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Mina S, Yaakoub H, Razafimandimby B, Dwars E, Wéry M, Papon N, Meyer W, Bouchara JP. First environmental survey of Scedosporium species in Lebanon. Front Cell Infect Microbiol 2025; 15:1547800. [PMID: 40099015 PMCID: PMC11911385 DOI: 10.3389/fcimb.2025.1547800] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2024] [Accepted: 02/13/2025] [Indexed: 03/19/2025] Open
Abstract
Background Scedosporium species are filamentous fungi causing a wide spectrum of infections in healthy and debilitated individuals. Despite their clinical significance, the ecology of Scedosporium species remains understudied, particularly in the Middle East. Methods In this context, we conducted an environmental study to elucidate the distribution and ecological preferences of Scedosporium species in the North of Lebanon. One hundred and fifty-five soil samples were collected from different environmental areas and analyzed for several chemical parameters. Scedosporium isolates were then selected for species identification and genotyping. Results Overall, 39 (25.16%) were positive for Scedosporium species, with a predominance of S. apiospermum (80.56%). Soil analysis revealed associations between the fungal presence and pH, nitrogen, phosphorus, and organic matter content. Moreover, genotyping analysis using MultiLocus Sequence Typing identified five major clusters. Interestingly, a number of Lebanese isolates formed an Asian-specific cluster (V) with one clinical Chinese isolate, whereas two clusters (II and III) showed a close association with German isolates, and clusters (I and IV) contained isolates with a global distribution. Conclusion These findings provide new insights into the ecology of Scedosporium species, bridging a gap in our knowledge of their distribution on the Asian continent and laying the groundwork for future clinical investigations. Future international collaborations are essential to trace the origin of S. apiospermum.
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Affiliation(s)
- Sara Mina
- Department of Medical Laboratory Sciences, Faculty of Health Sciences, Beirut Arab University, Beirut, Lebanon
| | - Hajar Yaakoub
- Univ Angers, Univ Brest, IRF, SFR ICAT, Angers, France
- Nantes Université, INRAE UMR-1280 PhAN, Nantes, France
| | | | - Elske Dwars
- Westerdijk Fungal Biodiversity Institute, Utrecht, Netherlands
| | | | - Nicolas Papon
- Univ Angers, Univ Brest, IRF, SFR ICAT, Angers, France
| | - Wieland Meyer
- Westerdijk Fungal Biodiversity Institute, Utrecht, Netherlands
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Wu HM, Fan YH, Phang GJ, Zeng WT, Abdrabo KAES, Wu YT, Sun PL, Lin YH, Huang YT. Human activity, not environmental factors, drives Scedosporium and Lomentospora distribution in Taiwan. Med Mycol 2025; 63:myaf022. [PMID: 40052326 DOI: 10.1093/mmy/myaf022] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2024] [Revised: 02/08/2025] [Accepted: 03/05/2025] [Indexed: 03/14/2025] Open
Abstract
Scedosporium and Lomentospora species are emerging fungal pathogens capable of causing severe infections in both immunocompetent and immunocompromised individuals. Previous environmental surveys have suggested potential associations between these fungi and various soil chemical parameters, though the relative influence of human activity versus environmental factors has not been systematically evaluated. Here, we conducted a comprehensive survey of 406 soil samples from 132 locations across Taiwan, analyzing fungal abundance alongside soil physicochemical parameters and the Human Footprint Index (HFI). We recovered 236 fungal isolates comprising 10 species, with S. boydii (32.2%), S. apiospermum (30.9%), and S. dehoogii (14.4%) being the most prevalent. The highest fungal burdens were observed in urban environments (up to 1293 CFU/g), particularly in public spaces and healthcare facilities. Statistical analysis revealed a significant positive correlation between fungal abundance and HFI (r = 0.143, P = .005), while soil chemical parameters including nitrogen, carbon, pH, electrical conductivity, and various base cations showed no significant associations despite their wide ranges. These findings indicate that anthropogenic disturbance of environments, rather than soil chemistry, is the primary driver of Scedosporium and Lomentospora distribution in Taiwan. This understanding holds important implications for predicting infection risks and developing targeted public health strategies, particularly in rapidly urbanizing regions. Future studies incorporating more specific indicators of human impact may further elucidate the mechanisms underlying these distribution patterns.
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Affiliation(s)
- Hsin-Mao Wu
- Department of Biomedical Science and Environmental Biology, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Yu-Hsuan Fan
- Department of Biomedical Science and Environmental Biology, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Guan-Jie Phang
- Department of Biomedical Science and Environmental Biology, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Wen-Ting Zeng
- Department of Biomedical Science and Environmental Biology, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Khaled Abdrabo El-Sayid Abdrabo
- Department of Biomedical Science and Environmental Biology, Kaohsiung Medical University, Kaohsiung, Taiwan
- Botany and Microbiology Department, Faculty of Science, Assiut University, Assiut, Egypt
| | - Yu-Ting Wu
- Department of Forestry, National Pingtung University of Science and Technology, Pingtung, Taiwan
| | - Pei-Lun Sun
- Department of Dermatology, Chang Gung Memorial Hospital, Taoyuan, Taiwan
- College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Ying-Hong Lin
- Department of Plant Medicine, National Pingtung University of Science and Technology, Pingtung, Taiwan
| | - Yin-Tse Huang
- Department of Biomedical Science and Environmental Biology, Kaohsiung Medical University, Kaohsiung, Taiwan
- Department of Medical Research, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
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3
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Vanbiervliet Y, Van Nieuwenhuyse T, Aerts R, Lagrou K, Spriet I, Maertens J. Review of the novel antifungal drug olorofim (F901318). BMC Infect Dis 2024; 24:1256. [PMID: 39511507 PMCID: PMC11542455 DOI: 10.1186/s12879-024-10143-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2024] [Accepted: 10/29/2024] [Indexed: 11/15/2024] Open
Abstract
There is clearly a need for novel antifungal agents, not only concerning spectrum, but also oral bioavailability, tolerability, and drug-drug interactions. There is growing concern for antifungal resistance for current available antifungals, mainly driven by environmental fungicide use or long-term exposure to antifungals, in the setting of mould-active prophylaxis or for chronic antifungal infections, such as chronic pulmonary aspergillosis. Moreover, the incidence of breakthrough infections is increasing, because of the introduction of (mould-active) prophylaxis (1-4). There is emergence of difficult to treat invasive fungal infections, such as those caused by Lomentospora prolificans, cryptic species of Aspergillus, Scedosporium and Coccidioides. Olorofim (F901318) is the first-in class of the orotomides, a novel antifungal class targeting dihydroorotate dehydrogenase (DHODH), a key enzyme in the biosynthesis of pyrimidines. Olorofim shows good in vitro and in vivo activity against Aspergillus species, rare and difficult to treat moulds and endemic dimorphic fungi, including azole- and amphotericin-resistant isolates. It lacks activity against yeasts and the Mucorales species. It is only orally available and shows very promising results in ongoing clinical trials. In this review we will describe the mechanism of action of olorofim, the spectrum of activity in vitro and in vivo, pharmacokinetics, pharmacodynamics, drug-drug interactions, resistance, and clinical outcomes.
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Affiliation(s)
- Yuri Vanbiervliet
- Department of Haematology, Department of Microbiology, Immunology and Transplantation, University Hospitals Leuven, KU Leuven, Herestraat 49, Leuven, 3000, Belgium.
| | - Tine Van Nieuwenhuyse
- Pharmacy Department, University Hospitals Leuven, Herestraat 49, Leuven, 3000, Belgium
| | - Robina Aerts
- Department of Haematology, Department of Microbiology, Immunology and Transplantation, University Hospitals Leuven, KU Leuven, Herestraat 49, Leuven, 3000, Belgium
| | - Katrien Lagrou
- Department of Laboratory Medicine and National Reference Center for Mycosis, Department of Microbiology, Immunology and Transplantation, University Hospitals Leuven, KU Leuven, Herestraat 49, Leuven, 3000, Belgium
| | - Isabel Spriet
- Department Of Pharmaceutical and Pharmacological Sciences, Pharmacy Department University Hospitals Leuven, KU Leuven, Herestraat 49, Leuven, 3000, Belgium
| | - Johan Maertens
- Department of Haematology, Department of Microbiology, Immunology and Transplantation, University Hospitals Leuven, KU Leuven, Herestraat 49, Leuven, 3000, Belgium
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Lino R, Guimarães AR, Sousa E, Azevedo M, Santos L. Emerging Fungal Infections of the Central Nervous System in the Past Decade: A Literature Review. Infect Dis Rep 2024; 16:952-976. [PMID: 39452161 PMCID: PMC11507179 DOI: 10.3390/idr16050076] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/15/2024] [Revised: 09/29/2024] [Accepted: 10/04/2024] [Indexed: 10/26/2024] Open
Abstract
INTRODUCTION Invasive fungal infections affecting the central nervous system (CNS) are a major health concern worldwide associated with high mortality rates. Their increased incidence is largely due to an increase in the vulnerable immunocompromised population, changing environmental factors, and development of more accurate diagnostic methods. The aim of this article is to identify fungal causes of CNS infections that are recently emerging or have the potential to become emerging pathogens in the near future, as well as their clinical characteristics, including: Candida auris, Trichosporon spp., Blastomyces spp., Sporothrix spp., Talaromyces marneffei, Lomentospora prolificans, and Scedosporium spp. METHODS A review of the literature in PubMed in the last ten years was conducted to identify central nervous system infections caused by each of these fungi. RESULTS The review identified 10 cases caused by C. auris, 5 cases by Trichosporon spp., 82 cases by Blastomyces spp., 36 cases by Sporothrix spp., 21 cases by T. marneffei, 22 cases by Lomentospora prolificans, and 42 cases by Scedosporium spp. DISCUSSION The exact burden of these diseases remains difficult to ascertain, but their apparent rise underscores the urgent need for improved diagnostic, treatment, and management strategies against CNS fungal pathogens to improve outcomes against these life-threatening infections.
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Affiliation(s)
- Rita Lino
- Infectious Diseases Department, Hospital de São João—Unidade Local de Saúde São João, 4200-319 Porto, Portugal; (A.R.G.); (E.S.); (M.A.); (L.S.)
- Faculty of Medicine, University of Porto, 4200-319 Porto, Portugal
| | - André Rodrigues Guimarães
- Infectious Diseases Department, Hospital de São João—Unidade Local de Saúde São João, 4200-319 Porto, Portugal; (A.R.G.); (E.S.); (M.A.); (L.S.)
- Faculty of Medicine, University of Porto, 4200-319 Porto, Portugal
| | - Estela Sousa
- Infectious Diseases Department, Hospital de São João—Unidade Local de Saúde São João, 4200-319 Porto, Portugal; (A.R.G.); (E.S.); (M.A.); (L.S.)
- Faculty of Medicine, University of Porto, 4200-319 Porto, Portugal
| | - Mariana Azevedo
- Infectious Diseases Department, Hospital de São João—Unidade Local de Saúde São João, 4200-319 Porto, Portugal; (A.R.G.); (E.S.); (M.A.); (L.S.)
| | - Lurdes Santos
- Infectious Diseases Department, Hospital de São João—Unidade Local de Saúde São João, 4200-319 Porto, Portugal; (A.R.G.); (E.S.); (M.A.); (L.S.)
- Faculty of Medicine, University of Porto, 4200-319 Porto, Portugal
- ESCMID Study Group for Infectious Diseases of the Brain (ESGIB), 4051 Basel, Switzerland
- ESCMID Study Group for Infections in Compromised Hosts (ESGICH), 4051 Basel, Switzerland
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Neoh CF, Chen SCA, Lanternier F, Tio SY, Halliday CL, Kidd SE, Kong DCM, Meyer W, Hoenigl M, Slavin MA. Scedosporiosis and lomentosporiosis: modern perspectives on these difficult-to-treat rare mold infections. Clin Microbiol Rev 2024; 37:e0000423. [PMID: 38551323 PMCID: PMC11237582 DOI: 10.1128/cmr.00004-23] [Citation(s) in RCA: 9] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/14/2024] Open
Abstract
SUMMARYAlthough Scedosporium species and Lomentospora prolificans are uncommon causes of invasive fungal diseases (IFDs), these infections are associated with high mortality and are costly to treat with a limited armamentarium of antifungal drugs. In light of recent advances, including in the area of new antifungals, the present review provides a timely and updated overview of these IFDs, with a focus on the taxonomy, clinical epidemiology, pathogenesis and host immune response, disease manifestations, diagnosis, antifungal susceptibility, and treatment. An expansion of hosts at risk for these difficult-to-treat infections has emerged over the last two decades given the increased use of, and broader population treated with, immunomodulatory and targeted molecular agents as well as wider adoption of antifungal prophylaxis. Clinical presentations differ not only between genera but also across the different Scedosporium species. L. prolificans is intrinsically resistant to most currently available antifungal agents, and the prognosis of immunocompromised patients with lomentosporiosis is poor. Development of, and improved access to, diagnostic modalities for early detection of these rare mold infections is paramount for timely targeted antifungal therapy and surgery if indicated. New antifungal agents (e.g., olorofim, fosmanogepix) with novel mechanisms of action and less cross-resistance to existing classes, availability of formulations for oral administration, and fewer drug-drug interactions are now in late-stage clinical trials, and soon, could extend options to treat scedosporiosis/lomentosporiosis. Much work remains to increase our understanding of these infections, especially in the pediatric setting. Knowledge gaps for future research are highlighted in the review.
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Affiliation(s)
- Chin Fen Neoh
- National Centre for Infections in Cancer, Peter MacCallum Cancer Centre, Melbourne, Australia
- Department of Infectious Diseases, Peter MacCallum Cancer Centre, Melbourne, Australia
- Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, Australia
| | - Sharon C-A Chen
- Centre for Infectious Diseases and Microbiology Laboratory Services, New South Wales Health Pathology, Westmead Hospital, Sydney, Australia
- The University of Sydney, Sydney, Australia
- Department of Infectious Diseases, Westmead Hospital, Sydney, Australia
| | - Fanny Lanternier
- Service de Maladies Infectieuses et Tropicales, Hôpital universitaire Necker-Enfants malades, Paris, France
- National Reference Center for Invasive Mycoses and Antifungals, Translational Mycology research group, Mycology Department, Institut Pasteur, Université Paris Cité, Paris, France
| | - Shio Yen Tio
- National Centre for Infections in Cancer, Peter MacCallum Cancer Centre, Melbourne, Australia
- Department of Infectious Diseases, Peter MacCallum Cancer Centre, Melbourne, Australia
- Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, Australia
| | - Catriona L. Halliday
- Centre for Infectious Diseases and Microbiology Laboratory Services, New South Wales Health Pathology, Westmead Hospital, Sydney, Australia
| | - Sarah E. Kidd
- National Mycology Reference Centre, SA Pathology, Adelaide, Australia
- School of Biological Sciences, Faculty of Sciences, University of Adelaide, Adelaide, Australia
| | - David C. M. Kong
- National Centre for Infections in Cancer, Peter MacCallum Cancer Centre, Melbourne, Australia
- The National Centre for Antimicrobial Stewardship, The Peter Doherty Institute for Infections and Immunity, Melbourne, Australia
- Centre for Medicine Use and Safety, Monash Institute of Pharmaceutical Sciences, Faculty of Pharmacy and Pharmaceutical Sciences, Monash University, Melbourne, Australia
- School of Medicine, Deakin University, Waurn Ponds, Geelong, Australia
| | - Wieland Meyer
- The University of Sydney, Sydney, Australia
- Westerdijk Fungal Biodiversity Institute, Utrecht, the Netherlands
| | - Martin Hoenigl
- Division of Infectious Diseases, Department of Internal Medicine, Medical University of Graz, Graz, Austria
- Translational Medical Mycology Research Group, ECMM Excellence Center for Clinical Mycology, Medical University of Graz, Graz, Austria
| | - Monica A. Slavin
- National Centre for Infections in Cancer, Peter MacCallum Cancer Centre, Melbourne, Australia
- Department of Infectious Diseases, Peter MacCallum Cancer Centre, Melbourne, Australia
- Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, Australia
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Ravenel K, Guegan H, Gastebois A, Bouchara JP, Gangneux JP, Giraud S. Fungal Colonization of the Airways of Patients with Cystic Fibrosis: the Role of the Environmental Reservoirs. Mycopathologia 2024; 189:19. [PMID: 38407729 DOI: 10.1007/s11046-023-00818-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2023] [Accepted: 11/23/2023] [Indexed: 02/27/2024]
Abstract
Filamentous fungi frequently colonize the airways of patients with cystic fibrosis and may cause severe diseases, such as the allergic bronchopulmonary aspergillosis. The most common filamentous fungi capable to chronically colonize the respiratory tract of the patients are Aspergillus fumigatus and Scedosporium species. Defining the treatment strategy may be challenging, the number of available drugs being limited and some of the causative agents being multiresistant microorganisms. The knowledge of the fungal niches in the outdoor and indoor environment is needed for understanding the origin of the contamination of the patients. In light of the abundance of some of the causative molds in compost, agricultural and flower fields, occupational activities related to such environments should be discouraged for patients with cystic fibrosis (CF). In addition, the microbiological monitoring of their indoor environment, including analysis of air and dust on surfaces, is essential to propose preventive measures aiming to reduce the exposure to environmental molds. Nevertheless, some specific niches were also identified in the indoor environment, in relation with humidity which favors the growth of thermotolerant molds. Potted plants were reported as indoor reservoirs for Scedosporium species. Likewise, Exophiala dermatitidis may be spread in the kitchen via dishwashers. However, genotype studies are still required to establish the link between dishwashers and colonization of the airways of CF patients by this black yeast. Moreover, as nothing is known regarding the other filamentous fungi associated with CF, further studies should be conducted to identify other potential specific niches in the habitat.
