway colonization was mostly seen in patients with mucosal dysfunction, i.e. patients with cystic fibrosis. The mortality rate was closely related to the infection type, being 26.8% in non-invasive type (fungus balls) and 57.2% in invasive type(AU)

Glycoconjugates and polysaccharides from the Scedosporium/Pseudallescheria boydii complex: structural characterisation, involvement in cell differentiation, cell recognition and virulence.

Peptidorhamnomannans (PRMs), rhamnomannans and α-glucans are especially relevant for the architecture of the Scedosporium/Pseudallescheria boydii cell wall, but many of them are immunologically active, with great potential as regulators of pathogenesis and the immune response of the host. In addition, some of them can be specifically recognised by antibodies from the sera of patients, suggesting that they could also be useful in diagnosis of fungal infections. Their primary structures have been determined, based on a combination of techniques including gas chromatography, electrospray ionization - mass spectrometry (ESI-MS), (1)H-COSY and TOCSY, (13)C and (1)H/(13)C NMR spectroscopy. Using monoclonal antibodies to PRM, we showed that it is involved in germination and viability of P. boydii conidia, in the phagocytosis of P. boydii conidia by macrophages and non-phagocytic cells and in the survival of mice with P. boydii infection. Also, components of the fungal cell wall, such as α-glucans, are involved. Rhamnomannans are immunostimulatory and participate in the recognition and uptake of fungal cells by the immune system. These glycosylated polymers, being present in the fungal cell wall, are mostly absent from mammalian cells, and are excellent targets for the design of new agents capable of inhibiting fungal growth and differentiation of pathogens.

Phylogeny and immune evasion: a putative correlation for cerebral Pseudallescheria/Scedosporium infections.

Representatives of the genus Pseudallescheria (anamorph: Scedosporium) are saprobes and the aetiologic agent of invasive mycosis in humans. After dissemination, the central nervous system (CNS) is one of the most affected organs. Prerequisites for the survival of Pseudallescheria/Scedosporium in the host are the ability to acquire nutrients and to evade the immune attack. The cleavage of complement compounds via the secretion of fungal proteases might meet both challenges since proteolytic degradation of proteins can provide nutrients and destroy the complement factors, a fast and effective immune weapon in the CNS. Therefore, we studied the capacity of different Pseudallescheria/Scedosporium species to degrade key elements of the complement cascade in the cerebrospinal fluid and investigated a correlation with the phylogenetic background. The majority of the Pseudallescheria apiosperma isolates tested were demonstrated to efficiently eliminate proteins like complement factors C3 and C1q, thus affecting two main components of a functional complement cascade, presumably by proteolytic degradation, and using them as nutrient source. In contrast, the tested strains of Pseudallescheria boydii have no or only weak capacity to eliminate these complement proteins. We hypothesise that the ability of Pseudallescheria/Scedosporium strains to acquire nutrients and to undermine the complement attack is at least partly phylogenetically determined.

Infections caused by fungi of the Scedosporium/Pseudallescheria complex in veterinary species.

Fungi belonging to the Scedosporium/Pseudallescheria complex (SPCF) have been known to cause human infections for nearly a century and are important human pathogens, with an increasing frequency of infection in patients with underlying conditions. There appears to be a lower incidence of infections with SPCF in veterinary species, although this may be related to a lack of awareness of these diseases. Important recent taxonomic changes in this group of fungi include the classification of Pseudallescheria boydii and Scedosporium apiospermum as two distinct species and the identification of new pathogenic species of SPCF. In this article, the literature on natural and experimental infections caused by SPCF in veterinary species is reviewed. The importance of an accurate identification of veterinary isolates by molecular methods is stressed, especially since virulence and susceptibility to antimycotic drugs of different species may vary.

Characterization of pseudacyclins A-E, a suite of cyclic peptides produced by Pseudallescheria boydii.

Pseudallescheria boydii sensu lato is an emerging fungal pathogen causing fatal infections in both immunocompromised and immunocompetent hosts. In this work, two P. boydii isolates (human and animal origin) have been identified as being producers of cyclic peptides. Five putative nonribosomal peptides with a unique structure, which have been named pseudacyclins, were characterized by nuclear magnetic resonance spectroscopy and mass spectrometry. The most abundant representative of the pseudacyclins was quantified also on fungal spores. The presence of these peptides on inhaled fungal spores creates the possibility for exploitation of pseudacyclins as early indicators of fungal infections caused by Pseudallescheria species.

