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Gressens SB, Rouzaud C, Lamoth F, Calandra T, Lanternier F, Lortholary O. Duration of systemic antifungal therapy for patients with invasive fungal diseases: A reassessment. Mol Aspects Med 2025; 103:101347. [PMID: 40088509 DOI: 10.1016/j.mam.2025.101347] [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: 10/01/2024] [Accepted: 01/17/2025] [Indexed: 03/17/2025]
Abstract
Invasive fungal diseases are associated with significant morbidity and mortality, especially among immunocompromised patients, and often prompt for rapid and aggressive treatment aiming cure. Due to the expanding magnitude of patients burdened by chronic immunosuppression and affected by fungal diseases, the diversity of clinical settings has risen. This often results in prolonged therapy (induction, consolidation and maintenance) associated with potentially severe side effects, and clinicians face the challenging decisions of when and how to stop anti-fungal therapy. Adequate duration of therapy is poorly defined, hampered by the lack of dedicated trials to the question, the heterogeneity of cases (type of fungal pathogen, localization of infection, underlying host conditions) and various confounding factors that may influence the clinical response (e.g. persistence vs recovery of immunosuppression, impact of surgery). In this review, we aim to evaluate the existing data underlying the guidelines and recommendations of treatment duration for the most frequent invasive fungal diseases (cryptococcal meningitis, Pneumocystis pneumonia, invasive aspergillosis, invasive candidiasis and mucormycosis), as well as specific localizations of deep-seated diseases (osteo-articular or central nervous system diseases and endocarditis) and emerging considerations and strategies.
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Affiliation(s)
- Simon B Gressens
- Department of Infectious Diseases and Tropical Medicine, Hôpital Universitaire Necker-Enfants Malades, Assistance Publique -Hôpitaux de Paris, Université de Paris Cité, Paris, France
| | - Claire Rouzaud
- Department of Infectious Diseases and Tropical Medicine, Hôpital Universitaire Necker-Enfants Malades, Assistance Publique -Hôpitaux de Paris, Université de Paris Cité, Paris, France; Institut Pasteur, Centre d'Infectiologie Necker-Pasteur, National Reference Center for Invasive Mycoses and Antifungals, France
| | - Frederic Lamoth
- Infectious Diseases Service, Department of Medicine, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland; Institute of Microbiology, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland
| | - Thierry Calandra
- Infectious Diseases Service, Department of Medicine, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland
| | - Fanny Lanternier
- Department of Infectious Diseases and Tropical Medicine, Hôpital Universitaire Necker-Enfants Malades, Assistance Publique -Hôpitaux de Paris, Université de Paris Cité, Paris, France; Institut Pasteur, Centre d'Infectiologie Necker-Pasteur, National Reference Center for Invasive Mycoses and Antifungals, France
| | - Olivier Lortholary
- Department of Infectious Diseases and Tropical Medicine, Hôpital Universitaire Necker-Enfants Malades, Assistance Publique -Hôpitaux de Paris, Université de Paris Cité, Paris, France; Institut Pasteur, Centre d'Infectiologie Necker-Pasteur, National Reference Center for Invasive Mycoses and Antifungals, France.
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Yang J, Agrawal R, Mikolajzcyk A. An Unexpected Case of Hyperammonemia in Cirrhosis. Am J Med 2025:S0002-9343(25)00319-5. [PMID: 40412786 DOI: 10.1016/j.amjmed.2025.05.027] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/15/2025] [Accepted: 05/16/2025] [Indexed: 05/27/2025]
Affiliation(s)
- James Yang
- Department of Medicine, Section of Hospital Medicine, University of Chicago Medical Center, Chicago, IL.
| | - Rohit Agrawal
- Gastroenterology and Hepatology, Department of Medicine, Loyola University Medical Center, Maywood IL
| | - Adam Mikolajzcyk
- Department of Medicine, Division of Gastroenterology and Hepatology, Department of Medicine, University of Illinois at Chicago, Chicago, IL, USA
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Fiorica G, Cervera-Hernandez ME, Pirofski LA, Hemmige VS, Yoon H. High Mortality and Associated Risk Factors in Kidney Transplant Recipients With Cryptococcosis-A Nationwide Cohort Study Over a Decade Using USRDS Data. Open Forum Infect Dis 2025; 12:ofaf263. [PMID: 40395458 PMCID: PMC12089938 DOI: 10.1093/ofid/ofaf263] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2024] [Accepted: 04/25/2025] [Indexed: 05/22/2025] Open
Abstract
Background Cryptococcosis is an invasive fungal disease that significantly contributes to morbidity and mortality among kidney transplant recipients (KTRs). Although various prognostic factors predictive of mortality have been identified, most research has been limited to single-center and small-scale studies. Methods We conducted a retrospective cohort study using data from the United States Renal Data System to investigate hospitalizations and outcomes for cryptococcosis among KTRs in the United States from 2006 to 2016. Collected data included demographics, comorbid conditions, hospitalization- and transplant-related complications, and mortality. Results A total of 1265 KTRs were hospitalized for cryptococcosis. The mean age was 59.1 ± 11.2 years; 857 (67.7%) were male, 852 (67.4%) were White, 603 (47.7%) resided in the South, and 648 (51.2%) had a diagnosis of cryptococcal meningitis (CM). The overall 6-month mortality rate was 22%. Multivariable logistic regression analyses identified several factors associated with increased 6-month mortality: cirrhosis (adjusted odds ratio [aOR], 3.1; 95% CI, 1.2-7.7), intensive care unit admission (aOR, 2.9; 95% CI, 2.0-4.0), need for pretransplant dialysis (aOR, 2.7; 95% CI, 1.5-4.9), lack of tacrolimus use at follow-up (aOR, 2.2; 95% CI, 1.4-3.3), age ≥60 years (aOR, 2.0; 95% CI, 1.4-2.8), acute kidney injury (aOR, 1.7; 95% CI, 1.2-2.4), post-transplant period exceeding 2 years (aOR, 1.7; 95% CI, 1.1-2.4), and previous hospitalization for complications related to the transplanted kidney (aOR, 1.5; 95% CI, 1.1-2.2). Conclusions Early mortality remains high among KTRs hospitalized for cryptococcosis, with cirrhosis identified as the strongest independent risk factor for mortality.
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Affiliation(s)
- Giuseppe Fiorica
- Department of Medicine, Mount Sinai Hospital, New York, New York, USA
| | | | - Liise-anne Pirofski
- Division of Infectious Diseases, Department of Medicine, Albert Einstein College of Medicine and Montefiore Medical Center, Bronx, New York, USA
- Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, New York, USA
| | - Vagish S Hemmige
- Division of Infectious Diseases, Department of Medicine, Albert Einstein College of Medicine and Montefiore Medical Center, Bronx, New York, USA
| | - Hyunah Yoon
- Division of Infectious Diseases, Department of Medicine, Albert Einstein College of Medicine and Montefiore Medical Center, Bronx, New York, USA
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4
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Vanhoffelen E, Van Win T, Van Braeckel E, Reséndiz-Sharpe A, Cammue BPA, Lagrou K, Thevissen K, Vande Velde G. Combinations of posaconazole and tacrolimus are effective against infections with azole-resistant Aspergillus fumigatus. Front Cell Infect Microbiol 2025; 15:1550457. [PMID: 40353221 PMCID: PMC12062170 DOI: 10.3389/fcimb.2025.1550457] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2024] [Accepted: 03/24/2025] [Indexed: 05/14/2025] Open
Abstract
Background Solid organ transplant recipients on immunosuppressants such as tacrolimus are at increased risk of developing pulmonary aspergillosis, a severe to deadly complication with limited treatment options, especially against azole-resistant strains. This study investigates the antifungal interaction between posaconazole and tacrolimus, prompted by a case where a liver transplant recipient on tacrolimus experienced unexpected eradication of chronic Aspergillus fumigatus colonization following posaconazole prophylaxis. Methods We compared the combined antifungal activity of posaconazole and tacrolimus against azole-sensitive and resistant A. fumigatus in vitro against planktonic isolates and biofilm formation and in vivo in Galleria mellonella larvae, to evaluate the potential benefit over posaconazole monotherapy. Results The posaconazole-tacrolimus combination demonstrated a 4-fold increase in efficacy against azole-resistant isolates and a 30-fold increase against an azole-sensitive strain, in contrast to voriconazole. Moreover, this combination enhanced antifungal activity by 4- to 15-fold against biofilm formation of azole-sensitive strains, though no synergy was observed against azole-resistant biofilms. In vivo studies in Galleria mellonella confirmed a 2- to 7-fold decrease in fungal burden of both azole-sensitive and azole-resistant strains when combining posaconazole with tacrolimus, relative to posaconazole alone. Conclusion In vitro and in vivo findings confirm that posaconazole may offer therapeutic benefits for treating A. fumigatus infections in patients receiving tacrolimus. These results warrant further confirmation in mice and exploration of their clinical implications.
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Affiliation(s)
- Eliane Vanhoffelen
- Department of Imaging and Pathology, Biomedical MRI Unit, KU Leuven, Leuven, Belgium
| | - Tine Van Win
- Department of Imaging and Pathology, Biomedical MRI Unit, KU Leuven, Leuven, Belgium
| | - Eva Van Braeckel
- Department of Respiratory Medicine, Ghent University Hospital, Ghent, Belgium
- Department of Internal Medicine and Pediatrics, Respiratory Infection and Defense Lab (RIDL), Faculty of Medicine and Health Sciences, Ghent University, Ghent, Belgium
| | | | - Bruno P. A. Cammue
- Department of Microbial and Molecular Systems (M²S), Microbial and Plant Genetics (CMPG), KU Leuven, Leuven, Belgium
- Leuven Plant Institute, KU Leuven, Leuven, Belgium
| | - Katrien Lagrou
- Department of Microbiology, Immunology and Transplantation, Laboratory of Clinical Microbiology, KU Leuven, Leuven, Belgium
- Department of Laboratory Medicine, National Reference Center for Mycosis, University Hospitals Leuven, Leuven, Belgium
| | - Karin Thevissen
- Department of Microbial and Molecular Systems (M²S), Microbial and Plant Genetics (CMPG), KU Leuven, Leuven, Belgium
| | - Greetje Vande Velde
- Department of Imaging and Pathology, Biomedical MRI Unit, KU Leuven, Leuven, Belgium
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Andrade IBD, Alves V, Correa-Junior D, Avellar-Moura I, Soares J, Sousa Araújo GRD, Pontes B, Nosanchuk JD, Almeida-Paes R, Frases S. The biofilm produced by Cryptococcus neoformans protects the fungus from the antifungal and anti-melanin effects of cyclosporine. Microb Pathog 2025; 198:107124. [PMID: 39551108 PMCID: PMC11778809 DOI: 10.1016/j.micpath.2024.107124] [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: 07/31/2024] [Revised: 11/01/2024] [Accepted: 11/14/2024] [Indexed: 11/19/2024]
Abstract
Understanding Cryptococcus neoformans pathogenesis requires a detailed analysis of the various virulence factors that contribute to its ability to cause disease. Cyclosporine, calcineurin inhibitor, impairs C. neoformans production of a polysaccharide capsule and secretion of urease, which are critical for cryptococcal pathogenesis. Two particularly important virulence factors are the production of cell wall melanin and formation of biofilm. In this study, we investigated cyclosporine's effects on melanin production and biofilm formation in C. neoformans. Initially, we examined melanin production in planktonic cells treated with cyclosporine using an L-DOPA containing melanin-inducing medium. Visual inspection and optical microscopy revealed a notable reduction in the characteristic dark coloration of cultures treated with cyclosporine, which indicate decreased melanin production in daughter cells compared to mother cells. Spectrophotometric analysis also demonstrated a significantly altered ultraviolet-visible (UV/vis) absorption spectra in cyclosporine-treated yeast cells, indicative of structural changes in melanin. Additionally, cyclosporine-treated cells exhibited reduced conductance (P-value < 0.0001), suggesting altered cellular ionic properties. The impact of cyclosporine on biofilm formation and mature biofilm disruption was also assessed. Despite cyclosporine's efficacy in modifying virulence factors during planktonic growth, cyclosporine did not inhibit biofilm formation or melanization under biofilm growth conditions, nor did it disrupt mature biofilms in terms of biomass or metabolic activity. However, there was a significant reduction in extracellular matrix production in cyclosporine-treated non-melanized biofilms. Our findings underscore the complex interplay between cyclosporine and C. neoformans, highlighting its differential effects on melanization and biofilm dynamics, which provides new insights into the shortcomings of cyclosporin for combatting cryptococcosis and informs pathways for future therapeutic strategies against cryptococcosis.