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Affiliation(s)
- Kévin Ravenel
- IRF (Infections Respiratoires Fongiques), SFR ICAT 4208, Univ Angers, Univ Brest, Angers, France
| | - Hélène Guegan
- EHESP, IRSET (Institut de Recherche en Santé Environnement et Travail), UMR_S 1085, CHU Rennes, INSERM, Univ Rennes, 35000, Rennes, France
| | - Amandine Gastebois
- IRF (Infections Respiratoires Fongiques), SFR ICAT 4208, Univ Angers, Univ Brest, Angers, France
| | - Jean-Philippe Bouchara
- IRF (Infections Respiratoires Fongiques), SFR ICAT 4208, Univ Angers, Univ Brest, Angers, France
| | - Jean-Pierre Gangneux
- EHESP, IRSET (Institut de Recherche en Santé Environnement et Travail), UMR_S 1085, CHU Rennes, INSERM, Univ Rennes, 35000, Rennes, France
| | - Sandrine Giraud
- IRF (Infections Respiratoires Fongiques), SFR ICAT 4208, Univ Angers, Univ Brest, Angers, France.
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Schwarz C, Eschenhagen PN, Mainz JG, Schmidergall T, Schuette H, Romanowska E. Pulmonary Aspergillosis in People with Cystic Fibrosis. Semin Respir Crit Care Med 2024; 45:128-140. [PMID: 38286138 DOI: 10.1055/s-0043-1777267] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/31/2024]
Abstract
In the last decade, fungal respiratory diseases have been increasingly investigated for their impact on the clinical course of people with cystic fibrosis (CF), with a particular focus on infections caused by Aspergillus spp. The most common organisms from this genus detected from respiratory cultures are Aspergillus fumigatus and Aspergillus terreus, followed by Aspergillus flavus, Aspergillus niger, and Aspergillus nidulans. These species have been identified to be both chronic colonizers and sources of active infection and may negatively impact lung function in people with CF. This review article discusses definitions of aspergillosis, challenges in clinical practice, and current literature available for laboratory findings, clinical diagnosis, and treatment options for pulmonary diseases caused by Aspergillus spp. in people with CF.
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Affiliation(s)
- C Schwarz
- HMU-Health and Medical University, Potsdam, Germany
- Division Cystic Fibrosis, Clinic Westbrandenburg, Potsdam, Germany
| | - P N Eschenhagen
- HMU-Health and Medical University, Potsdam, Germany
- Division Cystic Fibrosis, Clinic Westbrandenburg, Potsdam, Germany
| | - J G Mainz
- Department of Paediatric Pneumology, Allergology, Cystic Fibrosis Center, Klinikum Westbrandenburg, Brandenburg a. d. Havel, Germany
- University Hospital of the Brandenburg Medical School, Brandenburg a. d. Havel, Germany
| | - T Schmidergall
- HMU-Health and Medical University, Potsdam, Germany
- Division Cystic Fibrosis, Clinic Westbrandenburg, Potsdam, Germany
| | - H Schuette
- Pneumology and Respiratory Medicine, Ernst von Bergmann Klinikum, Potsdam, Germany
| | - E Romanowska
- HMU-Health and Medical University, Potsdam, Germany
- Division Cystic Fibrosis, Clinic Westbrandenburg, Potsdam, Germany
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8
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Mahmoud DE, Hanachi M, Yaakoub H, Blanchard S, Pignon P, Souiai O, Delneste Y, Bouchara JP, Papon N, Hérivaux A. Functional insights into human macrophage response against Scedosporium apiospermum and Scedosporium dehoogii. Cytokine 2023; 172:156384. [PMID: 37832161 DOI: 10.1016/j.cyto.2023.156384] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2023] [Revised: 09/06/2023] [Accepted: 09/26/2023] [Indexed: 10/15/2023]
Abstract
Fungal infections caused by Scedosporium species are rising among immunocompromised and immunocompetent patients. Within the immunocompetent group, patients with cystic fibrosis (pwCF) are at high risk of developing a chronic airway colonization by these molds. While S. apiospermum is one of the major species encountered in the lungs of pwCF, S. dehoogii has rarely been reported. The innate immune response is believed to be critical for host defense against fungal infections. However, its role has only recently been elucidated and the immune mechanisms against Scedosporium species are currently unknown. In this context, we undertook a comparative investigation of macrophage-mediated immune responses toward S. apiospermum and S. dehoogii conidia. Our data showed that S. apiospermum and S. dehoogii conidia strongly stimulated the expression of a set of pro-inflammatory cytokines and chemokines such as IL-1β, IL-8, IL-6 and TNFα. We demonstrated that S. dehoogii was more potent in stimulating the early release of pro-inflammatory cytokines and chemokines while S. apiospermum induced a late inflammatory response at a higher level. Flow cytometry analysis showed that M1-like macrophages were able to internalize both S. apiospermum and S. dehoogii conidia, with a similar intracellular killing rate for both species. In conclusion, these results suggest that M1-like macrophages can rapidly initiate a strong immune response against both S. apiospermum and S. dehoogii. This response is characterized by a similar killing of internalized conidia, but a different time course of cytokine production.
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Affiliation(s)
| | - Mariem Hanachi
- Laboratory of Bioinformatics, Biomathematics and Biostatistics-LR16IPT09, Institut Pasteur de Tunis, Tunis, Tunisia
| | - Hajar Yaakoub
- Univ Angers, Univ Brest, IRF, SFR ICAT, 49000 Angers, France
| | - Simon Blanchard
- Univ Angers, Nantes Université, Inserm, CNRS, CRCI2NA, SFR ICAT, F-49000 Angers, France
| | - Pascale Pignon
- Univ Angers, Nantes Université, Inserm, CNRS, CRCI2NA, SFR ICAT, F-49000 Angers, France
| | - Oussama Souiai
- Laboratory of Bioinformatics, Biomathematics and Biostatistics-LR16IPT09, Institut Pasteur de Tunis, Tunis, Tunisia
| | - Yves Delneste
- Univ Angers, Nantes Université, Inserm, CNRS, CRCI2NA, SFR ICAT, F-49000 Angers, France; Immunology and Allergology Laboratory, University Hospital of Angers, Angers, France
| | | | - Nicolas Papon
- Univ Angers, Univ Brest, IRF, SFR ICAT, 49000 Angers, France
| | - Anaïs Hérivaux
- Univ Angers, Univ Brest, IRF, SFR ICAT, 49000 Angers, France.
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9
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Kurbessoian T, Murante D, Crocker A, Hogan DA, Stajich JE. In host evolution of Exophiala dermatitidis in cystic fibrosis lung micro-environment. G3 (BETHESDA, MD.) 2023; 13:jkad126. [PMID: 37293838 PMCID: PMC10484061 DOI: 10.1093/g3journal/jkad126] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/26/2022] [Revised: 09/26/2022] [Accepted: 05/18/2023] [Indexed: 06/10/2023]
Abstract
Individuals with cystic fibrosis (CF) are susceptible to chronic lung infections that lead to inflammation and irreversible lung damage. While most respiratory infections that occur in CF are caused by bacteria, some are dominated by fungi such as the slow-growing black yeast Exophiala dermatitidis. Here, we analyze isolates of E. dermatitidis cultured from two samples, collected from a single subject 2 years apart. One isolate genome was sequenced using long-read Nanopore technology as an in-population reference to use in comparative single nucleotide polymorphism and insertion-deletion variant analyses of 23 isolates. We then used population genomics and phylo-genomics to compare the isolates to each other as well as the reference genome strain E. dermatitidis NIH/UT8656. Within the CF lung population, three E. dermatitidis clades were detected, each with varying mutation rates. Overall, the isolates were highly similar suggesting that they were recently diverged. All isolates were MAT 1-1, which was consistent with their high relatedness and the absence of evidence for mating or recombination between isolates. Phylogenetic analysis grouped sets of isolates into clades that contained isolates from both early and late time points indicating there are multiple persistent lineages. Functional assessment of variants unique to each clade identified alleles in genes that encode transporters, cytochrome P450 oxidoreductases, iron acquisition, and DNA repair processes. Consistent with the genomic heterogeneity, isolates showed some stable phenotype heterogeneity in melanin production, subtle differences in antifungal minimum inhibitory concentrations, and growth on different substrates. The persistent population heterogeneity identified in lung-derived isolates is an important factor to consider in the study of chronic fungal infections, and the analysis of changes in fungal pathogens over time may provide important insights into the physiology of black yeasts and other slow-growing fungi in vivo.
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Affiliation(s)
- Tania Kurbessoian
- Department of Microbiology and Plant Pathology and Institute of Integrative Genome Biology, University of California Riverside, Riverside, CA 92521, USA
| | - Daniel Murante
- Department of Microbiology and Immunology, Geisel School of Medicine, Dartmouth College, Hanover, NH 03755, USA
| | - Alex Crocker
- Department of Microbiology and Immunology, Geisel School of Medicine, Dartmouth College, Hanover, NH 03755, USA
| | - Deborah A Hogan
- Department of Microbiology and Immunology, Geisel School of Medicine, Dartmouth College, Hanover, NH 03755, USA
| | - Jason E Stajich
- Department of Microbiology and Plant Pathology and Institute of Integrative Genome Biology, University of California Riverside, Riverside, CA 92521, USA
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10
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Brito Devoto T, Hermida-Alva K, Posse G, Finquelievich JL, García-Effrón G, Cuestas ML. Antifungal susceptibility patterns for Aspergillus, Scedosporium, and Exophiala isolates recovered from cystic fibrosis patients against amphotericin B, and three triazoles and their impact after long-term therapies. Med Mycol 2023; 61:myad089. [PMID: 37591630 DOI: 10.1093/mmy/myad089] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2023] [Revised: 06/29/2023] [Accepted: 08/15/2023] [Indexed: 08/19/2023] Open
Abstract
In cystic fibrosis (CF) patients, fungal colonization of the respiratory tract is frequently found. Aspergillus fumigatus, Scedosporium genus, and Exophiala dermatitidis are the most commonly isolated moulds from the respiratory tract secretions of CF patients. The aim of this 5-year surveillance study was to identify trends in species distribution and susceptibility patterns of 212 mould strains identified as Aspergillus spp., Scedosporium spp., and Exophiala spp., isolated from sputum of 63 CF patients who received long-term therapy with itraconazole (ITR) and/or voriconazole (VRC). The Aspergillus isolates were identified as members of the sections Fumigati (n = 130), Flavi (n = 22), Terrei (n = 20), Nigri (n = 8), Nidulantes (n = 1), and Usti (n = 1). Among the 16 species of the genus Scedosporium, 9 were S. apiospermum, 3 S. aurantiacum, and 4 S. boydii. Among the 14 Exophiala species, all were molecularly identified as E. dermatitidis. Overall, 94% (15/16) of Scedosporium spp., 50% (7/14) of E. dermatitidis, and 7.7% (14/182) of Aspergillus spp. strains showed high MIC values (≥8 µg/ml) for at least one antifungal. Particularly, 8.9% (19/212) of isolates showed high MIC values for amphotericin B, 11.7% (25/212) for ITR, 4.2% (9/212) for VRC, and 3.3% (7/212) for posaconazole. In some cases, such as some A. fumigatus and E. dermatitidis isolates recovered from the same patient, susceptibility to antifungal azoles decreased over time. We show that the use of azoles for a long time in CF patients causes the selection/isolation of mould strains with higher MIC values.
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Affiliation(s)
- Tomás Brito Devoto
- Laboratorio de Investigación y Desarrollo en Micología, Instituto de Investigaciones en Microbiología y Parasitología Médica, Universidad de Buenos Aires-CONICET, Buenos Aires, Argentina
| | - Katherine Hermida-Alva
- Laboratorio de Investigación y Desarrollo en Micología, Instituto de Investigaciones en Microbiología y Parasitología Médica, Universidad de Buenos Aires-CONICET, Buenos Aires, Argentina
| | - Gladys Posse
- Laboratorio de Micología, Hospital Nacional Profesor Alejandro Posadas, Buenos Aires, Argentina
| | - Jorge L Finquelievich
- Centro de Micología, Facultad de Medicina, Universidad de Buenos Aires, Buenos Aires, Argentina
| | - Guillermo García-Effrón
- Laboratorio de Micología y Diagnóstico Molecular, Cátedra de Parasitología y Micología, Facultad de Bioquímica y Ciencias Biológicas, Universidad Nacional del Litoral, Santa Fe, Argentina
- Consejo Nacional de Investigaciones Científicas y Tecnológicas (CONICET), Santa Fe, Argentina
| | - María L Cuestas
- Laboratorio de Investigación y Desarrollo en Micología, Instituto de Investigaciones en Microbiología y Parasitología Médica, Universidad de Buenos Aires-CONICET, Buenos Aires, Argentina
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11
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O’Dea AL, Feng R, Glaser LJ, Kubrak C, Rubenstein RC, Dorgan DJ, Hadjiliadis D, Kawut SM, Hong G. The Clinical Association between Aspergillus fumigatus and Respiratory Outcomes in Adolescents and Adults with Cystic Fibrosis. Ann Am Thorac Soc 2023; 20:984-992. [PMID: 36800434 PMCID: PMC12039955 DOI: 10.1513/annalsats.202210-852oc] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2022] [Accepted: 02/17/2023] [Indexed: 02/19/2023] Open
Abstract
Rationale: The clinical significance of Aspergillus fumigatus (Af) detection in the absence of allergic bronchopulmonary aspergillosis in cystic fibrosis (CF) airways remains unclear. Yet, some clinicians initiate antifungal therapy for Af-positive respiratory cultures out of concern for infection in people with CF. Objectives: To determine the association between the presence of Af and respiratory outcomes in individuals with CF. Methods: We conducted a prospective longitudinal cohort study of 206 adults and adolescents (age 14 yr and older) with CF and collected sputum for selective fungus culture. We assessed clinical outcome measurements, including patient-reported outcomes (measured by the Cystic Fibrosis Questionnaire-Revised), spirometry, and number of pulmonary exacerbations (PEx) for a 1-year period. We used mixed-effects linear models to determine the association between positive Af culture results, defined as Af detection in sputum culture at the study visit, with both respiratory domain score and forced expiratory volume in 1 second (FEV1) percent predicted, adjusted for confounders. Mixed-effects Poisson regression models were employed to examine the association between positive Af culture results and PEx events. We explored the association between Af history, defined as Af detection at baseline or within 2 years of enrollment, and respiratory outcomes. Results: Af prevalence was 10.3% (95% confidence interval [CI], 6.8, 15.7) at baseline. Forty-eight (23.3%; 95% CI, 17.7, 29.7) participants had at least one Af-positive culture result during the study period. Positive Af culture result was not associated with lower respiratory domain score. However, Af history was associated with a 6.48-point lower respiratory domain score, reflective of worse respiratory quality of life (95% CI, -11.96, -0.99; P = 0.02). Positive Af culture result was associated with a 2.54% lower FEV1 percent predicted (95% CI, -4.64, -0.44; P = 0.02) and a 1.71-fold increase in severe PEx incidence (95% CI, 1.05, 2.76; P = 0.03). Conclusions: Positive Af culture result was not associated with lower patient-reported, respiratory-related quality of life. Yet, positive Af culture result was associated with both lower FEV1 percent predicted and increased frequency of severe PEx warranting intravenous antibiotics in adolescents and adults with CF. Future studies are required to better understand the direct role of Af in lung disease progression in CF.
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Affiliation(s)
- Anna L. O’Dea
- Division of Pulmonary, Allergy and
Critical Care, Department of Medicine
| | - Rui Feng
- Center for Clinical Epidemiology and
Biostatistics, and
| | - Laurel J. Glaser
- Department of Pathology and Laboratory
Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia,
Pennsylvania
| | - Christina Kubrak
- Division of Allergy and Pulmonary
Medicine, Department of Pediatrics, Washington University School of Medicine in
Saint Louis, St. Louis, Missouri; and
| | - Ronald C. Rubenstein
- Division of Allergy and Pulmonary
Medicine, Department of Pediatrics, Washington University School of Medicine in
Saint Louis, St. Louis, Missouri; and
| | - Daniel J. Dorgan
- Division of Pulmonary, Allergy and
Critical Care, Department of Medicine
| | - Denis Hadjiliadis
- Division of Pulmonary, Allergy and
Critical Care, Department of Medicine, Hospital of the University of
Pennsylvania, Philadelphia, Pennsylvania
| | - Steven M. Kawut
- Division of Pulmonary, Allergy and
Critical Care, Department of Medicine
- Center for Clinical Epidemiology and
Biostatistics, and
| | - Gina Hong
- Division of Pulmonary, Allergy and
Critical Care, Department of Medicine
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12
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Pieta A, Venetsanopoulou AI, Kittas C, Christaki E, Voulgari PV. Recurrent Scedosporium apiospermum Cutaneous Infection in a Patient with Rheumatoid Arthritis: The Potent Role of IL-6 Signaling Pathway Blockade: A Case-Based Review. J Fungi (Basel) 2023; 9:683. [PMID: 37367619 DOI: 10.3390/jof9060683] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2023] [Revised: 06/08/2023] [Accepted: 06/13/2023] [Indexed: 06/28/2023] Open
Abstract
Rheumatoid arthritis (RA) patients deal with a higher risk of bacterial and fungal infections compared to the general population because of their dysregulated immune system as well as the immunosuppressive therapy they usually receive. Scedosporium spp. is a fungal pathogen responsible for cutaneous, lung, central nervous system, and eye infections, mostly in immunocompromised patients, leading to death in disseminated cases. We report the case of an 81-year-old woman with rheumatoid arthritis treated with steroids and an IL-6 inhibitor who was diagnosed with scedosporiosis of the upper limb. She was treated with voriconazole for one month, which was discontinued due to adverse events, and when scedosporiosis relapsed, she switched to itraconazole. We also reviewed the current literature on RA patients presenting with Scedosporium infections. Early and accurate diagnosis of scedosporiosis has therapeutic and prognostic implications, as traditionally this fungus is resistant to commonly used antifungals. Clinical alertness regarding uncommon infections, including fungal, in patients with autoimmune diseases on immunomodulatory agents is essential for effective treatment.