Different virulence of the species of the Pseudallescheria boydii complex.

Pseudallescheria boydii sensu lato is a complex of species involved in severe human infections. We have evaluated, using a murine model, the virulence of 2 strains of each of the most representative species of the complex, i.e., P. boydii sensu stricto, P. minutispora, Scedosporium apiospermum, S. aurantiacum and S. dehoogii. We used two different inocula, i.e., 5 x 10(4) conidia/ml (for immunosuppressed animals) and 1 x 10(6) conidia/ml (for immunocompetent animals), which were administered intravenously. Scedosporium aurantiacum and S. dehoogii were the most virulent species, causing the death of 80% and 70% of the immunocompetent mice, respectively. The remaining species only killed 0-20% of the animals.

A study of the growth of Pseudallescheria boydii isolates from sewage sludge and clinical sources on tributyrin, rapeseed oil, biodiesel oil and diesel oil.

The study compared the growth of Pseudallescheria boydii isolates from sewage sludge and from clinical sources on tributyrin, rapeseed oil, biodiesel oil and diesel oil agars. The isolates grew on all substrates tested. The highest growth was observed on rapeseed oil agar, while the lowest on diesel agar. On tributyrin agar, hydrolysis zones were observed around or underneath the colonies. On rapeseed oil agar, no hydrolysis zones were formed, while most isolates formed such a zone on biodiesel oil agar. Rapeseed oil and biodiesel oil stimulated the growth of P. boydii isolates, while tributyrin inhibited fungal growth. The stimulation or inhibition effect of diesel oil was dependent on the specified strain. In clinical isolates, fungal growth and activity were found to be more variable compared to sludge isolates. The data suggest that contamination of the environment with these oils could favor the growth of P. boydii. However, no association was found between the growth and oil utilization by this fungus and its pathogenicity.

Pseudallescheria boydii or Aspergillus fumigatus in a lady with an unresolving lung infiltrate, and a literature review.

A 53-year-old lady with blood-stained sputum and pleuritic pain had a lingular opacity on CXR which failed to resolve. A bronchial aspirate and transbronchial biopsy revealed features of bronchocentric granulomatosis with dichotomous branching hyphae suggestive of Aspergillus infection. However, subsequent fungal culture grew Pseudallescheria boydii. This case demonstrates the similarity of clinical and histological features caused by these two fungi. This appears to be the first reported case of pulmonary pseudallescheria with a bronchocentric granulomatous response.

Subcutaneous infection with Pseudallescheria boydii in an immunocompromised patient.

With the broad employment of immunosuppressive therapy, the incidence of Pseudallescheria boydii infections is rising. We report a first case of the localized subcutaneous P. boydii infection in a patient with microscopic polyangiitis. Favorable outcome related to the treatment with voriconazole adds to the growing body of evidence supporting the use of this particular agent in P. boydii infections.

Pseudallescheria boydii keratitis.

A case of Pseudallescheria boydii keratitis is presented. The patient was successfully treated with topical natamycin and systemic itraconazole in conjunction with penetrating keratoplasty, leading to visual acuity of 20/40.

Invasive fungal sinusitis caused by Pseudallescheria boydii: case report and literature review.

Fungal sinusitis secondary to Pseudallescheria boydii is rare, as only 25 cases have been previously reported in the literature. Although Pboydii resembles Aspergillus on pathologic examination, it is typically resistant to amphotericin B. Therefore, culture is necessary to differentiate the two. Patients with P boydii sinusitis should generally be treated with a combination of surgery and antifungal therapy. Combination treatment is particularly important for immunocompromised patients with fungal invasion because mortality among these patients is high. The prognosis is better for immunocompetent patients, even those with fungal invasion. We describe a new case of invasive fungal sinusitis secondary to P. boydii infection, and we review the literature on this emerging pathogen.

Pseudallescheriasis in the 21st century.

Since its discovery as an agent of mycetoma nearly a century ago, Pseudallescheria boydii with its asexual (synanamorphic) form, Scedosporium apiospermum, is now recognized as an important emerging opportunistic pathogen causing invasive mycosis in immunocompromised patients. The clinical spectrum of pseudallescheriasis is wide. Invasive disease of the lung, CNS and dissemination are serious manifestations in immunocompromised patients. This organism responds poorly to amphotericin B, and its histopathologic resemblance to aspergillosis often results in a delay in diagnosis. In vitro data, animal models and accumulating clinical experience support the use of voriconazole as a primary treatment for pseudallescheriasis. This paper reviews the microbiology, ecology, epidemiologic trends, clinical manifestations and current treatment options of pseudallescheriasis.