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Affiliation(s)
- Iara Bastos de Andrade
- Laboratório de Biofísica de Fungos, Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, Brazil
| | - Vinícius Alves
- Laboratório de Biofísica de Fungos, Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, Brazil; Departments of Medicine (Division of Infectious Diseases) and Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY, USA
| | - Dario Correa-Junior
- Laboratório de Biofísica de Fungos, Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, Brazil
| | - Igor Avellar-Moura
- Laboratório de Biofísica de Fungos, Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, Brazil
| | - Juliana Soares
- Laboratório de Pinças Ópticas Moysés Nussenzveig (LPO), Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, Brazil
| | - Glauber Ribeiro de Sousa Araújo
- Laboratório de Biofísica de Fungos, Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, Brazil
| | - Bruno Pontes
- Laboratório de Pinças Ópticas Moysés Nussenzveig (LPO), Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, Brazil; Centro Nacional de Biologia Estrutural e Bioimagem (CENABIO), Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, Brazil; Rede Micologia RJ, FAPERJ, Rio de Janeiro, Brazil
| | - Joshua D Nosanchuk
- Departments of Medicine (Division of Infectious Diseases) and Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY, USA
| | - Rodrigo Almeida-Paes
- Rede Micologia RJ, FAPERJ, Rio de Janeiro, Brazil; Laboratório de Micologia, Instituto Nacional de Infectologia Evandro Chagas, Fundação Oswaldo Cruz, Rio de Janeiro, RJ, Brazil.
| | - Susana Frases
- Laboratório de Biofísica de Fungos, Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, Brazil; Rede Micologia RJ, FAPERJ, Rio de Janeiro, Brazil
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Barut D, Kunay B, Yıldırım Arslan S, Aydın Uysal A, Şahbudak Bal Z, Yazıcı P, Karakoyun M, Aydoğdu S. Disseminated cryptococcosis in a child with liver transplantation: a case report. Turk J Pediatr 2024; 66:499-504. [PMID: 39387422 DOI: 10.24953/turkjpediatr.2024.4817] [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: 06/07/2024] [Accepted: 07/22/2024] [Indexed: 10/15/2024]
Abstract
BACKGROUND Cryptococcus neoformans causes cryptococcosis, primarily affecting immunocompromised individuals, including solid-organ transplant recipients, and, less frequently, immunocompetent people. CASE A 15-year-old male with congenital hepatic fibrosis, portal hypertension, and cirrhosis underwent orthotopic liver transplantation. He received perioperative antimicrobial and antifungal prophylaxis and continued immunosuppressive treatment. Thirty months post-transplant, he presented with fever, hypertension, and sacroiliac joint pain. Peripheral blood cultures showed C. neoformans, confirmed by pan-fungal polymerase chain reaction assay and latex agglutination tests. Despite initial treatment with intravenous (IV) fluconazole, his condition worsened, necessitating intubation for acute hypoxic respiratory failure. Magnetic resonance imaging and computed tomography scans indicated disseminated cryptococcosis with lymphadenitis, possible meningitis, and pneumonia. Treatment was escalated to IV liposomal amphotericin B and 5-flucytosine, while reducing immunosuppressive treatment. Despite negative fungal cultures on the tenth day, the patient deteriorated, developing pancreatitis, pneumonia, and massive gastrointestinal bleeding, leading to death on the 35th day of hospitalization. CONCLUSION This case shows the severity and complexity of managing disseminated cryptococcosis in pediatric liver transplant recipients. Aggressive therapy and early identification are essential for improving outcomes in these high-risk patients.
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Affiliation(s)
- Doğan Barut
- Division of Gastroenterology, Hepatology and Nutrition Disease, Department of Pediatrics, Medical School of Ege University, İzmir, Türkiye
| | - Bora Kunay
- Division of Gastroenterology, Hepatology and Nutrition Disease, Department of Pediatrics, Medical School of Ege University, İzmir, Türkiye
| | - Sema Yıldırım Arslan
- Division of Infectious Disease, Department of Pediatrics, Medical School of Ege University, İzmir, Türkiye
| | - Ayça Aydın Uysal
- Department of Microbiology, Medical School of Ege University, İzmir, Türkiye
| | - Zümrüt Şahbudak Bal
- Division of Infectious Disease, Department of Pediatrics, Medical School of Ege University, İzmir, Türkiye
| | - Pınar Yazıcı
- Division of Pediatric Intensive Care, Department of Pediatrics, Medical School of Ege University, İzmir, Türkiye
| | - Miray Karakoyun
- Division of Gastroenterology, Hepatology and Nutrition Disease, Department of Pediatrics, Medical School of Ege University, İzmir, Türkiye
| | - Sema Aydoğdu
- Division of Gastroenterology, Hepatology and Nutrition Disease, Department of Pediatrics, Medical School of Ege University, İzmir, Türkiye
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Sardar Z, Kim CY, Thakur KT. Clinical Characteristics and Risk Factors for Cryptococcal Meningitis in Diverse Patient Populations in New York City. Open Forum Infect Dis 2024; 11:ofae576. [PMID: 39450395 PMCID: PMC11500443 DOI: 10.1093/ofid/ofae576] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2024] [Accepted: 10/07/2024] [Indexed: 10/26/2024] Open
Abstract
Background Cryptococcal meningitis (CM) is responsible for 15%-20% of human immunodeficiency virus (HIV)-associated mortalities. CM prevalence has also increased in other immunocompromised populations of transplant recipients, patients with cancer, and individuals on immunomodulatory medication. Methods This retrospective review included 51 definitive patients with CM hospitalized at a tertiary academic medical center in New York City between 2010 and 2023. We assessed clinical features and outcomes of CM, with additional analysis of factors related to antiretroviral therapy (ART) adherence in HIV-infected cases and immunomodulatory medication history of HIV-negative cases. Results The cohort had a mean (standard deviation) age of 47.1 ± 15.1 years, and was predominantly male (37, 72.5%). Of 32 patients with HIV, 3 (9.4%) were newly diagnosed with HIV at the time of CM hospitalization, 5 (15.6%) had recurrent CM, and 2 (6.3%) had a CM relapse. The majority (30, 93.8%) of patients with HIV were ART nonadherent. Of 19 HIV-negative patients, 8 (42.1%) were solid-organ transplant recipients, 5 (26.3%) had autoimmune conditions of sarcoidosis or systemic lupus erythematosus, and 3 (15.8%) had chronic lymphocytic leukemia. Six (11.8%) patients died during hospitalization, 4 of whom had HIV. Conclusions The burden of CM in people with HIV and immunocompromised patients continues even in settings with accessible standard antifungal treatment though interventions of increased ART adherence for those with HIV and antifungal prophylaxis may improve morbidity and mortality.
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Affiliation(s)
- Zomer Sardar
- Department of Neurology, Columbia University Irving Medical Center, New York, New York, USA
- Department of Neurology, Mayo Hospital, Lahore, Punjab, Pakistan
| | - Carla Y Kim
- Department of Neurology, Columbia University Irving Medical Center, New York, New York, USA
| | - Kiran T Thakur
- Department of Neurology, Columbia University Irving Medical Center, New York, New York, USA
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Omer I, Khalil I, Abdalmumin A, Molefe PF, Sabeel S, Farh IZA, Mohamed HA, Elsharif HA, Mohamed ALAH, Awad‐Elkareem MA, Salih M. Design of an epitope-based peptide vaccine against Cryptococcus neoformans. FEBS Open Bio 2024; 14:1471-1489. [PMID: 39020466 PMCID: PMC11492362 DOI: 10.1002/2211-5463.13858] [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: 01/20/2023] [Revised: 04/11/2024] [Accepted: 06/21/2024] [Indexed: 07/19/2024] Open
Abstract
Cryptococcus neoformans is the highest-ranked fungal pathogen in the Fungal Priority Pathogens List (FPPL) released by the World Health Organization (WHO). In this study, through in silico simulations, a multi-epitope vaccine against Cryptococcus neoformans was developed using the mannoprotein antigen (MP88) as a vaccine candidate. Following the retrieval of the MP88 protein sequences, these were used to predict antigenic B-cell and T-cell epitopes via the bepipred tool and the artificial neural network, respectively. Conserved B-cell epitopes AYSTPA, AYSTPAS, PASSNCK, and DSAYPP were identified as the most promising B-cell epitopes. While YMAADQFCL, VSYEEWMNY, and FQQRYTGTF were identified as the best candidates for CD8+ T-cell epitopes; and YARLLSLNA, ISYGTAMAV, and INQTSYARL were identified as the most promising CD4+ T-cell epitopes. The vaccine construct was modeled along with adjuvant and peptide linkers and the expasy protparam tool was used to predict the physiochemical properties. According to this, the construct vaccine was predicted to be antigenic, nontoxic, nonallergenic, soluble, stable, hydrophilic, and thermostable. Furthermore, the three-dimensional structure was also used in docking analyses with Toll-like receptor (TLR4). Finally, the cDNA of vaccine was successfully cloned into the E. coli pET-28a (+) expression vector. The results presented here could contribute towards the design of an effective vaccine against Cryptococcus neoformans.
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Affiliation(s)
- Ibtihal Omer
- Department of Therapeutic Drug Monitoring LaboratoryNational Center for Kidney Diseases and SurgeryKhartoumSudan
| | - Isra Khalil
- Department of Microbiology, Faculty of Medical Laboratory ScienceSudan University of Science and TechnologyKhartoumSudan
| | - Ahmed Abdalmumin
- Biomedical Research InstituteSudan National UniversityKhartoumSudan
| | - Philisiwe Fortunate Molefe
- Hair and Skin Research Laboratory, Department of Medicine, Division Dermatology, Groote Schuur HospitalUniversity of Cape TownCape TownSouth Africa
| | - Solima Sabeel
- Department of Pathology, Faculty of Health Sciences, Institute of Infectious Diseases and Molecular Medicine (IDM)University of Cape TownSouth Africa
| | | | - Hanaa Abdalla Mohamed
- Department of Microbiology, Faculty of Medical Laboratory ScienceSudan University of Science and TechnologyKhartoumSudan
| | - Hajr Abdallha Elsharif
- General Administration of Quarantine and Animal HealthRegional Training InstituteKhartoumSudan
| | | | | | - Mohamed Salih
- Department of BiotechnologyAfrica City of TechnologyKhartoumSudan
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Schweitzer L, Miko BA, Pereira MR. Infectious Disease Prophylaxis During and After Immunosuppressive Therapy. Kidney Int Rep 2024; 9:2337-2352. [PMID: 39156157 PMCID: PMC11328545 DOI: 10.1016/j.ekir.2024.04.043] [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: 01/18/2024] [Revised: 04/17/2024] [Accepted: 04/19/2024] [Indexed: 08/20/2024] Open
Abstract
Immune-mediated renal diseases are a diverse group of disorders caused by antibody, complement, or cell-mediated autosensitization. Although these diseases predispose to infection on their own, a growing array of traditional and newer, more targeted immunosuppressant medications are used to treat these diseases. By understanding their mechanisms of action and the infections associated with suppression of each arm of the immune system, nephrologists can better anticipate these risks and effectively prevent and recognize opportunistic infections. Focusing specifically on nonkidney transplant recipients, this review discusses the infections that can be associated with each of the commonly used immunosuppressants by nephrologists and suggest interventions to prevent infectious complications in patients with immune-mediated renal disease.