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Affiliation(s)
- Antigone Pieta
- Department of Rheumatology, School of Health Sciences, Faculty of Medicine, University of Ioannina, 45110 Ioannina, Greece
| | - Aliki I Venetsanopoulou
- Department of Rheumatology, School of Health Sciences, Faculty of Medicine, University of Ioannina, 45110 Ioannina, Greece
| | - Christos Kittas
- Microbiology Laboratory, School of Health Sciences, Faculty of Medicine, University of Ioannina, 45110 Ioannina, Greece
| | - Eirini Christaki
- 1st Division of Internal Medicine & Infectious Diseases Unit, University General Hospital of Ioannina, Faculty of Medicine, University of Ioannina, 45110 Ioannina, Greece
| | - Paraskevi V Voulgari
- Department of Rheumatology, School of Health Sciences, Faculty of Medicine, University of Ioannina, 45110 Ioannina, Greece
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13
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Schwarz C, Eschenhagen P, Schmidt H, Hohnstein T, Iwert C, Grehn C, Roehmel J, Steinke E, Stahl M, Lozza L, Tikhonova E, Rosati E, Stervbo U, Babel N, Mainz JG, Wisplinghoff H, Ebel F, Jia LJ, Blango MG, Hortschansky P, Brunke S, Hube B, Brakhage AA, Kniemeyer O, Scheffold A, Bacher P. Antigen specificity and cross-reactivity drive functionally diverse anti-Aspergillus fumigatus T cell responses in cystic fibrosis. J Clin Invest 2023; 133:161593. [PMID: 36701198 PMCID: PMC9974102 DOI: 10.1172/jci161593] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2022] [Accepted: 01/19/2023] [Indexed: 01/27/2023] Open
Abstract
BACKGROUNDThe fungus Aspergillus fumigatus causes a variety of clinical phenotypes in patients with cystic fibrosis (pwCF). Th cells orchestrate immune responses against fungi, but the types of A. fumigatus-specific Th cells in pwCF and their contribution to protective immunity or inflammation remain poorly characterized.METHODSWe used antigen-reactive T cell enrichment (ARTE) to investigate fungus-reactive Th cells in peripheral blood of pwCF and healthy controls.RESULTSWe show that clonally expanded, high-avidity A. fumigatus-specific effector Th cells, which were absent in healthy donors, developed in pwCF. Individual patients were characterized by distinct Th1-, Th2-, or Th17-dominated responses that remained stable over several years. These different Th subsets target different A. fumigatus proteins, indicating that differential antigen uptake and presentation directs Th cell subset development. Patients with allergic bronchopulmonary aspergillosis (ABPA) are characterized by high frequencies of Th2 cells that cross-recognize various filamentous fungi.CONCLUSIONOur data highlight the development of heterogenous Th responses targeting different protein fractions of a single fungal pathogen and identify the development of multispecies cross-reactive Th2 cells as a potential risk factor for ABPA.FUNDINGGerman Research Foundation (DFG), under Germany's Excellence Strategy (EXC 2167-390884018 "Precision Medicine in Chronic Inflammation" and EXC 2051-390713860 "Balance of the Microverse"); Oskar Helene Heim Stiftung; Christiane Herzog Stiftung; Mukoviszidose Institut gGmb; German Cystic Fibrosis Association Mukoviszidose e.V; German Federal Ministry of Education and Science (BMBF) InfectControl 2020 Projects AnDiPath (BMBF 03ZZ0838A+B).
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Affiliation(s)
- Carsten Schwarz
- Klinikum Westbrandenburg, Campus Potsdam, Cystic Fibrosis Section, Potsdam, Germany
| | - Patience Eschenhagen
- Klinikum Westbrandenburg, Campus Potsdam, Cystic Fibrosis Section, Potsdam, Germany
| | - Henrijette Schmidt
- Institute of Clinical Molecular Biology, Christian-Albrecht University of Kiel, Kiel, Germany.,Institute of Immunology, Christian-Albrecht University of Kiel and UKSH Schleswig-Holstein, Kiel, Germany
| | - Thordis Hohnstein
- Department of Microbiology, Infectious Diseases and Immunology, Charité – Universitätsmedizin Berlin, Berlin, Germany
| | - Christina Iwert
- Berlin Institute of Health at Charité – Universitätsmedizin Berlin, Translational Immunology, Berlin, Germany
| | - Claudia Grehn
- Berlin Institute of Health at Charité – Universitätsmedizin Berlin, Berlin, Germany
| | - Jobst Roehmel
- Department of Pediatric Respiratory Medicine, Immunology and Critical Care Medicine and Cystic Fibrosis Center, Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt – Universität zu Berlin, Berlin, Germany
| | - Eva Steinke
- Berlin Institute of Health at Charité – Universitätsmedizin Berlin, Berlin, Germany.,Department of Pediatric Respiratory Medicine, Immunology and Critical Care Medicine and Cystic Fibrosis Center, Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt – Universität zu Berlin, Berlin, Germany.,German Center for Lung Research (DZL), associated partner site, Berlin, Germany
| | - Mirjam Stahl
- Berlin Institute of Health at Charité – Universitätsmedizin Berlin, Berlin, Germany.,Department of Pediatric Respiratory Medicine, Immunology and Critical Care Medicine and Cystic Fibrosis Center, Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt – Universität zu Berlin, Berlin, Germany.,German Center for Lung Research (DZL), associated partner site, Berlin, Germany
| | - Laura Lozza
- Cell Biology Laboratory, Precision for Medicine GmbH, Berlin, Germany
| | - Ekaterina Tikhonova
- Institute of Clinical Molecular Biology, Christian-Albrecht University of Kiel, Kiel, Germany.,Institute of Immunology, Christian-Albrecht University of Kiel and UKSH Schleswig-Holstein, Kiel, Germany
| | - Elisa Rosati
- Institute of Clinical Molecular Biology, Christian-Albrecht University of Kiel, Kiel, Germany.,Institute of Immunology, Christian-Albrecht University of Kiel and UKSH Schleswig-Holstein, Kiel, Germany
| | - Ulrik Stervbo
- Center for Translational Medicine and Immune Diagnostics Laboratory, Marien Hospital Herne, University Hospital of the Ruhr University Bochum, Herne, Germany
| | - Nina Babel
- Berlin Institute of Health at Charité – Universitätsmedizin Berlin, Berlin, Germany.,Center for Translational Medicine and Immune Diagnostics Laboratory, Marien Hospital Herne, University Hospital of the Ruhr University Bochum, Herne, Germany
| | - Jochen G. Mainz
- Brandenburg Medical School/Medizinische Hochschule Brandenburg (MHB), University, Pediatric Pulmonology/Cystic Fibrosis, Klinikum Westbrandenburg, Brandenburg an der Havel, Germany
| | - Hilmar Wisplinghoff
- Labor Dr. Wisplinghoff, Cologne, Germany.,Institute for Virology and Microbiology, Witten/Herdecke University, Witten, Germany
| | - Frank Ebel
- Institute for Infectious Diseases and Zoonoses, LMU, Munich, Germany
| | - Lei-Jie Jia
- Department of Molecular and Applied Microbiology, Leibniz Institute for Natural Product Research and Infection Biology (Leibniz-HKI), Jena, Germany
| | - Matthew G. Blango
- Department of Molecular and Applied Microbiology, Leibniz Institute for Natural Product Research and Infection Biology (Leibniz-HKI), Jena, Germany
| | - Peter Hortschansky
- Department of Molecular and Applied Microbiology, Leibniz Institute for Natural Product Research and Infection Biology (Leibniz-HKI), Jena, Germany
| | - Sascha Brunke
- Department of Microbial Pathogenicity Mechanisms, Leibniz Institute for Natural Product Research and Infection Biology (Leibniz-HKI), Jena, Germany
| | - Bernhard Hube
- Department of Microbial Pathogenicity Mechanisms, Leibniz Institute for Natural Product Research and Infection Biology (Leibniz-HKI), Jena, Germany.,Institute of Microbiology, Friedrich Schiller University, Jena, Germany
| | - Axel A. Brakhage
- Department of Molecular and Applied Microbiology, Leibniz Institute for Natural Product Research and Infection Biology (Leibniz-HKI), Jena, Germany.,Institute of Microbiology, Friedrich Schiller University, Jena, Germany
| | - Olaf Kniemeyer
- Department of Molecular and Applied Microbiology, Leibniz Institute for Natural Product Research and Infection Biology (Leibniz-HKI), Jena, Germany
| | - Alexander Scheffold
- Institute of Immunology, Christian-Albrecht University of Kiel and UKSH Schleswig-Holstein, Kiel, Germany
| | - Petra Bacher
- Institute of Clinical Molecular Biology, Christian-Albrecht University of Kiel, Kiel, Germany.,Institute of Immunology, Christian-Albrecht University of Kiel and UKSH Schleswig-Holstein, Kiel, Germany
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14
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Yu C, Kotsimbos T. Respiratory Infection and Inflammation in Cystic Fibrosis: A Dynamic Interplay among the Host, Microbes, and Environment for the Ages. Int J Mol Sci 2023; 24:ijms24044052. [PMID: 36835487 PMCID: PMC9966804 DOI: 10.3390/ijms24044052] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2023] [Revised: 02/13/2023] [Accepted: 02/14/2023] [Indexed: 02/22/2023] Open
Abstract
The interplay between airway inflammation and infection is now recognized as a major factor in the pathobiology in cystic fibrosis (CF). A proinflammatory environment is seen throughout the CF airway resulting in classic marked and enduring neutrophilic infiltrations, irreversibly damaging the lung. Although this is seen to occur early, independent of infection, respiratory microbes arising at different timepoints in life and the world environment perpetuate this hyperinflammatory state. Several selective pressures have allowed for the CF gene to persist until today despite an early mortality. Comprehensive care systems, which have been a cornerstone of therapy for the past few decades, are now revolutionized by CF transmembrane conductance regulator (CTFR) modulators. The effects of these small-molecule agents cannot be overstated and can be seen as early as in utero. For an understanding of the future, this review looks into CF studies spanning the historical and present period.
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Affiliation(s)
- Christiaan Yu
- Department of Respiratory Medicine, Alfred Health, Melbourne, VIC 3004, Australia
- Correspondence: ; Tel.: +61-3-9076-20000
| | - Tom Kotsimbos
- Department of Respiratory Medicine, Alfred Health, Melbourne, VIC 3004, Australia
- Department of Medicine, Monash University, Alfred Campus, Melbourne, VIC 3004, Australia
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15
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Georgacopoulos O, Nunnally N, Law D, Birch M, Berkow EL, Lockhart SR. In Vitro Activity of the Novel Antifungal Olorofim against Scedosporium and Lomentospora prolificans. Microbiol Spectr 2023; 11:e0278922. [PMID: 36629417 PMCID: PMC9927477 DOI: 10.1128/spectrum.02789-22] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2022] [Accepted: 12/02/2022] [Indexed: 01/12/2023] Open
Abstract
Scedosporium spp. and Lomentospora prolificans are an emerging group of fungi refractory to current antifungal treatments. These species largely affect immunocompromised individuals but can also be lung colonizers in cystic fibrosis patients. Although Scedosporium apiospermum is thought to be the predominant species, the group has been expanded to a species complex. The distribution of species within the S. apiospermum species complex and other closely related species in the United States is largely unknown. Here, we used β-tubulin and ITS sequences to identify 37 Scedosporium isolates to the species level. These Scedosporium isolates as well as 13 L. prolificans isolates were tested against a panel of nine antifungal drugs, including the first in novel class orotimide, olorofim. IMPORTANCE Scedosporium and Lomentospora infections are notoriously hard to treat as these organisms can be resistant to numerous antifungals. The manuscript contributes to our knowledge of the activity of the new antifungal agent olorofim and comparator agents against Lomentospora and against Scedosporium isolates that have been molecularly identified to the species level. The efficacy of olorofim against all species of Scedosporium and Lomentospora was confirmed.
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Affiliation(s)
- Ourania Georgacopoulos
- Mycotic Diseases Branch, Centers for Disease Control and Prevention, Atlanta, Georgia, USA
| | - Natalie Nunnally
- Mycotic Diseases Branch, Centers for Disease Control and Prevention, Atlanta, Georgia, USA
| | - Derek Law
- F2G Ltd., Manchester, United Kingdom
| | | | - Elizabeth L. Berkow
- Mycotic Diseases Branch, Centers for Disease Control and Prevention, Atlanta, Georgia, USA
| | - Shawn R. Lockhart
- Mycotic Diseases Branch, Centers for Disease Control and Prevention, Atlanta, Georgia, USA
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16
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Non- Aspergillus Hyaline Molds: A Host-Based Perspective of Emerging Pathogenic Fungi Causing Sinopulmonary Diseases. J Fungi (Basel) 2023; 9:jof9020212. [PMID: 36836326 PMCID: PMC9964096 DOI: 10.3390/jof9020212] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2023] [Revised: 01/31/2023] [Accepted: 02/01/2023] [Indexed: 02/09/2023] Open
Abstract
The incidence of invasive sino-pulmonary diseases due to non-Aspergillus hyaline molds is increasing due to an enlarging and evolving population of immunosuppressed hosts as well as improvements in the capabilities of molecular-based diagnostics. Herein, we review the following opportunistic pathogens known to cause sinopulmonary disease, the most common manifestation of hyalohyphomycosis: Fusarium spp., Scedosporium spp., Lomentospora prolificans, Scopulariopsis spp., Trichoderma spp., Acremonium spp., Paecilomyces variotii, Purpureocillium lilacinum, Rasamsonia argillacea species complex, Arthrographis kalrae, and Penicillium species. To facilitate an understanding of the epidemiology and clinical features of sino-pulmonary hyalohyphomycoses in the context of host immune impairment, we utilized a host-based approach encompassing the following underlying conditions: neutropenia, hematologic malignancy, hematopoietic and solid organ transplantation, chronic granulomatous disease, acquired immunodeficiency syndrome, cystic fibrosis, and healthy individuals who sustain burns, trauma, or iatrogenic exposures. We further summarize the pre-clinical and clinical data informing antifungal management for each pathogen and consider the role of adjunctive surgery and/or immunomodulatory treatments to optimize patient outcome.
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17
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Guegan H, Poirier W, Ravenel K, Dion S, Delabarre A, Desvillechabrol D, Pinson X, Sergent O, Gallais I, Gangneux JP, Giraud S, Gastebois A. Deciphering the Role of PIG1 and DHN-Melanin in Scedosporium apiospermum Conidia. J Fungi (Basel) 2023; 9:jof9020134. [PMID: 36836250 PMCID: PMC9965090 DOI: 10.3390/jof9020134] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2022] [Revised: 01/10/2023] [Accepted: 01/16/2023] [Indexed: 01/20/2023] Open
Abstract
Scedosporium apiospermum is a saprophytic filamentous fungus involved in human infections, of which the virulence factors that contribute to pathogenesis are still poorly characterized. In particular, little is known about the specific role of dihydroxynaphtalene (DHN)-melanin, located on the external layer of the conidia cell wall. We previously identified a transcription factor, PIG1, which may be involved in DHN-melanin biosynthesis. To elucidate the role of PIG1 and DHN-melanin in S. apiospermum, a CRISPR-Cas9-mediated PIG1 deletion was carried out from two parental strains to evaluate its impact on melanin biosynthesis, conidia cell-wall assembly, and resistance to stress, including the ability to survive macrophage engulfment. ΔPIG1 mutants did not produce melanin and showed a disorganized and thinner cell wall, resulting in a lower survival rate when exposed to oxidizing conditions, or high temperature. The absence of melanin increased the exposure of antigenic patterns on the conidia surface. PIG1 regulates the melanization of S. apiospermum conidia, and is involved in the survival to environmental injuries and to the host immune response, that might participate in virulence. Moreover, a transcriptomic analysis was performed to explain the observed aberrant septate conidia morphology and found differentially expressed genes, underlining the pleiotropic function of PIG1.
