Deciphering Unexpected Vascular Locations of Scedosporium spp. and Lomentospora prolificans Fungal Infections, France.

Scedosporium spp. and Lomentospora prolificans are emerging non-Aspergillus filamentous fungi. The Scedosporiosis/lomentosporiosis Observational Study we previously conducted reported frequent fungal vascular involvement, including aortitis and peripheral arteritis. For this article, we reviewed 7 cases of Scedosporium spp. and L. prolificans arteritis from the Scedosporiosis/lomentosporiosis Observational Study and 13 cases from published literature. Underlying immunosuppression was reported in 70% (14/20) of case-patients, mainly those who had solid organ transplants (10/14). Osteoarticular localization of infection was observed in 50% (10/20) of cases; infections were frequently (7/10) contiguous with vascular infection sites. Scedosporium spp./Lomentospora prolificans infections were diagnosed in 9 of 20 patients ≈3 months after completing treatment for nonvascular scedosporiosis/lomentosporiosis. Aneurysms were found in 8/11 aortitis and 6/10 peripheral arteritis cases. Invasive fungal disease--related deaths were high (12/18 [67%]). The vascular tropism of Scedosporium spp. and L. prolificans indicates vascular imaging, such as computed tomography angiography, is needed to manage infections, especially for osteoarticular locations.

A systematic review and disability-adjusted life years of Scedosporium/Lomentospora infection in patients after near-drowning.

Scedosporium/Lomentospora species exist as saprophytic moulds that can potentially lead to serious infections in patients who have experienced near-drowning incidents. Scedosporium species are distributed across different regions of the world while Lomentospora prolificans has quite a restricted geographic distribution. We aimed to systematically review scedosporiosis cases after near-drowning, their clinical manifestations, underlying diseases, treatments, outcomes and its impact through disability-adjusted life years (DALYs). Five available sources were searched from 1 January 2007, to 20 April 2022. Thirty-eight studies, including 41 patients, were evaluated. Mean age was 33.6 ± 18.6 years (range 1-68), and 28 were male (68.3%). Central nervous system (CNS) dissemination predominated (36/41; 87.8%), presenting mainly as multiple brain abscesses (26/41; 63.4%), followed by lung involvement (22/41; 56.4%). Scedosporium apiospermum species complex was the most causative agent (38/41; 92.7%). Overall mortality was 51.2%. Half of the patients (18/37) were cured after receiving proper treatment, and in most cases, voriconazole alone or in combination with surgery or other antifungals caused survival. The mean survival time was 123 ± 27 days. Mean DALYs in 1980-2022 were 46.110 ± 3.318 (39.607-52.612). Time to diagnosis was estimated to be 120 days, and there was no association between time to diagnosis and outcome. Voriconazole is a potentially effective therapy, and combination of surgery and antifungal treatment may lead to more favourable outcome. Advances in early diagnosis and appropriate antifungal therapy may have contributed to reducing its mortality.

Invasive bone and joint infections from the French Scedosporiosis/lomentosporiosis Observational Study (SOS) cohort: no mortality with long-term antifungal treatment and surgery.

Little is known about localized osteoarticular Scedosporiosis (LOS). Most data come from case reports and small case series. Here we present an ancillary study of the nationwide French Scedosporiosis Observational Study (SOS), describing 15 consecutive cases of LOS diagnosed between January 2005 and March 2017. Adult patients diagnosed with LOS defined by osteoarticular involvement without distant foci reported in SOS were included. Fifteen LOS were analyzed. Seven patients had underlying disease. Fourteen patients had prior trauma as potential inoculation. Clinical presentation was arthritis (n = 8), osteitis (n = 5), and thoracic wall infection (n = 2). The most common clinical manifestation was pain (n = 9), followed by localized swelling (n = 7), cutaneous fistulization (n = 7), and fever (n = 5). The species involved were Scedosporium apiospermum (n = 8), S. boydii (n = 3), S. dehoogii (n = 1), and Lomentospora prolificans (n = 3). The species distribution was unremarkable except for S. boydii, which was associated with healthcare-related inoculations. Management was based on medical and surgical treatment for 13 patients. Fourteen patients received antifungal treatment for a median duration of 7 months. No patients died during follow-up. LOS exclusively occurred in the context of inoculation or systemic predisposing factors. It has a non-specific clinical presentation and is associated with an overall good clinical outcome, provided there is a prolonged course of antifungal therapy and adequate surgical management.