Involvement of peptidorhamnomannan in the interaction of Pseudallescheria boydii and HEp2 cells.

Pseudallescheria boydii is an emerging fungal pathogen that has a worldwide distribution. Virulence mechanisms of P. boydii are largely unknown. We studied the interaction between P. boydii and HEp2 cells and demonstrated that conidia of P. boydii attached to, and were ingested by, HEp2 cells in a time-dependent process. After 2 h of interaction, the conidia produced a germ-tube like projection, which was able to penetrate the epithelial cell membrane. Recently, our group characterized a peptidorhamnomannan (PRM) antigen on the cell surface of P. boydii. In order to better understand the role played by this surface glycoconjugate during cell adhesion and endocytosis, inhibition assays were performed using intact PRM and anti-PRM polyclonal antibody. When HEp2 cells were pre-treated with whole PRM molecule, the adhesion and endocytic indices were, respectively, 50% and 60% lower than in non-treated epithelial cells. Moreover, when the conidial cells were pre-incubated with anti-PRM antibodies, the adherence and endocytosis processes were inhibited in a dose-dependent manner. As PRM influenced the conidia P. boydii-HEp2 cell interaction, we also performed inhibition assays in order to observe which PRM moieties could be involved in this process. Treatment of PRM with proteinase K promoted a slight inhibition of adhesion. However, the de-O-glycosylated PRM molecule as well as the monosaccharide mannose was able to efficiently inhibit the adhesion and endocytic processes. In addition, our results indicate for the first time that P. boydii PRM binds to a polypeptide of 25 kDa on the HEp2 cell surface.

Artritis séptica por Scedosporium apiospermum en pacientes inmunocompetentes. A propósito de dos casos / Septic arthritis due to Scedosporium apiospermum in immunocompetent patients. A report of two cases

Las infecciones osteoarticulares causadas por hongos son entidades poco frecuentes. Scedosporium apiospermum es un hongo filamentoso saprofito que puede causar infecciones en la piel, sistema respiratorio, sistema nervioso central o huesos, siendo grave su asociación con estados de inmunosupresión. Presentamos dos casos de artritis causada por este patógeno en rodilla y tobillo de dos hombres sanos después de cirugía e infiltración articular respectivamente. Tras desbridamiento radical y tratamiento antifúngico específico se consiguió la resolución del cuadro (AU)

Experimental murine model of disseminated Pseudallescheria infection.

Pseudallescheria boydii is found in soil and has a worldwide distribution. This fungus was initially identified as a pathogen targeting a variety of tissues. There are fragmentary data in the literature on the in vitro susceptibility of P. boydii to different antifungal compounds. P. boydii is highly refractory to antifungal treatments. In this study, a murine model of disseminated Pseudallescheria infection was developed to evaluate efficacy of different treatment regimens. A clinical strain of P. boydii was studied in normal and neutropenic outbred ICR mice. Several inocula were tested over a range from 1 x 10(3) to 5 x 10(6) cfu. Groups of eight mice were injected with a intravenous dose of one inoculum. Mortality correlated with the dose of the inoculum, and with immunosuppression. Quantitative cultures of various tissues showed initial dissemination of disease in immune competent mice. This was followed by, reduction of tissue burden, except in the brain. In contrast, disseminated infection persisted in most organs in immunosuppressed animals (p < 0.0001). This model should be appropriate for in vivo evaluation of antifungal chemotherapy.

Disseminated Pseudallescheria boydii (Scedosporium apiospermum) infection in a renal transplant patient.

Transplant recipients receive a number of immunosuppressive medications that result in an increased risk of infection, including infections with microbes that are normally not pathogenic. We describe a patient with end-stage renal disease who underwent kidney transplantation. Six months postoperatively, he presented with a lesion on his ankle, multiple thigh nodules, and right testicular pain. Biopsy of the ankle lesion demonstrated Pseudallescheria boydii (Scedosporium apiospermum), a common environmental fungus. Following orchiectomy, multiple fungal elements were found that were initially described as Aspergillus species, but later identified as P. boydii. In addition, multiple brain abscesses were found on magnetic resonance imaging. Despite treatment with multiple antifungal medications, the patient died of cardiac dysrhythmia. Current diagnostic and therapeutic alternatives for P. boydii are reviewed.