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Affiliation(s)
- Hélène Guegan
- CHU Rennes, INSERM, EHESP, IRSET (Institut de Recherche en Santé Environnement et Travail)—UMR_S 1085, 35000 Rennes, France
- Correspondence: ; Tel.: +33-223233496
| | - Wilfried Poirier
- University of Angers, University of Brest, IRF, SFR ICAT, 49000 Angers, France
| | - Kevin Ravenel
- University of Angers, University of Brest, IRF, SFR ICAT, 49000 Angers, France
| | - Sarah Dion
- INSERM, EHESP, IRSET (Institut de Recherche en Santé Environnement et Travail)—UMR_S 1085, 35000 Rennes, France
| | - Aymeric Delabarre
- INSERM, EHESP, IRSET (Institut de Recherche en Santé Environnement et Travail)—UMR_S 1085, 35000 Rennes, France
| | - Dimitri Desvillechabrol
- Institut Pasteur, Université Paris Cité, Plate-Forme Technologique Biomics, 75015 Paris, France
- Institut Pasteur, Université Paris Cité, Bioinformatics and Biostatistics Hub, 75015 Paris, France
| | - Xavier Pinson
- CNRS, INSERM, Biosit UAR 3480 US_S 018, MRic Core Facility, 35000 Rennes, France
| | - Odile Sergent
- INSERM, EHESP, IRSET (Institut de Recherche en Santé Environnement et Travail)—UMR_S 1085, 35000 Rennes, France
| | - Isabelle Gallais
- INSERM, EHESP, IRSET (Institut de Recherche en Santé Environnement et Travail)—UMR_S 1085, 35000 Rennes, France
| | - Jean-Pierre Gangneux
- CHU Rennes, INSERM, EHESP, IRSET (Institut de Recherche en Santé Environnement et Travail)—UMR_S 1085, 35000 Rennes, France
| | - Sandrine Giraud
- University of Angers, University of Brest, IRF, SFR ICAT, 49000 Angers, France
| | - Amandine Gastebois
- University of Angers, University of Brest, IRF, SFR ICAT, 49000 Angers, France
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18
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Hong G. Progress and challenges in fungal lung disease in cystic fibrosis. Curr Opin Pulm Med 2022; 28:584-590. [PMID: 36101907 PMCID: PMC9547960 DOI: 10.1097/mcp.0000000000000921] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
PURPOSE OF REVIEW This review is an overview of the recent progress made for the diagnosis and understanding of fungal lung disease in people with cystic fibrosis (CF), with a focus on Aspergillus fumigatus , the most common filamentous fungus in the CF airway. Currently, the longstanding question of the clinical significance of Aspergillus fumigatus and other fungi in CF respiratory cultures, in the absence of allergy, remains. Clinical criteria and biomarkers are needed to classify fungal lung disease and determine who may warrant therapy. RECENT FINDINGS Several retrospective and prospective studies have described the prevalence of A. fumigatus and other fungi in the CF lung and factors contributing to the changes in fungal epidemiology. Selective fungus culture testing for the detection of fungi in CF sputa has been well studied, yet a standardized fungus culture protocol has yet to be defined. Culture-independent molecular studies and other fungal diagnostic testing have been conducted in the CF population, leading to efforts to better understand the clinical role of these tests. Recent works have aimed to determine whether chronic A. fumigatus colonization is associated with lung disease progression measured by FEV 1 percentage predicted, structural lung disease, lung clearance index and respiratory quality-of-life. However, the existing knowledge gaps remain: definition of a fungal respiratory infection, the association between fungal infection and clinical outcomes, and indications for antifungal therapy. SUMMARY Significant progress has been made for the detection and diagnosis of fungal lung disease. Yet, the role and impact of A. fumigatus and other fungal infections on respiratory health in people with CF remains to be determined.
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Affiliation(s)
- Gina Hong
- Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA
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19
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Chen M, Zhu X, Cong Y, Chen H, Hou Q, Hong N, Chen X, Lei W, Cai J, Lu X, Shuai L, Li X, Deng S, Xu J, Liao W, Pan W, Xu H, de Hoog S. Genotypic diversity and antifungal susceptibility of Scedosporium species from clinical settings in China. Mycoses 2022; 65:1159-1169. [PMID: 35899426 DOI: 10.1111/myc.13507] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2022] [Revised: 07/19/2022] [Accepted: 07/25/2022] [Indexed: 11/29/2022]
Abstract
BACKGROUND Scedosporium species have drawn significant interest as inhabitants of polluted soil and water and as cause of high mortality in near-drowning patients. So far, most cases have been reported from Europe and Australia, while knowledge on their prevalence and genotypic diversity from Asia is scant. OBJECTIVES To increase knowledge of the genetic diversity and in vitro antifungal susceptibility of Scedosporium species involved in human infections from China. METHODS Here we applied the ISHAM-MLST consensus scheme for molecular typing of Scedosporium species and revealed both high species diversity and high genotypic diversity among 45 Chinese clinical Scedosporium isolates. RESULTS Among the five species, Scedosporium boydii (n=22) was the most common, followed by S. apiospermum (n=18), S. aurantiacum (n=4) and S. dehoogii (n=1). S. aurantiacum was reported for the first time from clinical samples in China. The predominant sequence types (STs) were ST17 in S. apiospermum, ST4 in S. boydii and ST92 in S. aurantiacum, including four novel STs (ST40, ST41, ST42 and ST43) in S. apiospermum. Based on the CLSI-M38 A2 criterion, voriconazole was the only antifungal compound with low MIC values (MIC90 ≤ 1 μg/mL) for all Scedosporium isolates in our study. CONCLUSIONS The genetic diversity of clinical isolates of Scedosporium species from China is extremely high, with S. boydii being predominant and S. aurantiacum being firstly reported here. VOR was the only antifungal compound with low MIC values for all Scedosporium isolates in our study, which should be recommended as the first-line antifungal treatment against scedosporiosis in China.
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Affiliation(s)
- Min Chen
- Department of Dermatology, Shanghai Key Laboratory of Medical Mycology, Changzheng Hospital, Shanghai, China.,Institute of Biodiversity and Ecosystem Dynamics, University of Amsterdam, Amsterdam, The Netherlands
| | - Xinlin Zhu
- Department of Dermatology, Shanghai Key Laboratory of Medical Mycology, Changzheng Hospital, Shanghai, China
| | - Yang Cong
- Department of Ultrasound Diagnostic, Shanghai Pulmonary Hospital, Shanghai, China
| | - Hulin Chen
- Department of Dermatology, Guangdong Women and Children Hospital, Guangzhou, China
| | - Qing Hou
- Department of Dermatology, Shanghai Key Laboratory of Medical Mycology, Changzheng Hospital, Shanghai, China
| | - Nan Hong
- Department of Dermatology, Jinling Hospital, Nanjing University School of Medicine, Nanjing, China
| | - Xinchun Chen
- Department of Laboratory Medicine, People's Hospital of Guangxi Zhuang Autonomous Region, Nanning, China
| | - Wenzhi Lei
- Department of Dermatology, Shanghai Key Laboratory of Medical Mycology, Changzheng Hospital, Shanghai, China
| | - Jie Cai
- Xiamen Eye Center affiliated to Xiamen University, Xiamen, China
| | - Xiuhai Lu
- Shandong Eye Hospital, State Key Laboratory Cultivation Base, Shandong Provincial Key Laboratory of Ophthalmology, Shandong Eye Institute, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, China
| | - Lihua Shuai
- Department of Laboratory Medicine, The Affiliated Hospital of Jiujiang College, Jiujiang, China
| | - Xinhua Li
- Department of Dermatology, Taiyuan Central Hospital, Taiyuan, China
| | - Shuwen Deng
- Department of Medical Microbiology, People's Hospital of Suzhou National New & Hi-Tech Industrial Development Zone, Suzhou, China
| | - Jianping Xu
- Department of Biology, McMaster University, Hamilton, Canada
| | - Wanqing Liao
- Department of Dermatology, Shanghai Key Laboratory of Medical Mycology, Changzheng Hospital, Shanghai, China
| | - Weihua Pan
- Department of Dermatology, Shanghai Key Laboratory of Medical Mycology, Changzheng Hospital, Shanghai, China
| | - Heping Xu
- Department of Laboratory Medicine, The First Affiliated Hospital of Xiamen University, Xiamen, China
| | - Sybren de Hoog
- Center of Expertise in Mycology, Radboud University Medical Center/Canisius Wilhelmina Hospital, Nijmegen, The Netherlands
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20
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Shi XW, Li ST, Lou JP, Xu B, Wang J, Wang X, Liu H, Li SK, Zhen P, Zhang T. Scedosporium apiospermum infection of the lumbar vertebrae: A case report. World J Clin Cases 2022; 10:3251-3260. [PMID: 35647125 PMCID: PMC9082694 DOI: 10.12998/wjcc.v10.i10.3251] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/18/2021] [Revised: 12/31/2021] [Accepted: 02/23/2022] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Scedosporium apiospermum (S. apiospermum) is a clinically rare and aggressive fungus mainly found in contaminated water, wetlands, decaying plants, stagnant water, and potted plants in hospitals. The lung, bone, joint, eye, brain, skin, and other sites are easily infected, and there is a marked risk of misdiagnosis. There have been few case reports of infection by S. apiospermum of the lumbar vertebrae; most reports have focused on infection of the lung.
CASE SUMMARY An otherwise healthy 60-year-old man presented with a 4-mo history of lumbosacral pain, stooping, and limited walking. The symptoms were significantly aggravated 10 d prior to hospitalization, and radiating pain in the back of his left lower leg developed, which was so severe that he could not walk. Movement of the lumbar spine was significantly limited, anterior flexion was about 30°; backward extension, right and left lateral curvature, and rotational mobility were about 10°; tenderness of the spinous processes of the lumbar 3-5 vertebrae was evident, and the muscle strength of both lower limbs was grade IV. Imaging suggested bony destruction of the lumbar 3, 4, and 5 vertebrae and sacral 1 vertebra; in addition, the corresponding intervertebral spaces were narrowed and the lumbar 5 vertebra was posteriorly displaced and unstable. Lumbar vertebral infection was also noted, and the possibility of lumbar tuberculosis was considered. We first performed surgical intervention on the lesioned lumbar vertebrae, cleared the infected lesion, and performed stable fixation of the lesioned vertebral body using a lumbar internal fixation device, which restored the stability of the lumbar vertebrae. Cytological and pathological examination of the lesioned tissue removed during surgery confirmed S. apiospermum infection of the lumbar vertebrae; on this basis, the patient was administered voriconazole. At the 6-mo follow-up, efficacy was significant, no drug-related side effects were observed, and imaging examination showed no evidence of recurrence.
CONCLUSION S. apiospermum infection can occur in immunocompetent individuals with no history of near drowning. Voriconazole is effective for the treatment of S. apiospermum infection of the lumbar vertebrae for which it is suitable as the first-line therapy.
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Affiliation(s)
- Xue-Wen Shi
- Orthopaedic Centers, The 940th Hospital of Joint Logistics Support Force of Chinese People’s Liberation Army, Lanzhou 730050, Gansu Province, China
- Orthopaedic Centers, The Clinical Medical College of Ningxia Medical University, Yinchuan 750000, Ningxia Hui Autonomous Region, China
| | - Sheng-Tang Li
- Orthopaedic Centers, The 940th Hospital of Joint Logistics Support Force of Chinese People’s Liberation Army, Lanzhou 730050, Gansu Province, China
- Orthopaedic Centers, The Second Clinical Medical College of Lanzhou University, Lanzhou 730000, Gansu Province, China
| | - Jin-Peng Lou
- Orthopaedic Centers, The 940th Hospital of Joint Logistics Support Force of Chinese People’s Liberation Army, Lanzhou 730050, Gansu Province, China
- Orthopaedic Centers, The Clinical Medical College of Ningxia Medical University, Yinchuan 750000, Ningxia Hui Autonomous Region, China
| | - Bo Xu
- Orthopaedic Centers, The 940th Hospital of Joint Logistics Support Force of Chinese People’s Liberation Army, Lanzhou 730050, Gansu Province, China
- Orthopaedic Centers, The Second Clinical Medical College of Lanzhou University, Lanzhou 730000, Gansu Province, China
| | - Jian Wang
- Orthopaedic Centers, The 940th Hospital of Joint Logistics Support Force of Chinese People’s Liberation Army, Lanzhou 730050, Gansu Province, China
- Orthopaedic Centers, The Clinical Medical College of Gansu University of Traditional Chinese Medicine, Lanzhou 730000, Gansu Province, China
| | - Xin Wang
- Orthopaedic Centers, The 940th Hospital of Joint Logistics Support Force of Chinese People’s Liberation Army, Lanzhou 730050, Gansu Province, China
- Orthopaedic Centers, The Clinical Medical College of Ningxia Medical University, Yinchuan 750000, Ningxia Hui Autonomous Region, China
| | - Hua Liu
- Orthopaedic Centers, The 940th Hospital of Joint Logistics Support Force of Chinese People’s Liberation Army, Lanzhou 730050, Gansu Province, China
| | - Song-Kai Li
- Orthopaedic Centers, The 940th Hospital of Joint Logistics Support Force of Chinese People’s Liberation Army, Lanzhou 730050, Gansu Province, China
| | - Ping Zhen
- Orthopaedic Centers, The 940th Hospital of Joint Logistics Support Force of Chinese People’s Liberation Army, Lanzhou 730050, Gansu Province, China
| | - Tao Zhang
- Orthopaedic Centers, The 940th Hospital of Joint Logistics Support Force of Chinese People’s Liberation Army, Lanzhou 730050, Gansu Province, China
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21
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Irinyi L, Rope M, Meyer W. In depth search of the Sequence Read Archive database reveals global distribution of the emerging pathogenic fungus Scedosporium aurantiacum. Med Mycol 2022; 60:6542442. [PMID: 35244718 PMCID: PMC8994208 DOI: 10.1093/mmy/myac019] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2021] [Revised: 01/30/2022] [Accepted: 03/01/2022] [Indexed: 11/24/2022] Open
Abstract
Scedosporium species are emerging opportunistic fungal pathogens causing various infections mainly in immunocompromised patients, but also in immunocompetent individuals, following traumatic injuries. Clinical manifestations range from local infections, such as subcutaneous mycetoma or bone and joint infections, to pulmonary colonization and severe disseminated diseases. They are commonly found in soil and other environmental sources. To date S. aurantiacum has been reported only from a handful of countries. To identify the worldwide distribution of this species we screened publicly available sequencing data from fungal metabarcoding studies in the Sequence Read Archive (SRA) of The National Centre for Biotechnology Information (NCBI) by multiple BLAST searches. S. aurantiacum was found in 26 countries and two islands, throughout every climatic region. This distribution is like that of other Scedosporium species. Several new environmental sources of S. aurantiacum including human and bovine milk, chicken and canine gut, freshwater, and feces of the giant white-tailed rat (Uromys caudimaculatus) were identified. This study demonstrated that raw sequence data stored in the SRA database can be repurposed using a big data analysis approach to answer biological questions of interest.
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Affiliation(s)
- Laszlo Irinyi
- Molecular Mycology Research Laboratory, Centre for Infectious Diseases and Microbiology, Faculty of Medicine and Health, Sydney Medical School, Westmead Clinical School, The University of Sydney, Sydney, NSW, Australia.,Marie Bashir Institute for Infectious Diseases and Biosecurity, The University of Sydney, Sydney, NSW, Australia.,Westmead Institute for Medical Research, Westmead, NSW Australia
| | - Michael Rope
- Division of Biomedical Science and Biochemistry, Australian National University, Canberra, ACT, Australia
| | - Wieland Meyer
- Molecular Mycology Research Laboratory, Centre for Infectious Diseases and Microbiology, Faculty of Medicine and Health, Sydney Medical School, Westmead Clinical School, The University of Sydney, Sydney, NSW, Australia.,Marie Bashir Institute for Infectious Diseases and Biosecurity, The University of Sydney, Sydney, NSW, Australia.,Westmead Institute for Medical Research, Westmead, NSW Australia.,Westmead Hospital (Research and Education Network), Westmead, NSW, Australia
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22
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Poore TS, Meier M, Towler E, Martiniano SL, Brinton JT, DeBoer EM, Sagel SD, Wagner BD, Zemanick ET. Clinical characteristics of people with cystic fibrosis and frequent fungal infection. Pediatr Pulmonol 2022; 57:152-161. [PMID: 34687280 PMCID: PMC8665034 DOI: 10.1002/ppul.25741] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/04/2021] [Revised: 09/30/2021] [Accepted: 10/19/2021] [Indexed: 01/16/2023]
Abstract
BACKGROUND Individuals with cystic fibrosis (CF) and fungal airway infection may present with fungal bronchitis, allergic bronchopulmonary aspergillosis (ABPA) or may appear unaffected despite fungal detection. We sought to characterize people with CF with frequent detection of fungi from airway samples and determine clinical outcomes. METHODS This retrospective study included individuals with CF with ≥4 lower airway cultures over a 2-year baseline period and ≥2 years of follow-up. We defined two groups: ≤1 positive fungus culture (rare) or ≥2 positive cultures during baseline (frequent). Clinical characteristics and outcomes were determined. RESULTS Between 2004 and 2016, 294 individuals met inclusion with 62% classified as rare and 38% as frequent fungi during baseline. Median follow-up was 6 years (range: 2-9 years). Aspergillus fumigatus was the most common fungal species detected. Individuals with frequent fungi were older (13.7 vs. 11.7 years, p = .02) and more likely to have Stenotrophomonas maltophilia (35% vs. 17%, p < .001) at baseline, but did not differ in lung function or ABPA diagnosis. During follow-up, those with frequent fungi were more likely to have chronic Pseudomonas aeruginosa and S. maltophilia. Individuals with ABPA and frequent fungi had the highest rates of co-infection and co-morbidities, and a trend towards more rapid lung function decline. DISCUSSION Fungal infection in CF was associated with frequent P. aeruginosa and S. maltophilia co-infection even in those without ABPA. Individuals with frequent fungi and ABPA had worse outcomes, highlighting the potential contribution of fungi to CF pulmonary disease.