Localized osteoarticular scedosporiosis mostly occurs following direct inoculation. Management was most often based on voriconazole therapy and concomitant surgery. Unlike other invasive scedosporiosis, no patient died during follow-up.

Early production of proinflammatory cytokines in response to Scedosporium apiospermum during murine pulmonary infection.

Scedosporium apiospermum is an opportunistic pathogen that can cause pulmonary infections in both immunosuppressive and immunocompetent patients. Cytokines are molecules that mediate the immune response to promote or eliminate fungal infections. In this work, we evaluated the cytokines profile in the lung and serum of mice infected with Scedosporium apiospermum. We found early production of IL-6, IL-1ß and TNF-α cytokines in the lung of infected mice during the first 5 days of infection. We suggest that release of pro-inflammatory cytokines could play a role in the control of fungal invasion.

In Vivo Efficacy of Olorofim against Systemic Scedosporiosis and Lomentosporiosis.

Clinically relevant members of the Scedosporium/Pseudallescheria species complex and Lomentospora prolificans are generally resistant against currently available systemic antifungal agents in vitro, and infection due to these species is difficult to treat. We studied the in vivo efficacy of a new fungicidal agent, olorofim (formerly F901318), against scedosporiosis and lomentosporiosis in neutropenic animals. Cyclophosphamide-immunosuppressed CD-1 mice infected by Scedosporium apiospermum, Pseudallescheria boydii (Scedosporium boydii), and Lomentospora prolificans were treated by intraperitoneal administration of olorofim (15 mg/kg of body weight every 8 h for 9 days). The efficacy of olorofim treatment was assessed by the survival rate at 10 days postinfection, levels of serum (1-3)-ß-d-glucan (BG), histopathology, and fungal burdens of kidneys 3 days postinfection. Olorofim therapy significantly improved survival compared to that of the untreated controls; 80%, 100%, and 100% of treated mice survived infection by Scedosporium apiospermum, Pseudallescheria boydii, and Lomentospora prolificans, respectively, while less than 20% of the control mice (phosphate-buffered saline [PBS] treated) survived at 10 days postinfection. In the olorofim-treated neutropenic CD-1 mice infected with any of the three species, serum BG levels were significantly suppressed and fungal DNA detected in the target organs was significantly lower than in controls. Furthermore, histopathology of kidneys revealed no or only a few lesions with hyphal elements in the olorofim-treated mice, while numerous fungal hyphae were present in control mice. These results indicate olorofim to be a promising therapeutic agent for systemic scedosporiosis/lomentosporiosis, devastating emerging fungal infections that are difficult to treat with currently available antifungals.

Phenomic profiling of a novel sibling species within the Scedosporium complex in Thailand.

BACKGROUND: Scedosporium species are a group of pathogenic fungi, which can be found worldwide around high human-impacted areas. Infections of Scedosporium have been reported in several immunocompromised and immunocompetent patients with a high mortality rate. Recently, we have isolated and identified several Scedosporium strains during an environmental survey in Thailand. RESULTS: We describe the isolate, TMMI-012, possibly a new species isolated from soils in the Chatuchak public park, Bangkok, Thailand. TMMI-012 is phylogenetically related to the Scedosporium genus and is a sibling to S. boydii but shows distinct morphological and pathological characteristics. It is fast growing and highly resistant to antifungal drugs and abiotic stresses. Pathological studies of in vitro and in vivo models confirm its high virulence and pathogenicity. CONCLUSION: TMMI-012 is considered a putative novel Scedosporium species. The high antifungal resistance of TMMI-012 compared with its sibling, Scedosporium species is likely related to its clinical impact on human health.

Scedosporiosis/lomentosporiosis observational study (SOS): Clinical significance of Scedosporium species identification.