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Affiliation(s)
- Lorne Schweitzer
- Division of Infectious Diseases, Department of Medicine, Columbia University Irving Medical Center, New York, New York, USA
- Vagelos College of Physicians and Surgeons, Columbia University, New York, New York, USA
- Columbia Center for Translational Immunology, Columbia University Irving Medical Center, New York, New York, USA
| | - Benjamin A. Miko
- Division of Infectious Diseases, Department of Medicine, Columbia University Irving Medical Center, New York, New York, USA
- Vagelos College of Physicians and Surgeons, Columbia University, New York, New York, USA
| | - Marcus R. Pereira
- Division of Infectious Diseases, Department of Medicine, Columbia University Irving Medical Center, New York, New York, USA
- Vagelos College of Physicians and Surgeons, Columbia University, New York, New York, USA
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Lo CK, Rampersad C, Barr J, Husain S. Less Is More? Two Cases of Cryptococcosis Treated Using Single-dose Liposomal Amphotericin B as Part of Induction Therapy in Solid Organ Transplant Recipients. Transplant Direct 2024; 10:e1648. [PMID: 38817629 PMCID: PMC11139460 DOI: 10.1097/txd.0000000000001648] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2024] [Revised: 03/08/2024] [Accepted: 03/18/2024] [Indexed: 06/01/2024] Open
Affiliation(s)
- Carson K.L. Lo
- Division of Infectious Diseases, Department of Medicine, McMaster University, Hamilton, ON, Canada
- Transplant Infectious Diseases and Ajmera Transplant Centre, University Health Network, University of Toronto, Toronto, ON, Canada
| | - Christie Rampersad
- Transplant Nephrology and Ajmera Transplant Centre, University Health Network, University of Toronto, Toronto, ON, Canada
- Institute of Health Policy, Management and Evaluation (IHPME), Dalla Lana School of Public Health, University of Toronto, Toronto, ON, Canada
| | - Justin Barr
- Department of Abdominal Transplant Surgery, Ajmera Transplant Centre, University Health Network, University of Toronto, Toronto, ON, Canada
| | - Shahid Husain
- Transplant Infectious Diseases and Ajmera Transplant Centre, University Health Network, University of Toronto, Toronto, ON, Canada
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Miwa T, Okamoto K, Ikeuchi K, Yamamoto S, Okugawa S, Ichida A, Akamatsu N, Hasegawa K, Tsutsumi T. The Role of Frequent Screening or Diagnostic Testing of Serum Cryptococcal Antigen in Liver Transplant Recipients: A Descriptive Epidemiology. Open Forum Infect Dis 2024; 11:ofae255. [PMID: 38774792 PMCID: PMC11108085 DOI: 10.1093/ofid/ofae255] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2024] [Indexed: 05/24/2024] Open
Abstract
BACKGROUND Cryptococcosis is a notable infectious complication of liver transplantation. Currently, there is no recommendation for screening serum cryptococcal antigen (CrAg) levels in solid organ transplant recipients. We aimed to explore the role of serum CrAg in liver transplant recipients at an institution where posttransplant serum CrAg has been widely tested. METHODS This retrospective study was conducted at a tertiary care center in Japan. All liver transplant recipients with serum CrAg measured either for screening or for diagnostic testing at least once after transplantation between April 2005 and March 2022 were included. For participants with either a positive CrAg test result or positive culture for Cryptococcus, we manually reviewed clinical manifestations, management, and prognosis from the medical records. RESULTS During the study period, 12 885 serum CrAg tests (median, 16 tests per patient) were performed in 468 liver transplant recipients. The 1-year posttransplant incidence of positive serum CrAg test results and culture-proven cryptococcosis was 1.9% (9/468) and 0.6% (3/468), respectively. No patient with persistently negative serum CrAg test results showed growth of Cryptococcus in culture. Four patients had clinical manifestations consistent with cryptococcosis, of whom 2 (50.0%) started antifungal therapy promptly based on a positive serum CrAg test result. In contrast, 5 patients had no clinical manifestations. Three of the 5 (60.0%) patients did not receive antifungal therapy and remained free of clinical manifestations. CONCLUSIONS Serum CrAg test was more sensitive than culture among liver transplant recipients and prompted early diagnosis and antifungal therapy in symptomatic patients. However, serial screening of serum CrAg in asymptomatic patients may be of little value, with the potential for false-positive results.
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Affiliation(s)
- Toshiki Miwa
- Department of Infectious Diseases, The University of Tokyo Hospital, Tokyo, Japan
| | - Koh Okamoto
- Department of Infectious Diseases, The University of Tokyo Hospital, Tokyo, Japan
- Department of Infectious Diseases, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan
| | - Kazuhiko Ikeuchi
- Department of Infectious Diseases, The University of Tokyo Hospital, Tokyo, Japan
| | - Shinya Yamamoto
- Department of Infectious Diseases, The University of Tokyo Hospital, Tokyo, Japan
| | - Shu Okugawa
- Department of Infectious Diseases, The University of Tokyo Hospital, Tokyo, Japan
| | - Akihiko Ichida
- Artificial Organ and Transplantation Surgery Division, Department of Surgery, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Nobuhisa Akamatsu
- Artificial Organ and Transplantation Surgery Division, Department of Surgery, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Kiyoshi Hasegawa
- Artificial Organ and Transplantation Surgery Division, Department of Surgery, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Takeya Tsutsumi
- Department of Infectious Diseases, The University of Tokyo Hospital, Tokyo, Japan
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12
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Amar Z, Rehman M, Ahmed Y. Cutaneous Cryptococcosis Manifested as a Large Cystic Mass: A Rare Manifestation of Cryptococcus Infection. Cureus 2024; 16:e58040. [PMID: 38737999 PMCID: PMC11088364 DOI: 10.7759/cureus.58040] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/10/2024] [Indexed: 05/14/2024] Open
Abstract
Cryptococcus infection is an invasive fungal infection common in immunocompromised hosts, especially in organ transplant recipients and in patients with HIV. Its presentation varies from localized skin lesions to systemic disseminated infection involving the lungs and the central nervous system (CNS). We present the case of a 50-year-old woman with diabetes mellitus type 2 (DM-2), end-stage renal disease (ESRD) status post deceased donor kidney transplantation seven and a half years ago who presented with a low-grade fever, cough, nausea, vomiting, and a large cystic mass on the right foot. A CT scan of the chest showed a 14 mm cavitary lesion in the middle lobe of the right lung. Serum and cerebrospinal fluid cryptococcal antigens were detected. MRI of the right foot showed a large multilocular lobulated septated cystic mass. Histopathology showed cryptococcus; the diagnosis was made as disseminated cryptococcus infection. She was treated with antifungal therapy successfully. A large cutaneous cystic mass is a rare cutaneous presentation of cryptococcus infection; clinicians should keep it in the differential diagnosis, especially in transplant recipient patients.
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Affiliation(s)
- Zain Amar
- Infectious Diseases, Ascension St. John Hospital, Tulsa, USA
| | - Muneeb Rehman
- Infectious Diseases, Ascension St. John Hospital, Tulsa, USA
| | - Yasir Ahmed
- Infectious Diseases, Ascension St. John Medical Center, Tulsa, USA
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13
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Meena P, Bhargava V, Singh K, sethi J, Prabhakar A, panda S. Cryptococcosis in kidney transplant recipients: Current understanding and practices. World J Nephrol 2023; 12:120-131. [PMID: 38230297 PMCID: PMC10789088 DOI: 10.5527/wjn.v12.i5.120] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/03/2023] [Revised: 10/15/2023] [Accepted: 11/02/2023] [Indexed: 12/22/2023] Open
Abstract
Cryptococcosis is the third most commonly occurring invasive fungal disease in solid organ transplant recipients (SOT). It is caused by encapsulated yeast, Cryptococcus species, predominantly Cryptococcus neoformans and Cryptococcus gattii. Though kidney transplant recipients are at the lowest risk of cryptococcosis when compared to other solid organ transplant recipients such as lung, liver or heart, still this opportunistic infection causes significant morbidity and mortality in this subset of patients. Mortality rates with cryptococcosis range from 10%-25%, while it can be as high as 50% in SOT recipients with central nervous system involvement. The main aim of diagnosis is to find out if there is any involvement of the central nervous system in disseminated disease or whether there is only localized pulmonary involvement as it has implications for both prognostication and treatment. Detection of cryptococcal antigen (CrAg) in cerebrospinal fluid or plasma is a highly recommended test as it is more sensitive and specific than India ink and fungal cultures. The CrAg lateral flow assay is the single point of care test that can rapidly detect cryptococcal polysaccharide capsule. Treatment of cryptococcosis is challenging in kidney transplant recipients. Apart from the reduction or optimization of immunosuppression, lipid formulations of amphotericin B are preferred as induction antifungal agents. Consolidation and maintenance are done with fluconazole; carefully monitoring its interactions with calcineurin inhibitors. This review further discusses in depth the evolving developments in the epidemiology, pathogenesis, diagnostic assays, and management approach of cryptococcosis in kidney transplant recipients.
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Affiliation(s)
- Priti Meena
- Department of Nephrology, All India Institute of Medical Sciences, Bhubaneswar 751019, Odhisha, India
| | - Vinant Bhargava
- Department of Nephrology, Sir Ganga Ram Hospital New Delhi, New Delhi 110001, New Delhi, India
| | - Kulwant Singh
- Department of Nephrology, Ivy Hospital, Mohali Punjab, Mohali 160071, Punjab, India
| | - Jasmine sethi
- Department of Nephrology, Post Graduate Institute of Medical Education & Research, Chandigarh 160012, Punjab, India
| | - Aniketh Prabhakar
- Department of Nephrology, Consultant Nephrologist, Sigma Hospital, Mysore 570009, Karnataka, India
| | - Sandip panda
- Department of Nephrology, All India Institute of Medical Sciences, Bhubaneswar 751019, Odhisha, India
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14
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Lu YA, Lin CH, Chang CJ, Shu KH, Chung MC, Chou CC. Non-meningeal, non-pulmonary cryptococcosis with limited posterior uveitis in a kidney organ transplant recipient with antibody-mediated rejection: a case report. BMC Ophthalmol 2023; 23:409. [PMID: 37817150 PMCID: PMC10565975 DOI: 10.1186/s12886-023-03130-w] [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: 05/09/2023] [Accepted: 09/11/2023] [Indexed: 10/12/2023] Open
Abstract
BACKGROUND Cryptococcosis is one of the most frequent fungal eye infections in patients with immunosuppression. Currently, treatment approaches for non-meningeal, non-pulmonary cryptococcosis are based on those used for cryptococcal meningitis or pneumonia. CASE PRESENTATION We present a rare case of non-meningeal, non-pulmonary cryptococcosis with clinical manifestations limited to one eye of a cadaveric kidney transplant recipient with chronic-active antibody-mediated rejection. Typical manifestations, diagnosis, and treatments, including antifungal therapies, adjunctive therapies, and immunosuppression reduction, are discussed. After timely diagnosis and treatment, her visual acuity recovered to baseline without recurrence or sequelae of cryptococcosis. CONCLUSIONS Clinicians should be aware of rare presentations of fungal infections, especially when a kidney transplant recipient with rejection has been treated with intensive immunosuppressants. Early diagnosis with individualized therapies may have a favorable prognosis.
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Affiliation(s)
- Yi-An Lu
- Department of Ophthalmology, Taichung Veterans General Hospital, 1650 Taiwan Boulevard Sect. 4, Taichung, 407219, Taiwan
| | - Chun-Hsien Lin
- Department of Ophthalmology, Taichung Veterans General Hospital, 1650 Taiwan Boulevard Sect. 4, Taichung, 407219, Taiwan
| | - Chia-Jen Chang
- Department of Ophthalmology, Taichung Veterans General Hospital, 1650 Taiwan Boulevard Sect. 4, Taichung, 407219, Taiwan
| | - Kuo-Hsiung Shu
- Division of Nephrology, Department of Internal Medicine, Lin Shin Hospital, No.36, Sec. 3, Huizhong Rd., Nantun District, Taichung City, 40867, Taiwan
| | - Mu-Chi Chung
- Division of Nephrology, Department of Medicine, Taichung Veterans General Hospital, 1650 Taiwan Boulevard Sect. 4, Taichung, 407219, Taiwan.
- PhD Program in Translational Medicine, National Chung Hsing University, Taichung, Taiwan.
- Rong Hsing Research Center for Translational Medicine, National Chung Hsing University, Taichung, Taiwan.
- Department of Medical Laboratory Science and Biotechnology, Asia University, Taichung, Taiwan.
| | - Chien-Chih Chou
- Department of Ophthalmology, Taichung Veterans General Hospital, 1650 Taiwan Boulevard Sect. 4, Taichung, 407219, Taiwan.
- Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan.
- School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan.
- College of Medicine, National Chung Hsing University, Taichung, Taiwan.
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15
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Barros N, Rosenblatt RE, Phipps MM, Fomin V, Mansour MK. Invasive fungal infections in liver diseases. Hepatol Commun 2023; 7:e0216. [PMID: 37639701 PMCID: PMC10462082 DOI: 10.1097/hc9.0000000000000216] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/01/2022] [Accepted: 06/07/2023] [Indexed: 08/31/2023] Open
Abstract
Patients with liver diseases, including decompensated cirrhosis, alcohol-associated hepatitis, and liver transplant recipients are at increased risk of acquiring invasive fungal infections (IFIs). These infections carry high morbidity and mortality. Multiple factors, including host immune dysfunction, barrier failures, malnutrition, and microbiome alterations, increase the risk of developing IFI. Candida remains the most common fungal pathogen causing IFI. However, other pathogens, including Aspergillus, Cryptococcus, Pneumocystis, and endemic mycoses, are being increasingly recognized. The diagnosis of IFIs can be ascertained by the direct observation or isolation of the pathogen (culture, histopathology, and cytopathology) or by detecting antigens, antibodies, or nucleic acid. Here, we provide an update on the epidemiology, pathogenesis, diagnosis, and management of IFI in patients with liver disease and liver transplantation.