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Affiliation(s)
- T. Spencer Poore
- Division of Pulmonary and Sleep Medicine, Department of PediatricsUniversity of Alabama at BirminghamBirminghamAlabamaUSA
| | - Maxene Meier
- Department of Biostatistics and InformaticsAnschutz Medical Campus, University of ColoradoAuroraColoradoUSA
| | - Elinor Towler
- Section of Pediatric Pulmonary and Sleep Medicine and Children's Hospital Colorado, Department of PediatricsAnschutz Medical Campus, University of ColoradoAuroraColoradoUSA
| | - Stacey L. Martiniano
- Section of Pediatric Pulmonary and Sleep Medicine and Children's Hospital Colorado, Department of PediatricsAnschutz Medical Campus, University of ColoradoAuroraColoradoUSA
| | - John T. Brinton
- Department of Biostatistics and InformaticsAnschutz Medical Campus, University of ColoradoAuroraColoradoUSA
| | - Emily M. DeBoer
- Section of Pediatric Pulmonary and Sleep Medicine and Children's Hospital Colorado, Department of PediatricsAnschutz Medical Campus, University of ColoradoAuroraColoradoUSA
| | - Scott D. Sagel
- Section of Pediatric Pulmonary and Sleep Medicine and Children's Hospital Colorado, Department of PediatricsAnschutz Medical Campus, University of ColoradoAuroraColoradoUSA
| | - Brandie D. Wagner
- Department of Biostatistics and InformaticsAnschutz Medical Campus, University of ColoradoAuroraColoradoUSA
| | - Edith T. Zemanick
- Section of Pediatric Pulmonary and Sleep Medicine and Children's Hospital Colorado, Department of PediatricsAnschutz Medical Campus, University of ColoradoAuroraColoradoUSA
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23
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Brackin AP, Hemmings SJ, Fisher MC, Rhodes J. Fungal Genomics in Respiratory Medicine: What, How and When? Mycopathologia 2021; 186:589-608. [PMID: 34490551 PMCID: PMC8421194 DOI: 10.1007/s11046-021-00573-x] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2021] [Accepted: 06/14/2021] [Indexed: 12/20/2022]
Abstract
Respiratory infections caused by fungal pathogens present a growing global health concern and are a major cause of death in immunocompromised patients. Worryingly, coronavirus disease-19 (COVID-19) resulting in acute respiratory distress syndrome has been shown to predispose some patients to airborne fungal co-infections. These include secondary pulmonary aspergillosis and mucormycosis. Aspergillosis is most commonly caused by the fungal pathogen Aspergillus fumigatus and primarily treated using the triazole drug group, however in recent years, this fungus has been rapidly gaining resistance against these antifungals. This is of serious clinical concern as multi-azole resistant forms of aspergillosis have a higher risk of mortality when compared against azole-susceptible infections. With the increasing numbers of COVID-19 and other classes of immunocompromised patients, early diagnosis of fungal infections is critical to ensuring patient survival. However, time-limited diagnosis is difficult to achieve with current culture-based methods. Advances within fungal genomics have enabled molecular diagnostic methods to become a fast, reproducible, and cost-effective alternative for diagnosis of respiratory fungal pathogens and detection of antifungal resistance. Here, we describe what techniques are currently available within molecular diagnostics, how they work and when they have been used.
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Affiliation(s)
- Amelie P. Brackin
- MRC Centre for Global Disease Analysis, Imperial College London, London, UK
| | - Sam J. Hemmings
- Department of Infectious Disease Epidemiology, Imperial College London, London, UK
| | - Matthew C. Fisher
- Department of Infectious Disease Epidemiology, Imperial College London, London, UK
| | - Johanna Rhodes
- Department of Infectious Disease Epidemiology, Imperial College London, London, UK
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24
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Mir WAY, Shrestha DB, Khan Suheb MZ, Reddy S, Gaire S. Scedosporium apiospermum Pneumonia in an Immunocompetent Host. Cureus 2021; 13:e16891. [PMID: 34513465 PMCID: PMC8416566 DOI: 10.7759/cureus.16891] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/04/2021] [Indexed: 11/25/2022] Open
Abstract
Invasive fungal infections are being increasingly identified recently. Scedosporium is a significant cause of non-Aspergillus mold infection. It can cause disseminated disease in an immunocompromised host and localized pulmonary infection in immunocompetent ones, especially in those with preformed lung cavities. We present a case of scedosporiosis in an elderly female with bronchiectasis who presented with refractory pulmonary symptoms and infiltrates. The case emphasizes the need to keep the fungal infection in the differential diagnosis of refractory infiltrates in immunocompetent individuals without preformed cavities if they have bronchiectasis. Voriconazole monotherapy can be used as the first-line in proven cases of scedosporiosis.
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Affiliation(s)
| | | | | | - Shravani Reddy
- Department of Internal Medicine, Rush University Hospital, Chicago, USA
| | - Suman Gaire
- Department of Emergency Medicine, Palpa Hospital, Palpa, NPL
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25
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Staerck C, Yaakoub H, Vandeputte P, Tabiasco J, Godon C, Gastebois A, Giraud S, Guillemette T, Calenda A, Delneste Y, Fleury M, Bouchara JP. The Glycosylphosphatidylinositol-Anchored Superoxide Dismutase of Scedosporium apiospermum Protects the Conidia from Oxidative Stress. J Fungi (Basel) 2021; 7:575. [PMID: 34356954 PMCID: PMC8304446 DOI: 10.3390/jof7070575] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2021] [Revised: 07/13/2021] [Accepted: 07/13/2021] [Indexed: 02/07/2023] Open
Abstract
Scedosporium species are common fungal pathogens in patients with cystic fibrosis (CF). To colonize the CF lungs, fungi must cope with the host immune response, especially the reactive oxygen species (ROS) released by phagocytic cells. To this aim, pathogens have developed various antioxidant systems, including superoxide dismutases (SODs) which constitute the first-line protection against oxidative stress. Interestingly, one of the S. apiospermum SOD-encoding genes (SODD gene) exhibits a glycosylphosphatidylinositol (GPI) anchor-binding site and encodes a conidial-specific surface SOD. In this study, a SODDΔ mutant was engineered from a non-homologous end joining-deficient strain (KU70Δ) of S. apiospermum. Compared to its parent strain, the double mutant KU70Δ/SODDΔ exhibited increased susceptibility to various oxidizing agents and triazole antifungals. In addition, the loss of SodD resulted in an increased intracellular killing of the conidia by M1 macrophages derived from human blood monocytes, suggesting the involvement of this superoxide dismutase in the evasion to the host defenses. Nevertheless, one cannot disregard an indirect role of the enzyme in the synthesis or assembly of the cell wall components since transmission electron microscopic analysis revealed a thickening of the inner cell wall layer of the conidia. Further studies are needed to confirm the role of this enzyme in the pathogenesis of Scedosporium infections, including the production of a recombinant protein and study of its protective effect against the infection in a mouse model of scedosporiosis.
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Affiliation(s)
- Cindy Staerck
- Université d’Angers, Université de Bretagne Occidentale, CHU Angers, Groupe d’Etude des Interactions Hôte-Pathogène (GEIHP, EA3142), SFR ICAT, F-49000 Angers, France; (C.S.); (H.Y.); (P.V.); (C.G.); (A.G.); (S.G.); (A.C.); (M.F.)
| | - Hajar Yaakoub
- Université d’Angers, Université de Bretagne Occidentale, CHU Angers, Groupe d’Etude des Interactions Hôte-Pathogène (GEIHP, EA3142), SFR ICAT, F-49000 Angers, France; (C.S.); (H.Y.); (P.V.); (C.G.); (A.G.); (S.G.); (A.C.); (M.F.)
| | - Patrick Vandeputte
- Université d’Angers, Université de Bretagne Occidentale, CHU Angers, Groupe d’Etude des Interactions Hôte-Pathogène (GEIHP, EA3142), SFR ICAT, F-49000 Angers, France; (C.S.); (H.Y.); (P.V.); (C.G.); (A.G.); (S.G.); (A.C.); (M.F.)
| | - Julie Tabiasco
- Université d’Angers, Université de Nantes, CHU Angers, Inserm, CRCINA, SFR ICAT, F-49000 Angers, France; (J.T.); (Y.D.)
| | - Charlotte Godon
- Université d’Angers, Université de Bretagne Occidentale, CHU Angers, Groupe d’Etude des Interactions Hôte-Pathogène (GEIHP, EA3142), SFR ICAT, F-49000 Angers, France; (C.S.); (H.Y.); (P.V.); (C.G.); (A.G.); (S.G.); (A.C.); (M.F.)
| | - Amandine Gastebois
- Université d’Angers, Université de Bretagne Occidentale, CHU Angers, Groupe d’Etude des Interactions Hôte-Pathogène (GEIHP, EA3142), SFR ICAT, F-49000 Angers, France; (C.S.); (H.Y.); (P.V.); (C.G.); (A.G.); (S.G.); (A.C.); (M.F.)
| | - Sandrine Giraud
- Université d’Angers, Université de Bretagne Occidentale, CHU Angers, Groupe d’Etude des Interactions Hôte-Pathogène (GEIHP, EA3142), SFR ICAT, F-49000 Angers, France; (C.S.); (H.Y.); (P.V.); (C.G.); (A.G.); (S.G.); (A.C.); (M.F.)
| | - Thomas Guillemette
- Université d’Angers, Institut Agro, INRAE, IRHS, SFR QUASAV, F-49000 Angers, France;
| | - Alphonse Calenda
- Université d’Angers, Université de Bretagne Occidentale, CHU Angers, Groupe d’Etude des Interactions Hôte-Pathogène (GEIHP, EA3142), SFR ICAT, F-49000 Angers, France; (C.S.); (H.Y.); (P.V.); (C.G.); (A.G.); (S.G.); (A.C.); (M.F.)
| | - Yves Delneste
- Université d’Angers, Université de Nantes, CHU Angers, Inserm, CRCINA, SFR ICAT, F-49000 Angers, France; (J.T.); (Y.D.)
| | - Maxime Fleury
- Université d’Angers, Université de Bretagne Occidentale, CHU Angers, Groupe d’Etude des Interactions Hôte-Pathogène (GEIHP, EA3142), SFR ICAT, F-49000 Angers, France; (C.S.); (H.Y.); (P.V.); (C.G.); (A.G.); (S.G.); (A.C.); (M.F.)
| | - Jean-Philippe Bouchara
- Université d’Angers, Université de Bretagne Occidentale, CHU Angers, Groupe d’Etude des Interactions Hôte-Pathogène (GEIHP, EA3142), SFR ICAT, F-49000 Angers, France; (C.S.); (H.Y.); (P.V.); (C.G.); (A.G.); (S.G.); (A.C.); (M.F.)
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26
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Poirier W, Ravenel K, Bouchara JP, Giraud S. Lower Funneling Pathways in Scedosporium Species. Front Microbiol 2021; 12:630753. [PMID: 34276578 PMCID: PMC8283699 DOI: 10.3389/fmicb.2021.630753] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2020] [Accepted: 06/10/2021] [Indexed: 11/17/2022] Open
Abstract
Lignin, a natural polyaromatic macromolecule, represents an essential component of the lignocellulose biomass. Due to its complexity, the natural degradation of this molecule by microorganisms still remains largely misunderstood. Extracellular oxidative degradation is followed by intracellular metabolic degradation of conserved aromatic intermediate compounds (protocatechuate, catechol, hydroxyquinol, and gentisic acid) that are used as carbon and energy sources. The lower funneling pathways are characterized by the opening of the aromatic ring of these molecules through dioxygenases, leading to degradation products that finally enter into the tricarboxylic acid (TCA) cycle. In order to better understand the adaptation mechanisms of Scedosporium species to their environment, these specific catabolism pathways were studied. Genes encoding ring-cleaving dioxygenases were identified in Scedosporium genomes by sequence homology, and a bioinformatic analysis of the organization of the corresponding gene clusters was performed. In addition, these predictions were confirmed by evaluation of the expression level of the genes of the gentisic acid cluster. When the fungus was cultivated in the presence of lignin or gentisic acid as sole carbon source, experiments revealed that the genes of the gentisic acid cluster were markedly overexpressed in the two Scedosporium species analyzed (Scedosporium apiospermum and Scedosporium aurantiacum). Only the gene encoding a membrane transporter was not overexpressed in the gentisic acid-containing medium. Together, these data suggest the involvement of the lower funneling pathways in Scedosporium adaptation to their environment.
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Affiliation(s)
- Wilfried Poirier
- UNIV Angers, UNIV Brest, Groupe d'Etude des Interactions Hôte-Pathogène (GEIHP), SFR ICAT, Angers, France
| | - Kevin Ravenel
- UNIV Angers, UNIV Brest, Groupe d'Etude des Interactions Hôte-Pathogène (GEIHP), SFR ICAT, Angers, France
| | - Jean-Philippe Bouchara
- UNIV Angers, UNIV Brest, Groupe d'Etude des Interactions Hôte-Pathogène (GEIHP), SFR ICAT, Angers, France
| | - Sandrine Giraud
- UNIV Angers, UNIV Brest, Groupe d'Etude des Interactions Hôte-Pathogène (GEIHP), SFR ICAT, Angers, France
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Kirchhoff L, Dittmer S, Weisner AK, Buer J, Rath PM, Steinmann J. Antibiofilm activity of antifungal drugs, including the novel drug olorofim, against Lomentospora prolificans. J Antimicrob Chemother 2021; 75:2133-2140. [PMID: 32386411 DOI: 10.1093/jac/dkaa157] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2019] [Revised: 03/12/2020] [Accepted: 03/23/2020] [Indexed: 12/24/2022] Open
Abstract
OBJECTIVES Patients with immunodeficiency or cystic fibrosis frequently suffer from respiratory fungal infections. In particular, biofilm-associated fungi cause refractory infection manifestations, linked to increased resistance to anti-infective agents. One emerging filamentous fungus is Lomentospora prolificans. Here, the biofilm-formation capabilities of L. prolificans isolates were investigated and the susceptibility of biofilms to various antifungal agents was analysed. METHODS Biofilm formation of L. prolificans (n = 11) was estimated by crystal violet stain and antibiofilm activity was additionally determined via detection of metabolically active biofilm using an XTT assay. Amphotericin B, micafungin, voriconazole and olorofim were compared with regard to their antibiofilm effects when added prior to adhesion, after adhesion and on mature and preformed fungal biofilms. Imaging via confocal laser scanning microscopy was carried out to demonstrate the effect of drug treatment on the fungal biofilm. RESULTS Antibiofilm activities of the tested antifungal agents were shown to be most effective on adherent cells whilst mature biofilm was the most resistant. The most promising antibiofilm effects were detected with voriconazole and olorofim. Olorofim showed an average minimum biofilm eradication concentration (MBEC) of 0.06 mg/L, when added prior to and after adhesion. The MBECs of voriconazole were ≤4 mg/L. On mature biofilm the MBECs of olorofim and voriconazole were higher than the previously determined MICs against planktonic cultures. In contrast, amphotericin B and especially micafungin did not exhibit sufficient antibiofilm activity against L. prolificans. CONCLUSIONS To our knowledge, this is the first study demonstrating the antibiofilm potential of olorofim against the human pathogenic fungus L. prolificans.
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Affiliation(s)
- Lisa Kirchhoff
- Institute of Medical Microbiology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
| | - Silke Dittmer
- Institute of Medical Microbiology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
| | - Ann-Kathrin Weisner
- Institute of Medical Microbiology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
| | - Jan Buer
- Institute of Medical Microbiology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
| | - Peter-Michael Rath
- Institute of Medical Microbiology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
| | - Joerg Steinmann
- Institute of Medical Microbiology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.,Institute of Clinical Hygiene, Medical Microbiology and Infectiology, Klinikum Nürnberg, Paracelsus Medical University, Nuremberg, Germany
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de Jong CCM, Slabbers L, Engel TGP, Yntema JB, van Westreenen M, Croughs PD, Roeleveld N, Brimicombe R, Verweij PE, Meis JF, Merkus PJ. Clinical relevance of Scedosporium spp. and Exophiala dermatitidis in patients with cystic fibrosis: A nationwide study. Med Mycol 2021; 58:859-866. [PMID: 32030418 PMCID: PMC7527267 DOI: 10.1093/mmy/myaa003] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2019] [Revised: 01/09/2020] [Accepted: 01/24/2020] [Indexed: 12/17/2022] Open
Abstract
An increased prevalence of various filamentous fungi in sputum samples of patients with cystic fibrosis (CF) has been reported. The clinical significance, however, is mostly unclear. The aim of this study was to investigate the clinical relevance of Scedosporium spp. and Exophiala dermatitidis from sputum samples of patients with CF in the Netherlands. In this cross-sectional study, all CF patients of the Dutch national CF registry who were treated at five of the seven recognized CF centers during a 3-year period were included. We linked clinical data of the national CF registry with the national Dutch filamentous fungal database. We investigated the association between clinical characteristics and a positive sputum sample for Scedosporium spp. and E. dermatitidis, using logistic regression. Positive cultures for fungi were obtained from 3787 sputum samples from 699 of the 1312 patients with CF. Scedosporium spp. was associated with severe genotype, CF-related diabetes, several microorganisms, and inhaled antibiotics. E. dermatitidis was associated with older age, female sex, and Aspergillus spp. CF patients with and without Scedosporium spp. or E. dermatitidis seemed comparable in body mass index and lung function. This study suggests that Scedosporium spp. and E. dermatitidis are probably no major pathogens in CF patients in the Netherlands. Greater understanding of epidemiologic trends, risk factors, and pathogenicity of filamentous fungi in the respiratory tracts of patients with CF is needed.