Scedosporiosis/lomentosporiosis is a devastating emerging fungal infection. Our objective was to describe the clinical pattern and to analyze whether taxonomic grouping of the species involved was supported by differences in terms of clinical presentations or outcomes. We retrospectively studied cases of invasive scedosporiosis in France from 2005 through 2017 based on isolates characterized by polyphasic approach. We recorded 90 cases, mainly related to Scedosporium apiospermum (n = 48), S. boydii/S. ellipsoideum (n = 20), and Lomentospora prolificans (n = 14). One-third of infections were disseminated, with unexpectedly high rates of cerebral (41%) and cardiovascular (31%) involvement. In light of recent Scedosporium taxonomic revisions, we aimed to study the clinical significance of Scedosporium species identification and report for the first time contrasting clinical presentations between infections caused S. apiospermum, which were associated with malignancies and cutaneous involvement in disseminated infections, and infections caused by S. boydii, which were associated with solid organ transplantation, cerebral infections, fungemia, and early death. The clinical presentation of L. prolificans also differed from that of other species, involving more neutropenic patients, breakthrough infections, fungemia, and disseminated infections. Neutropenia, dissemination, and lack of antifungal prescription were all associated with 3-month mortality. Our data support the distinction between S. apiospermum and S. boydii and between L. prolificans and Scedosporium sp. Our results also underline the importance of the workup to assess dissemination, including cardiovascular system and brain.

Scedosporiosis/lomentosporiosis is a devastating emerging fungal infection. Our objective was to describe the clinical pattern and to analyze whether taxonomic grouping of the species involved was supported by differences in terms of clinical presentations or outcomes.

Fatal recurrent disseminated Lomentospora prolificans infection during autologous hematopoietic stem cell transplantation: A case report and review, and discussion on the importance of prolonged neutropenia.

Infections with Scedosporium and Lomentospora species, in particular Lomentospora (previously Scedosporium) prolificans, are nearly universally fatal and rapidly-progressive in the transplant population. We report a case of a patient with diffuse large B-cell lymphoma undergoing myelosuppressive chemotherapy who developed disseminated L. prolificans infection which afterward persisted in his knee joint. The infection was treated with early empiric triple antifungal therapy tailored to synergy studies, growth factors to quickly resolve neutropenia, and aggressive debridement (where possible) of infection sites, including amputation. He achieved an 11-month remission until undergoing autologous hematopoietic stem cell transplantation with deep myelosuppression, wherein recrudescent L. prolificans infection occurred, causing death. We highlight the importance of early treatment, synergy studies, and especially recovery of neutropenia in treating this devastating condition.

Consensus guidelines for the diagnosis and management of invasive fungal disease due to moulds other than Aspergillus in the haematology/oncology setting, 2021.

Invasive fungal disease (IFD) due to moulds other than Aspergillus is a significant cause of mortality in patients with malignancies or post haemopoietic stem cell transplantation. The current guidelines focus on the diagnosis and management of the common non-Aspergillus moulds (NAM), such as Mucorales, Scedosporium species (spp.), Lomentospora prolificans and Fusarium spp. Rare but emerging NAM including Paecilomyces variotii, Purpureocillium lilacinum and Scopulariopsis spp. are also reviewed. Culture and histological examination of tissue biopsy specimens remain the mainstay of diagnosis, but molecular methods are increasingly being used. As NAM frequently disseminate, blood cultures and skin examination with biopsy of any suspicious lesions are critically important. Treatment requires a multidisciplinary approach with surgical debridement as a central component. Other management strategies include control of the underlying disease/predisposing factors, augmentation of the host response and the reduction of immunosuppression. Carefully selected antifungal therapy, guided by susceptibility testing, is critical to cure. We also outline novel antifungal agents still in clinical trial which offer substantial potential for improved outcomes in the future. Paediatric recommendations follow those of adults. Ongoing epidemiological research, improvement in diagnostics and the development of new antifungal agents will continue to improve the poor outcomes that have been traditionally associated with IFD due to NAM.

Isolation of fungal communities and identification of Scedosporium species complex with pathogenic potentials from a pigsty in Phra Nakhon Si Ayutthaya, Thailand.

