1. Cryptococcus neoformans Infection in Organ Transplant Recipients Downloded from www.pharmacy123.blogfa.com

2. 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 Downloded from www.pharmacy123.blogfa.com

3. 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 Downloded from www.pharmacy123.blogfa.com

4. Results (1) Totally, 178 cases of C. neoformans infection renal 145 cases liver 20 cases heart 10 cases lung 3 cases Downloded from www.pharmacy123.blogfa.com

5. Result (2) The mean incidence: 2.8 % In these patients 79%, azathioprine as the primary immunosuppressive 7%, tacrolimus 9%, cyclosporine 6% cyclosporine and azathioprine Downloded from www.pharmacy123.blogfa.com

6. Result (3) Incidence of cryptococcosis in different groups 4.5 %, tacrolimus 2.4 %, cyclosporine 3.4 % azathioprine Downloded from www.pharmacy123.blogfa.com

7. 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 Downloded from www.pharmacy123.blogfa.com

8. 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 Downloded from www.pharmacy123.blogfa.com

9. 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 Downloded from www.pharmacy123.blogfa.com

10. Time to onset (4) not correlate with early or late cryptococcal infection: age cytomegalovirus infection prior rejection episodes Downloded from www.pharmacy123.blogfa.com

11. 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 Downloded from www.pharmacy123.blogfa.com

12. 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 Downloded from www.pharmacy123.blogfa.com

13. Pulmonary Infection Most radiographic signs unilateral nodular cavitary infiltrates 100% of 12 patients: positive serum cryptococcal antigen Downloded from www.pharmacy123.blogfa.com

14. 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. Downloded from www.pharmacy123.blogfa.com

15. Death Rate The overall death rate: 42% No difference between using tacrolimus and primary immunosuppressive regimens Downloded from www.pharmacy123.blogfa.com

16. Predictors of death Only renal failure on admission was predictive of death Downloded from www.pharmacy123.blogfa.com

17. 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 Downloded from www.pharmacy123.blogfa.com

18. Discussion 2.8% cryptococcus infection rate in organ transplant recipients 42% overall death rate Immunosuppressant will influence the predominant clinical manifestation Downloded from www.pharmacy123.blogfa.com

19. Discussion (2) Tacrolimus and cyclosporin more skin, soft tissue, osteoarticular less CNS involvement compared with azathioprine Downloded from www.pharmacy123.blogfa.com

20. 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 Downloded from www.pharmacy123.blogfa.com

21. 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 Downloded from www.pharmacy123.blogfa.com

22. Cyclosporine effect Cyclosporine also possess antifungal activity by inhibition of calcineurin Cyclosporine poorly penetrate the CNS, while tacrolimus crosses the blood-brain barrier Downloded from www.pharmacy123.blogfa.com

23. 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 Downloded from www.pharmacy123.blogfa.com

24. 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. Downloded from www.pharmacy123.blogfa.com

25. 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 Downloded from www.pharmacy123.blogfa.com

26. 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 Downloded from www.pharmacy123.blogfa.com

27. 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, Downloded from www.pharmacy123.blogfa.com

28. 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 Downloded from www.pharmacy123.blogfa.com

29. 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. Downloded from www.pharmacy123.blogfa.com

30. 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 Downloded from www.pharmacy123.blogfa.com

31. 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 Downloded from www.pharmacy123.blogfa.com

32. Prevention of cryptococcosis Fluconazole is very effective in preventing cryptococcal meningitis in patients with AIDS. dose lower than 200 mg/day may be effective Downloded from www.pharmacy123.blogfa.com

33. 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. Georges Hospital Medical School,Cranmer Terrace, London SW17 ORE, U.K. 3.Basic and Clinical Pharmacology, 8 th edition 4. Journal of Infection (2000) 41, 18–22, Division of Infectious Diseases, Washington University School of Medicine, St. Louis, Downloded from www.pharmacy123.blogfa.com

34. Thank for your attention Downloded from www.pharmacy123.blogfa.com