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Affiliation(s)
- C C M de Jong
- Department of Pediatrics, Radboud University Medical Center, Nijmegen, The Netherlands
| | - L Slabbers
- Department of Pediatrics, Radboud University Medical Center, Nijmegen, The Netherlands
| | - T G P Engel
- Department of Medical Micriobiology, Radboud University Medical Center, Nijmegen, The Netherlands.,Centre of Expertise in Mycology Radboudumc/CWZ, Nijmegen, The Netherlands
| | - J B Yntema
- Department of Pediatrics, Radboud University Medical Center, Nijmegen, The Netherlands
| | - M van Westreenen
- Department of Medical Microbiology and Infectious Diseases, Erasmus Medical Centre, Rotterdam, The Netherlands
| | - P D Croughs
- Department of Medical Microbiology and Infectious Diseases, Erasmus Medical Centre, Rotterdam, The Netherlands
| | - N Roeleveld
- Department for Health Evidence, Radboud Institute for Health Sciences, Radboud University Medical Center, Nijmegen, The Netherlands
| | - R Brimicombe
- Department of Medical Microbiology, HagaZiekenhuis, The Hague, The Netherlands
| | - P E Verweij
- Department of Medical Micriobiology, Radboud University Medical Center, Nijmegen, The Netherlands.,Department of Medical Microbiology and Infectious Diseases, Canisius Wilhelmina Hospital (CWZ), Nijmegen, The Netherlands
| | - J F Meis
- Department of Medical Micriobiology, Radboud University Medical Center, Nijmegen, The Netherlands.,Centre of Expertise in Mycology Radboudumc/CWZ, Nijmegen, The Netherlands.,Department of Medical Microbiology and Infectious Diseases, Canisius Wilhelmina Hospital (CWZ), Nijmegen, The Netherlands
| | - P J Merkus
- Department of Pediatrics, Radboud University Medical Center, Nijmegen, The Netherlands
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Scedosporium and Lomentospora infections in lung transplant recipients. CURRENT FUNGAL INFECTION REPORTS 2021. [DOI: 10.1007/s12281-021-00416-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
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Pneumonia With Scedosporium apiospermum and Lomentospora prolificans in a Patient After Bilateral Lung Transplantation for Pulmonary Hypertension: A Case Report. Transplant Proc 2021; 53:1375-1378. [PMID: 33707042 DOI: 10.1016/j.transproceed.2021.02.002] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2020] [Revised: 01/22/2021] [Accepted: 02/01/2021] [Indexed: 11/23/2022]
Abstract
Infections caused by the Scedosporium genus have become recognized as a fatal complication after lung transplantation in Europe and Australia, but the reports have been rare from Asian countries including Japan. We present a case of pneumonia caused by a mixed infection of Scedosporium apiospermum (SA) and Lomentospora prolificans (LP) that developed after augmentation of immunosuppression for chronic lung allograft dysfunction (CLAD) after lung transplantation. A 13-year-old man underwent bilateral lung transplantation for pulmonary hypertension. One year after surgery, he was treated with a series of augmented immunosuppressive therapy for severe acute rejection and subsequent CLAD. Three months following the first steroid pulse therapy, his serum β-D-glucan elevated without any sign of fungal infection by other tests. The serum β-D-glucan once returned to a normal level by empirical administration of micafungin; however, the patient's condition worsened again by discontinuation of it. He did not recover by restarting micafungin, and computed tomography (CT) scans eventually demonstrated new infiltrates in his lung field 6 weeks after the elevation of serum β-D-glucan. Microscopic findings of transbronchial lung biopsy specimens showed filamentous fungi, and the culture of bronchoalveolar lavage fluid revealed the growth of SA and LP. Despite subsequent voriconazole administration, he died 14 days after the start of voriconazole. Early and aggressive inspection including bronchoscopy should be performed for the diagnosis of Scedosporium infection in immunocompromised patients, even if CT scans and sputum culture show no evidence of infection.
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Di Paolo M, Hewitt L, Nwankwo E, Ni M, Vidal-Diaz A, Fisher MC, Armstrong-James D, Shah A. A retrospective 'real-world' cohort study of azole therapeutic drug monitoring and evolution of antifungal resistance in cystic fibrosis. JAC Antimicrob Resist 2021; 3:dlab026. [PMID: 34223100 PMCID: PMC8210303 DOI: 10.1093/jacamr/dlab026] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2020] [Accepted: 02/11/2021] [Indexed: 12/25/2022] Open
Abstract
BACKGROUND Individuals with cystic fibrosis (CF) have an increased susceptibility to fungal infection/allergy, with triazoles often used as first-line therapy. Therapeutic drug monitoring (TDM) is essential due to significant pharmacokinetic variability and the recent emergence of triazole resistance worldwide. OBJECTIVES In this retrospective study we analysed the 'real-world' TDM of azole therapy in a large CF cohort, risk factors for subtherapeutic dosing, and the emergence of azole resistance. METHODS All adults with CF on azole therapy in a large single UK centre were included. Clinical demographics, TDM and microbiology were analysed over a 2 year study period (2015-17) with multivariate logistic regression used to identify risk factors for subtherapeutic dosing. RESULTS 91 adults were treated with azole medication during the study period. A high prevalence of chronic subtherapeutic azole dosing was seen with voriconazole (60.8%) and itraconazole capsule (59.6%) use, representing significant risk factors for subtherapeutic levels. Rapid emergence of azole resistance was additionally seen over the follow-up period with a 21.4% probability of CF patients developing a resistant fungal isolate after 2 years. No significant relationship was found however between subtherapeutic azole dosing and azole resistance emergence. CONCLUSIONS Our study demonstrates a high prevalence of subtherapeutic azole levels in CF adults with increased risk using itraconazole capsules and voriconazole therapy. We show rapid emergence of azole resistance highlighting the need for effective antifungal stewardship. Further large longitudinal studies are needed to understand the effects of antifungal resistance on outcome in CF and the implications of subtherapeutic dosing on resistance evolution.
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Affiliation(s)
- M Di Paolo
- Department of Respiratory Medicine, Royal Brompton and Harefield NHS Foundation Trust, London, UK
| | - L Hewitt
- Department of Respiratory Medicine, Royal Brompton and Harefield NHS Foundation Trust, London, UK
- Faculty of Medicine, Department of Infectious Diseases, Imperial College London, London, UK
| | - E Nwankwo
- Department of Respiratory Medicine, Royal Brompton and Harefield NHS Foundation Trust, London, UK
| | - M Ni
- London In Vitro Diagnostics Collaborative, Department of Surgery and Cancer, Imperial College London, UK
| | - A Vidal-Diaz
- London In Vitro Diagnostics Collaborative, Department of Surgery and Cancer, Imperial College London, UK
| | - M C Fisher
- MRC Centre of Global Infectious Disease Analysis, Department of Infectious Disease Epidemiology, School of Public Health, Imperial College London, UK
| | - D Armstrong-James
- Department of Respiratory Medicine, Royal Brompton and Harefield NHS Foundation Trust, London, UK
- Faculty of Medicine, Department of Infectious Diseases, Imperial College London, London, UK
| | - A Shah
- Department of Respiratory Medicine, Royal Brompton and Harefield NHS Foundation Trust, London, UK
- MRC Centre of Global Infectious Disease Analysis, Department of Infectious Disease Epidemiology, School of Public Health, Imperial College London, UK
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Kitisin T, Ampawong S, Muangkaew W, Sukphopetch P. Phenomic profiling of a novel sibling species within the Scedosporium complex in Thailand. BMC Microbiol 2021; 21:42. [PMID: 33563219 PMCID: PMC7874643 DOI: 10.1186/s12866-021-02105-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2020] [Accepted: 01/18/2021] [Indexed: 11/16/2022] Open
Abstract
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.
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Affiliation(s)
- T Kitisin
- Department of Microbiology and Immunology, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand
| | - S Ampawong
- Department of Tropical Pathology, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand
| | - W Muangkaew
- Department of Microbiology and Immunology, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand
| | - P Sukphopetch
- Department of Microbiology and Immunology, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand.
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The Host Immune Response to Scedosporium/ Lomentospora. J Fungi (Basel) 2021; 7:jof7020075. [PMID: 33499053 PMCID: PMC7912657 DOI: 10.3390/jof7020075] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2020] [Revised: 01/15/2021] [Accepted: 01/19/2021] [Indexed: 12/14/2022] Open
Abstract
Infections caused by the opportunistic pathogens Scedosporium/Lomentospora are on the rise. This causes problems in the clinic due to the difficulty in diagnosing and treating them. This review collates information published on immune response against these fungi, since an understanding of the mechanisms involved is of great interest in developing more effective strategies against them. Scedosporium/Lomentospora cell wall components, including peptidorhamnomannans (PRMs), α-glucans and glucosylceramides, are important immune response activators following their recognition by TLR2, TLR4 and Dectin-1 and through receptors that are yet unknown. After recognition, cytokine synthesis and antifungal activity of different phagocytes and epithelial cells is species-specific, highlighting the poor response by microglial cells against L. prolificans. Moreover, a great number of Scedosporium/Lomentospora antigens have been identified, most notably catalase, PRM and Hsp70 for their potential medical applicability. Against host immune response, these fungi contain evasion mechanisms, inducing host non-protective response, masking fungal molecular patterns, destructing host defense proteins and decreasing oxidative killing. In conclusion, although many advances have been made, many aspects remain to be elucidated and more research is necessary to shed light on the immune response to Scedosporium/Lomentospora.
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Influence of relevant cystic fibrosis bacteria on Scedosporium apiospermum and Scedosporium boydii growth and viability. Braz J Microbiol 2021; 52:185-193. [PMID: 33442865 DOI: 10.1007/s42770-020-00415-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2020] [Accepted: 12/18/2020] [Indexed: 10/22/2022] Open
Abstract
Cystic fibrosis (CF) causes a variety of symptoms in different organs, but the majority of the morbidity and mortality of CF is related with pulmonary conditions. Primary infections are usually bacterial, and when treated with antibiotics, yeast infections appear or become more evident. Studies show that different microorganisms can co-inhabit the same environment and the interactions could be synergistic or antagonistic. Using techniques including viable and non-viable cell-to-cell interactions, mixed culture in liquid, and solid media sharing or not the supernatant, this study has evaluated interactions between the fungal species Scedosporium apiospermum and Scedosporium boydii with the bacterial species Staphylococcus aureus, Pseudomonas aeruginosa, and Burkholderia cepacia. Cell-to-cell interactions in liquid medium showed that P. aeruginosa and B. cepacia were able to reduce fungal viability but only in the presence of alive bacteria. Interactions without cell contact using a semi-permeable membrane showed that all bacteria were able to inhibit both fungal growths/viabilities. Cell-free supernatants from bacterial growth reduced fungal viability in planktonic fungal cells as well as in some conditions for preformed fungal biomass. According to the chemical analysis of the bacterial supernatants, the predominant component is protein. In this work, we verified that bacterial cells and their metabolites, present in the supernatants, can play anti-S. apiospermum and anti-S. boydii roles on fungal growth and viability.
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Martin-Souto L, Buldain I, Areitio M, Aparicio-Fernandez L, Antoran A, Bouchara JP, Martin-Gomez MT, Rementeria A, Hernando FL, Ramirez-Garcia A. ELISA Test for the Serological Detection of Scedosporium/ Lomentospora in Cystic Fibrosis Patients. Front Cell Infect Microbiol 2020; 10:602089. [PMID: 33324582 PMCID: PMC7726441 DOI: 10.3389/fcimb.2020.602089] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2020] [Accepted: 10/28/2020] [Indexed: 12/19/2022] Open
Abstract
The detection and diagnosis of the opportunistic fungi Scedosporium spp. and Lomentospora prolificans still relies mainly on low-sensitive culture-based methods. This fact is especially worrying in Cystic Fibrosis (CF) patients in whom these fungal species are frequently isolated and may increase the risk of suffering from an infection or other health problems. Therefore, with the purpose of developing a serologic detection method for Scedosporium/Lomentospora, four different Scedosporium boydii protein extracts (whole cell protein extract, secretome, total cell surface and conidial surface associated proteins) were studied by ELISA to select the most useful for IgG detection in sera from CF patients. The four extracts were able to discriminate the Scedosporium/Lomentospora-infected from Aspergillus-infected and non-infected patients. However, the whole cell protein extract was the one selected, as it was the one with the highest output in terms of protein concentration per ml of fungal culture used, and its discriminatory capacity was the best. The ELISA test developed was then assayed with 212 sera from CF patients and it showed to be able to detect Scedosporium spp. and Lomentospora prolificans with very high sensitivity and specificity, 86%–100% and 93%–99%, respectively, depending on the cut-off value chosen (four values were proposed A450nm= 0.5837, A450nm= 0.6042, A450nm= 0.6404, and A450nm= 0.7099). Thus, although more research is needed to reach a standardized method, this ELISA platform offers a rapid, low-cost and easy solution to detect these elusive fungi through minimally invasive sampling, allowing the monitoring of the humoral response to fungal presence.
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Affiliation(s)
- Leire Martin-Souto
- Fungal and Bacterial Biomics Research Group, Department of Immunology, Microbiology and Parasitology, University of the Basque Country (UPV/EHU), Leioa, Spain
| | - Idoia Buldain
- Fungal and Bacterial Biomics Research Group, Department of Immunology, Microbiology and Parasitology, University of the Basque Country (UPV/EHU), Leioa, Spain
| | - Maialen Areitio
- Fungal and Bacterial Biomics Research Group, Department of Immunology, Microbiology and Parasitology, University of the Basque Country (UPV/EHU), Leioa, Spain
| | - Leire Aparicio-Fernandez
- Fungal and Bacterial Biomics Research Group, Department of Immunology, Microbiology and Parasitology, University of the Basque Country (UPV/EHU), Leioa, Spain
| | - Aitziber Antoran
- Fungal and Bacterial Biomics Research Group, Department of Immunology, Microbiology and Parasitology, University of the Basque Country (UPV/EHU), Leioa, Spain
| | - Jean-Philippe Bouchara
- Groupe d'Etude des Interactions Hôte-Pathogène (EA 3142), SFR ICAT 4208, Institut de Biologie en Santé-IRIS, Centre Hospitalier Universitaire, Angers, France
| | | | - Aitor Rementeria
- Fungal and Bacterial Biomics Research Group, Department of Immunology, Microbiology and Parasitology, University of the Basque Country (UPV/EHU), Leioa, Spain
| | - Fernando L Hernando
- Fungal and Bacterial Biomics Research Group, Department of Immunology, Microbiology and Parasitology, University of the Basque Country (UPV/EHU), Leioa, Spain
| | - Andoni Ramirez-Garcia
- Fungal and Bacterial Biomics Research Group, Department of Immunology, Microbiology and Parasitology, University of the Basque Country (UPV/EHU), Leioa, Spain
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Mello TP, Lackner M, Branquinha MH, Santos ALS. Impact of biofilm formation and azoles' susceptibility in Scedosporium/Lomentospora species using an in vitro model that mimics the cystic fibrosis patients' airway environment. J Cyst Fibros 2020; 20:303-309. [PMID: 33334714 DOI: 10.1016/j.jcf.2020.12.001] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2020] [Revised: 11/30/2020] [Accepted: 12/01/2020] [Indexed: 01/09/2023]
Abstract
BACKGROUND Scedosporium species are the second most isolated filamentous fungi from cystic fibrosis (CF) patients; however, little is known about their virulence aspects in a CF environment. In this context, the current study aimed to evaluate the (i) antifungal susceptibility profiles, (ii) ability to form biofilm and (iii) impact of biofilm formation on the susceptibility to azoles in 21 clinical isolates of Scedosporium recovered from CF patients. METHODS Scedosporium apiospermum (n=6), S. aurantiacum (n=6), S. minutisporum (n=3) and Lomentospora prolificans (n=6) were firstly used to compare the antifungal susceptibility profile using a standard culture broth (RPMI-1640) and a mucin (M)-containing synthetic CF sputum medium (SCFM). The ability to form biofilms was investigated in polystyrene microtiter plates containing Sabouraud-dextrose (a classical medium), SCFM and SCFM+M. Mature biofilms were tested for their susceptibility to azoles by microdilution assay. RESULTS Our results showed that the minimum inhibitory concentrations (MICs) for planktonic conidia ranged from 0.25 to >16.0 mg/L for voriconazole and 1.0 to >16.0 mg/L for posaconazole. Overall, the MICs for azoles increased from 2- to 8-folds when the susceptibility tests were performed using SCFM+M compared to RPMI-1640. All fungi formed robust biofilms on polystyrene surface at 72 h, with a significant increase in the MICs (ranging from 128- to 1024-times) against both azoles compared to the planktonic cells. CONCLUSION These findings confirm the challenge of antifungal treatment of CF patients infected with Scedosporium/Lomentospora and also demonstrated a strong biofilm formation, with extensive increase in antifungal resistance, triggered underconditions mimicking the CF patient airway.
