Cryptococcus neoformans Infection in Organ Transplant Recipients Downloded from .

Cryptococcus neoformans Infection in Organ Transplant

Recipients

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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


Cryptococcus neoformans Infection in Organ Transplant Recipients Downloded from .

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