Soil fungal communities play an important role in regulating biogeochemical transformations, yet soil-related fungal pathogens are emerging threats to humans. Our previous studies have revealed the pathogenic Scedosporium species in soils samples from public parks with high human activities in Thailand. However, measurement and survey of soil fungal communities in other areas with high human/animal activities, such as the pigsty, are poorly determined. In this study, soil fungal pathogens from a pigsty were isolated and identified. Soil samples were collected from the surrounding drainage areas. Fungal species were identified using morphological and molecular analyses. Isolation of soil samples from the pigsty revealed at least 11 species that have been identified. The most abundant fungal species belonged to genera Aspergillus and Penicillium. Moreover, Scedo-Select III culturing and phylogenetic analysis with ß-tubulin gene sequencing revealed the three environmental isolates of Scedosporium species, which were consistent with the S.apiospermum. These three Scedosporium isolates were susceptible to voriconazole and caused pathological characteristics of scedosporiosis similar to S. apiospermum in vivo. In conclusion, our findings contribute towards a better understanding of soil-borne pathogenic fungi in the pigsty. The isolation of Scedosporium species with pathogenic potentials in the present study can be beneficial for the management of public health surveillance, epidemiologists, as well as physicians to reduce the risk of soil fungal contamination among pigsty workers.

Development of an immunocompetent murine model of pulmonary infection due to Scedosporium apiospermum.

A pulmonary infection model due to Scedosporium apiospermum in immunocompetent mice was developed. BALB/c mice were infected by endotracheal intubation with 5 × 106 conidia/mouse and disease progression was evaluated on days 1, 3, 5, 7, 11, 16, 21, 30, 50 and 60 post-infection through quantitative culture and histopathological analysis of lungs, livers, spleens, brains, and kidneys. There was no extrapulmonary dissemination during the study nor shown to be a lethal infection. The fungal burden in lungs was maintained from day 1-5 and gradually decreased by day 30 post-challenge. On day 60, 30% of mice showed complete elimination of the fungus. Severe alterations in the lung tissue were observed, as well as the presence of conidia and hyphae surrounded by a cellular infiltrate composed mainly of neutrophils in the first days of the infection. The elimination of fungal cells and normal tissue morphology were recovered throughout the study.

Therapeutic Challenges of Non-Aspergillus Invasive Mold Infections in Immunosuppressed Patients.

While Aspergillus spp. remain the major cause of invasive mold infections in hematologic cancer patients and transplant recipients, other opportunistic molds, such as Mucorales, Fusarium, and Scedosporium spp. are increasingly encountered in an expanding population of patients with severe and prolonged immunosuppression. High potential for tissue invasion and dissemination, resistance to multiple antifungals and high mortality rates are hallmarks of these non-Aspergillus invasive mold infections (NAIMIs). Assessment of drug efficacy is particularly difficult in the complex treatment scenarios of NAIMIs. Specifically, correlation between in vitro susceptibility and in vivo responses to antifungals is hard to assess, in view of the multiple, frequently interrelated factors influencing outcomes, such as pharmacokinetic/pharmacodynamic parameters determining drug availability at the site of infection, the net state of immune suppression, delay in diagnosis, or surgical debulking of infectious foci. Our current therapeutic approach of NAIMIs should evolve toward a better integration of the dynamic interactions between the pathogen, the drug and the host. Innovative concepts of experimental research may consist in manipulating the host immune system to induce a specific antifungal response or targeted drug delivery. In this review, we discuss the challenges in the management of NAIMIs and provide an update about the latest advances in diagnostic and therapeutic approaches.

Prognostic factors in 264 adults with invasive Scedosporium spp. and Lomentospora prolificans infection reported in the literature and FungiScope®.