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Affiliation(s)
- Thaís P Mello
- Laboratório de Estudos Avançados de Microrganismos Emergentes e Resistentes (LEAMER), Departamento de Microbiologia Geral, Instituto de Microbiologia Paulo de Góes (IMPG), Centro de Ciências da Saúde (CCS), Universidade Federal do Rio de Janeiro (UFRJ), Rio de Janeiro, Brazil
| | - Michaela Lackner
- Medical University of Innsbruck, Institute for Hygiene and Medical Microbiology, Schöpfstrasse 41, 6020 Innsbruck, Austria
| | - Marta H Branquinha
- Laboratório de Estudos Avançados de Microrganismos Emergentes e Resistentes (LEAMER), Departamento de Microbiologia Geral, Instituto de Microbiologia Paulo de Góes (IMPG), Centro de Ciências da Saúde (CCS), Universidade Federal do Rio de Janeiro (UFRJ), Rio de Janeiro, Brazil
| | - André L S Santos
- Laboratório de Estudos Avançados de Microrganismos Emergentes e Resistentes (LEAMER), Departamento de Microbiologia Geral, Instituto de Microbiologia Paulo de Góes (IMPG), Centro de Ciências da Saúde (CCS), Universidade Federal do Rio de Janeiro (UFRJ), Rio de Janeiro, Brazil; Programa de Pós-Graduação em Bioquímica (PPGBq), Instituto de Química (IQ), Universidade Federal do Rio de Janeiro (UFRJ) , Rio de Janeiro, Brazil.
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Comparative transcriptome analysis unveils the adaptative mechanisms of Scedosporium apiospermum to the microenvironment encountered in the lungs of patients with cystic fibrosis. Comput Struct Biotechnol J 2020; 18:3468-3483. [PMID: 33294141 PMCID: PMC7691682 DOI: 10.1016/j.csbj.2020.10.034] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2020] [Revised: 10/30/2020] [Accepted: 10/30/2020] [Indexed: 11/21/2022] Open
Abstract
Scedosporium species rank second among the filamentous fungi colonizing the lungs of patients with cystic fibrosis (CF). Apart from the context of immunodeficiency (lung transplantation), the colonization of the CF airways by these fungi usually remains asymptomatic. Why the colonization of the lower airways by Scedosporium species is fairly tolerated by CF patients while these fungi are able to induce a marked inflammatory reaction in other clinical contexts remains questionable. In this regards, we were interested here in exploring the transcriptional reprogramming that accompanies the adaptation of these fungi to the particular microenvironment encountered in the airways of CF patients. Cultivation of Scedosporium apiospermum in conditions mimicking the microenvironment in the CF lungs was shown to induce marked transcriptional changes. This includes notably the down-regulation of enzymes involved in the synthesis of some major components of the plasma membrane which may reflect the ability of the fungus to evade the host immune response by lowering the biosynthesis of some major antigenic determinants or inhibiting their targeting to the cell surface through alterations of the membrane fluidity. In addition, this analysis revealed that some genes encoding enzymes involved in the biosynthesis of some mycotoxins were down-regulated suggesting that, during the colonization process, S. apiospermum reduces the production of some toxic secondary metabolites to prevent exacerbation of the immune system response. Finally, a strong up-regulation of many genes encoding enzymes involved in the degradation of aromatic compounds was observed, suggesting that these catabolic properties would predispose the fungus to particular patterns of human pathogenicity. Together these data provide new insights into the adaptative mechanisms developed by S. apiospermum in the CF lungs, which should be considered for identification of potential targets for drug development, but also for the experimental conditions to be used in in vitro susceptibility testing of clinical isolates to current antifungals.
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Fungal Infections and ABPA. Respir Med 2020. [DOI: 10.1007/978-3-030-42382-7_6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/24/2022]
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Bouchara JP, Le Govic Y, Kabbara S, Cimon B, Zouhair R, Hamze M, Papon N, Nevez G. Advances in understanding and managing Scedosporium respiratory infections in patients with cystic fibrosis. Expert Rev Respir Med 2019; 14:259-273. [PMID: 31868041 DOI: 10.1080/17476348.2020.1705787] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Introduction: Considered for a long time to be exclusively responsible for chronic localized infections, fungi of the genus Scedosporium have recently received a renewed interest because of their recognition as common colonizing agents of the respiratory tract of patients with cystic fibrosis, and of the description of severe disseminated infections in patients undergoing lung transplantation. Recently, several studies have been carried out on these opportunistic pathogens, which led to some advances in the understanding of their pathogenic mechanisms and in the biological diagnosis of the airway colonization/respiratory infections caused by these fungi.Areas covered: From a bibliographic search on the Pubmed database, we summarize the current knowledge about the taxonomy of Scedosporium species, the epidemiology of these fungi and their pathogenic mechanisms, and present the improvements in the detection of the airway colonization and diagnosis of Scedosporium respiratory infections, the difficulties in their therapeutic management, and the antifungal drugs in development.Expert opinion: As described in this review, many advances have been made regarding the taxonomy and ecology of Scedosporium species or the molecular determinants of their pathogenicity, but also in the management of Scedosporium infections, particularly by improving the biological diagnostic and publishing evidence for the efficacy of combined therapy.
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Affiliation(s)
- Jean-Philippe Bouchara
- Groupe d'Etude des Interactions Hôte-Pathogène (GEIHP, EA 3142), UNIV Angers, UNIV Brest, SFR 4208 ICAT, Angers, France
| | - Yohann Le Govic
- Groupe d'Etude des Interactions Hôte-Pathogène (GEIHP, EA 3142), UNIV Angers, UNIV Brest, SFR 4208 ICAT, Angers, France
| | - Samar Kabbara
- Groupe d'Etude des Interactions Hôte-Pathogène (GEIHP, EA 3142), UNIV Angers, UNIV Brest, SFR 4208 ICAT, Angers, France
| | - Bernard Cimon
- Groupe d'Etude des Interactions Hôte-Pathogène (GEIHP, EA 3142), UNIV Angers, UNIV Brest, SFR 4208 ICAT, Angers, France
| | - Rachid Zouhair
- Groupe d'Etude des Interactions Hôte-Pathogène (GEIHP, EA 3142), UNIV Angers, UNIV Brest, SFR 4208 ICAT, Angers, France
| | - Monzer Hamze
- Laboratoire Microbiologie Santé et Environnement (LMSE), Ecole Doctorale des Sciences et de Technologie, Faculté de Santé Publique, Université Libanaise, Tripoli, Liban
| | - Nicolas Papon
- Groupe d'Etude des Interactions Hôte-Pathogène (GEIHP, EA 3142), UNIV Angers, UNIV Brest, SFR 4208 ICAT, Angers, France
| | - Gilles Nevez
- Groupe d'Etude des Interactions Hôte-Pathogène (GEIHP, EA 3142), UNIV Angers, UNIV Brest, Brest, France
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Thornton CR. Detection of the 'Big Five' mold killers of humans: Aspergillus, Fusarium, Lomentospora, Scedosporium and Mucormycetes. ADVANCES IN APPLIED MICROBIOLOGY 2019; 110:1-61. [PMID: 32386603 DOI: 10.1016/bs.aambs.2019.10.003] [Citation(s) in RCA: 38] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
Fungi are an important but frequently overlooked cause of morbidity and mortality in humans. Life-threatening fungal infections mainly occur in immunocompromised patients, and are typically caused by environmental opportunists that take advantage of a weakened immune system. The filamentous fungus Aspergillus fumigatus is the most important and well-documented mold pathogen of humans, causing a number of complex respiratory diseases, including invasive pulmonary aspergillosis, an often fatal disease in patients with acute leukemia or in immunosuppressed bone marrow or solid organ transplant recipients. However, non-Aspergillus molds are increasingly reported as agents of disseminated diseases, with Fusarium, Scedosporium, Lomentospora and mucormycete species now firmly established as pathogens of immunosuppressed and immunocompetent individuals. Despite well-documented risk factors for invasive fungal diseases, and increased awareness of the risk factors for life-threatening infections, the number of deaths attributable to molds is likely to be severely underestimated driven, to a large extent, by the lack of readily accessible, cheap, and accurate tests that allow detection and differentiation of infecting species. Early diagnosis is critical to patient survival but, unlike Aspergillus diseases, where a number of CE-marked or FDA-approved biomarker tests are now available for clinical diagnosis, similar tests for fusariosis, scedosporiosis and mucormycosis remain experimental, with detection reliant on insensitive and slow culture of pathogens from invasive bronchoalveolar lavage fluid, tissue biopsy, or from blood. This review examines the ecology, epidemiology, and contemporary methods of detection of these mold pathogens, and the obstacles to diagnostic test development and translation of novel biomarkers to the clinical setting.
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Rammaert B, Puyade M, Cornely OA, Seidel D, Grossi P, Husain S, Picard C, Lass-Flörl C, Manuel O, Le Pavec J, Lortholary O. 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. Transpl Infect Dis 2019; 21:e13141. [PMID: 31283872 DOI: 10.1111/tid.13141] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2019] [Revised: 06/24/2019] [Accepted: 07/01/2019] [Indexed: 12/20/2022]
Abstract
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.
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Affiliation(s)
- Blandine Rammaert
- Faculté de médecine et pharmacie, Univ Poitiers, Poitiers, France
- Service de maladies infectieuses et tropicales, CHU Poitiers, Poitiers, France
- INSERM U1070, Poitiers, France
| | - Mathieu Puyade
- Service de médecine interne, CHU Poitiers, Poitiers, France
| | - Oliver A Cornely
- Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), Department I of Internal Medicine, Clinical Trials Centre Cologne (ZKS), German Centre for Infection Research (DZIF), Partner site Bonn-Cologne, University of Cologne, Cologne, Germany
| | - Danila Seidel
- Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), Department I of Internal Medicine, Clinical Trials Centre Cologne (ZKS), German Centre for Infection Research (DZIF), Partner site Bonn-Cologne, University of Cologne, Cologne, Germany
| | - Paolo Grossi
- Department of Medicine & Surgery, Infectious and Tropical Diseases Unit, University of Insubria, Varese, Italy
| | - Shahid Husain
- Multi-Organ Transplant Program, Division of Infectious Diseases, University Health Network, University of Toronto, Toronto, Canada
| | | | - Cornelia Lass-Flörl
- Division of Hygiene and Medical Microbiology, Medical University of Innsbruck, Innsbruck, Austria
| | - Oriol Manuel
- Transplantation Center and Infectious Diseases Service, University Hospital (CHUV) and University of Lausanne, Lausanne, Switzerland
| | - Jérôme Le Pavec
- Université Paris-Sud, Faculté de Médecine, Université Paris Saclay, Le Kremlin Bicêtre, France
- Service de Chirurgie Thoracique, Vasculaire et Transplantation Cardio-pulmonaire, Hôpital Marie-Lannelongue, Le Plessis-Robinson, France
- UMR-S 999, Universite Paris-Sud, INSERM, Hôpital Marie Lannelongue, Le Plessis-Robinson, France
| | - Olivier Lortholary
- Université de Paris, APHP, Service des Maladies Infectieuses et Tropicales, Hôpital Necker-Enfants Malades, Centre d'Infectiologie Necker-Pasteur, Institut Imagine, Paris, France
- Institut Pasteur, Unité de Mycologie Moléculaire, Centre National de Référence Mycoses Invasives et Antifongiques, CNRS UMR 2000, Paris, France
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Boyle M, Moore JE, Whitehouse JL, Bilton D, Downey DG. The diagnosis and management of respiratory tract fungal infection in cystic fibrosis: A UK survey of current practice. Med Mycol 2019; 57:155-160. [PMID: 29554296 DOI: 10.1093/mmy/myy014] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2017] [Accepted: 02/19/2018] [Indexed: 12/30/2022] Open
Abstract
Aspergillus fumigatus is commonly found in the airways of patients with cystic fibrosis (CF), and allergic bronchopulmonary aspergillosis (ABPA) is the most recognized associated clinical condition. However, accurate diagnosis remains challenging, and there is a paucity of clinical trials to guide clinical management of fungal disease. The aim of this survey was to assess the variability in current practice across the UK in diagnosis and management of fungal lung disease in CF patients. A 21 question anonymous online survey was sent to 94 paediatric and adult CF consultants in the UK. The response rate was 60.6% (32 adult physicians, 25 pediatricians) with 55 full and 2 partially completed surveys. For a first diagnosis of ABPA 20 (35.1%) treat with prednisolone alone, 38 (66.7%) use prednisolone with itraconazole and 2 (3.5%) choose voriconazole. Only 5 (8.8%) treat with prednisolone alone for a 1st relapse, 33 (58%) used prednisolone with itraconazole. To reduce treatment, 21 (36.8%) decrease steroids to zero over time and maintain azole therapy, 18 (31.6%) stop the azole and steroid after a fixed time, and 5 (8.8%) stop the azole after a fixed time and maintain a small steroid dose. Thirty-eight (66.7%) respondents believe Aspergillus colonization of the airway can cause clinical deterioration, and 37 (66.1%) would treat this. Scedosporium apiospermum infection has been diagnosed and treated by 35 (61.4%) of respondents. Results of this survey highlight the variance in clinical practice and the limited evidence available to guide management of fungal infection in CF.
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Affiliation(s)
- M Boyle
- Northern Ireland Regional Adult CF Centre, Belfast City Hospital, Belfast, Northern Ireland, UK
| | - J E Moore
- Northern Ireland Regional Adult CF Centre, Belfast City Hospital, Belfast, Northern Ireland, UK
| | | | - D Bilton
- Royal Brompton Hospital, London, UK
| | - D G Downey
- Northern Ireland Regional Adult CF Centre, Belfast City Hospital, Belfast, Northern Ireland, UK.,Centre for Experimental Medicine, Queen's University of Belfast, Belfast, Northern Ireland, UK
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Le Govic Y, Papon N, Le Gal S, Bouchara JP, Vandeputte P. Non-ribosomal Peptide Synthetase Gene Clusters in the Human Pathogenic Fungus Scedosporium apiospermum. Front Microbiol 2019; 10:2062. [PMID: 31551992 PMCID: PMC6737921 DOI: 10.3389/fmicb.2019.02062] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2019] [Accepted: 08/21/2019] [Indexed: 11/13/2022] Open
Abstract
Scedosporium species are opportunistic fungi which preferentially affect patients with underlying conditions such as immunosuppression or cystic fibrosis (CF). While being the second most common molds capable to chronically colonize the CF lungs, the natural history of infection remains unclear. In filamentous fungi, a broad range of important secondary metabolites that are recognized as virulence factors are produced by multidomain non-ribosomal peptide synthetases (NRPSs). The aim of this study was to provide a global in silico analysis of NRPS-encoding genes based on the recently sequenced Scedosporium apiospermum genome. We uncovered a total of nine NRPS genes, of which six exhibited sufficient similarity scores with other fungal NRPSs to predict the class of the generated peptide: siderophores (n = 2), epidithiodioxopiperazines (n = 2), and cyclopeptides (n = 2). Phylogenetic trees based on the multiple alignments of adenylation (A) domain sequences corroborated these findings. Nevertheless, substrate prediction methods for NRPS A-domains tended to fail, thus questioning about the exact nature of the peptide produced. Further studies should be undertaken since NRPSs, which are not synthesized by human cells, could represent attractive therapeutic targets.
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Affiliation(s)
- Yohann Le Govic
- Groupe d'Etude des Interactions Hôte-Pathogène (GEIHP, EA 3142), SFR ICAT 4208, Université d'Angers, Angers, France.,Laboratoire de Parasitologie-Mycologie, Centre Hospitalier Universitaire, Université d'Angers, Angers, France
| | - Nicolas Papon
- Groupe d'Etude des Interactions Hôte-Pathogène (GEIHP, EA 3142), SFR ICAT 4208, Université d'Angers, Angers, France
| | - Solène Le Gal
- Groupe d'Etude des Interactions Hôte-Pathogène (GEIHP, EA 3142), SFR ICAT 4208, Université de Bretagne Occidentale, Brest, France.,Laboratoire de Parasitologie-Mycologie, Centre Hospitalier Universitaire, Université de Bretagne Occidentale, Brest, France
| | - Jean-Philippe Bouchara
- Groupe d'Etude des Interactions Hôte-Pathogène (GEIHP, EA 3142), SFR ICAT 4208, Université d'Angers, Angers, France.,Laboratoire de Parasitologie-Mycologie, Centre Hospitalier Universitaire, Université d'Angers, Angers, France
| | - Patrick Vandeputte
- Groupe d'Etude des Interactions Hôte-Pathogène (GEIHP, EA 3142), SFR ICAT 4208, Université d'Angers, Angers, France.,Laboratoire de Parasitologie-Mycologie, Centre Hospitalier Universitaire, Université d'Angers, Angers, France
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Bobokhojaev OI, Osmanov A, Aliev SP, Radjabzoda AS, Avgonov ZT, Manonov ST, Denning DW. The Burden of Serious Fungal Infections in Tajikistan. J Fungi (Basel) 2019; 5:jof5030068. [PMID: 31330914 PMCID: PMC6787594 DOI: 10.3390/jof5030068] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2019] [Revised: 07/16/2019] [Accepted: 07/19/2019] [Indexed: 12/12/2022] Open
Abstract
Tajikistan is a low-income country in Middle Asia with a population of 8.9 million people. Five percent of the population lives on less than 1.9 USD a day and 54% live on less than 5.5 USD a day. We have estimated the burden of serious fungal infections in Tajikistan. It was estimated that 168,834 Tajik women develop recurrent vulvovaginal candidiasis. Among HIV-positive patients, we estimate 490 patients with oesophageal candidiasis and 1260 patients with oral candidiasis, 41 cases of cryptococcal meningitis and 210 cases of Pneumocystis pneumonia annually. According to our estimations there are 774 cases of chronic pulmonary aspergillosis (CPA) as a sequel of tuberculosis; CPA may occur as a consequence of multiple pulmonary conditions and the total prevalence of 4161 cases was estimated. We have estimated 6008 cased of allergic bronchopulmonary aspergillosis (ABPA) and 7930 cases of severe asthma with fungal sensitisation (SAFS), and 137 fungal asthma deaths annually. We have estimated 445 cases of candidemia a year applying a low European rate. There are approximately 283 cases of invasive aspergillosis annually. There are 189,662 (2.1% of the population) people suffering from serious fungal infections in Tajikistan. Hence, improving diagnostics is the first step of understanding a scale of the fungal burden.