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Affiliation(s)
- Nicolas Barros
- Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA
- Division of Infectious Diseases, Department of Medicine, Indiana University Health, Indianapolis, Indiana, USA
| | - Russell E. Rosenblatt
- Department of Gastroenterology and Hepatology, Weill Cornell Medicine, New York, New York, USA
| | - Meaghan M. Phipps
- Division of Digestive and Liver Diseases, Department of Medicine, Columbia University Irving Medical Center, New York, New York, USA
| | - Vladislav Fomin
- Department of Gastroenterology and Hepatology, Weill Cornell Medicine, New York, New York, USA
| | - Michael K. Mansour
- Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA
- Division of Infectious Diseases, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA
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16
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Cho O, Takada S, Odaka T, Futamura S, Kurakado S, Sugita T. Tacrolimus (FK506) Exhibits Fungicidal Effects against Candida parapsilosis Sensu Stricto via Inducing Apoptosis. J Fungi (Basel) 2023; 9:778. [PMID: 37504766 PMCID: PMC10381508 DOI: 10.3390/jof9070778] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2023] [Revised: 07/18/2023] [Accepted: 07/19/2023] [Indexed: 07/29/2023] Open
Abstract
Tacrolimus (FK506), an immunosuppressant and calcineurin inhibitor, has fungicidal effects. However, its fungicidal effect is thought to be limited to basidiomycetes, such as Cryptococcus and Malassezia, and not to ascomycetes. FK506 had no fungicidal effect on Candida albicans, C. auris, C. glabrata, C. guilliermondii, C. kefyr, C. krusei, and C. tropicalis (>8 µg/mL); however, C. parapsilosis was susceptible to it at low concentrations of 0.125-0.5 µg/mL. C. metapsilosis and C. orthopsils, previously classified as C. parapsilosis, are molecularly and phylogenetically closely related to C. parapsilosis, but neither species was sensitive to FK506. FK506 increased the mitochondrial reactive oxygen species production and cytoplasmic and mitochondrial calcium concentration and activated metacaspases, nuclear condensation, and DNA fragmentation, suggesting that it induced mitochondria-mediated apoptosis in C. parapsilosis. Elucidating why FK506 exhibits fungicidal activity only against C. parapsilosis will provide new information for developing novel antifungal drugs.
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Affiliation(s)
- Otomi Cho
- Department of Microbiology, Meiji Pharmaceutical University, Noshio, Kiyose 204-8588, Japan
| | - Shintaro Takada
- Department of Microbiology, Meiji Pharmaceutical University, Noshio, Kiyose 204-8588, Japan
| | - Takahiro Odaka
- Department of Microbiology, Meiji Pharmaceutical University, Noshio, Kiyose 204-8588, Japan
| | - Satoshi Futamura
- Department of Microbiology, Meiji Pharmaceutical University, Noshio, Kiyose 204-8588, Japan
| | - Sanae Kurakado
- Department of Microbiology, Meiji Pharmaceutical University, Noshio, Kiyose 204-8588, Japan
| | - Takashi Sugita
- Department of Microbiology, Meiji Pharmaceutical University, Noshio, Kiyose 204-8588, Japan
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17
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Escamilla JE, January SE, Vazquez Guillamet R. Diagnosis and Treatment of Fungal Infections in Lung Transplant Recipients. Pathogens 2023; 12:pathogens12050694. [PMID: 37242364 DOI: 10.3390/pathogens12050694] [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: 03/25/2023] [Revised: 04/27/2023] [Accepted: 05/05/2023] [Indexed: 05/28/2023] Open
Abstract
Fungal infections are a significant source of morbidity in the lung transplant population via direct allograft damage and predisposing patients to the development of chronic lung allograft dysfunction. Prompt diagnosis and treatment are imperative to limit allograft damage. This review article discusses incidence, risk factors, and symptoms with a specific focus on diagnostic and treatment strategies in the lung transplant population for fungal infections caused by Aspergillus, Candida, Coccidioides, Histoplasma, Blastomyces, Scedosporium/Lomentospora, Fusarium, and Pneumocystis jirovecii. Evidence for the use of newer triazole and inhaled antifungals to treat isolated pulmonary fungal infections in lung transplant recipients is also discussed.
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Affiliation(s)
- Jesus E Escamilla
- Department of Pharmacy, Barnes-Jewish Hospital, Saint Louis, MO 63110, USA
| | - Spenser E January
- Department of Pharmacy, Barnes-Jewish Hospital, Saint Louis, MO 63110, USA
| | - Rodrigo Vazquez Guillamet
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, Washington University School of Medicine, Saint Louis, MO 63110, USA
- Rodrigo Vazquez Guillamet, 4921 Parkview Place, Saint Louis, MO 63110, USA
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18
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de Andrade IB, Corrêa-Junior D, Alves V, Figueiredo-Carvalho MHG, Santos MV, Almeida MA, Valdez AF, Nimrichter L, Almeida-Paes R, Frases S. Cyclosporine Affects the Main Virulence Factors of Cryptococcus neoformans In Vitro. J Fungi (Basel) 2023; 9:487. [PMID: 37108941 PMCID: PMC10140927 DOI: 10.3390/jof9040487] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2023] [Revised: 04/13/2023] [Accepted: 04/17/2023] [Indexed: 04/29/2023] Open
Abstract
This study aimed to investigate the effects of cyclosporine on the morphology, cell wall structure, and secretion characteristics of Cryptococcus neoformans. The minimum inhibitory concentration (MIC) of cyclosporine was found to be 2 µM (2.4 µg/mL) for the H99 strain. Yeast cells treated with cyclosporine at half the MIC showed altered morphology, including irregular shapes and elongated projections, without an effect on cell metabolism. Cyclosporine treatment resulted in an 18-fold increase in chitin and an 8-fold increase in lipid bodies, demonstrating changes in the fungal cell wall structure. Cyclosporine also reduced cell body and polysaccharide capsule diameters, with a significant reduction in urease secretion in C. neoformans cultures. Additionally, the study showed that cyclosporine increased the viscosity of secreted polysaccharides and reduced the electronegativity and conductance of cells. The findings suggest that cyclosporine has significant effects on C. neoformans morphology, cell wall structure, and secretion, which could have implications for the development of new antifungal agents.
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Affiliation(s)
- Iara Bastos de Andrade
- Laboratório de Biofísica de Fungos, Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-902, Brazil
| | - Dario Corrêa-Junior
- Laboratório de Biofísica de Fungos, Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-902, Brazil
| | - Vinicius Alves
- Laboratório de Biofísica de Fungos, Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-902, Brazil
| | | | - Marcos Vinicius Santos
- Laboratório de Micologia, Instituto Nacional de Infectologia Evandro Chagas, Fundação Oswaldo Cruz, Rio de Janeiro 21941-902, Brazil (M.A.A.)
| | - Marcos Abreu Almeida
- Laboratório de Micologia, Instituto Nacional de Infectologia Evandro Chagas, Fundação Oswaldo Cruz, Rio de Janeiro 21941-902, Brazil (M.A.A.)
| | - Alessandro Fernandes Valdez
- Instituto de Microbiologia Paulo de Góes, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-902, Brazil (L.N.)
| | - Leonardo Nimrichter
- Instituto de Microbiologia Paulo de Góes, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-902, Brazil (L.N.)
- Rede Micologia RJ, FAPERJ, Rio de Janeiro 21941-902, Brazil
| | - Rodrigo Almeida-Paes
- Laboratório de Micologia, Instituto Nacional de Infectologia Evandro Chagas, Fundação Oswaldo Cruz, Rio de Janeiro 21941-902, Brazil (M.A.A.)
- Rede Micologia RJ, FAPERJ, Rio de Janeiro 21941-902, Brazil
| | - Susana Frases
- Laboratório de Biofísica de Fungos, Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-902, Brazil
- Rede Micologia RJ, FAPERJ, Rio de Janeiro 21941-902, Brazil
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19
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Lee SB, Mota C, Thak EJ, Kim J, Son YJ, Oh DB, Kang HA. Effects of altered N-glycan structures of Cryptococcus neoformans mannoproteins, MP98 (Cda2) and MP84 (Cda3), on interaction with host cells. Sci Rep 2023; 13:1175. [PMID: 36670130 PMCID: PMC9859814 DOI: 10.1038/s41598-023-27422-9] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2022] [Accepted: 01/02/2023] [Indexed: 01/22/2023] Open
Abstract
Cryptococcus neoformans is an opportunistic human fungal pathogen causing lethal meningoencephalitis. It has several cell wall mannoproteins (MPs) identified as immunoreactive antigens. To investigate the structure and function of N-glycans assembled on cryptococcal cell wall MPs in host cell interactions, we purified MP98 (Cda2) and MP84 (Cda3) expressed in wild-type (WT) and N-glycosylation-defective alg3 mutant (alg3Δ) strains. HPLC and MALDI-TOF analysis of the MP proteins from the WT revealed protein-specific glycan structures with different extents of hypermannosylation and xylose/xylose phosphate addition. In alg3Δ, MP98 and MP84 had truncated core N-glycans, containing mostly five and seven mannoses (M5 and M7 forms), respectively. In vitro adhesion and uptake assays indicated that the altered core N-glycans did not affect adhesion affinities to host cells although the capacity to induce the immune response of bone-marrow derived dendritic cells (BMDCs) decreased. Intriguingly, the removal of all N-glycosylation sites on MP84 increased adhesion to host cells and enhanced the induction of cytokine secretion from BMDCs compared with that on MP84 carrying WT N-glycans. Therefore, the structure-dependent effects of N-glycans suggested their complex roles in modulating the interaction of MPs with host cells to avoid nonspecific adherence to host cells and host immune response hyperactivation.
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Affiliation(s)
- Su-Bin Lee
- Department of Life Science, College of Natural Science, Chung-Ang University, Seoul, 156-756, South Korea
| | - Catia Mota
- Department of Life Science, College of Natural Science, Chung-Ang University, Seoul, 156-756, South Korea
| | - Eun Jung Thak
- Department of Life Science, College of Natural Science, Chung-Ang University, Seoul, 156-756, South Korea
| | - Jungho Kim
- Department of Life Science, College of Natural Science, Chung-Ang University, Seoul, 156-756, South Korea
| | - Ye Ji Son
- Department of Life Science, College of Natural Science, Chung-Ang University, Seoul, 156-756, South Korea
| | - Doo-Byoung Oh
- Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, 34141, South Korea.,Department of Biosystems and Bioengineering, KRIBB School, University of Science and Technology (UST), Daejeon, 34113, South Korea
| | - Hyun Ah Kang
- Department of Life Science, College of Natural Science, Chung-Ang University, Seoul, 156-756, South Korea.
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20
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Hamed MF, Enriquez V, Munzen ME, Charles-Niño CL, Mihu MR, Khoshbouei H, Alviña K, Martinez LR. Clinical and pathological characterization of Central Nervous System cryptococcosis in an experimental mouse model of stereotaxic intracerebral infection. PLoS Negl Trop Dis 2023; 17:e0011068. [PMID: 36656900 PMCID: PMC9888703 DOI: 10.1371/journal.pntd.0011068] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2022] [Revised: 01/31/2023] [Accepted: 01/02/2023] [Indexed: 01/20/2023] Open
Abstract
Infection of the Central Nervous System (CNS) by the encapsulated fungus Cryptococcus neoformans can lead to high mortality meningitis, most commonly in immunocompromised patients. While the mechanisms by which the fungus crosses the blood-brain barrier to initiate infection in the CNS are well recognized, there are still substantial unanswered questions about the disease progression once the fungus is established in the brain. C. neoformans is characterized by a glucuronoxylomannan (GXM)-rich polysaccharide capsule which has been implicated in immune evasion, but its role during the host CNS infection needs further elucidation. Therefore, the present study aims to examine these key questions about the mechanisms underlying cryptococcal meningitis progression and the impact of fungal GXM release by using an intracerebral rodent infection model via stereotaxic surgery. After developing brain infection, we analyzed distinct brain regions and found that while fungal load and brain weight were comparable one-week post-infection, there were region-specific histopathological (with and without brain parenchyma involvement) and disease manifestations. Moreover, we also observed a region-specific correlation between GXM accumulation and glial cell recruitment. Furthermore, mortality was associated with the presence of subarachnoid hemorrhaging and GXM deposition in the meningeal blood vessels and meninges in all regions infected. Our results show that using the present infection model can facilitate clinical and neuropathological observations during the progression of neurocryptococcosis. Importantly, this mouse model can be used to further investigate disease progression as it develops in humans.