Invasive Scedosporium spp. and Lomentospora prolificans infections are an emerging threat in immunocompromised and occasionally in healthy hosts. Scedosporium spp. is intrinsically resistant to most, L. prolificans to all the antifungal drugs currently approved, raising concerns about appropriate treatment decisions. High mortality rates of up to 90% underline the need for comprehensive diagnostic workup and even more for new, effective antifungal drugs to improve patient outcome. For a comprehensive analysis, we identified cases of severe Scedosporium spp. and L. prolificans infections from the literature diagnosed in 2000 or later and the FungiScope® registry. For 208 Scedosporium spp. infections solid organ transplantation (n = 58, 27.9%) and for 56 L. prolificans infection underlying malignancy (n = 28, 50.0%) were the most prevalent risk factors. L. prolificans infections frequently presented as fungemia (n = 26, 46.4% versus n = 12, 5.8% for Scedosporium spp.). Malignancy, fungemia, CNS and lung involvement predicted worse outcome for scedosporiosis and lomentosporiosis. Patients treated with voriconazole had a better overall outcome in both groups compared to treatment with amphotericin B formulations. This review discusses the epidemiology, prognostic factors, pathogen susceptibility to approved and investigational antifungals, and treatment strategies of severe infections caused by Scedosporium spp. and L. prolificans.

Perspectives on Scedosporium species and Lomentospora prolificans in lung transplantation: Results of an international practice survey from ESCMID fungal infection study group and study group for infections in compromised hosts, and European Confederation of Medical Mycology.

BACKGROUND: Scedosporium species and Lomentospora prolificans (S/L) are the second most common causes of invasive mold infections following Aspergillus in lung transplant recipients. METHODS: We assessed the current practices on management of S/L colonization/infection of the lower respiratory tract before and after lung transplantation in a large number of lung transplant centers through an international practice survey from October 2016 to March 2017. RESULTS: A total of 51 respondents from 45 lung transplant centers (17 countries, 4 continents) answered the survey (response rate 58%). S/L colonization was estimated to be detected in candidates by 48% of centers. Only 18% of the centers used a specific medium to detect S/L colonization. Scedosporium spp. colonization was a contraindication to transplantation in 10% of centers whereas L prolificans was a contraindication in 31%; 22% of centers declared having had 1-5 recipients infected with S/L in the past 5 years. CONCLUSIONS: This survey gives an overview of the current practices regarding S/L colonization and infection in lung transplant centers worldwide and underscores the need of S/L culture procedure standardization before implementing prospective studies.

A cluster of scedosporiosis in lung transplant candidates and recipients: The Zurich experience and review of the literature.

Scedosporium species are fungal pathogens increasingly recognized in cystic fibrosis (CF). They can cause multiresistant, life-threatening infections that are of particular concern in CF patients undergoing lung transplantation, as optimal treatment remains unclear. Here, we describe our Zurich experience of CF patients with Scedosporium infection. Disseminated infection occurred in one patient after transplantation and was successfully treated. We propose a step-by-step approach to treat candidates with colonization, and discuss our cases in the context of the current literature.

Spontaneous Remission of Subcutaneous Scedosporiosis Caused by Scedosporium dehoogii in a Psoriatic Patient.

To date, only one case of post-traumatic endophthalmitis caused by Scedosporium dehoogii has been reported, but its contamination or colonization might not be precluded due to the absence of pathogenic isolation and/or pathological examination. We report the first case to our knowledge of S. dehoogii-induced subcutaneous scedosporiosis in a psoriatic patient. A 58-year-old man with 5-year history of psoriasis vulgaris and immunosuppressant therapy developed pyrexia and multiple subcutaneous abscesses on both knees. Direct microscopy of the yellowish pus showed masses of bright green short spores. Skin biopsy revealed some branched septate hyphae within the granuloma. Two aspirated pus specimens collected at a 1-week interval produced white cottony colonies on Sabouraud dextrose agar. Bacterial cultures of one blood and two purulent samples were negative, and fungal culture of blood sample was not performed. The isolate was identified as S. dehoogii using ß-tubulin phylogeny and species-specific PCR with primer MSDE1/MSA2. Without addition of antifungal treatment, subcutaneous lesions disappeared spontaneously after immunosuppressant withdrawal and no relapse occurred during 64-month follow-up. The spontaneous recovery may result from immune reconstitution following immunosuppressant discontinuation.

Pulmonary scedosporiosis mimicking aspergilloma in an immunocompetent host: a case report and review of the literature.

A case of localized lung scedosporiosis is reported here that mimicked aspergilloma in an immunocompetent host. Through this case the importance of considering Scedosporium spp. in differential diagnosis of locally invasive lung infections and fungal ball is highlighted. As it is difficult to differentiate Scedosporium from Aspergillus on clinical grounds, microscopy, radiology and histopathology, this case is further emphasizing the significance of the definitive etiological characterization of Scedosporium through culture or molecular diagnostic tools. Accurate identification of Scedosporium, surgical resection and high-dose voriconazole has been associated with favorable outcome in most reported cases of scedosporiosis.