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Affiliation(s)
- Oktam I Bobokhojaev
- Department of Phthisiopneumology, Tajik State Medical University, 734003 Dushanbe, Tajikistan
| | - Ali Osmanov
- Global Action Fund for Fungal Infections, 1208 Geneva, Switzerland.
| | - Samariddin P Aliev
- Research Scientific Institute of Preventive Medicine, Ministry of Health and Social Protection of the population, 734025 Dushanbe, Tajikistan
| | - Asliddin S Radjabzoda
- Republican Center of the Protection Population from Tuberculosis Ministry of Health and Social Protection of the Population, 734000 Dushanbe, Tajikistan
| | - Ziyovuddin T Avgonov
- Secretariat of the National Coordination Committee to Fight AIDS, TB and Malaria, 734018 Dushanbe, Tajikistan
| | - Safarbek T Manonov
- Republican Center of Medical Statistics, Ministry of Health and Social Protection of the Population, 734025 Dushanbe, Tajikistan
| | - David W Denning
- Global Action Fund for Fungal Infections, 1208 Geneva, Switzerland
- Faculty of Biology, Medicine and Health, University of Manchester, Manchester Academic Health Science Centre, Manchester M13 9NT, UK
- National Aspergillosis Centre, Wythenshawe Hospital, Manchester University NHS Foundation Trust, Manchester Academic Health Science Centre, Southmoor Road, Manchester M23 9LT, UK
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Erro Iribarren M, Girón Moreno RM, Diab Cáceres L, Pastor Sanz MT, Buendía Moreno B, Alarcón Cavero T, Granja Torrecillas S, Zurita Cruz ND, Ancochea Bermúdez J. Study of a Cohort of Patients With Cystic Fibrosis and Isolation of Scedosporium spp. Arch Bronconeumol 2019; 55:559-564. [PMID: 31178266 DOI: 10.1016/j.arbres.2019.02.018] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2018] [Revised: 01/22/2019] [Accepted: 02/14/2019] [Indexed: 11/18/2022]
Abstract
INTRODUCTION In recent years an increase in the prevalence of colonization and infection by Scedosporium spp. in patients with cystic fibrosis (CF) has been observed. In this article, we study the frequency of isolation of Scedosporium spp. in an adult CF Unit, analyzing characteristics of the patients and predisposing factors. METHODS A retrospective observational study was conducted in 87 adult CF patients in whom the presence of positive culture for Scedosporium spp. was tested for a 5-year period (January 2012-July 2017). We recorded the following clinical variables: age, sex, body mass index, genotype, presence of pancreatic insufficiency, bacterial colonization, lung function, other complications, exacerbations and treatment, and the modified Bhalla score from the last high-resolution computed tomography. Results were analyzed with IBM SPSS Statistics Version 22.0 software. RESULTS Scedosporium spp. was isolated in 25.3% of patients. In the bivariate analysis, these patients showed a higher rate of Pseudomonas aeruginosa infection, worse score in the Bhalla classification (highlighting the following items: bronchiectasis, mucus plugs and bronchial generations), a slight decrease in the lung diffusion capacity and more frequently received inhaled antibiotics. In the logistic regression multivariate analysis, only the bronchial generations item was significant. CONCLUSION Scedosporium spp. must be considered an emerging opportunistic pathogen in patients with CF whose clinical involvement, risk factors or need for treatment is unknown.
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Affiliation(s)
- Marta Erro Iribarren
- Servicio de Neumología, Hospital Universitario de la Princesa, Madrid, España; Instituto de Investigación Sanitaria de la Princesa, Madrid, España.
| | - Rosa María Girón Moreno
- Servicio de Neumología, Hospital Universitario de la Princesa, Madrid, España; Instituto de Investigación Sanitaria de la Princesa, Madrid, España
| | - Layla Diab Cáceres
- Servicio de Neumología, Hospital Universitario de la Princesa, Madrid, España; Instituto de Investigación Sanitaria de la Princesa, Madrid, España
| | - María Teresa Pastor Sanz
- Servicio de Neumología, Hospital Universitario de la Princesa, Madrid, España; Instituto de Investigación Sanitaria de la Princesa, Madrid, España
| | - Buenaventura Buendía Moreno
- Instituto de Investigación Sanitaria de la Princesa, Madrid, España; Servicio de Microbiología y Parasitología, Hospital Universitario de la Princesa, Madrid, España
| | - Teresa Alarcón Cavero
- Instituto de Investigación Sanitaria de la Princesa, Madrid, España; Servicio de Microbiología y Parasitología, Hospital Universitario de la Princesa, Madrid, España
| | - Silvia Granja Torrecillas
- Instituto de Investigación Sanitaria de la Princesa, Madrid, España; Servicio de Microbiología y Parasitología, Hospital Universitario de la Princesa, Madrid, España
| | - Nelly Daniela Zurita Cruz
- Instituto de Investigación Sanitaria de la Princesa, Madrid, España; Servicio de Microbiología y Parasitología, Hospital Universitario de la Princesa, Madrid, España
| | - Julio Ancochea Bermúdez
- Servicio de Neumología, Hospital Universitario de la Princesa, Madrid, España; Instituto de Investigación Sanitaria de la Princesa, Madrid, España
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Delfino E, Del Puente F, Briano F, Sepulcri C, Giacobbe DR. Respiratory Fungal Diseases in Adult Patients With Cystic Fibrosis. CLINICAL MEDICINE INSIGHTS-CIRCULATORY RESPIRATORY AND PULMONARY MEDICINE 2019; 13:1179548419849939. [PMID: 31205434 PMCID: PMC6537484 DOI: 10.1177/1179548419849939] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/29/2019] [Accepted: 04/18/2019] [Indexed: 12/20/2022]
Abstract
Clinical manifestations of respiratory fungal diseases in adult cystic fibrosis (CF) patients are very heterogeneous, ranging from asymptomatic colonization to chronic infections, allergic disorders, or invasive diseases in immunosuppressed CF patients after lung transplantation. In this narrative review, mainly addressed to clinicians without expertise in CF who may nonetheless encounter adult CF patients presenting with acute and chronic respiratory syndromes, we briefly summarize the most representative clinical aspects of respiratory fungal diseases in adult CF patients.
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Affiliation(s)
- Emanuele Delfino
- Clinica Malattie Infettive e Tropicali, Ospedale Policlinico San Martino-IRCCS, Genoa, Italy
| | - Filippo Del Puente
- Clinica Malattie Infettive e Tropicali, Ospedale Policlinico San Martino-IRCCS, Genoa, Italy.,Department of Health Sciences, University of Genoa, Genoa, Italy
| | - Federica Briano
- Clinica Malattie Infettive e Tropicali, Ospedale Policlinico San Martino-IRCCS, Genoa, Italy.,Department of Health Sciences, University of Genoa, Genoa, Italy
| | - Chiara Sepulcri
- Clinica Malattie Infettive e Tropicali, Ospedale Policlinico San Martino-IRCCS, Genoa, Italy.,Department of Health Sciences, University of Genoa, Genoa, Italy
| | - Daniele Roberto Giacobbe
- Clinica Malattie Infettive e Tropicali, Ospedale Policlinico San Martino-IRCCS, Genoa, Italy.,Department of Health Sciences, University of Genoa, Genoa, Italy
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Shoham S, Dominguez EA. Emerging fungal infections in solid organ transplant recipients: Guidelines of the American Society of Transplantation Infectious Diseases Community of Practice. Clin Transplant 2019; 33:e13525. [PMID: 30859651 DOI: 10.1111/ctr.13525] [Citation(s) in RCA: 38] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2019] [Accepted: 02/27/2019] [Indexed: 12/13/2022]
Abstract
These updated AST-IDCOP guidelines review the epidemiology, diagnosis, and management of emerging fungi after organ transplantation. Infections due to numerous generally innocuous fungi are increasingly recognized in solid organ transplant (SOT) recipients, comprising about 7%-10% of fungal infections in this setting. Such infections are collectively referred to as emerging fungal infections and include Mucormycetes, Fusarium, Scedosporium, and dematiaceous fungi among others. The causative organisms are diverse in their pathophysiology, uncommon in the clinical setting, have evolving nomenclature, and are often resistant to multiple commonly used antifungal agents. In recent years significant advances have been made in understanding of the epidemiology of these emerging fungal infections, with improved diagnosis and expanded treatment options. Still, treatment guidelines are generally informed by and limited to experience from cohorts of patients with hematological malignancies and/or solid and stem cell transplants. While multicenter randomized controlled trials are not feasible for these uncommon infections in SOT recipients, collaborative prospective studies can be valuable in providing information on the epidemiology, clinical manifestations, treatment strategies, and outcomes associated with the more commonly encountered infections.
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Affiliation(s)
- Shmuel Shoham
- Transplant and Oncology Infectious Diseases Program, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Edward A Dominguez
- Organ Transplant Infectious Disease, Methodist Transplant Specialists, Dallas, Texas
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Staerck C, Tabiasco J, Godon C, Delneste Y, Bouchara JP, Fleury MJJ. Transcriptional profiling of Scedosporium apiospermum enzymatic antioxidant gene battery unravels the involvement of thioredoxin reductases against chemical and phagocytic cells oxidative stress. Med Mycol 2019; 57:363-373. [PMID: 29889264 DOI: 10.1093/mmy/myy033] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2018] [Revised: 03/22/2018] [Accepted: 05/01/2018] [Indexed: 12/15/2022] Open
Abstract
Scedosporium species rank the second, after Aspergillus fumigatus, among the filamentous fungi colonizing the airways of patients with cystic fibrosis (CF). Development of microorganisms in the respiratory tract depends on their capacity to evade killing by the host immune system, particularly through the oxidative response of macrophages and neutrophils, with the release of reactive oxygen species (ROS) and reactive nitrogen species (RNS). This is particularly true in the airways of CF patients which display an exacerbated inflammatory reaction. To protect themselves, pathogens have developed various enzymatic antioxidant systems implicated in ROS degradation, including superoxide dismutases, catalases, cytochrome C peroxidases, chloroperoxidases and enzymes of the glutathione and thioredoxin systems, or in RNS degradation, that is, flavohemoglobins, nitrate reductases, and nitrite reductases. Here we investigated the transcriptional regulation of the enzymatic antioxidant gene battery in 24-h-old hyphae of Scedosporium apiospermum in response to oxidative stress induced chemically or by exposure to activated phagocytic cells. We showed that 21 out of the 33 genes potentially implicated in the oxidative or nitrosative stress response were overexpressed upon exposure of the fungus to various chemical oxidants, while they were only 13 in co-cultures with macrophages or neutrophils. Among them, genes encoding two thioredoxin reductases and to a lesser extent, a peroxiredoxin and one catalase were found to be overexpressed after chemical oxidative stress as well as in co-cultures. These results suggest that thioredoxin reductases, which are known to be virulence factors in other pathogenic fungi, play a key role in pathogenesis of scedosporiosis, and may be new drug targets.
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Affiliation(s)
- Cindy Staerck
- Groupe d'Etude des Interactions Hôte-Pathogène (EA 3142), UNIV Angers, UNIV Brest, Université Bretagne-Loire, Angers, France
| | - Julie Tabiasco
- CRCINA, INSERM, Université de Nantes, Université d'Angers, Angers, France
| | - Charlotte Godon
- Groupe d'Etude des Interactions Hôte-Pathogène (EA 3142), UNIV Angers, UNIV Brest, Université Bretagne-Loire, Angers, France
| | - Yves Delneste
- CRCINA, INSERM, Université de Nantes, Université d'Angers, Angers, France.,Laboratoire d'Immunologie et Allergologie, Centre Hospitalier Universitaire d'Angers, France
| | - Jean-Philippe Bouchara
- Groupe d'Etude des Interactions Hôte-Pathogène (EA 3142), UNIV Angers, UNIV Brest, Université Bretagne-Loire, Angers, France.,Laboratoire de Parasitologie-Mycologie, Centre Hospitalier Universitaire, Angers, France
| | - Maxime J J Fleury
- Groupe d'Etude des Interactions Hôte-Pathogène (EA 3142), UNIV Angers, UNIV Brest, Université Bretagne-Loire, Angers, France
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Warris A, Bercusson A, Armstrong-James D. Aspergillus colonization and antifungal immunity in cystic fibrosis patients. Med Mycol 2019; 57:S118-S126. [PMID: 30816976 DOI: 10.1093/mmy/myy074] [Citation(s) in RCA: 36] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2018] [Revised: 06/20/2018] [Accepted: 07/26/2018] [Indexed: 12/11/2022] Open
Abstract
Cystic fibrosis (CF), caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, is the most common inherited life-limiting disease in North European people affecting 90,000 people worldwide. Progressive lung damage caused by recurrent infection and chronic airway inflammation is the major determinant of survival with a median age at death of 29 years. Approximately 60% of CF patients are infected with Aspergillus fumigatus, a ubiquitous environmental fungus, and its presence has been associated with accelerated lung function decline. Half of the patients infected with Aspergillus are <18 years of age. Yet time of acquisition of this fungus and determinants of CF-related Aspergillus disease severity and progression are not known. CFTR expression has been demonstrated in cells of the innate and adaptive immune system and has shown to be critical for normal function. Research delineating the role of CFTR-deficient phagocytes in Aspergillus persistence and infection in the CF lung, has only recently received attention. In this concise review we aim to present the current understanding with respect to when people with CF acquire infection with A. fumigatus and antifungal immune responses by CF immune cells.
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Affiliation(s)
- Adilia Warris
- MRC Centre for Medical Mycology, Aberdeen Fungal Group, University of Aberdeen, United Kingdom
| | - Amelia Bercusson
- National Heart and Lung Institute, Imperial College London, United Kingdom
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Nasri E, Fakhim H, Vaezi A, Khalilzadeh S, Ahangarkani F, Laal Kargar M, Abtahian Z, Badali H. Airway colonisation by Candida and Aspergillus species in Iranian cystic fibrosis patients. Mycoses 2019; 62:434-440. [PMID: 30681747 DOI: 10.1111/myc.12898] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2018] [Revised: 01/12/2019] [Accepted: 01/22/2019] [Indexed: 12/20/2022]
Abstract
Cystic fibrosis (CF) is associated with increased rates of morbidity and mortality due to fungal and bacterial colonisation of the airways or respiratory infections. The prevalence of fungi in Iranian CF population has been underestimated. Therefore, the current study was conducted to define the frequency of fungi in respiratory specimens obtained from Iranian CF patients based on conventional and molecular assays. Furthermore, in vitro antifungal susceptibility testing was performed on the obtained isolates according to the guidelines from the Clinical and Laboratory Standards Institute. A cohort of 42 CF patients, including 29 males and 13 females, were categorised according to the referenced diagnostic criteria. Candida albicans (n = 24, 80%), C. dubliniensis (n = 2, 6.6%), C. parapsilosis (n = 2, 6.6%), C. tropicalis (n = 1, 3.3%), C. glabrata (n = 1, 3.3%) and Meyerozyma caribbica (n = 1, 3.3%) were isolated from 73.8% of the CF patients. Aspergillus terreus (n = 3, 42.8%) was identified as the most common Aspergillus species, followed by A. fumigatus (n = 2, 28.5%), A. oryzae (n = 1, 14.2%) and A. flavus (n = 1, 14.2%). Bacterial and fungal co-colonisation was detected in 7 (16.6%) and 22 (52.3%) samples that were positive for Aspergillus and Candida species, respectively. However, Scedosporium species and Exophiala dermatitidis never were detected. In terms of geometric mean (GM) minimum inhibitory concentrations (MICs), posaconazole (0.018 μg/mL) and caspofungin (0.083 μg/mL) exhibited the highest antifungal activities against all Candida species. In addition, posaconazole exhibited the lowest MIC range (0.008-0.063 μg/mL) against all Aspergillus species, followed by caspofungin (0.016-0.125 μg/mL) and voriconazole (0.125-0.25 μg/mL). To conclude, it is essential to adopt a consistent method for the implementation of primary diagnosis and determination of treatment regimen for the CF patients. However, further studies are still needed to better define the epidemiology of fungal organisms in CF patients from the Middle East and the clinical significance of their isolation.
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Affiliation(s)
- Elahe Nasri
- Infectious Diseases and Tropical Medicine Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Hamed Fakhim
- Department of Medical Parasitology and Mycology, Faculty of Medicine, Urmia University of Medical Sciences, Urmia, Iran.,Cellular and Molecular Research Center, Urmia University of Medical Sciences, Urmia, Iran
| | - Afsane Vaezi
- Student Research Committee, Mazandaran University of Medical Sciences, Sari, Iran
| | - Soheila Khalilzadeh
- Pediatric Respiratory Diseases Research Center, National Research Institute of Tuberculosis and Lung Diseases, Masih Daneshvari Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Fatemeh Ahangarkani
- Student Research Committee, Mazandaran University of Medical Sciences, Sari, Iran
| | - Melika Laal Kargar
- Student Research Committee, Mazandaran University of Medical Sciences, Sari, Iran
| | - Zahra Abtahian
- Infectious Diseases and Tropical Medicine Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Hamid Badali
- Department of Medical Mycology, School of Medicine, Mazandaran University of Medical Sciences, Sari, Iran.,Invasive Fungi Research Center, School of Medicine, Mazandaran University of Medical Sciences, Sari, Iran
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