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Affiliation(s)
- Mohamed F. Hamed
- Department of Oral Biology, University of Florida College of Dentistry, Gainesville, Florida, United States of America
- Department of Pathology, Faculty of Veterinary Medicine, Mansoura University, Mansoura, Egypt
| | - Vanessa Enriquez
- Department of Oral Biology, University of Florida College of Dentistry, Gainesville, Florida, United States of America
| | - Melissa E. Munzen
- Department of Oral Biology, University of Florida College of Dentistry, Gainesville, Florida, United States of America
| | - Claudia L. Charles-Niño
- Department of Oral Biology, University of Florida College of Dentistry, Gainesville, Florida, United States of America
- Department of Microbiology and Pathology, University Health Sciences Center, University of Guadalajara, Guadalajara, Mexico
| | - Mircea Radu Mihu
- Advanced Critical Care, Nazih Zuhdi Transplant Institute, Advanced Cardiac Care and 24/7 Shock Service, Integris Baptist Medical Center, Oklahoma City, Oklahoma, United States of America
- Department of Medicine/Cardiology, Oklahoma State University Health Science Center, Tulsa, Oklahoma, United States of America
| | - Habibeh Khoshbouei
- Department of Neuroscience, University of Florida, Gainesville, Florida, United States of America
- Center for Translational Research in Neurodegenerative Disease, University of Florida, Gainesville, United States of America
| | - Karina Alviña
- Department of Neuroscience, University of Florida, Gainesville, Florida, United States of America
- Center for Translational Research in Neurodegenerative Disease, University of Florida, Gainesville, United States of America
| | - Luis R. Martinez
- Department of Oral Biology, University of Florida College of Dentistry, Gainesville, Florida, United States of America
- Center for Translational Research in Neurodegenerative Disease, University of Florida, Gainesville, United States of America
- Center for Immunology and Transplantation, University of Florida, Gainesville, United States of America
- Emerging Pathogens Institute, University of Florida, Gainesville, Florida, United States of America
- * E-mail:
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21
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Ssebambulidde K, Anjum SH, Hargarten JC, Chittiboina P, Shoham S, Seyedmousavi S, Marr KA, Hammoud DA, Billioux BJ, Williamson PR. Treatment recommendations for non-HIV associated cryptococcal meningoencephalitis including management of post-infectious inflammatory response syndrome. Front Neurol 2022; 13:994396. [PMID: 36530631 PMCID: PMC9751747 DOI: 10.3389/fneur.2022.994396] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2022] [Accepted: 11/04/2022] [Indexed: 08/29/2023] Open
Abstract
Cryptococcal meningoencephalitis (CM) continues to cause major morbidity and mortality in a range of patients such as those immunosuppressed from HIV and with biologic immunosuppressants, including treatments of autoimmunity, malignancies, and conditioning regimens for transplantation. It is currently the most common cause of non-viral meningitis in the United States. Infections in previously healthy patients also develop with autoantibodies to granulocyte-macrophage colony stimulating factor or with monogenetic defects. In all populations, mortality and significant long-term morbidity occur in 30-50% despite therapy, and immune reconstitution and post-infectious inflammatory response syndromes complicate management. To help with these difficult cases, we present here a practical tutorial of the care of a range of patients with CM in the absence of HIV/AIDS.
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Affiliation(s)
- Kenneth Ssebambulidde
- Translational Mycology Section, Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, United States
| | - Seher H. Anjum
- Translational Mycology Section, Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, United States
| | - Jessica C. Hargarten
- Translational Mycology Section, Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, United States
| | - Prashant Chittiboina
- Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, Bethesda, MD, United States
| | - Shmuel Shoham
- Johns Hopkins School of Medicine, Baltimore, MD, United States
| | - Seyedmojtaba Seyedmousavi
- Microbiology Service, Department of Laboratory Medicine, Clinical Center, National Institutes of Health, Bethesda, MD, United States
| | - Kieren A. Marr
- Johns Hopkins School of Medicine, Baltimore, MD, United States
| | - Dima A. Hammoud
- Center for Infectious Disease Imaging (CIDI), Radiology and Imaging Sciences, Clinical Center, National Institutes of Health, Bethesda, MD, United States
| | - Bridgette Jeanne Billioux
- Section of Infections of the Nervous System, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, United States
| | - Peter R. Williamson
- Translational Mycology Section, Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, United States
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22
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Barasa L, Sokwala A, Riunga F, Sokhi DS. A Case Report of Concurrent Cryptococcal and Tuberculous Meningitis in an Immunosuppressed Renal Transplant Patient. Cureus 2022; 14:e31012. [DOI: 10.7759/cureus.31012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/02/2022] [Indexed: 11/06/2022] Open
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23
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Qurashi S, Saleem T, Kovalenko I, Golubykh K, Holleran L. Cryptococcus neoformans Presenting as a Lung Mass in an Immunocompromised Patient. AMERICAN JOURNAL OF CASE REPORTS 2022; 23:e936968. [PMID: 36183161 PMCID: PMC9536145 DOI: 10.12659/ajcr.936968] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2022] [Revised: 08/29/2022] [Accepted: 08/17/2022] [Indexed: 09/06/2024]
Abstract
BACKGROUND Pulmonary cryptococcosis is an uncommon infection mainly affecting immunocompromised individuals. Presentation of cryptococcal disease ranges from asymptomatic pulmonary colonization to severe pneumonia. It can progress to acute respiratory failure and life-threatening meningoencephalitis. CASE REPORT A 55-year-old woman with a history of a kidney transplant, on immunosuppressive therapy, presented to the hospital with persistent low-grade fever, headache, weight loss, and fatigue for 2 weeks. On arrival, she was tachycardic, normotensive, and saturating 99% on room air. Her chest X-ray showed right middle lung opacity measuring 1.9×2.8 cm. She was admitted and started on broad-spectrum antibiotics for suspected pneumonia. Her chest computed tomography (CT) scan showed a 3.0×1.7 cm hypo-dense opacity at the right upper lobe. Overnight, she developed a severe headache and neck stiffness. Her serum cryptococcal antigen and cerebrospinal fluid culture results were positive. The patient was started on intravenous liposomal amphotericin B plus flucytosine. A CT-guided lung biopsy was performed to rule out malignancy. Cultures came back positive for Cryptococcus neoformans. She completed a 2-week course of amphotericin and flucytosine and was switched to oral fluconazole to complete an 8-week course. CONCLUSIONS Prompt diagnosis and effective management of the cryptococcal disease can decrease morbidity and mortality. Diagnosis requires CT-guided lung biopsy, with culture growing mucoid colonies of Cryptococcus neoformans. Antifungal therapy with intravenous liposomal amphotericin B plus flucytosine is the mainstay of treatment. Clinicians should be aware of the various presentations of pulmonary cryptococcosis, especially in immunocompromised patients.
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Affiliation(s)
- Siddique Qurashi
- Department of Internal Medicine, University of Pittsburgh Medical Center (UPMC), Harrisburg, PA, USA
| | - Tabinda Saleem
- Department of Internal Medicine, University of Pittsburgh Medical Center (UPMC), Harrisburg, PA, USA
| | - Iuliia Kovalenko
- Department of Internal Medicine, University of Pittsburgh Medical Center (UPMC), Harrisburg, PA, USA
| | - Konstantin Golubykh
- Department of Internal Medicine, University of Pittsburgh Medical Center (UPMC), Harrisburg, PA, USA
| | - Lauren Holleran
- Department of Internal Medicine, Drexel University, Philadelphia, PA, USA
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24
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Runyo F, Rotstein CMF. Epidemiology of Invasive Fungal Infections in Solid Organ Transplant Recipients: a North American Perspective. CURRENT FUNGAL INFECTION REPORTS 2022. [DOI: 10.1007/s12281-022-00442-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/14/2022]
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25
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Fungal Infections in Intestinal Transplantation. CURRENT FUNGAL INFECTION REPORTS 2022. [DOI: 10.1007/s12281-022-00437-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
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26
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Cryptococcal Meningitis in Kidney Transplant Recipients: A Two-Decade Cohort Study in France. Pathogens 2022; 11:pathogens11060699. [PMID: 35745553 PMCID: PMC9227085 DOI: 10.3390/pathogens11060699] [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: 04/15/2022] [Revised: 05/04/2022] [Accepted: 06/09/2022] [Indexed: 12/04/2022] Open
Abstract
Cryptococcosis is the third most common cause of invasive fungal infection in solid organ transplant recipients and cryptococcal meningitis (CM) its main clinical presentation. CM outcomes, as well as its clinical features and radiological characteristics, have not yet been considered on a large scale in the context of kidney transplantation (KT). We performed a nationwide retrospective study of adult patients diagnosed with cryptococcosis after KT between 2002 and 2020 across 30 clinical centers in France. We sought to describe overall and graft survival based on whether KT patients with cryptococcosis developed CM or not. Clinical indicators of CNS involvement and brain radiological characteristics were assessed. Eighty-eight cases of cryptococcosis were diagnosed during the study period, with 61 (69.3%) cases of CM. Mortality was high (32.8%) at 12 months (M12) but not significantly different whether or not patients presented with CM. Baseline hyponatremia and at least one neurological symptom were independently associated with CM (p < 0.001). Positive serum cryptococcal antigen at diagnosis was also significantly associated with CM (p < 0.001). On magnetic resonance imaging (MRI), three patterns of brain injury were identified: parenchymal, meningeal, and vascular lesions. Although CM does not affect graft function directly, it entails a grim prognosis.
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27
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Yoon H, Nakouzi A, Pappas PG, Hemmige VS, Pirofski LA. Cryptococcus neoformans-specific and non- Cryptococcous neoformans-specific antibody profiles in organ transplant recipients with and without cryptococcosis. Open Forum Infect Dis 2022; 9:ofac211. [PMID: 35794949 PMCID: PMC9253883 DOI: 10.1093/ofid/ofac211] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2022] [Accepted: 04/18/2022] [Indexed: 11/12/2022] Open
Abstract
Antibody immunity has not been studied in organ transplant recipients (OTRs) with cryptococcosis. We determined serum antibody levels in OTRs: 23 cryptococcosis cases and 21 controls. Glucuronoxylomannan immunoglobulin M (IgM) and laminarin IgM were lower in cases than controls, were inversely associated with cryptococcosis status, and may hold promise as markers of cryptococcosis.
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Affiliation(s)
- Hyunah Yoon
- Division of Infectious Diseases, Department of Medicine, Albert Einstein College of Medicine, Montefiore Medical Center, Bronx, New York, USA
| | - Antonio Nakouzi
- Division of Infectious Diseases, Department of Medicine, Albert Einstein College of Medicine, Montefiore Medical Center, Bronx, New York, USA
- Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, New York, USA
| | - Peter G Pappas
- Division of Infectious Diseases, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA
| | - Vagish S Hemmige
- Division of Infectious Diseases, Department of Medicine, Albert Einstein College of Medicine, Montefiore Medical Center, Bronx, New York, USA
| | - Liise anne Pirofski
- Correspondence: Liise-anne Pirofski, MD, Division of Infectious Diseases, Department of Medicine, Albert Einstein College of Medicine, 1300 Morris Park Ave, Room 610, Belfer Bldg, Bronx, NY 10461, USA ()
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28
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Rossato L, Venturini TP, de Azevedo MI, Santurio JM, Alves SH. In vitro activity of immunosuppressive agents against Cryptococcus neoformans. ENFERMEDADES INFECCIOSAS Y MICROBIOLOGIA CLINICA (ENGLISH ED.) 2022; 40:86-88. [PMID: 35120653 DOI: 10.1016/j.eimce.2020.09.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/10/2020] [Accepted: 09/19/2020] [Indexed: 06/14/2023]
Abstract
INTRODUCTION Infections caused by Cryptococcus neoformans are a major cause of fungal mortality in HIV-infected/AIDS patients and in those receiving organ transplants. We evaluated the in vitro activity of tacrolimus and cyclosporine in combination with amphotericin B and fluconazole against C. neoformans. METHODS MICs were determined against a total of 30 clinical isolates of C. neoformans by the microdilution method following the CLSI M27-A3 guidelines and by the checkerboard method. RESULTS Tacrolimus and cyclosporine A showed in vitro activity against cryptococcal isolates. The combination of amphotericin B with cyclosporine A or tacrolimus was synergistic against 90% and 30% of isolates, respectively. Synergism was also observed with the combination of fluconazole with cyclosporine A or tacrolimus, against 70% and 20% of isolates, respectively. CONCLUSIONS The synergistic interactions between the calcineurin inhibitors and antifungal drugs against C. neoformans isolates, could potentially have a role in devising novel therapeutic strategies for this opportunistic mycosis.
