"Cryptococcus neoformans Infection in Organ Transplant Recipients"
Cryptococcus neoformans Infection in Organ Transplant Recipients Ri 張振昌 2003/05/19 Background Incidence: 2.8% of organ transplant recipients Death rate: 42% Immunosuppressant affect cryptococcosis manifestation Invasive candidiasis decline: fluconazole use and technologic advances in surgery The importance in transplant p’t HIV related C. neoformans infection declined In the group of immunocompromised p’t, transplant p’t more important in C. neoformance infection Results (1) Totally, 178 cases of C. neoformans infection renal 145 cases liver 20 cases heart 10 cases lung 3 cases Result (2) The mean incidence: 2.8 % In these patients 79%, azathioprine as the primary immunosuppressive 7%, tacrolimus 9%, cyclosporine 6% cyclosporine and azathioprine Result (3) Incidence of cryptococcosis in different groups 4.5 %, tacrolimus 2.4 %, cyclosporine 3.4 % azathioprine Time to Onset (1) Occurred 1.6 years after transplantation 15% within 3 months 11% in 3 to 6 months 16% in 6 to 12 months 59% >12 months Time to onset (2) In view of diffenrent organ transplantation 35 months for kidney 25 months for heart 8.8 months for liver 3 months for lung Time to onset (3) Infection tends to occur later in using azathioprine than tacrolimus or cyclosporine In view of different immunosuppresant 11.4 m in cyclosporine 9.2 m in tacrolimus 27 m in azathioprine Time to onset (4) not correlate with early or late cryptococcal infection: age cytomegalovirus infection prior rejection episodes Clinical Manifestations Site of infection 55% infection at the CNS only 13% skin, soft tissue, osteoarticular infection 6% pulmonary infection 24% more than one site of infection CNS Infection 63 p’t with CNS cryptococcosis 62% had headache 48% had confusion or lethargy 86% of 21 p’t with CNS: positive serum cryptococcal antigen 100% of 37 p’t: positive CSF cryptococcal antigen 93% of 82 p’t: CSF cultures yielded C. neoformans 77% of 47 p’t: positive India ink Pulmonary Infection Most radiographic signs unilateral nodular cavitary infiltrates 100% of 12 patients: positive serum cryptococcal antigen Skin, Soft Tissue, Osteoarticular Infection 27% of patients with cutaneous cryptococcosis had cellulitis 90% of 21 patients with skin or osteoarticula infections: positive serum cryptococcal antigen. Death Rate The overall death rate: 42% No difference between using tacrolimus and primary immunosuppressive regimens Predictors of death Only renal failure on admission was predictive of death Factors influencing prognosis Poor outcome in CNS cryptococcal infection abnormal mental status absence of headache No correlation with bad outcome presence of fever, CSF pleocytosis positive blood cultures, CSF cryptococcal antigen titer Discussion 2.8% cryptococcus infection rate in organ transplant recipients 42% overall death rate Immunosuppressant will influence the predominant clinical manifestation Discussion (2) Tacrolimus and cyclosporin more skin, soft tissue, osteoarticular less CNS involvement compared with azathioprine Tacrolimus effect (1) Tacrolimus, a natural macrolide antifungal agent found from Streptocyces tsukubaensis Use as immunosuppressive agent outweighs its antifungal effect Toxic to C. neoformans by inhibition of calcineurin Suppress C. neoformans at 37°C,not 24°C, suggesting calcineurin funtion at higher body temperatures Tacrolimus (2) Mechanism of action: 1.bind to cytoplasmic peptidyl-prolyl isomerases (FK-binding protein) 2.the same as cyclosporine, inhibit cytoplasmic phosphatase, calcineurin, necessary for T cell-specific transcription factor, thus inhibit IL-2 synthesis Cyclosporine effect Cyclosporine also possess antifungal activity by inhibition of calcineurin Cyclosporine poorly penetrate the CNS, while tacrolimus crosses the blood-brain barrier How infected (1) newly acquired or a reactivation of latent infection ?? Reactivation: 1. Autopsy show granuloma with C. neoformans 2. Molecular typing of Africans in Europe 3. Serologic evidence in most children in NY city How infected (2) Isolates from 29 patients diagnosed with cryptococcosis in France, nine of whom were from Africa but had lived in France for a median of over 9 years. There was a significant clustering of isolates from patients originating in Africa compared to those from Europe, suggesting that the patients had acquired their isolates long before the development of clinical disease. Geograghic factor Northeastern United States with more cryptococcus infection than other US areas Epidemiologic studies of C. neoformans have been hampered by lack of sensitive and specific immunologic tests to evaluate the prevalence of latent infection In pediatric patient The relative rarity of cryptococcal infections in pediatric organ transplant recipients has been noted – pediatric transplant recipients may not yet have acquired the infection. C. neoformans – thymic regeneration in bone marrow transplant recipients may render T cells more efficacious against cryptococci Immunology Evidence from animal studies and the epidemiology of human infection clearly demonstrate that specific T-cell-mediated immunity is critical in a protective immune response. Only limited evidence for a role for specific antibody in natural immunity, Immunology Macrophages are central to the immune response to C. neoforman, through antigen presentation and co-stimulation of T cells C. neoformans is capable of survival and multiplication within macrophages Cutaneous infection Cutaneous cryptococcosis represents disseminated infection and should be treated with systemic antifungal agents. Cutaneous cryptococcal infection most frequently mimicked (and was clinically indistinguishable from) bacterial cellulitis. Laboratory diagnosis Elevated CSF pressure without evidence of obstructive hydrocephalus: 1.basilar meningitis 2.impaired reabsorption of CSF across arachnoid villi important complication of cryptococcal meningitis high baseline opening pressure:correlated inversely and independently with survival intracranial pressure >140 mm of H2O : high death rate Predictor of prognosis 42% the transplant recipients with C. neoformans infection died Preexistent renal failure was an independently significant predictor of death in transplant recipients with cryptococcosis Prevention of cryptococcosis Fluconazole is very effective in preventing cryptococcal meningitis in patients with AIDS. dose lower than 200 mg/day may be effective Reference 1.From Veterans Affairs Medical Center and University of Pittsburgh, Thomas E. Starzl Transplantation Institute, Pittsburgh, Pennsylvania, USA 2. Journal of Infection (2000) 41, 12–17 Department of Infectious Diseases, Division of Cellular and Molecular Sciences, St. George’s Hospital Medical School,Cranmer Terrace, London SW17 ORE, U.K. 3.Basic and Clinical Pharmacology, 8th edition 4. Journal of Infection (2000) 41, 18–22, Division of Infectious Diseases, Washington University School of Medicine, St. Louis, Thank for your attention