Epidemiology, clinical manifestations, and outcomes of Scedosporium infections among solid organ transplant recipients.

BACKGROUND: Few studies of Scedosporium infections following solid organ transplantation have been performed in the era of induction immunosuppression and widespread antifungal prophylaxis. METHODS: We performed a single-center, retrospective study of transplant recipients from 2000 through 2010 who had a positive Scedosporium culture. RESULTS: Among 27 patients, 67% (n = 18) and 33% (n = 9) were infected with Scedosporium apiospermum and Scedosporium prolificans, respectively. A total of 67% received induction immunosuppression and 74% received prior antifungal therapy. Isolates were broadly resistant to antifungals. Of these patients, 59% (n = 16) were colonized by Scedosporium, and 41% (n = 11) had disease (scedosporiosis). No significant clinical differences were seen between species. Colonization occurred exclusively in the lungs of lung transplant recipients (LTR). Scedosporiosis followed lung transplantation in 55%, and other organ transplants (multivisceral [18%]; and heart, liver, small intestine [9% each]) in 45%. Scedosporiosis was preceded by colonization in 36%. Diseases included pneumonia (64%), mediastinitis (18%), and fungemia/disseminated infections (18%). The 6-month outcomes were death in 55%, progression in 18%, stability in 9%, and resolution in 18%. Patients who died had earlier onset scedosporiosis post transplant (median: 80.5 vs. 1388 days; P = 0.04), and were more likely to have mediastinitis or disseminated infections than pneumonia (100% vs. 29%; P = 0.06). The 3 patients who developed scedosporiosis >1 year post transplant survived. All patients who survived were treated with a voriconazole-containing regimen. CONCLUSIONS: LTR were most susceptible to Scedosporium colonization and scedosporiosis, particularly within the lungs. Death was common with scedosporiosis in the first year after all types of organ transplants, consistent with profound immunosuppression and antifungal resistance, but not encountered thereafter.

Pulmonary scedosporiosis in an intractable immunocompetent host: A case report and literature review.

Pulmonary scedosporiosis is a rare pulmonary infection that often presents with nonspecific symptoms and radiological findings. In this report, we present a case of localized pulmonary scedosporiosis in an immunocompetent patient and analyze a total of 25 immunocompetent patients with pulmonary scedosporiosis. Through this case and the literature, we highlight the importance of considering pulmonary scedosporiosis in patients with nonspecific clinical symptoms and radiological findings resembling aspergilloma. This case and the literature further emphasize the significance of surgical intervention. Regardless of the use of antifungal drugs, surgery should be conducted as soon as possible.

PCR diagnostic platforms for non-Aspergillus mold infections: ready for routine implementation in the clinic?

INTRODUCTION: While Aspergillus spp. remain the predominant cause of invasive mold infections, non-Aspergillus molds, such as the Mucorales or Fusarium spp., account for an increasing proportion of cases. The diagnosis of non-Aspergillus invasive mold infections (NAIMI) is challenging because of the low sensitivity and delay of conventional microbiological tests. Therefore, there is a particular interest to develop molecular tools for their early detection in blood or other clinical samples. AREAS COVERED: This extensive review of the literature discusses the performance of Mucorales-specific PCR and other genus-specific or broad-range fungal PCR that can be used for the diagnosis of NAIMI in diverse clinical samples, with a focus on novel technologies. EXPERT OPINION: PCR currently represents the most promising approach, combining good sensitivity/specificity and ability to detect NAIMI in clinical samples before diagnosis by conventional cultures and histopathology. Several PCR assays have been designed for the detection of Mucorales in particular, but also Fusarium spp. or Scedosporium/Lomentospora spp. Some commercial Mucorales PCRs are now available. While efforts are still needed for standardized protocols and the development of more rapid and simpler techniques, PCR is on the way to becoming an essential test for the early diagnosis of mucormycosis and possibly other NAIMIs.