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Affiliation(s)
- Luana Rossato
- Postgraduate Program in Pharmaceutical Sciences, Health Sciences Centre, Federal University of Santa Maria (UFSM), Santa Maria, RS, Brazil.
| | - Tarcieli P Venturini
- Postgraduate Program in Pharmaceutical Sciences, Health Sciences Centre, Federal University of Santa Maria (UFSM), Santa Maria, RS, Brazil
| | - Maria Isabel de Azevedo
- Department of Preventive Veterinary Medicine, Veterinary School, Federal University of Minas Gerais, Belo Horizonte, Minas Gerais, Brazil
| | - Janio M Santurio
- Postgraduate Program in Pharmacology, Health Sciences Centre, Federal University of Santa Maria (UFSM), Santa Maria, RS, Brazil
| | - Sydney H Alves
- Postgraduate Program in Pharmaceutical Sciences, Health Sciences Centre, Federal University of Santa Maria (UFSM), Santa Maria, RS, Brazil
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29
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Gough S, Borgetti S, Fernandes CR. Orthostatic hypotension as the initial presentation of disseminated cryptococcosis in a kidney transplant recipient. IDCases 2022; 29:e01567. [PMID: 35865083 PMCID: PMC9294536 DOI: 10.1016/j.idcr.2022.e01567] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2022] [Revised: 07/03/2022] [Accepted: 07/09/2022] [Indexed: 12/02/2022] Open
Abstract
Background Solid organ transplant recipients are immunocompromised and at risk for invasive viral, fungal, and bacterial pathogens. Cryptococcus neoformans is the third most common invasive fungal infection in transplant recipients, and the clinical presentation of Cryptococcus neoformans infection can vary widely. Cryptococcal disease can affect the brain, lungs, skin, or vasculature, and it is frequently disseminated. Meningitis typically presents with fever, headache, and altered mental status. Solid organ transplant recipients with cryptococcosis tend to have poorer outcomes than HIV patients with cryptococcosis. Case presentation In this case report, we describe the case of a 69 year-old man with a past medical history of a deceased donor kidney transplant who presented with severe orthostatic hypotension and was found to have disseminated cryptococcosis. Conclusions This case report emphasizes the importance of broadening the differential diagnosis in transplant recipients who present with non-specific chief concerns. Availability of data and materials No datasets were used in the preparing of this manuscript. All patient information comes from the electronic health record and authors personal care of this patient.
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30
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Chang CC, Hall V, Cooper C, Grigoriadis G, Beardsley J, Sorrell TC, Heath CH. Consensus guidelines for the diagnosis and management of cryptococcosis and rare yeast infections in the haematology/oncology setting, 2021. Intern Med J 2021; 51 Suppl 7:118-142. [PMID: 34937137 DOI: 10.1111/imj.15590] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Cryptococcosis caused by the Cryptococcus neoformans-Cryptococcus gattii complex is an important opportunistic infection in people with immunodeficiency, including in the haematology/oncology setting. This may manifest clinically as cryptococcal meningitis or pulmonary cryptococcosis, or be detected incidentally by cryptococcal antigenemia, a positive sputum culture or radiological imaging. Non-Candida, non-Cryptococcus spp. rare yeast fungaemia are increasingly common in this population. These consensus guidelines aim to provide clinicians working in the Australian and New Zealand haematology/oncology setting with clear guiding principles and practical recommendations for the management of cryptococcosis, while also highlighting important and emerging rare yeast infections and their recommended management.
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Affiliation(s)
- Christina C Chang
- Department of Infectious Diseases, Alfred Hospital and Central Clinical School, Monash University, Melbourne, Victoria, Australia.,Therapeutic and Vaccine Research Programme, Kirby Institute, University of New South Wales, Sydney, New South Wales, Australia.,Centre for the AIDS Programme of Research in South Africa (CAPRISA), Durban, KwaZulu Natal, South Africa
| | - Victoria Hall
- Department of Infectious Diseases, Alfred Hospital and Central Clinical School, Monash University, Melbourne, Victoria, Australia.,Transplant Infectious Diseases and Multi-Organ Transplant Program, University Health Network, Toronto, Ontario, Canada
| | - Celia Cooper
- Department of Microbiology and Infectious Diseases, Women's and Children's Hospital, North Adelaide, South Australia, Australia
| | - George Grigoriadis
- Monash Haematology, Monash Health, Melbourne, Victoria, Australia.,School of Clinical Sciences, Monash University, Melbourne, Victoria, Australia.,Centre for Cancer Research, Hudson Institute of Medical Research, Clayton, Victoria, Australia.,Department of Haematology, Alfred Hospital, Prahran, Victoria, Australia
| | - Justin Beardsley
- Marie Bashir Institute for Infectious Diseases & Biosecurity, University of Sydney, Sydney, New South Wales, Australia.,Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, Oxford, UK.,Department of Infectious Diseases, Prince of Wales Hospital, Randwick, New South Wales, Australia
| | - Tania C Sorrell
- Marie Bashir Institute for Infectious Diseases & Biosecurity, University of Sydney, Sydney, New South Wales, Australia.,Centre for Infectious Diseases and Microbiology, Westmead Institute for Medical Research, Westmead, New South Wales, Australia.,Infectious Diseases and Sexual Health, Western Sydney Local Health District, Parramatta, New South Wales, Australia
| | - Christopher H Heath
- Department of Microbiology, Fiona Stanley Hospital Network, PathWest Laboratory Medicine, Murdoch, Western Australia, Australia.,Department of Infectious Diseases, Fiona Stanley Hospital, Murdoch, Western Australia, Australia.,Department of Infectious Diseases, Royal Perth Hospital, Perth, Western Australia, Australia.,Faculty of Health and Medical Sciences, University of Western Australia, Murdoch, Western Australia, Australia
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31
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Haidar G. Coronavirus Disease 2019 (COVID-19), Organ Transplantation, and the Nuances of Immunomodulation: Lessons Learned and What Comes Next. Clin Infect Dis 2021; 73:e4100-e4102. [PMID: 32780792 PMCID: PMC7454313 DOI: 10.1093/cid/ciaa1193] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2020] [Accepted: 08/10/2020] [Indexed: 12/23/2022] Open
Affiliation(s)
- Ghady Haidar
- Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
- Division of Infectious Diseases, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA
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32
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Li K, Khan A, Mishra S, Zhabokritsky A. Disseminated cryptococcal infection in a patient with a remote renal transplant. CMAJ 2021; 193:E211-E214. [PMID: 33558407 PMCID: PMC7954546 DOI: 10.1503/cmaj.200825] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022] Open
Affiliation(s)
- Kelli Li
- Divisions of General Internal Medicine (Li), Nephrology (Khan) and Infectious Diseases (Mishra, Zhabokritsky), Department of Medicine, Faculty of Medicine, University of Toronto; Division of Infectious Diseases (Mishra), Department of Medicine, St. Michael's Hospital, Unity Health Toronto, Toronto, Ont
| | - Abid Khan
- Divisions of General Internal Medicine (Li), Nephrology (Khan) and Infectious Diseases (Mishra, Zhabokritsky), Department of Medicine, Faculty of Medicine, University of Toronto; Division of Infectious Diseases (Mishra), Department of Medicine, St. Michael's Hospital, Unity Health Toronto, Toronto, Ont
| | - Sharmistha Mishra
- Divisions of General Internal Medicine (Li), Nephrology (Khan) and Infectious Diseases (Mishra, Zhabokritsky), Department of Medicine, Faculty of Medicine, University of Toronto; Division of Infectious Diseases (Mishra), Department of Medicine, St. Michael's Hospital, Unity Health Toronto, Toronto, Ont
| | - Alice Zhabokritsky
- Divisions of General Internal Medicine (Li), Nephrology (Khan) and Infectious Diseases (Mishra, Zhabokritsky), Department of Medicine, Faculty of Medicine, University of Toronto; Division of Infectious Diseases (Mishra), Department of Medicine, St. Michael's Hospital, Unity Health Toronto, Toronto, Ont.
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33
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Fungal Infections in Liver Transplant Recipients. J Fungi (Basel) 2021; 7:jof7070524. [PMID: 34210106 PMCID: PMC8304186 DOI: 10.3390/jof7070524] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2021] [Revised: 05/25/2021] [Accepted: 06/21/2021] [Indexed: 01/03/2023] Open
Abstract
Invasive fungal infections (IFIs) are one of the most feared complications associated with liver transplantation, with high rates of morbidity and mortality. We discuss the most common invasive fungal infections in the setting of liver transplant, including Candida, Aspergillus, and Cryptococcal infections, and some less frequent but devastating mold infections. Further, we evaluate the use of prophylaxis to prevent invasive fungal infection in this population as a promising mechanism to reduce risks to patients after liver transplant.
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34
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Yamamura D, Xu J. Update on Pulmonary Cryptococcosis. Mycopathologia 2021; 186:717-728. [PMID: 34181160 DOI: 10.1007/s11046-021-00575-9] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2020] [Accepted: 06/22/2021] [Indexed: 12/24/2022]
Abstract
Pulmonary cryptococcosis is a common but underdiagnosed opportunistic fungal infection in both immunocompromised and immunocompetent patients. The causal agents include at least eight evolutionary distinct haploid lineages as well as their hybrids of the human pathogenic Cryptococcus complex. In this update, we review recent advances in epidemiology, mode of transmission, risk factors, diagnostic methods, and therapy of pulmonary cryptococcosis. Our review suggests significant challenges and opportunities for research, from bedside to benchside and back to bedside.
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Affiliation(s)
- Deborah Yamamura
- Microbiology Department, Hamilton Regional Laboratory Medicine Program, Hamilton General Hospital, Hamilton, ON, L8L 2X2, Canada.,Department of Pathology and Molecular Medicine, McMaster University, Hamilton, L8S 4K1, Canada
| | - Jianping Xu
- Department of Biology, McMaster University, Hamilton, L8S 4K1, Canada.
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35
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Wilmes D, Coche E, Rodriguez-Villalobos H, Kanaan N. Fungal pneumonia in kidney transplant recipients. Respir Med 2021; 185:106492. [PMID: 34139578 DOI: 10.1016/j.rmed.2021.106492] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/16/2021] [Revised: 05/26/2021] [Accepted: 05/28/2021] [Indexed: 10/21/2022]
Abstract
Fungal pneumonia is a dreaded complication encountered after kidney transplantation, complicated by increased mortality and often associated with graft failure. Diagnosis can be challenging because the clinical presentation is non-specific and diagnostic tools have limited sensitivity and specificity in kidney transplant recipients and must be interpreted in the context of the clinical setting. Management is difficult due to the increased risk of dissemination and severity, multiple comorbidities, drug interactions and reduced immunosuppression which should be applied as an important adjunct to therapy. This review will focus on the main causes of fungal pneumonia in kidney transplant recipients including Pneumocystis, Aspergillus, Cryptococcus, mucormycetes and Histoplasma. Epidemiology, clinical presentation, laboratory and radiographic features, specific characteristics will be discussed with an update on diagnostic procedures and treatment.
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Affiliation(s)
- D Wilmes
- Division of Internal Medicine, Cliniques Universitaires Saint-Luc, Université Catholique de Louvain, Brussels, Belgium
| | - E Coche
- Division of Radiology, Cliniques Universitaires Saint-Luc, Université Catholique de Louvain, Brussels, Belgium
| | - H Rodriguez-Villalobos
- Division of Microbiology, Cliniques Universitaires Saint-Luc, Université Catholique de Louvain, Brussels, Belgium
| | - N Kanaan
- Division of Nephrology, Cliniques Universitaires Saint-Luc, Université Catholique de Louvain, Brussels, Belgium.
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36
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Squizani ED, Reuwsaat JC, Motta H, Tavanti A, Kmetzsch L. Calcium: a central player in Cryptococcus biology. FUNGAL BIOL REV 2021. [DOI: 10.1016/j.fbr.2021.03.004] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022]
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37
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Li K, Khan A, Mishra S, Zhabokritsky A. Cryptococcose disséminée chez une greffée rénale de longue date. CMAJ 2021; 193:E585-E588. [PMID: 33875468 PMCID: PMC8084560 DOI: 10.1503/cmaj.200825-f] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Affiliation(s)
- Kelli Li
- Divisions de médecine interne générale (Li), de néphrologie (Khan) et d'infectiologie (Mishra, Zhabokritsky), Département de médecine, Faculté de médecine, Université de Toronto; Division d'infectiologie (Mishra), Service de médecine, Hôpital St. Michael, Unity Health Toronto, Toronto, Ont
| | - Abid Khan
- Divisions de médecine interne générale (Li), de néphrologie (Khan) et d'infectiologie (Mishra, Zhabokritsky), Département de médecine, Faculté de médecine, Université de Toronto; Division d'infectiologie (Mishra), Service de médecine, Hôpital St. Michael, Unity Health Toronto, Toronto, Ont
| | - Sharmistha Mishra
- Divisions de médecine interne générale (Li), de néphrologie (Khan) et d'infectiologie (Mishra, Zhabokritsky), Département de médecine, Faculté de médecine, Université de Toronto; Division d'infectiologie (Mishra), Service de médecine, Hôpital St. Michael, Unity Health Toronto, Toronto, Ont
| | - Alice Zhabokritsky
- Divisions de médecine interne générale (Li), de néphrologie (Khan) et d'infectiologie (Mishra, Zhabokritsky), Département de médecine, Faculté de médecine, Université de Toronto; Division d'infectiologie (Mishra), Service de médecine, Hôpital St. Michael, Unity Health Toronto, Toronto, Ont.
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38
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Liu M, Sun LY, Zhu ZJ, Wei L, Qu W, Zeng ZG, Liu Y. Successful Treatment of Pulmonary Cryptococcosis in a Liver Transplant Recipient Before and After Liver Transplant: Case Report and Literature Review. EXP CLIN TRANSPLANT 2021; 19:264-268. [PMID: 33535937 DOI: 10.6002/ect.2020.0222] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
Cryptococcosis is the third most common invasive fungal infection in solid-organ transplant recipients. Patients with cirrhosis are susceptible to pretransplant cryptococcosis infections. Outcomes and optimal treatment of patients with cirrhosis who develop pulmonary cryptococcosis before and after liver transplant are still not defined. Here, we describe a case of cholestatic cirrhosis in a 50-year-old woman with a pretransplant asymptomatic pulmonary nodule. She had taken steroids for more than 1 year before she was admitted to our hospital. This asymptomatic case with a lung nodule was detected via an abnormal chest computed tomography. Cryptococcal pneumonia was diagnosed according to lung biopsy results. Testing for cryptococcal antigens was negative in the serum. The patient received antifungal therapy with amphotericin B followed by oral fluconazole, which was then followed by liver transplant. After antifungal therapy with fluconazole posttransplant, a sustained clinical response was achieved. After literature review of patients with pulmonary cryptococcosis before and after liver transplant, we identified previously reported cases with pulmonary cryptococcosis that resembled lung nodule on imaging. In this report, we aimed to raise the awareness of unrecognized pretransplant cryptococ-cosis infections in patients with cirrhosis who are waiting for liver transplant and showed the successful management of a patient with pretransplant pulmonary cryptococcosis.
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Affiliation(s)
- Min Liu
- From the National Clinical Research Center for Digestive Diseases, Beijing Friendship Hospital, Capital Medical University, Beijing, China
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39
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Bretón-Martínez JR, Alcolea A, Quintero-García D, Méndez-Echevarria A, Ramos E, Bueno F, Colomina J, Marí-López J, Crehuá-Gaudiza E, García-Rodriguez J, Martínez-Costa C. Non-wild-type cryptococcosis in a child with multivisceral organ transplant who owned bird pets. Transpl Infect Dis 2021; 23:e13558. [PMID: 33386674 DOI: 10.1111/tid.13558] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2020] [Revised: 12/07/2020] [Accepted: 12/22/2020] [Indexed: 02/06/2023]
Affiliation(s)
- José R Bretón-Martínez
- Department of Pediatrics, Hospital Clínico Universitario de Valencia, Valencia, Spain.,University of Valencia, Valencia, Spain
| | - Alida Alcolea
- Pediatric Gastroenterology Department, Hospital Universitario La Paz, Madrid, Spain
| | | | - Ana Méndez-Echevarria
- Pediatric Infectious Diseases Department, Hospital Universitario La Paz, Madrid, Spain.,Translational Research Network in Pediatric Infectious Diseases (RITIP), Madrid, Spain
| | - Esther Ramos
- Pediatric Gastroenterology Department, Hospital Universitario La Paz, Madrid, Spain
| | - Felipe Bueno
- Department of Microbiology, Hospital Clínico Universitario de Valencia, Valencia, Spain
| | - Javier Colomina
- Department of Microbiology, Hospital Clínico Universitario de Valencia, Valencia, Spain
| | - Jorge Marí-López
- Department of Pediatrics, Hospital Clínico Universitario de Valencia, Valencia, Spain
| | - Elena Crehuá-Gaudiza
- Department of Pediatrics, Hospital Clínico Universitario de Valencia, Valencia, Spain
| | | | - Cecilia Martínez-Costa
- Department of Pediatrics, Hospital Clínico Universitario de Valencia, Valencia, Spain.,University of Valencia, Valencia, Spain
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Rossato L, Camargo Dos Santos M, Vitale RG, de Hoog S, Ishida K. Alternative treatment of fungal infections: Synergy with non-antifungal agents. Mycoses 2020; 64:232-244. [PMID: 33098146 DOI: 10.1111/myc.13203] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2020] [Revised: 10/16/2020] [Accepted: 10/19/2020] [Indexed: 12/11/2022]
Abstract
Fungal infections are responsible for high mortality rates in immunocompromised and high-risk surgical patients. Therapy failures during the last decades due to increasing multidrug resistance demand innovative strategies for novel and effective antifungal drugs. Synergistic combinations of antifungals with non-antifungal agents highlight a pragmatic strategy to reduce the development of drug resistance and potentially repurpose known compounds with other functions to bypass costly and time-consuming novel drug development.
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Affiliation(s)
- Luana Rossato
- Faculdade de Ciências da Saúde, Federal University of Grande Dourados, Mato Grosso do Sul, Brazil
| | | | - Roxana G Vitale
- Consejo Nacional de Investigaciones Científicas y Tecnológicas (CONICET) and Hospital JM Ramos Mejía, Ciudad Autónoma de Buenos Aires, Argentina
| | - Sybren de Hoog
- Center of Expertise in Mycology of Radboud University Medical Center, Canisius Wilhelmina Hospital, Nijmegen, The Netherlands
| | - Kelly Ishida
- Laboratory of Antifungal Chemotherapy, Department of Microbiology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil
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41
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Rossato L, Venturini TP, de Azevedo MI, Santurio JM, Alves SH. In vitro activity of immunosuppressive agents against Cryptococcus neoformans. Enferm Infecc Microbiol Clin 2020; 40:S0213-005X(20)30308-6. [PMID: 33160707 DOI: 10.1016/j.eimc.2020.09.014] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2020] [Revised: 09/17/2020] [Accepted: 09/19/2020] [Indexed: 11/03/2022]
Abstract
INTRODUCTION Infections caused by Cryptococcus neoformans are a major cause of fungal mortality in HIV-infected/AIDS patients and in those receiving organ transplants. We evaluated the in vitro activity of tacrolimus and cyclosporine in combination with amphotericin B and fluconazole against C. neoformans. METHODS MICs were determined against a total of 30 clinical isolates of C. neoformans by the microdilution method following the CLSI M27-A3 guidelines and by the checkerboard method. RESULTS Tacrolimus and cyclosporine A showed in vitro activity against cryptococcal isolates. The combination of amphotericin B with cyclosporine A or tacrolimus was synergistic against 90% and 30% of isolates, respectively. Synergism was also observed with the combination of fluconazole with cyclosporine A or tacrolimus, against 70% and 20% of isolates, respectively. CONCLUSIONS The synergistic interactions between the calcineurin inhibitors and antifungal drugs against C. neoformans isolates, could potentially have a role in devising novel therapeutic strategies for this opportunistic mycosis.
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Affiliation(s)
- Luana Rossato
- Postgraduate Program in Pharmaceutical Sciences, Health Sciences Centre, Federal University of Santa Maria (UFSM), Santa Maria, RS, Brazil.
| | - Tarcieli P Venturini
- Postgraduate Program in Pharmaceutical Sciences, Health Sciences Centre, Federal University of Santa Maria (UFSM), Santa Maria, RS, Brazil
| | - Maria Isabel de Azevedo
- Department of Preventive Veterinary Medicine, Veterinary School, Federal University of Minas Gerais, Belo Horizonte, Minas Gerais, Brazil
| | - Janio M Santurio
- Postgraduate Program in Pharmacology, Health Sciences Centre, Federal University of Santa Maria (UFSM), Santa Maria, RS, Brazil
| | - Sydney H Alves
- Postgraduate Program in Pharmaceutical Sciences, Health Sciences Centre, Federal University of Santa Maria (UFSM), Santa Maria, RS, Brazil
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Lier AJ, Virmani S, Ilagan-Ying Y, Leelatian N, Darbinyan A, Malinis MF. Unilateral leg pain caused by cryptococcal myositis: An unusual presentation of disseminated cryptococcosis in a kidney transplant recipient. Transpl Infect Dis 2020; 23:e13491. [PMID: 33040432 DOI: 10.1111/tid.13491] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2020] [Accepted: 10/04/2020] [Indexed: 02/06/2023]
Abstract
Cryptococcal disease is a rare but often serious infection in solid organ transplant recipients, commonly presenting as meningitis and pneumonia but can rarely cause myositis. We report the case of a 43-year-old female kidney transplant recipient with two previous graft failures requiring re-transplantations who presented with a 1-month duration of worsening unilateral leg pain, swelling, and shortness of breath. Blood cultures isolated Cryptococcus neoformans. A calf biopsy was performed and histopathology revealed myonecrosis with yeast forms consistent with Cryptococcus spp. Liposomal amphotericin B (LamB) was administered. Her course was complicated by hypoxemic respiratory failure with development of ground glass opacities on chest imaging. Work-up revealed bacterial and C neoformans pneumonia and probable Pneumocystis jirovecii pneumonia (PJP) She received trimethoprim-sulfamethoxazole and LamB and was discharged on fluconazole. Shortly thereafter she was re-admitted with confusion, septic shock, and multi-organ failure. Work-up revealed PJP with subsequent development of cryptococcal meningitis. Despite aggressive management, she expired. Disseminated cryptococcal infection may manifest as myositis. Presence of cryptococcal infection is a marker of severe net state of immunosuppression (IS), hence, presence of other opportunistic infections is likely. Early recognition of cryptococcal infection, institution of targeted therapy, and IS reduction are important to improve overall survival.
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Affiliation(s)
- Audun J Lier
- Section of Infectious Diseases, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT, USA
| | - Sarthak Virmani
- Section of Nephrology, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT, USA
| | - Ysabel Ilagan-Ying
- Department of Internal Medicine, Yale University School of Medicine, New Haven, CT, USA
| | - Nalin Leelatian
- Department of Pathology, Yale University School of Medicine, New Haven, CT, USA
| | - Armine Darbinyan
- Department of Pathology, Yale University School of Medicine, New Haven, CT, USA
| | - Maricar F Malinis
- Section of Infectious Diseases, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT, USA
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Schwarz P, Schwarz PV, Felske-Zech H, Dannaoui E. In vitro interactions between isavuconazole and tacrolimus, cyclosporin A or sirolimus against Mucorales. J Antimicrob Chemother 2020; 74:1921-1927. [PMID: 30934052 DOI: 10.1093/jac/dkz102] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2018] [Revised: 02/16/2019] [Accepted: 02/19/2019] [Indexed: 02/07/2023] Open
Abstract
OBJECTIVES To evaluate the in vitro interactions of isavuconazole with immune suppressors (tacrolimus, cyclosporin A or sirolimus) against 30 Mucorales isolates belonging to the most common species responsible for mucormycosis in humans (Rhizopus arrhizus, Rhizopus delemar, Rhizopus microsporus, Lichtheimia corymbifera, Lichtheimia ramosa, Mucor circinelloides and Rhizomucor pusillus). METHODS In vitro interaction was evaluated by a microdilution chequerboard technique. RESULTS Combination of isavuconazole with tacrolimus, cyclosporin A or sirolimus, was synergistic for 50%, 46% and 7% of the isolates, respectively. Antagonistic interaction was observed for 4% of the isolates for the combination with cyclosporin A (one R. arrhizus isolate) and for 32% of the isolates for the combination with sirolimus (six R. arrhizus isolates and three R. pusillus isolates). CONCLUSIONS These in vitro data show that calcineurin inhibitors are more likely than inhibitors of the mTOR pathway to enhance the activity of isavuconazole against Mucorales. These in vitro results warrant further animal experiments.
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Affiliation(s)
- Patrick Schwarz
- Department of Internal Medicine, Respiratory and Critical Care Medicine, University Hospital Marburg, Marburg, Germany.,Center for Invasive Mycoses and Antifungals, Philipps University Marburg, Marburg, Germany
| | - Petra V Schwarz
- Center for Invasive Mycoses and Antifungals, Philipps University Marburg, Marburg, Germany
| | - Heike Felske-Zech
- Department of Legal Medicine, University Hospital Gießen, Gießen, Germany
| | - Eric Dannaoui
- Université Paris Descartes, Faculté de Médecine, AP-HP, Hôpital Européen Georges Pompidou, Unité de Parasitologie-Mycologie, Paris, France.,Dynamyc Research Group (EA 7380), Paris Est Créteil University, Créteil, France
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In Vitro Interaction between Isavuconazole and Tacrolimus, Cyclosporin A, or Sirolimus against Aspergillus Species. J Fungi (Basel) 2020; 6:jof6030103. [PMID: 32650564 PMCID: PMC7560155 DOI: 10.3390/jof6030103] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2020] [Revised: 06/07/2020] [Accepted: 06/16/2020] [Indexed: 12/13/2022] Open
Abstract
The interaction of isavuconazole with immunosuppressors (tacrolimus, cyclosporin A, or sirolimus) against 30 Aspergillus isolates belonging to the most common species responsible for invasive aspergillosis in humans (Aspergillus flavus, Aspergillus fumigatus, Aspergillus nidulans, Aspergillus niger, and Aspergillus terreus) was evaluated in vitro by a microdilution checkerboard technique based on the EUCAST reference method for antifungal susceptibility testing. The interpretation of the results was performed based on the fractional inhibitory concentration index. The combination of isavuconazole with tacrolimus, cyclosporin A, or sirolimus, was synergistic for 56, 20, or 10% of the isolates, respectively. Interestingly synergy of the combination of isavuconazole with tacrolimus was also achieved for the majority of azole-resistant isolates of A. fumigatus, and for all A. niger isolates with isavuconazole minimal inhibitory concentrations ≥ 8 µg/mL. Antagonistic interactions were never observed for any combination tested.
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Mann S, Tobolowsky F, Purohit S, Henao-Martínez A, Bajrovic V, Ramanan P, Wolfel E, Khazanie P, Barron M, Madinger N, Benamu E. Cryptococcal pericarditis in a heart transplant recipient. Transpl Infect Dis 2020; 22:e13366. [PMID: 32533755 DOI: 10.1111/tid.13366] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2020] [Revised: 05/17/2020] [Accepted: 05/27/2020] [Indexed: 12/27/2022]
Abstract
We present a case of Cryptococcus neoformans pericarditis in a cardiac transplant recipient. This article reviews the diagnosis, treatment, and complications of cryptococcosis specifically in transplant patients. While pericarditis is a rare manifestation of Cryptococcus infection, this case highlights that cryptococcosis should be considered in the differential diagnosis for solid organ transplant and immunocompromised patients presenting with pericardial effusions.
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Affiliation(s)
- Sarah Mann
- Division of Infectious Diseases, University of Colorado School of Medicine, Aurora, Colorado, USA
| | - Farrell Tobolowsky
- Division of Infectious Diseases, University of Colorado School of Medicine, Aurora, Colorado, USA
| | - Suneet Purohit
- Division of Cardiology, University of Colorado School of Medicine, Aurora, Colorado, USA
| | - Andres Henao-Martínez
- Division of Infectious Diseases, University of Colorado School of Medicine, Aurora, Colorado, USA
| | - Valida Bajrovic
- Division of Infectious Diseases, University of Colorado School of Medicine, Aurora, Colorado, USA
| | - Poornima Ramanan
- Division of Infectious Diseases, University of Colorado School of Medicine, Aurora, Colorado, USA
| | - Eugene Wolfel
- Division of Cardiology, University of Colorado School of Medicine, Aurora, Colorado, USA
| | - Prateeti Khazanie
- Division of Cardiology, University of Colorado School of Medicine, Aurora, Colorado, USA
| | - Michelle Barron
- Division of Infectious Diseases, University of Colorado School of Medicine, Aurora, Colorado, USA
| | - Nancy Madinger
- Division of Infectious Diseases, University of Colorado School of Medicine, Aurora, Colorado, USA
| | - Esther Benamu
- Division of Infectious Diseases, University of Colorado School of Medicine, Aurora, Colorado, USA
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Cryptococcosis in Liver Transplant Candidates and Recipients. CURRENT FUNGAL INFECTION REPORTS 2020. [DOI: 10.1007/s12281-020-00399-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/24/2022]
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Pilmis B, Bougnoux M, Guery R, Senghor Y, Le Monnier A, Lanternier F, Bretagne S, Alanio A, Lortholary O. Failure of multiplex meningitis/encephalitis (ME) NAT during cryptococcal meningitis in solid organ recipients. Transpl Infect Dis 2020; 22:e13263. [DOI: 10.1111/tid.13263] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2019] [Revised: 01/23/2020] [Accepted: 02/02/2020] [Indexed: 01/29/2023]
Affiliation(s)
- Benoit Pilmis
- Service de Maladies Infectieuses et Tropicales Centre d'Infectiologie Necker‐Pasteur Hôpital Necker‐Enfants Malades Assistance Publique des Hôpitaux de Paris (AP‐HP) Université de Paris Paris France
- Equipe Mobile de Microbiologie Clinique Groupe Hospitalier Paris Saint‐Joseph Paris France
- EA4043 Unité Bactéries Pathogènes et Santé Université Paris‐Sud Saclay Chatenay‐Malabry France
| | - Marie‐Elizabeth Bougnoux
- Unité de Parasitologie Mycologie Hôpital Necker‐Enfants Malades Université de Paris Paris France
| | - Romain Guery
- Service de Maladies Infectieuses et Tropicales Centre d'Infectiologie Necker‐Pasteur Hôpital Necker‐Enfants Malades Assistance Publique des Hôpitaux de Paris (AP‐HP) Université de Paris Paris France
| | - Yaye Senghor
- Service de Microbiologie Clinique Groupe Hospitalier Paris Saint‐Joseph Paris France
| | - Alban Le Monnier
- Service de Microbiologie Clinique Groupe Hospitalier Paris Saint‐Joseph Paris France
| | - Fanny Lanternier
- Service de Maladies Infectieuses et Tropicales Centre d'Infectiologie Necker‐Pasteur Hôpital Necker‐Enfants Malades Assistance Publique des Hôpitaux de Paris (AP‐HP) Université de Paris Paris France
- Institut Pasteur Unité de Mycologie moléculaire Centre national de référence des mycoses invasives et antifongiques CNRS UMR2000 Paris France
| | - Stephane Bretagne
- Institut Pasteur Unité de Mycologie moléculaire Centre national de référence des mycoses invasives et antifongiques CNRS UMR2000 Paris France
- Laboratoire de Parasitologie‐Mycologie Hôpital Saint‐Louis Groupe Hospitalier Lariboisière, Saint‐Louis, Fernand Widal Assistance Publique des Hôpitaux de Paris (AP‐HP) Université Partis Diderot Sorbonne Paris Cité Paris France
- Université de Paris Paris France
| | - Alexandre Alanio
- Institut Pasteur Unité de Mycologie moléculaire Centre national de référence des mycoses invasives et antifongiques CNRS UMR2000 Paris France
- Laboratoire de Parasitologie‐Mycologie Hôpital Saint‐Louis Groupe Hospitalier Lariboisière, Saint‐Louis, Fernand Widal Assistance Publique des Hôpitaux de Paris (AP‐HP) Université Partis Diderot Sorbonne Paris Cité Paris France
| | - Olivier Lortholary
- Service de Maladies Infectieuses et Tropicales Centre d'Infectiologie Necker‐Pasteur Hôpital Necker‐Enfants Malades Assistance Publique des Hôpitaux de Paris (AP‐HP) Université de Paris Paris France
- Institut Pasteur Unité de Mycologie moléculaire Centre national de référence des mycoses invasives et antifongiques CNRS UMR2000 Paris France
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Cutaneous cryptococcosis: an underlying immunosuppression? Clinical manifestations, pathogenesis, diagnostic examinations and treatment. Postepy Dermatol Alergol 2020; 37:154-158. [PMID: 32489347 PMCID: PMC7262803 DOI: 10.5114/ada.2020.94833] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2018] [Accepted: 09/02/2018] [Indexed: 12/13/2022] Open
Abstract
Due to constantly growing population of immunocompromised patients the fungi became a widespread threat to modern medicine. HIV carriers, solid organ transplant recipients constitute most of those patients. Cryptococcosis is a frequent cause of life-threatening infections, affecting mostly immunosuppressed patients. This article presents current knowledge on cryptococcal infections, including epidemiology, clinical aspects, diagnosis and recommended treatment. In reference to our patient, who developed a disseminated and fulminant subtype of the disease, we wanted to underline the need to examine patients thoroughly. The highest aim of those measures would be to avoid lethal consequences.
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Coelho C, Farrer RA. Pathogen and host genetics underpinning cryptococcal disease. ADVANCES IN GENETICS 2020; 105:1-66. [PMID: 32560785 DOI: 10.1016/bs.adgen.2020.02.001] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Cryptococcosis is a severe fungal disease causing 220,000 cases of cryptococcal meningitis yearly. The etiological agents of cryptococcosis are taxonomically grouped into at least two species complexes belonging to the genus Cryptococcus. All of these yeasts are environmentally ubiquitous fungi (often found in soil, leaves and decaying wood, tree hollows, and associated with bird feces especially pigeon guano). Infection in a range of animals including humans begins following inhalation of spores or aerosolized yeasts. Recent advances provide fundamental insights into the factors from both the pathogen and its hosts which influence pathogenesis and disease. The complex interactions leading to disease in mammalian hosts have also updated from the availability of better genomic tools and datasets. In this review, we discuss recent genetic research on Cryptococcus, covering the epidemiology, ecology, and evolution of Cryptococcus pathogenic species. We also discuss the insights into the host immune response obtained from the latest genetic modified host models as well as insights from monogenic disorders in humans. Finally we highlight outstanding questions that can be answered in the near future using bioinformatics and genomic tools.
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Affiliation(s)
- Carolina Coelho
- Medical Research Council Centre for Medical Mycology at the University of Exeter, Exeter, United Kingdom
| | - Rhys A Farrer
- Medical Research Council Centre for Medical Mycology at the University of Exeter, Exeter, United Kingdom.
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50
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Barnett AE, Brust KB. Cirrhosis, gastrointestinal bleed, and cryptococcal peritonitis. Proc (Bayl Univ Med Cent) 2020; 33:195-198. [PMID: 32313460 DOI: 10.1080/08998280.2020.1723361] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2019] [Revised: 01/16/2020] [Accepted: 01/27/2020] [Indexed: 01/31/2023] Open
Abstract
Disseminated Cryptococcus neoformans infection rarely causes peritonitis in non-HIV-infected patients but does affect cirrhotic patients. Diagnostic challenges delay treatment, and mortality is high. We performed a literature search of proven cryptococcal peritonitis cases in HIV-negative adults with underlying cirrhosis, included our own case, and collected demographic, infection risk factor, diagnostic, treatment, and outcomes data. We identified 16 articles and 21 cases. Most patients were men. Alcohol abuse was the leading cause of underlying cirrhosis (n = 10, 48%). Eight (38%) patients experienced an upper gastrointestinal bleed (UGIB) within a month before peritonitis presentation. Peritoneal fluid analysis was abnormal and lymphocytic predominant. Half the patients were fungemic. When performed, peritoneal fluid cryptococcal antigen (CrAg) test results were positive. Amphotericin B was the primary treatment. Mortality was high at 76%. In conclusion, C. neoformans is an opportunistic pathogen that causes peritonitis in non-HIV, cirrhotic patients. People with recent UGIB seem to be at risk. Cryptococcus species infection should be suspected in patients with clinical signs and symptoms of spontaneous bacterial peritonitis whose lymphocytic-predominant peritoneal fluid and cultures are negative for bacterial growth. Peritoneal CrAg testing expedites diagnosis because growth on fungal media is slow. Mortality remains high, despite standard therapy with amphotericin B.
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Affiliation(s)
- Amy E Barnett
- Department of Internal Medicine, Baylor Scott & White Medical Center - TempleTempleTexas
| | - Karen B Brust
- Division of Infectious Diseases, Department of Internal Medicine, Baylor Scott & White Medical Center - TempleTempleTexas
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